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Cardiovascular lectures

Admin — Wed, 17 Mar 2010 14:22:28 GMT

Admin: moved Cardiovascular lectures to Cardiovascular lecture notes

#REDIRECT [[Cardiovascular lecture notes]]

Cardiovascular lecture notes

Admin — Wed, 17 Mar 2010 14:22:28 GMT

Admin: moved Cardiovascular lectures to Cardiovascular lecture notes

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart.
Really, the heart? or some big vein?
*Yes, it is actually the atrium into which they dump.
*The heart must have extensive blood flow and therefore the coronary circulation is very extensive.
**The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, one can compensate by using ATP reserves, switching to anarobic energy generation, using lactic acid or one can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, thus it must always have adequate oxygen.
*Ischemia means "reduced blood flow".
*Hypoxia means "low oxygen".
*Coronary atherosclerosis means "a buildup of plaque in heart".

====Coronary atherosclerosis====
*Coronary atherosclerosis is the same thing as coronary artery disease (CAD).
*Coronary artery disease is the leading causes of death in the US, by a large margin.
*Deposition of plaque in coronary vessels leads to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't contractive.
*Ultimately, CAD leads to a failing of the heart due to low blood supply.

=====Causes of CAD=====
*Hypertrophy of the endothelial cells.
*Cholesterol deposition.
*Endothelial cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suction.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like [Delude's_"Clot_Busters!!_-_Discovery_of_thrombolytic_therapy_for_heart_attack_and_stroke"_(2004)| tPA and streptokinase].
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is extremely invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it (but only in 20% of the population).
*Inflammatory responses, perhaps cuased by infections.

=====Cowley's Newsweek article: Cardiac Contagion=====
*Contagion: "A disease spread by contact; The spread or transmission of such a disease; The spread of anything harmful, as if it were such a disease...." [http://en.wiktionary.org/wiki/contagion ref]
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*The article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.
*The authors even suggest that CAD may be somewhat contagious because if you get respiratory chlamidia, you can end up with CAD.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endothelial cells.
**As in, it generates a peptide that looks like a host peptide and thus starts an auotinflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mitochondria so that they have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice.
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First, the electrical activity spreads from the SA node over the atrium, then it reconvenes at the AV node, then it spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials through nerves travel really fast--much faster than through cardiac muscle.
*All cells of the body have a spontaneous potential difference measured in volts.
**The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials.
**In pacemaker cells it is -40 millivolts (that is, -40 inside compared to outside).
*-40 mV is the threshold in pacemaker cells.
*After an action potential, the potential drops below threshold and then starts leaking back toward threshold such that another action potential is fired.
*The '''depolarization drift''' comes from the flow of Na+ through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then polarization is maintained by slow calcium channels that open late and stay open for a longer time.
*Then a nearly neutral level of polarization is maintained as potassium channels are opened such that Ca++ is coming in and K+ is going out.
*Then repolarization is achieved through the previously mentioned potassium channels remaining open while the slow calcium channels close, thus allowing potassium to continue out of the cell driving the potential back to the negatives.
*How often this whole process occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increased permiability to potassium which drives the refractory polarization to a lower (more negative) number such that it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the Ca++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you must have functional ventricles.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excite the cardiac muscle fibers.
*The cardiac action potentials last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: fast sodium, slow chloride, and slow potassium.
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel opening.
*When channels break:
**Long-qt syndrome can be exhibited.
**The first symptom is death.
**Stimulation of the heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (the QRS wave), then the potential spreads up the ventricles (still the QRS wave), and then the ventricles relax (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve (which would cause the hypertrophy of the atrium).
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A '''junctional rhythm''' marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volume
*Normal: 6000ml / min = 75 beats / min x 80 ml / beat.
*This can be increased 3-fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Stroke volume = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
**Remember that there is about 50ml left in the left ventricle at the end of the stroke; this is called the end systolic volume.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation (the end diastolic volume). This 60% is the stroke volume.

*Frank-Starling principle:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives (within limits).

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiac output.
***An increased blood volume.
***Increased heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**The parasympathetic system can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increasing parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal heart rate is much higher.
*Gender:
**We consider the standard measurements on 25 year olds with ideal weight.
**Women have faster heart rates than men.
**Fetuses have a much faster heart rate than women.
*Exercise increases HR because of sympathetic stimulation.
*Temperature decreases one's HR by slowing the rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - work mainly on vessels by opening vessels to reduce resistance
*ACE inhibitors - reduce cardiac afterload (that is, the pressure it takes to eject blood from ventricle)
*Diuretics - remove excess water (thus decreasing blood volume / pressure)
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the heart to stop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia and an exercise-induced rapid heartbeat!
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical results and some of the new directions that are contributing to successful heart transplants.
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing (even though the donors are older, the donor organs have longer ischemic times, and the recipients have more complicated conditions of increased intensity).
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should people with incurable illnesses get transplants?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies in their serum. They also have an incompetent complement system until 12-14 months, such that they cannot reject the organ as well as someone with a full complement cascade.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Nowadays we decrease the size of the internal unit by engineering some things (like the battery) to remain outside the patient.
*There is still a risk of infection because of the outside-inside interface.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One patient has made a transatlantic trip and lived 2 years with one of these devices.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increased stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Main Page

Admin — Wed, 17 Mar 2010 14:21:30 GMT

Admin:

==Exam 3==
===Reading notes===
*[[Warnock's "Liddle Syndrome: Clinical and Cellular Abnormalities" 1994]]
*[[He's "Epidemiology and Prevention of Hypertension" 1997]]
*[[Hajjar's "Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases" 2003]]
*[[Meneton's "Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases" 2005]]
*[[Bhalla's "Mechanisms of ENaC Regulation and Clinical Implications" 2008]]
*[[Chapter 26 notes (Renal)]]

===Lecture notes===
*[[Renal lectures notes]]

==Exam 2==
===Reading notes===
*[[Williams' "Cystic Fibrosis: A disease caused by a single defect in salt-transporting epithelial cells" 1992]]
*[[Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993]]
*[[Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994]]
*[[Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999]]
*[[Marshall's "Gene Therapy on Trial" 2000]]
*[[Rosenberg's "Gene Therapist, Heal Thyself" 2000]]
*[[Vogel's "FDA Moves against Penn Scientist" 2000]]
*[[Couzin's "As Gelsinger Case Ends,Gene Therapy Suffers Another Blow" 2005]]
*[[Kaiser's "Death Prompts a Review of Gene Therapy Vector" 2010]]
*[[Chapter 20 notes (Heart)]]

===Lecture notes===
*[[Cystic fibrosis lecture notes]]
*[[Respiration lecture notes]]
*[[Circulatory lecture notes]]
*[[Cardiovascular lecture notes]]

==Exam 1==
===Blood===
*[[Chapter 19 notes (Cardiovascular system)]]
*[[Blood lecture notes]]
*[[Eaton's "The biophysics of sickle cell hydroxyurea therapy" 1995]]
*[[Gareau's "Erythropoietin abuse in athletes" 1996]]
*[[Marshall's "Clinical promise, ethical quandry" 1996]]
*[[Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)"]]
*[[Walzog's "Adhesion molecules: the path to a new understanding of acute inflammation" (2000)]]
*[[Lee's "The Tangled Webs That Neutrophils Weave" (2004)]]
*[[Delude's "Clot Busters!! - Discovery of thrombolytic therapy for heart attack and stroke" (2004)]]
*[[Brunstein's "Umbilical cord blood transplantation and banking" 2006]]
*[[Geddis's "The root of platelet production" 2007]]

===Lymphatic / Immune===
*[[Chapter 22 notes (Lymphoid and immune systems)]]
*[[Ganz's "Versatile Defensins" 2002]]
*[[Couzin's "Wanted: pig transplants that work" 2002]]
*[[Wickelgren's "Can worms tame the immune system?" 2004]]
*[[Alexander's "Chimerism and tolerance in a recipient of a deceased-donor liver transplant" 2008]]
*[[Leslie's "Mast cells show their might" 2010]]
*[[Leslie's "Internal affairs" 2010]]
*[[Leslie's "Fetal immune system husches attack on maternal cells" 2010]]

Circulatory lectures

Admin — Wed, 17 Mar 2010 14:19:19 GMT

Admin: moved Circulatory lectures to Circulatory lecture notes

#REDIRECT [[Circulatory lecture notes]]

Circulatory lecture notes

Admin — Wed, 17 Mar 2010 14:19:07 GMT

Admin: moved Circulatory lectures to Circulatory lecture notes

*continued here from [[Cardiovascular lectures]] on 02/17/10.

==Vasculature==
*We will not cover all the circulatory routes.
**Don't read pages 748-767.

===Circulation===
*Arteries away, veins to; capillaries in between.
*Capillaries are site of exchange because of permeability and thin wall.

===Vasculature - control mechanisms===
*All vessels except capillaries have:
**smooth muscle cells so they can undergo constriction or dilation
**innervation that can control the constriction / dilation in response to the autonomic nervous system.
*Veins, in general, have much larger diameters.
*The artery has some layers.
**Throughout these layers are elastic fibers.
**The endothelial cells that line the inside of the artery are bunched up so they can expand outward and then spring back forward.
*Veins have some layers
**These include the outer and inner layers of smooth muscle.
**There are no elastic fibers.

*All three arteries, veins, and capillaries have:
**An endothelial layer, a basement membrane (on which the endothelial layer sits).

*Arteries and veins both have:
**Smooth muscle (except that arteries have larger layers of smooth muscle).

*Only arteries have:
**Two elastic layers between the smooth muscle and the basement membrane.
***These are important for handling pressure.

*Only the veins have:
**One way valves.

*In the arterioles, the smooth muscle layer has become very thin.

*Veins progress from capillaries as small venules, medium sized venuoles, and veins.

*When you have an increased stroke volume, it is handled by the expansion of the arteries.
**As you lose expansion ability (via disease or age), then the whole system pressure is increased, including backward pressure. This will cause problems with the afterload.

*Blood pressure measurement:
**Close off artery.
**Release pressure until you hear a sound, this is systolic pressure.
**Release more until you hear nothing, this is the diastolic pressure.

====Arterial system====
*Nature of the wall changes:
**Elasticity decreases, muscle decreases.
*Next level is known as the muscular or distributing arteries.
**These can change how much blood gets to the muscles.
**Uses vasoconstriction / dilation.

=====Fluid dynamics=====
*Resistance to flow is inversely proportional to the radius raised to the fourth power.
*Flow is proportional to the pressure divided by the resistance.
*Flow is proportional to the pressure times the resistance raised to the fourth power.
*Take home: change the radius a little, change the resistance and flow a lot (in opposite directions).

=====Arterioles=====
*Smallest of these is a single smooth muscle cells surrounding the endothelial lining of the vessel.
*Not much bigger than the capillary, but can still change diameter.
*There are both neuronal control and small molecule control that can change arteriole flow.
*This is where diameter changes will help to direct blood away from the skin if cold.

*There are arteriole systems that can bypass the capillaries. When closed it will increase the pressure in the capillaries.

====Capillaries====
*Very thin wall, with a basement membrane.
*Very small diameter.
*Not all capillaries are the same.
*Water, O2, Co2 just diffuse.
*There are intercellular clefts and pinocytic vesicles which can be used to move stuff across the membrane.
*You can move things across the endothelial membranes.
*You can move stuff through fenestrations; these are areas of membrane that do not have cytoplasm behind them that are adjacent to the endothelial cells. Think of them as a window into the extracellular space.
*Some capillaries don't let much through, like those in the brain.
*Some capillaries let lots thorugh, like the kidney and the intestinal tract.
**There will be more endo and exo cytosis.
**There will be fenestrations.
*There are some like the liver, bone, and lymphoid capillaries that have to move stuff.
*There are three classes:
**Continuous: no fenestrations, in the brain
**Fenestrated: in the intestinal tract and kidney,
**Sinusoid: liver, bone marrow, lymphoid tissue.

====Venous system====
*While there is smooth muscle, there is much less control.
*There are thinner walls.
*There is less pressure.
*61% of the blood in an at rest, healthy person, is found in the systemic venous system.
**Only 18% in systemic arterial system.

*We'll finish vasculature next time.

*stopped here on 02/17/10.
*started here on 02/22/10.

===Physiology of circulation===

====Control mechanisms====
*These are the key to physiology.

=====General control=====
*Pressure causes movement.
*ARterial blood pressure is what we measure.
*Hydrostatic pressure is in the capillary beds.
*Venous pressure rarely matters.
*Resistance is the force that opposes movement.
**Vascular resistance is a function of vessel length and diameter.
***As we gain weight, there is longer length and therefore more resistance.
**Viscocity of the blood can aslo affect resistance.
***The number of RBCs, the amount of protein, etc. can affect viscosity.
**Lastly, turbulence can change resistance.
***This only becomes an isusue when we're talking about disease states and are therefore not smooth on the inside (because of plaque, for example).
*The capillaries account for much more total cross-sectional area than the aorta.
*The blood pressure is highest closest to the heart.
*The velocity of the blood is inversely proportional to the cross-sectional area.
*Cardiac output is MABP / R (mean alteriol blood pressure over resistance).
**The MABP is not just the average of systolic and diastolic.
**It is the diastolic + 1/3rd of the difference between systolic and diastolic pressures.
*So, if the cardiac output rises to to increased stroke volume or HR, then the BP also rises.

====Blood flow in capillaries====
*By the time the blood gets to the capillaries the blood pressure is very low.
*This is important b/c they are so thin they cannot take high pressure (like the 120 mm/hg as in the heart).
*They are meant for exchange, not pressure.
*There are two opposing forces: hydrostolic pressure (blood pressure) and osmotic pressure.
**The hydrostolic blood pressure wants to force fluid forward and / or outward.
**The osmotic pressure keeps fluid in the veseel, however, because of the concentration of proteins in the blood.
*Fluid can move out because of the thin walls.
*On the arteriole end of the capillariy, the blood pressure is greater than the contradicting osmotic force so fluid is lost.
*Then, on the venous system, this is reversed such that fluid is gained back.
*Blood loses 24 ish liters and gains 20, the other four go through the lymphatic system.
*What happens when these are unbalanced? Edema!
**So if BP increases beyond the counter force of osmotic pressure, you get peripheral adema: swelling of the ankles, etc.
**You can also decrease the amount of blood protein content (in something like liver disease) and thus have decreased osmotic force and therefore the bp is more effective at forcing fluids out and edema occurs.
**If you have increased permeability of capillaries (because of infections, inflammation, etc.). This is more localized.
**You can also increase the extracellular fluid of the blood (by retention of ions at the kidney, for example) which will increase osmotic pressure and result in higher blood volume and thus extra pressure because of the increased volume. So we're looking for the shift one way or the other: edema or ...
**You can also block the lymph vessels. This will result in edema in the area. This will result in higher returns at the venous side, but not enough to relieve the edema.

====Extremes====
*A drastic decrease in volume and thus bp decrease and thus hydrostatic pressure decreases. Therefore, there is less pressure pushing things out of the blood stream and the patient will retain fluids, which is good!
*In dehydration, the patient has lost fluids through sweating (let's say). So they have the same number of plasma proteins and so the BCOP (blood coloital osmotic pressure) increases and therefore less fluid is lost to the intracellular area.

====Veins====
*Veins are low pressure.
*They need some help to move blood back to heart.
*We have to auxillary pumps: respiratory pump, muscular pump.
*Muscular pump:
**Veins have one-way valve.
**When muscle flexes, it squeezes the vein and blood can only go toward heart because of valves.
*Respiratory pump
**During inspiration, the diaphragm is moving and the skeletal muscles are contracting.
**These keep the blood moving.

====Homeostatic control of blood pressure====
*BP is dependent on resistance and cardiac output and blood volume.
*Cardiac output = blood pressure / peripheral resistance.
*So blood pressure = cardiac output * peripheral resistance.
*Remember that CO is controlled by stroke volume and heart rate.
*Blood viscocity does not change on an acute basis, really.
**You can add RBCs or water (via salt).
*You don't change blood vessel length in acute situations.
*You can, however, change blood vessel diameter acutely.
**Recall that the resistance is inversely proportional to the fourth power of the radius.

=====Regulation of peripheral resistance=====
*Important for temp regulation.
*Important for shunting toward GI tract after a meal.
*Important for stress and danger, getting blood to the heart, brain, and skeletal muscle.
*Peripheral resistance can be regulated in three ways: autoregulation, neuronal regulation, and endocrine regulation.

======Autoregulation======
*These are mechanisms that the vessel itself generates.
*Warming a vessel will dilate it, cooling it will vasoconstrict.
*Endothelin is released to constrict the vessel in low flow.
**NO is the opposite, it causes dilations in response to high blood flow.
*Inflammatory chemicals, which are likely to come from blood that is inside the vessels (like histamine). These can change the permeability of the vessels.
*Metabolic processes can generate both dilators and constrictors.
**Lactic acid is a dilator which makes sense because the muscles need to get that lactic acid out of there and to get oxygen to the muscle.
**K+ and H+ also cause dilation. These, too, make sense because they are like acids and metabolic processes generate acids which means there is work going on and that oxygen is needed.
**Prostaglandins are vasoconstrictors.
***This makes sense because they are released in inflammatiion / clotting.
*Response to oxygen:
**When oxygen levels are low, the systemic vessels will dilate to slow blood down so the oxygen can be dumped off at the tissues.
**When oxygen levels are low, the pulmonary vessels will constrict to increase ''blood velocity'' in order to absorb oxygen from the air at a faster rate.

======Neural controls======
*The cardiovascular center in the brain stem both positively and negatively affects cardiac output.
*This exact same area can also control the cardiovascular system.
*There are lots of receptors yielding input for the neural control system:
**Baroreceptors, higher brain centers, chemoreceptors, and propriocenters.
*The major affect on peripheral constriction is the sympathetic system.
*Smooth muscle and peripheral tissue are vasoconstricted:
**Mostly veins in order to release the resevoired blood.
*The sympathetic system vasoconstrics only the veins, the periphery, and the ... not the heart or brain.
*In skeletal muscle, heart, and brain, sympathetic causes dilation of arteries.

*Baroreceptors:
**Found in carotid arteries, in the aorta, in many of the major vessels.
**They sense the blood pressure.
**If bp goes up, there is feedback to the cardiovascular center which causes vasodilation of the vessels. This makes sense because dilating will decrease blood pressure. The heart rate and contractile force can also be decreased in order to decrease bp.
**If bp goes down, the cardiac output center can constrict blood vessls and increase heart rate / contractile force. This is done by
***stimulating the vasomotor centers which are trying to constrict the vessels
***stimulating the cardioacceleratory centers
***inhibiting the cardiovascular control function to allow the heart rate to increase.
**Some baroreceptors are set up to allow for individual responses to bp changes.
***For example, the carotid sinus reflex controls bp to the brain, even while the rest of the body is going for a fast run or what not.
***The aortic reflex is systemic.
***The atrial (right heart) reflex response to venous blood return (venous BP) and thus makes the heart pump faster and with more contractility to avoid a backlog of blood.
**These are all short term and only meant for acute changes.

*Chemoreceptors:
**Sense changes to gasses and pH in blood and cerebrospinal fluid.
**When stimulated, they cause vasoconstriction.
**Chemoreceptors have systemic effects, including the pulmonary branc, not just local.
**Found mostly in arteries.
**Also affects respiratory rate.

*Higher brain centers:
**Anxiety, fear, temperature, exercise can all change either vasodilation or cardiac output.

*Hormonal control:
**The endocrine controls act directly on vascular smooth muscle or on the vasomotor area.
**There is lots of overlap of neural and endo control because the two systems use similar molecules.
**Neural control didn't change blood volume but endocrine system can.
**Adrenal medulary hormones:
***Epi, norepi: vasoconstrictive, except for skeletal and cardiac muscle.
***ADH, AVP: produced by hypothalamus, released by posterior pit, released in response to decreased blood volume or increases in osmotic concentration. If levels are high enough, it will cause vasoconstriction. It stimulates the kidney to retain water.
***Renin-angiotensisn-aldosterone axis: when blood volume falls, renin is released which increases angiotensin II. Angiotensin II is vasoconstrictive and causes the release of aldosterone (long lasting steroid) and ADH (fast acting protein) which increase salt and water retention by the kidney. Aldosterone and ADH work on calcium and sodium channels (though I don't know which one is which). ADH also yields thirst.
***EPO: causes increase in RBC, which increases viscosity, so we must consider this when thinking about how to regulate BP.
***ANF (atrial naturetic factor / peptide): this is the exact opposite of ADH. It is a peptide hormone. This hormone is released by the cardiac atria upon increased pressure (particularly atrial return). The immediate affect is vasodilation. Long term, ANH causes the kidneys to excrete salt and water.
***Alcohol: immediate depresses vasomotor center which promotes vasodilation and gives you a flushed look. It also inhibits ADH and thus makes you have to go the bathroom.
On Friday, go over the related pictures.

*Illustration of changes in blood pumping rate and where all the blood gets directed and in what amounts.

=====Exercise=====
*Muscle activity is increased so blood gets moved there.
*Breathing rate has increased to get more oxygen but also increased venous return because the respiratory return is going fast.
*Frank Starling's principle is in effect: more blood comes in, more blood gets pumped.
*There is also increased heart rate in response to low oxygen..

=====Blood loss=====
*In the short term, the baroreceptors will cause peripheral vasoconstriction and increase the heart rate.
*The stress of losing blood stimulates the sympathetic nervous system which increases vasomotor tone and increases vaosconstriction.
*Epi and norepi will be released t increase CO and vasoconcstritno.
*ADH will be released which iwll cause vasoconstriction.
*Now for the longer term:
**Aldosterone will get become active and cause retention of fluid via salte and water of kidney.
**Thirst will go up because of ADH.
**EPO will be released to increase RBCs.

====Circulatory shock====
*Shock is when you cannot maintain normal flow through the system.
*Hypovolemic shock is a low blood volume, caused by vomiting, diahhrea, blood loss, etc.
*Vascular shock: an infection or reaction is causing dilation in vasculature such that blood pressure is low.
*Cardiogenic shock: the heart isn't pumping well.
*Orthostatic intolerance: under zero G force, body fluids shift to upper body, activate baroreceptors which trigger fluid loss because they think there is too much bp. When back to normal G force, blood rushes to lower limbs and is inadequate at the brain because the body has shed blood volume.

====Alterations in blood pressure====
*Hypotension: a chronic low blood pressure. Can be caused by:
**starvation (low protein in blood)
***This makes sense because you won't generate proteins and the viscocity of the blood will decrease.
**Addison's disease (inadequate adrenal cortex funcion)
***This makes sense because it won't make aldosterone so you can't regulate blood volume.
**Hypothyroidism (this will cause an increased metabolic rate)
Why would this cause hypotension?
**Orthostatic hypotension:
***Blood is not flowing correctly, perhaps still in the peripheral.
*Circulatory shock: talked about it already.
**It is found more often in older people.
*Hypertension
**Acute: fever, exercise, fear
**Chronic: affects 28% of adult Americans.
***Over age of 50, 55% of people have chronic hypertension.

*done with cardiovascular system.
*We'll do CF next.

*stopped here on 02/22/10.

Cystic fibrosis lectures

Admin — Wed, 17 Mar 2010 14:18:51 GMT

Admin: moved Cystic fibrosis lectures to Cystic fibrosis lecture notes

#REDIRECT [[Cystic fibrosis lecture notes]]

Cystic fibrosis lecture notes

Admin — Wed, 17 Mar 2010 14:18:51 GMT

Admin: moved Cystic fibrosis lectures to Cystic fibrosis lecture notes

*continued here from [[Respiration lectures]] on 03/03/10.

*We'll go over the basics of the disease.
*We'll talk about ethics.
*There is a potential volunteer opportunity:
**The state science fair is here at IUPUI on Saturday, March 28.
**Judging is open to graduate students.
**Email her or her husband if you're interest.

==Cystic fibrosis==
*It is the most common genetic disease in the Caucasian population.
*Many carriers.
*Heterozygotes are not affected. This is the textbook form.
**Many who are heterozygous have trouble with chronic pancreatitis.
*It affects 1 in 2000 live, Cuacasian births.
*It is an autosomal disease.
*It is uniformly fatal for homozygotes.
*25-30 years ago the average lifespan was 5 years.
**Now, treatments have expanded lifespan to late 30s, early 40s.
*There are various treatments and we'll talk about each of the organs affected.
*Regardless of the other organs, it is recurrent infections in the lungs that are the major cause of death.
**Therefore, most treatments target the lungs and infection control.
**One problem is antibiotic resistance which occurs when treating with large and long antibiotic treatment.

===History===
*Don't worry about the dates, this is just a background.
*By the 80s, we realized it had to do with ion transport.
**Some thought problem was in sodium channel, some though it was in a chlorid channel.
**At this point, the best diagnosis was to make them sweat in a bag and then test it.
***As we got better, they could put a little skin chamber on them.
*In 1984, there was a classic paper published
**Two pages, one table, one author.
**Author isolated sweat ducts and thus showed that the defect was in a chloride transporter.
*In 1989 we isolated the gene for CF: CFTR.
**It was a huge gene.
*In 1992 we isolated the gene product.
**Though we though we could predict the product, this one looked very different from any other chlorine channel that we knew of at the time.
**So we called it cystic fibrosis transmembrane regulator.
**Then we put it in a frog and did some patch channel experiments and showed it was a chloride channel.
*In 1994 we started clinical trials.

===Organ systems affected in CF===

====Sweat ducts====
*There is a coil where the sweat is formed.
*Initially the sweat is a plasma filtrate (no cells).
*This travels through the excretory duct.
*As it travels we reabsorb both sodium and chloride.
*The sweat is hypotonic on the skin.
**This is good because it will evaporate well and not leave much salt behind.
*So most of the Na and Cl has been reabsorbed.
*We knew for a long time that patients with CF had sweat that was 3-5x as concentrated with NaCl than normal.
**You could even see it on their skin!
*They found that their sweat was isotonic (that is, the same as the plasma) indicating that no Na or Cl was being reabsorbed.
*One early experiment:
**Either side of the sweat gland is canulated to a pipette.
**One pipette infuses fluid that travels through the sweat duct and the other sucks it out.
**This whole system is immersed in the bath.
**Researchers have control of what is going through and over the bath.
**There is an electrode in the pipette so we can measure the volts over the lumen and bath.
**We saw 10 mV in normal patients and 80 mV in patients with CF.
**So they perfused lots of different stuff and changed the bath with and without Na and / or Cl.
**They used samples from the lab members, including the diseases tissues which came from the PI (who is the longest living patient with CF).
**And thus they could show which ion mattered: Cl-.

====Pancreas====
*In the pancreas, there are two parts: exocrine and endocrine.
**Endocrine = islets of langerhans, make hormones.
**Exocrine = enzymes made in acini, secreted via ducts into GI tract to help with digestion.
*A sodium bicarbonate rich fluid is also secreted along with the enzymes.
**Note that CFTR is a Na / bicarbonate channel.
**Bicarbonate serves as a buffer, too.
*CFTR is used to generate this secretion.
*When ions are secreted into the lumen, water follows.
*So if you cannot secrete ions, you cannot get water to move.
*So if water doesn't join, all the enzymes and such will just sit there and it will eat away at the pancreas.
**This causes generation of diabetes as the pancreas' function decreases.

====Colon====
*Not really a problem in CF.
*However, an explanation of CF's prevalence in Caucasians might be explained via the colon.
*1:2000 births is high for a fatal disease.
*So the theory is that CF yields a selective advantage for heterozygous people.
**1 in 20 might be protected against cholera which was killing boat-loads of people at the same time that CF arose.
**CFTR is turned on by phosphorylation by a kinase that is activated by cAMP.
**Cholera toxin constitutively activates the stimulatory g-protein of adenylase cyclase causing an increase of cAMP.
**Then, CFTR gets turned on which secretes chloride which causes water secretion, which, when overdone causes diahrea and death.
*So if you have CF or are a carrier of CF, the chloride channels may not work so you don't die of diahhrea.

====Salivary glands====
*CF causes a lack of secretion.
*This includes male reproductive tract secretions.
*This causes an increase in viscocity and a decrease in organ function.

====Lung====
*CF will cause mucus and submucus layers to be much thicker.
*The mucus that sits on top of the epithelium of the airway helps to clear stuff and sits on the cilia.
*In CF the mucus is thick and it bends the cilia and the mucus cannot be moved.
*So we do percussion therapy to help clear the mucus from the lungs.
*Mucus is a great place for bacteria to colonize.
**Once you have biofilms building up in the lungs you get scarring and loss of air exchange function.

=====Apical membrane=====
*Epithelial cells line the lungs.
**They have tight junctions that define the luminal side from the basolateral membrane (blood side).
*There are transporters on both membranes and they are different.
**This allows polarized transport (the movement of ions in one direction or another).

*A classic hallmark of an absorptive lumen epitheial membrane is sodium channel which it is pumping into the cell (down it's chemical gradient).
**This channel doesn't require energy.
*There is a Na/K atp-ase on the basolateral membrane moving Na out of the cell and into the blood.
*When we say absorption and secretion, we are talking about from and to the blood.

*Secretry epithelial cells
**There is a tripple transporter: moving Cl, Na, and K all in.
**We care most about the chloride which is moved into the lumen from the blood.

*The sweat duct is impermiable to water (one of the few tissues of the body with this property).
*CFTR can transprot Cl in either direction depending on the driving forces.
*In a normal sweat gland:
**Both Na and Cl are moving in an absorptive direction.
***This is normal for Na but abnormal for Cl. Na is going with its concentration and electrical gradient.
***Cl is going with its concentration gradient and against its electrical gradient.
*In a CF sweat gland:
**Now you have a huge 80 mV potential because Chloride is not being moved into the cell.
**And then Na won't move much either because the electrical balance of the sweat must remain neutral and if chloride isn't moving then sodium can't move either.

===Gene therapy clinical trials===
*The rational was that the lungs are relatively accessible and that's what kills most people.
*So we thought that if we could introduce a non-mutated CFTR gene, we could save the patients.
*Rodent experiments were relatively successful.
*Then they went on to primates.
*But how do you get the gene into the cell?
**They had adenoviruses and retroviruses.

====Choice of vectors for CF gene therapy====
*Retroviruses:
**Good: They are well understood.
**Bad: They insert into the genome in a random fashion.
**So, this could cause oncogenesis because of interuption or changing of a genome product.
***This was only theory at the time.
**Also, once the lungs are formed, a barrier is put up and the cells stop dividing.
***This is bad because retroviruses infect dividing cells, mainly.
**Retrovirues have been used in gene therapy for SCIDs.
***They took the blood of the kids out and put in the mutated gene and put the blood back in.
***This cured them. Yay!
***However, it caused cancer in 3 of the 20 patients.
***So all those trials were stopped.

*Adenoviruses:
**They are fairly benign.
***75% of us have had an infection via one of these yielding only mild infection.
**Adenoviruses like lung cells.
**They can infect non-dividing cells.
**Also, a very good thing (in theory), is that these vectors will not insert their DNA into the host DNA but will be expressed (episomal).
***Insertion will follow the host DNA upon division.
***If it is only in episomal form, you have to have multiple doses as infected cells turn over.
***Lung cells turn over slowly, but the do turn over.
**Adenovirus has been reproduced in large quantities which is good.
**We've also engineered them to be replication defective so they don't run rampant.

====Preliminary animal studies====
*We did primate studies to assess safety and efficacy.
*Safety comes in two forms:
**To the organism receiving the treatment,
***We knew that there must be no toxicity to the host.
**To the environment
***We know we had to make sure that the virus couldn't recombine with a WT virus and start infecting other people.

*They wanted to make sure that the treatment worked, too.

*In checking for safety they look for:
**inflammation response of the lungs
***They administer it via direct application.
**clinical evaluation of the lungs
***via x-rays over time
***via autopsy of animals over time
**check for dissemination of the virus throughout the body
***looking for escape of the mutated virus into the environment or throughout the animal
**how much of the vector you get into the cells
**they looked at stability of vector expression
**how functional the vector was in the cells

====Results of primate studies====
*In general, no adverse affect on health.
*All blood work was normal.
*Urinalysis was normal.
*Blood gasses were some changes but were not statistically significance.
*They found no virus in other tissue of the animal (so it wasn't moving around or escaping into the environment).
*Chest x-ray results:
**Showed (especially in the long term animals) that in the highest doses the infiltrates took 30 to 70 days to clear.
*When they autopsied, they found severe inflammation that moved from the infiltrate and moved outward to other tissue of the lung.
*They said "it was unable to determine if inflammed area would recover and be able to participate in gas exchange".
*So we see that there are some problems in the lung.
*But did it work?
*The highest doses expressed the gene at 4 days but at 21 days they found no expression.
*So, it isn't really working.
*So it is safe for the environment, it is not safe for the animals, and it doesn't really work.
*Their conclusion was that gene transfer was possible and we should start human trials.

====Article: Administration of adenovirus (by Crystal)====
*This clinical trial got the furthest and was the reason all three others were stopped.
*The patients were in pretty good health to begin, even though they had CF.
*They administered stuff through the nose.
*They found that:
**the treatment (the vector) caused an immune response,
**there was inflammation,
**no matter how hard they looked they only found a very small amount of gene expression,
**that they could not dose a second time because of immune response,
**there was low rate of transfer, not enough to take an effect.
*Conclusions:
**"Correction of the CF phenotype of the airway epithelium might be achieved with this strategy".
**We'll probably have to readminister the treatment.
*Then the scientists became media stars!

====Public perception of the human trials====
*This was a huge deal; scientists on the cover of newsweek.
*Scientists were worried.
*Overplaying this type of "breakthrough" is bad because when it doesn't deliver, scientists and researchers are looked down on.
*NIH convened an investigation and concluded that commercial interest was pushing science too fast without heeding the results.
*So NIH put money into developing better vectors instead of into the trials.
**This went on for several years.

====Jesse Gelsinger case====
*This was part of the attempt to build new vectors.
*This version was supposed to reduce immune reaction so we could do multiple dosing.
*Jesse Gelsinger was 18.
**He had ornithine transcarbamylase deficiency.
**His older sibling had died before he was born.
**His diet was controlled so he could live (with medicine).
**He was "normal" and an athlete.
*He was recruited into the trial.
*He knew this vector would do nothing for his disease.
*The adenovirus they were using was targeting the liver.
*Leading up to this human trial:
**Mice, then monkeys, then baboons.
**It had been shown that there was some toxicity with the vector.
**They were turned down the first time they submitted for human trial permission.
**So they resubmitted and said they would only do low doses because primates had die at high dose.
**So they got permission to start at 5% of the highest dose.
**If they got no bad results they were allowed to increase dosage up to 75% of highest dosage.
**They had three patients in each group.
**Most patients in lowest group showed fever and moderate immune response.
**The 10th and 11th volunteers showed substantial increase in liver enzymes which shows change of function of liver, which was recovered.
**18th patient died of immune response to vector.
*The vector was patented by the lead investigator and the university (University of Pennsylvania).
**Now this cannot happen, which is one good thing about this whole fiasco.
*Five years later, the university settled (1 million to the Gelsingers).
*Lead investigator was barred from doing clinical trial for 5 years.
*Under the aggreement, however, the researchers do not admit responsibility for Gelsinger's death.

====Where do we go to here?====
*We're trying to make new vectors.
*We've made some progress with a small molecule that helps to move the mutated form into the plasma membrane.
**This affects the major CFTR mutant (F508) which breaks because the protein gets stuck in the ER.

*Test on Monday.
*No class on Wednesday (snow make-up day).

*stopped here on 03/03/10.

Respiration lectures

Admin — Wed, 17 Mar 2010 14:18:42 GMT

Admin: moved Respiration lectures to Respiration lecture notes

#REDIRECT [[Respiration lecture notes]]

Respiration lecture notes

Admin — Wed, 17 Mar 2010 14:18:41 GMT

Admin: moved Respiration lectures to Respiration lecture notes

*started here on 02/24/10.

==Respiration==
*Respiration requires some stuff:
**We'll talk about convection system (that is, ventilation and cirulation).
**We'll also talk about mechanisms for gas transport int he blood.

===Respiratory functions===
*We're going to talk about ventilation in general and which muscles of the chest wall are used.
*We'll tlak about negative pressure that pulls the air into the lungs.
*We're going to think about ...

===More requirements for respiration===
*We have to have a way for the air to flow. Ventilation perfusion coupling.
**We'll look at some problems of this, too.
*We'll look at the CNS's involvement in respiration and circulation.
*Oxygen level is important, but CO2 is the primary regulator of respiration.
*Figure 23.5.

===Non-respiratory functions===

====Filter and moisten air====

====Facilitate olfaction by transporting airborne molecules====

====Defense against airborne pathogens - mucocilliary elevator====

====Sound production====

====Trap small emboli in pulmonary circulation where they are dissolved====

====Blood reservoir for left ventricle====
*Lungs contain 500 ml of blood.
*Two beats can be supplied if pulmonary artery is clamped.

====Biochemical reactions====
*ACE converts angiotensin I to antiotensin II.
*Some prostaglandins are removed at the lungs.
*ACE is released by endothelium or this all takes place in endothelium.

===Organization of the respiratory system===
*Can be divided into upper (down to the pharynx) and lower (everything lower).
*We could also look at the system in terms of function instead of structure.
**The transition of function (from conducting zone to respiratory zone) occurs when alveoli start to occur.
*The tubes branch significantly. There are about 16 divisions (called generations) before there are any alveoli.
**At 17 is where alveoli start and the cartilage rings stop.
**Generation 11 is where bronchials start.
*There is also a change in type of cells found.
**We transition from columnar at the top to squamous at the bottom.
**We see a change from more to less (going down) of goblet cells because of the elevator.
**We see a decrease in cartilage because we have less and less structure.
**Elasticity goes the entire length. They are important for recoil in the chest wall and the alveoli.
*Bronchials are susceptible to collapse during expiration.
*At generation 17, alveoli start.

====The mucocilliary elevator====
*Goblet cells are releasing mucus on surface.
*Cillia are beating upward.
*As we get to the lower region, the size of pathogens is important because the smaller they are the deeper they can get and the better they can get across the endothelial cells when they land.

====Nose====
*The air enters through the external nares.
*There is mucus secretion and tears coming through ducts, these help to trap crap.
*Air passes through conchae around the turbanates (an outcropping of bone). This generates turbulance to facilitate smell and moistening.
*We have sinuses (four of them) which connect to the nose through the medemus (?).
**When this connection is blocked, pressure can build up.

====Palate====
*Separates nose to mouth.
*Hard and soft palate.
*Cleft can occur which is bad. Usually happens where bones come together in top of mouth.
**Can happen in hard or soft palate or both.
*Soft separates oral cavity from nasal pharynx and hard palate separates nasal and oral cavities.

====Nasopharynx====
*This is in common with digestive and respiration tracts.
*There are three regions but we won't dwell on them.
*Nasal connection is called the internal nares.
**This is the location of the adenoid.
**This is also where the opening to the ear occurs and it is important for good sound conductance and balance.

====Oropharynx and laryngopharynx====

====Larynx functions====
*This structure is trying to keep the airway open.
*Behind it is the esophagus.
*Epiglottis sits on the top with some cartilage that allows the epiglottis to cover the glottis (a slit-like opening).
*The vocal cords are on either side of the glottis.
*There is upward movement that helps to close off the glottis.

====Anatomy of larynx====
*The thyroid cartilage forms the adams apple.
*The adam's apple is caused by hormones.
*Cricoid cartilage provides posterior and anterior support.

====Tracheal cartilages====
*Begins at the base of the larynx.
*You can feel the cartilage rings with connective tissue in between.
*The rings are c shaped with the open part in the back.
*There is a muscle and a ligament on the back which are responsible for changing the diameter to change resistance.
*The esophagus is posterior to the trachea.

====Primary bronchi====
*Our first bifurcation occurs.
*The right and left are not equal.
*The angle of division are not equal.
*The right has a short bronchial tube and left has a straighter angle.
*This is a problem when kids breath something. Most likely it is in the right bronchial tube because the angle isn't as great.
*At the bifurction, the cartilage extends into the airway a little (think shelf).
**This is covered by endothelium and is very sensitive.
**This causes the coughing when you inhale something.

====Hilus====
*The hilus is the midline of the lung (theres one on the kidneys, too).
*This is the location where the major structures enter the organ (think veins, lymphatics, bronchii).
*The whole thing is held together by a mesh-work of connective tissue.

====Lungs====
*The right lobe is larger than left because the heart is taking up space on left side.
*You can see the fissure that helps separate the middle lobes from the upper lobes.
**Note that on the left there are only two lobes.
**Right has a middle lobe.

====Lung lobes====
*The lobes are divided into segments.
*The segments are able to be isolated by surrounding connective tissue.
**They can be removed for something like lung cancer or what-not.
*The reason for these sections is that the the lymphatics, respiratory, and circulation all branch together such that all the sections separate systems.
*Right has 10 lobes and left has 8 or 9.

====Lobules====
*Sections can be divided.
*Can be the size of a penny to an eraser.
*Respiration occurs at the level of the alveoli which are at the base of the lobules.
*Artery, vein, and lymphatics all supply each lobule and each alveoli.

===Smooth muscle control===
*The cartilage is gone, recall, so we rely on the muscle to keep the airway open.
*Therefore we can change the dilation.
*The sympathetic will open airways to reduce resistance and the parasympathetic will do the opposite.
*Histamine will also restrict to increase resistance.
*This is all further compounded by the fact that we need airpressure from the outside to help hold it open.

===Alveolar organization===
*There are capillaries that pass through avleolar, which means that we can get oxygen from either capillary.
*There are several cell types at this point: type 1 cells and type 2 cells.
**Type 1 are long and thin, these do gas exchange.
**Type 2 are important for generating surfactant.
*There are also macrophages in this space to help with protection.
*Neighboring alveoli have pores that connect them; we do not know the function.
**Might help to maintain stability; for example, gas may be able to move between alveoli.
*Surface area is very important:
**It increases significantly as we develop (3 to 75 square meters).
**Yet the number of alveoli stays about the same.

===Gas exchange===
*We have to oxygen and co2 across the respiratory membrane.
*We have to diffuse across the epithelial cell and the basement membrane that holds them together, then the interstitial space (not much), then the basal membrane, then the endothelial cells.
*So, there are 10 different diffusion steps that have to occur.
*If the wall is too wide, the time to cross will take too long and we're less likely to oxygenate the blood.
**We only have about 7/10ths of a second before the opportunity is lost.

====Respiratory membrane====
*The membrane works well when everything is functional.
*It is important that there is a difference in partial pressure (especially for O diffusion).
*Distance is small, which is good and key.
*Oxygen and Co2 and Co are lipid soluble so we don't have to have transporters but we do have to have a moist surface for efficient exchange.
**So we have to keep solublility issues in our minds.
*Large surface area is important.
*There must be good stability at the air-water interphase.
**Bad stability = alveolar collapse -> lung collapse = bad.
*Coordination of flow is important.
*The blood cell membrane must be thin with the blood cell close to the cell wall.

====10 stems to transport====
*Amazing it works at all, really.
*Notice that there are D1-d10 steps.
*from water-air place to inside a type 1 cell (step 1),
*through the cytoplasm of the type 1 cell (step 2),
*exiting the type 1 cell into the interstitial fluid (step 3),
*moving across the interstitial space (step 4),
*moving into the pulmonary capillary endothelial cell (step 5),
*across the pulmonary capillary endothelial cell cytoplasm (step 6),
*across the inner pulmonary endothelial cell membrane (step 7),
*through the blood plasma (step 8),
*across the blood cell membrane (step 9),
*and through the RBC cytoplasm (step 10).

===Air replacement===
*We don't replace all of our air with each breath.
*Even after 16th breaths, there are still some of the original air molecules before total replacement.

===Integration of two processes (respiration and circulation)===

====External respiration====
*Involves:
**Ventilation (breathing)
**Diffusion over capillaries
**Exchange of CO2 and O with Hb.

====Respiratory laws====
*There are four laws.

=====Dalton's law=====
*This is looking at the gas mixture itself.
*There is some total pressure, added to by each individual gas, which is a percentage of the total--the partial pressure.
*Remember that the partial pressure is only calculated from the free molecules of gas.

=====Henry's law=====
*Takes dalton one step further.
*Here we look at solubility issues.
*This law is important to respiratory process because we need to think about getting the gas dissolved in the liquid interface on the surface of alveoli.
*There is a different solub coeff for different liquieds

=====Graham's law=====
*Rate of diffusion is inversely proportional to the square root of molecular mass.
*The rate of diffusion is driven by difference in partial pressure of the gasses.
*There are solublility issues, too, but overall, it's the difference in pp.
*Oxygen gets used up so there is an inward gradient while co2 has an exit gradient because we're generating it.

=====Fick's law=====
*Ties everything together.
*The greater the pp difference (that is, the concentration gradient), the greater the rate of diffusion.
*The greater the permeability of the membrane the better the diffusion.
*The more surface area the more diffusion.
*The larger the molecule the lower the diffusion.
*The thicker the membrane the less diffusion.

====Balance====
*We have to have blood and gas flow balance.
*Incoming air is not always equally distributed because of mucus or disease or whatever.
*Therefore, there will be differences in concentration of oxygen in these different areas.
*This can generate hypoxia in a certain area, which will cause vasoconstriction.

====Ventilation perfusion coupling====
*This is how pps of O and CO2 change vasodilation.
*Let's say there's a blockage and a reduction of air coming into a certain lobule.
*So CO2 goes up, O goes down in the alveoli.
*The arterioles will restrict because there's no reason to go there because there is no oxygen.
*On the other hand, you can open the vessels where there is more oxygen.
*So this all balances the air with the blood.

====Never perfect perfusion balance====
*Gravity has an effect.
*Circulation at the top of the lungs isn't as effective as the bottom of the lungs so there is more perfusion at the bottom than at the top.

===Normal and abnormal respiration===

====Tissue structure and its affect on perfusion====
*A normal lung has nice, open, alveoli.
*With pneumonia, you start to lose openness of alveoli.
**Because the pneumocytes aren't working correctly.
*In emphasema, you have coelescing of the alveoli.

====Pneumonia====
*There is an impedance in the alveoli of the sick lung.
*This causes there to be much lower venous return in terms of saturation. So flow hasn't changed but there is a decrease of oxygen returned to the body because one lung is sucking at diffusion.
*Note that in pneumonia, you cannot change blood flow to compensate for the pneumonia.

====Collapsed lung====
*Edges are sticky, can't inflate.
*Now the circulation does change along with this problem.
*So circulation will be decreased to bad lung and it will be increased in the good lung such that we can offset the loss of oxygen.
*So, this person actually gets more oxygen returned than the penumonic lung patient.

====Surfactant and surface forces====
*We want the alveoli to be open, even while we exhale.
*The liquid on the inner interface interact differently as the surface becomes smaller.
*They then become part of the subphase and the surfactant keeps the alveoli from collapsing.
**More on this next time.

====Compliance====
*This is an indication of how well the lung is inflating relative to the pressure differences we're imposing.
*If it is highly compliant it won't expand as we expect.
*This can be affected by:
**Connective tissue of lung (elastic versus structural)
**amount of surfactant
**mobility of the thoracic cage
***For example, with arthritis and the inability to expand the rib cage.
*Hystoresis is the difference between lung volume during inspiration and expiration.
**Hystoresis: the lag of time between cause and effect.
**This won't occur if the lung is filled with saline.
**So looking at the volumes under some pleural pressure can tell us something about the tissue.
*Normal physiology will give a nice, steady change of volume relative to pressure.
*In emphasema, it will be high in compliance. There will be a huge volume change relative to pressure. That is, it is very easy to inflate (inhale). The problem is that it is hard to deflate. They make the last little 'hewh'.
*In low compliance, it is easy to exhale but hard to inhale. These people tend to develop a barrel chest under the struggle to inflate lungs.
*So we would say that with good compliance you should have a large change in pressure and a large change in volume.
**In emphasema, there is high volume change but low pressure change, and therefore it is easy to breath in but hard to breath out. This is called high compliance.
**In pneumonia (or a collapsed lunch), there is low volume change but high pressure change and therefore it is hard to breath in but easy to breath out. This is called low compliance.
*Ultimately, we say that compliance is the ability of the lung to expand. So high compliance is high ability to expand (easy to inhale).

====Pleural sac====
*The lungs are in the pleural sac.
*The pleural space is fluid-filled.
*The parietal membrane is right underneath the chest wall.
*The visceral membrane follows the Lung proper, including folds.

====Musculature====
*Diagraphm is main.
**Contraction means it is coming downward and inhaling.
**Relaxation causes a dome and exhaling.
*The intercostal muscles are between ribs and helps with expansion and reflexion.
*The sternocledomastoid muscles are also able to help lift the rib cage.

====Expriation====
*Generally passive.
*In active exercise, we can use muscles that make the chest smaller.
**REctus abdominus = pulling ndown.
**Intercostal pull ribs downward.
**External oblique muscle pull chest inward.

====Quiet breathing====
*Eupnea is normal, quiet breathing.
*Hypneria is the use of excessory muscles.

====Pressures of pleural sac====
*REcall that this is fluid filled.
*This is an area of lower pressure than atmospheric pressure (negative pressure).
*The transpulmonary pressure is that between the lung tissue and the pleural sac.
*We're not normally looking at much pressure change differences, usually just 1-2-3 mmHg changes.
*But when we really exercise hard, we can see big changes like -30 mmHg and +100 mmHg. This may not be a good idea.

====Pressure changes associated with ventilation====
*When normally inhaling, we decrease the pressure in the pleural space because the space gets larger because of muscle movement.
*So the pressure difference across the pulmonary space will increase (that is the transpulmonary pressure).
**This makes sense because pressure is increasing in the lung but decreasing in the pleural sac.
*The negative pressure pulls on the lung tissue which causes it to inflate.
*Then the pressure in the alveoli will drop below atmospheric pressure.
*Air enters lung until reaching atmostpheric pressure.
*Then intrapelural pressure decreases and transpulmonary pressure increases and the lung exhales.

====Chest wall breach====
*In the case of collapsed lung, the pressure in the pleural space is equal to the atmospheric pressure.
*This can happen from gunshot wound or tear.
*The lung will collapse.
*So we have to close the tear and reinflate the lung.

*stopped here on 02/24/10.
*started here on 03/01/10.

*We're going to talk about control points for rates and volumes issues.
*We're also going to talk about surfactant.

===Respiratory Rates and volumes===
*In order to meet the chaning needs, there has to be a way to balance the production with the need.
*So we can change how often we breath and how much volume occurs during each breath.
*The respiratory curve defines the volumes and how they are linked.
*In a normal inhale-exhale, we move the tidal volume: how much we move with each breath.
*With excersize we have to accomadate more volume so we do this with reserve volume (both on the respiratory size and expiratory side).
*Our total inspiratory capacity includes the inspiratory reserve and the tidal volume.
*The numbers on the slide are averages.
*Our functional residual capacity is the respiratory reserve (that which can be forced out) and the residual volume (that which you cannot exhale)
*The vital capacity is the total amount of room that could be moved in and out. Which is the two reserve volumes plus the tidal volume.
**There is always some that cannot be moved: residual volume. It is in an unusable area.
**In a forensic lab, you could test to see if an infant was stillborn or not by testing the floating capacity of the lung because if the baby ever took a breath, the residual volume will be filled with air.

===Respiratory minute ventilation===
*This is defined as how much air is moved per minute.
*It is a function of how frequently we're breathing and the volume of each ventilation.
*It is generally about 500 ml at 12 times per minute which is about 6 liters of air per minute.
*It goes beyond this, however, because we wonder how much air actually gets to the alveoli. This is important because that is hte only location where we can exchange air.

===Alveolar ventilation===
*So alveoloar ventilation is this idea of how much air gets to the alveoli.
*We include in this calculation any part of th elungs that can exchange, which begins at the respiratory bronchioles and includes everything deep to that.
*The dead space is all the area where air is conducted but cannot be exchanged with the blood (like in the bronchi).
*If you hold the minute ventilation constant and then increase dead space, you won't be able to keep exchanging well.
*There is a dynamic balance between our rate of ventilation and the tidal volume.
*We can put this dynamic into numbers, too, and generate some equations:
**Tidal volume - dead space ventiation x frequence = alveolar ventilation rate.
***Dead space is generally around 0.150 l
***Normal alveolar ventilation rate is 4.2 liters.
**This tells us how much is able to get to the alveoli and therefore is available for breathing.

*We wonder if there is an upper limit to all these things.
**We cannot exceed the oxygen levels of the partial pressure of oxygen in the environment's air.
**We can see that at lower oxygen levels, it will take a longer amount of time to reach the normal concentration of oxygen in the body.

===Oxygen transport===
*So we're thinking about the idea of oxygen and carbon dioxide transport.
*Plasma is not a good place for oxygen to disolve so 98% of it is bound to Hb.
*If you wanted to support a person simply on dissolved oxygen, you'd have o increase cardiac throughput by 17 fold!
*Iron is the binding site of the oxygen in Hb. The iron is surrounded by four heme groups.
*So we have the possibility for one RBC to transport over 1 billion molecules of oxygen. On average, it works out to be about 3.8 oxygens perl Hb.
*Oxygen binds to Hb in a cooperative manner: when one binds, the second and subsequent bind more and more easily.
**The opposite is true, also.
**The significance is that in a situation in which we really need oxygen, this increases our ability to carry oxygen.
*There are several ways we can affect Hb levels.
**We can increase RBC.
**We can increase Hb in a given RBC.
*In an anemic situation, we have decreased RBC counts and therefore Hb will only be 10% of the volume and we'll only transport 13.4 ml of oxygen to the alveoli. Normally, hb is 15% and we deliver 20.1 ml. With extra RBCs we have 30% and 26ish mls.

===Carbon dioxide transport===
*About 7% of CO2 is dissolved in blood.
*About 23% of it is combined with proteins and amino acids in blood (mostly those of Hb).
*And most (70%) of it is transported as HCO3-.
*In RBCs we have carbonic anhydrase which is a completely reversible enzyme so it can generate HCO3- and CO2 and subsequently Ho2.
**This enzyme converts CO2 and water into carbanic acid (H2CO3).
*So bicarbonate goes into the RBC exchanged for Chloride. Then Carbonic anhydrase converts bicarbonate into H20 and CO2. CO2 then gets released via the alveoli.

*When Hb binds hydrogens, it becomes acidified and it releases oxygen. This makes sense when thinking about lactic acid buildup and extra oxygen delivery of oxygen.

*So the cycle goes like this:
**A RBC arrives at peripheral tissue.
**CO2 moves from tissue to the plasma (and potentially lactic acid, too) via osmotic pressure such that acidity rises.
**Increase of acidity causes oxygen to be released.
***Note that it is the water and CO2 levels (which are high at the systemic tissues) that will drive pH changes and thus cause regulation.
***Hb can also bind CO2 and upon doing so it will favor release of oxygen.
**At the same time, carbanic anhydrase is converting CO2 to carbonic acid.
**Then carbonic acid gets converted to bicarbonate (via an unknown mechanism).
**Then bicarbonate is exchanged into the plasma in exchange for chloride ions (the '''chloride shift''').
**Bicarbonate is freely diffusable so it can go and dissolve in plasma. However, if we're going to let the negative molecule into the plasma, we have kick one out, too (Cl-). This is called the chloride shift.
**Then the blood travels back to the lung.
**At the lung, the partial pressure difference between the air and the RBC causes CO2 to move from the RBC to the air.
**This movement drives the previously described reaction in reverse.
***This causes carbonic acid to be converted to CO2.
***This causes bicarbonate to be converted to carbonic acid.
***This causes bicarbonate to be draw into the RBC (in exchange for chloride ions leaving the RBC).
*Oxygen is pretty much separate. It is driven by partial pressure.

http://lh6.ggpht.com/_mqoliJqPnsw/S5FKDGH42UI/AAAAAAAAU1Y/C_SEqaCOwMc/s800/co2_exchange_cycle.jpg

===Hemoglobin saturation curves===
*Saturation occurs based on partial pressure.
*As the curve rises, it represents the oxygen that we use during exercise and normal ventilation. And near the bottom, the curve represents the oxygen that never gets releases from Hb (which is common).
*Note the sigmoidal binding curve.
*Carbon monoxide binds very well to Hb and is very difficult to reverse which is bad because it binds much more readily than oxygen. Oxygen must be at very high partial pressures to overcome carbon monoxide (poisoning).

*Ultimately, as temperature increases and pH decreases, Hb will more readily dump oxygen which makes sense because when you're exercising these things will occur. So this is a shift to the right on a graph of Hb saturation versus partial pressure (of oxygen in the Hb).
**We see that oxygen binds more readily at the same partial pressure. With increased temperature, saturation occurs at a higher partial pressure of oxygen.
**And if you have fever or are working hard, the metabolism of the tissue is going up so you want to be sure you have oxygen for the tissues to use.
*And lower temperatures and a higher pH will cause retention of oxygen on Hb which makes sense because the Hb will be in its oxygen-binding conformation and will keep the oxygen (that is, when aa pK values drop, we see a conformational change in Hb such that oxygen can bind well) which is good because we need to conserve the oxygen in our hypothermic state (hybernation).

===Bohr effect===
*We can think about pH and CO2 and how they change the binding of oxygen.
*The bohr effect has to do with pH's effect on binding.
*Alkiline conditions will generate increased prevalance to bind at a given partial pressure.
**That is, as acidity goes up, oxygen deliver will go up. As acidity goes down, oxygen deliver goes down.

===Hb as a buffer===
*Hb is a good buffer.
*This makes sense because it binds and releases H+.

===Adult / fetal Hb===
*The partial pressure in the maternal blood after having passed through tissue that took some of it will be even lower than the environmental partial pressure, so the fetal blood has a higher affinity such that it can still take the blood from the mom's blood.
*2,3 biphosphoglycerate is generated by RBCs as part of normal glycolysis. It causes Oxygen to be dumped off of Hb.
*As you increase DPG (a right shift), one increases oxygen delivery because.
**We can increase DPG by an increase in pH, by some hormonal influence.
**DPG can be used as a marker for blood banks to determine how fresh and capable the blood is.
**DPG levels are decreased in the elderly.

===Haldane effect===
*Looks at CO2 levels as they affect oxygen binding.
*As CO2 rises, Hb will be less saturated with oxygen and vice versa.
*As CO2 goes up, the carbonic anhydrase reaction will generate bicarbonate and this will cause a shift to the right.

===Control of respiration===
*There are many things that occur to control ventilation; we need to think about changing the blood flow and oxygen delivery.
*We know we can change vessel diameter both in the periphery and in the lungs.
*There are many factors that affect dilation, including Hb, NO, and vasodilators.

*NO acts in both the tissue and the lung to control Hb saturation:
**In tissue:
***NO is released by endothelial cells, as the RBCs take up CO2 it also takes on NO, NO then binds to the globin portion of Hb, and increases dumping of oxygen at the tissue.
***NO causes vasodilation.
**In the lung:
***NO has been carried from the tissues via RBCs. NO is then released at the lungs which allows for easier loading of O on the Hb.
***NO causes vasodilation which should only be considered a side effect.

*This means that NO increases oxygen deliver in peripheral tissues but in the lung it facilitates the uptake of oxygen (because it increases blood flow through the lung).

How, exactly, does NO increase loading in lungs?

===Respiraotry centers of the brain===
*The voluntary centers are in the cerebral cortex but are only good for a period of time because involuntary (pons and medulla) are more important.
*The voluntary centers will only work as long as CO2 levels are low or normal. As soon as CO2 goes up, it over-rides voluntary choice.

===Respiratory centers in the pons and medulla===
*They are in the brain stem.
*The medulla is the major location of control. It has a location for inspiration and expiration (DRG, VRG).
*The pons has two different areas: pneumotaxic and apneustic areas.
**These are not necessary for life but it does help with fine tuning of rate and depth of respiration.

===Medulla===
*The dorsal respiratory group is primarily inspiratory.
**We inhale for 2-3 seconds and then shut fthe pathway off and let the passive time take over for exhalation.
**The DRG functions in quiet and forced breathing.
*During exercise we induce force respiration and we start to rely on the extra space and volume.
*Ventral respiratory group is the one that is active in forced breathing when in need of O2.
**This center can stimulate inhalation or exhalation depending on the situation.
**Basically, the VRG boosts the rate one way or the other.

===Quiet breathing===
*The respiratory center turns on and off; primarily we're working only with the DRG.
*Basic pace and depth of respiration are determined by the balance of the DRG and VRG.

===Forced breathing===
*The VRG kicks in and we see an impact on depth and rate.
*This will activate the accessory breathing muscles and expand the chest cavity and thus draw on the reserve volume.

===Respiratory centers and reflex controls===
*The apneustic center provides a continual level to the DRG (which regulates normal in and out cycle).
*The pnuemotatctc center turns off the DRG and thus limits the duration of the inhalation.
*The penumotactic center also helps inhibit the apneustic center.

===SIDS===
*One of the things we think happens is that the respiratory centers become disrupted in some way (though we don't know how). Then normal ventilation is affected and the baby dies.
*May result from connections between pacemaker complex and respiratory center.

===Sensory input modifies respiratory center activities===
*There are chemoreceptors in the body that are sensitive to co2, ph, or O2, (in that order) and can then feed back to (respiratory centers).
*There are also baroreceptors that will sense changes in blood pressure (caused by changes in vasoconstriction).
*We have stretch receptors, too, that respond to changes in lung volume.
*There is the brewer-reflex. There are sensors that sense how stretched the lungs are and feed backs to the respiratory centers in order to control inhalation.
**Babies don't have a fully calcified set of ribs so they can sometimes overinhale and rip their lungs on the bones.
*We also have sensors for irritants which can causes us to hold our breath, or lock our larynx (jumping into cold water; be careful with cold drinks in heat), bronchial tree.
*Other sensations like pain or abnormal visceral sensations.

===Influence of cranial nerve===
*Number 10 is in the aorta and senses changes in the aorta.
*Number 9 is the glossiopharyngeal carries info from the carotid bodies, stimulated by changes in pH and PO2.

===Receptors monitoring the CSF===
*The receptors in the CNS respond to changes as a result of ventilation while those in the periphery change because of changes in metabolism.
*So as CO2 levels change, the cells of the CSF in the spinal cord have carbonic anhydrase as well. So then CO2 levels change the pH of cerebral spinal fluid and thus can be used as a way to change respiratory rate and depth.

===CNS chemoreceptor responses to partial pressure of co2===
*This leads to increased depth and rate of respiration.
*There can be decreased sensitivity due to chronic stimulation.
*Hypoventilation: common cause of hypercapnia (elevated arterial Pco2), increase respiratory rate to fix
*Hyperventilation: results in abnormally low Pco2 (hypocapnia), decrease respiratory rate

===Baroreceptor reflexes===
*When BP falls, respiration rate goes up and ''vice versa''.
**This goes along quite nicely with needing to balance flow to demand.

===Hering-breuer relfexes===
*This has to do with over expansion of the lungs.

===Protective reflexes===
*The epithelium of the respiratory system and especially the korina (split in bronchials) have these receptors.
*This will turn off breathing so that you don't increase the irritant and in fact it increases the desire to breath out: sneezing / coughing.
*Apnea = lacking or suspending ventilation.
**Eupnea.
**Apnea can be used to balance out delivery of gasses.

===The cerebral cortex and respiratory centers===
*Strong emotions can activate the autonomic nervous system which can affect the airways and the diameter of the vessels, and thus can affect balance so as to change respiration.
*Anticipation is an involuntary summing up in the mind of how many motor units are needed. In parallel, our brain calculates how much breathing is required.

===Changes of respiration over time===
*Before birth, we have a little blood running through the pulmonary vessels; only enough to supply the lungs with blood.
*During deliver, the fetal CO2 levels will begin to rise. This will feed back on ventilation centers and cause an autostimulation of those receptors in order to cause breathing.
*At the very least, it make take a combination of CO2 and some tactile stimulation.
*So we think about lungs being able to be ventilated in babies. We have to overcome the surface tension that wants to keep the lung in a collapses position and overcome this collapsed state with the release of surfactant (a massive release, indeed).
*We also have to redirect blood flow (closing foramen valve).
*Add all this up and the lung should fully inflate.
*As we age, the chest wall becomes less elastic. There is a drop in performance rate of the lung.
**It seems that if you quit smoking, as long as you're not really old, you start to recoup some of the good properties of the lung.

===3 affects of aging===
*When elastisticity goes down we have decreased performance.
*Arthritis can cause decreased movement of the chest and therefore a decrease in perforamnce.
*Emphasema affects individuals over 50 depending exposure to irritants.

===Surfactant===
*We really started to understand this as a result of people studying Hyaline Membrane Disease (IRDS).
**This is when alveoli become clogged with dead tissue that resulted from strained breathing.
What is hysteresis?
*What is surfactant?
**He studied lipids of surfactnat for PhD.
**It's hard to find the proteins, easy to get lipids.
**There are two groups of proteins.
**We're tyring to decrease surface tensions.
**As the surface gets smaller, some of the molecules on the surface will go inward and the tension will become inward. So the aveiolus will want to collapse.
*The surfactant also helps with trapping of debris and thus eject it via the escalator.
*Note that you can take samples of amniotic fluid, look at the proteins, and determine whether an infant will be able to survive on its own.
**The ratio of lecithin to sphingomyelin must be greater than 2.
**You use gluccocorticoids to stimulate lung maturation.
*80% of surfactant is phospholipid, 10% neutral lipids, and 10% proteins.
*If you look at the phospholipids, 60% is in the form of DPPC. This lipid carries the property that lets the surface act the way it does.
*The second most important will be phosphotydl inositol.

*stopped here on 03/01/10.
*started here on 03/03/10.

*The DPPC is the major contributor to the reduction of surface tension.
*Phosphatidyl inositol makes up about 5-7% of the reduction of surface tension.

*There are two groups of proteins, either hydrophilic or hydrophobic.
*So while the lipids are important, the proteins were identified in the early eighties.
**The lipids have been around and known since the 50s.

===Hydrophilic surfactant proteins===
*SPA and SPD are hydrophillic.
**They are both glycosylated and in the aqueous (water soluble) phase.
**Both involved in defense through the activation of macrophages.
**So this is one of the ways we can take care of bacteria that get below the elevator.
**It is not odd to find macrophages at the air-water boundary.
*There are 28 types of cells in the lung.
*SPA is also involved in antiviral activity and surfactant cycling and secretion.
**It works closely with synthesis and secretion of miller bodies which is where something is located.
*SPB and SPC
**The spreading of the surfactant on the alveolar pocket is important and that's what B and C do.

===Lamellar bodies and tubular myelin===
*We're seeing a type II cell and a lamellar body inside.
**This is really a package of tubular myelin.
**The surfactant is on the tubular myelin.

*SPA / B are required for formation of lamellar bodies and tubular myelin.

*Respiratory distress in infants:
**One of the problems is that we're trying to open lungs without surfactant.
**This causes cellular and tissue damage because they are rubbed against each other.
**This can cause the tissue to become disfunctional.
**This can even tear the lung and cause lung collapse.

*continued on to [[Cystic fibrosis lectures]] on 03/03/10.

Geddis's "The root of platelet production"

Admin — Wed, 17 Mar 2010 14:17:40 GMT

Admin: moved Geddis's "The root of platelet production" to Geddis's "The root of platelet production" 2007

#REDIRECT [[Geddis's "The root of platelet production" 2007]]

Geddis's "The root of platelet production" 2007

Admin — Wed, 17 Mar 2010 14:17:40 GMT

Admin: moved Geddis's "The root of platelet production" to Geddis's "The root of platelet production" 2007

*Platelets are the first line of defense when bleeding occurs.
*Platelets are pathological in atherosclerosis, acute coronary syndromes, and some cancers.
*Exactly how platelets are deposited into the blood stream was previously unknown.
*A group shows that the platelets are fragments of long proplatelets that extend from megakaryocytes, through sinusoidal endothelial cells, and into the blood vessel.
*They demonstrate this through ''multiphoton intravital microsocopy''.
*Platelets are discoid, anucleate cells, ~2μm in diameter.
*Normally platelets flow along with no reaction to each other or cell the vessel wall. Upon injury, however, they change shape, adhere to the vessel wall and secrete cytokines which initiate vessel repair.
*Thrombocytopenia is the deficiency of blood platelets. This condition can lead to intracranial bleeding, simple bruising, gastrointestinal hemorrhage, or death.
*The body can increase platelet production (thrombopoiesis) 20-fold when needed.
*Thromopoiesis occurs in bone marrow.
*Hematopoietic stem cells generate megakaryocytes which generate platelets.
*We've learned lots about megakaryocytes recently, but we still didn't know how they produced platelets.
*For a long time there were two schools of thought: that cytoplasmic fragmentation occurred (the cytoplasm gotten separated into separate platelets) or that long proplatelet processes were generated via microtubules.
**Both of these hypotheses had microscopic evidence.
**Studies demonstrated factors that aided in platelet formation from long processes, but they still didn't know if they were seeing ''in vitro'' artifacts or not.
*By way of ''intravital fluorescence microscopy'' on the opened cranial marrow cavity of a mouse, Junt ''et al.'' showed pro-platelet chunks being sheered off of long, protruding processes by the flow of blood.
*They also showed that these chunks are further broken up on their occlusion of the vessel.
**"Their findings confirm the decades-old observation that the platelet count in the pulmonary veins (leading out of the lung) is higher than in the pulmonary arteries (leading into the lung), because single proplatelet processes undergo further hydrodynamic processing in the lung into two or more platelets."
*There are, of course, more questions now:
**How does a megakaryocyte know when to produce these processes?
**How does the process protrude through the megakaryocyte cell cytoskeleton?
**Does iron deficiency or inflammation change platelet size and number by affecting pro-platelet formation?
**Since platelets are only derived from polyploidy megakaryocytes, what is the mechanism by which DNA replication and cell division are uncoupled to generate polyploidiness?

Eaton's "The biophysics of sickle cell hydroxyurea therapy"

Admin — Wed, 17 Mar 2010 14:17:14 GMT

Admin: moved Eaton's "The biophysics of sickle cell hydroxyurea therapy" to Eaton's "The biophysics of sickle cell hydroxyurea therapy" 1995

#REDIRECT [[Eaton's "The biophysics of sickle cell hydroxyurea therapy" 1995]]

Eaton's "The biophysics of sickle cell hydroxyurea therapy" 1995

Admin — Wed, 17 Mar 2010 14:17:14 GMT

Admin: moved Eaton's "The biophysics of sickle cell hydroxyurea therapy" to Eaton's "The biophysics of sickle cell hydroxyurea therapy" 1995

*Hydroxyurea can help reduce symptoms of sickle cell patients.
*This is the first specific treatment for this class of genetic diseases.
*The pathology of sickle cell works like this:
**abnormal hemoglobin S gets deoxygenated and (because it is abnormal) it polymerizes to form a viscous gel,
**there is a large decrease in the deformability of RBCs with abnormal hemoglobin S,
**occlusion of microcirculation vessels occurs because of stiffened cells,
**insufficient oxygen supplication occurs,
**tissue is damaged by lack of oxygen, often resulting in episodes of severe pain called '''sickle cell crisis'''.
*It has been shown that in patients with a higher hemoglobin F to hemoglobin S ratio have decreases symptoms.
*Hydroxyurea increases the hemoglobin F side of the ratio.
*We don't know how hydroxyurea increases hemoglobin F, but we do know how an increase in hemoglobin F decreases symptoms.
*The kinetics of polymerization are very important in this disease:
**Polymerization is extremely sensitive to the concentration of (damaged )hemoglobin S; in the chemical reaction, the function of hemoglobin S is to the 30th power!
***The more hemoglobin S is present, the faster it will polymerize.
**It takes about 1 second for a RBC to get through the capillaries on it's circuit.
**Recall that deoxygenation occurs just before or during transit across capillaries.
**If polymerization occurs within the 1 second after deoxygenation, during which the RBC is in the capillaries, it will cause blockage and slow circulation.
**If the kinetics of polymerization are delayed beyond the 10 to 20 seconds it takes a RBC to get back to the lungs for re-oxygenation, then polymerization will not occur.
*The authors show that the great dependence on concentration is due to a double nucleation event. That is, it is due to the fact that polymerization takes place by two different mechanisms.
**The first mechanism is "homogenous" and slow and builds a linear polymer.
**The occurrence of the first polymerization allows for the second mechanism to occur.
**The second mechanism is called "heterogenous" polymerization and is fast.
**Polymerization is dependent on the first event occurring and is therefore delayed.
**Once started, polymerization grows rapidly because as the surface area grows, the surface area upon which polymerization can occur grows, too.
**They have showed these polymerization events occurring through optical images taken upon low (homogenous, linear polymerization) and high (heterogenous, branching polymerization) concentrations of damaged hemoglobin S.
*The Glu->Val mutation in hemoglobin S creates a "sticky" hydrophobic patch on the molecular surface resulting in the polymerization of cells.
*It has been shown that hemoglobin units that contain a gamma subunit do not polymerize very well.
*Hemoglobin F has two gamma subunits.
*It has been shown that when hemoglobin S and hemoglobin F are mixed, a third species arises, made up of two alpha units, the beta unit from hemoglobin S and a gamma subunit. This species does not polymerize well.
*So, anything with a gamma unit acts with a dilution effect against the hemoglobin S units' polymerization.
*There are ways to calculate the expected dilution (and therefore decreased polymerization) effect.
**Don't forget, however, that increased hemoglobin F will take up space in the cell and ... something about increasing the thermodynamics of polymerization.
*They calculated the critical concentration for polymerization (sickling) in an F cell: 0.3 grams / centimeter cubed.
*This means that any cells with a lower concentration of hemoglobin than this will never sickle. In vivo, cells can have higher concentrations because they cells don't have to '''never sickle''' they just can't sickle before they reach the lungs and get re-oxygenated.

Gareau's "Erythropoietin abuse in athletes"

Admin — Wed, 17 Mar 2010 14:16:52 GMT

Admin: moved Gareau's "Erythropoietin abuse in athletes" to Gareau's "Erythropoietin abuse in athletes" 1996

#REDIRECT [[Gareau's "Erythropoietin abuse in athletes" 1996]]

Gareau's "Erythropoietin abuse in athletes" 1996

Admin — Wed, 17 Mar 2010 14:16:51 GMT

Admin: moved Gareau's "Erythropoietin abuse in athletes" to Gareau's "Erythropoietin abuse in athletes" 1996

*Ergogenic = "Possessing the ability to enhance work output, particularly as it relates to athletic performance."
*Since we can make recombinant human erythropoietin (rHuEpo), it is popular among athletes.
*The mainstream media is still the main vehicle for disclosure of athlete use.
*Even though the IOC has banned EPO, it is still being used heavily.
*We have no reliable analytical way to measure EPO.
*It is hard to come up with a test because of EPO's short half-life and delayed effects.
*The authors believe that they can identify the use of EPO based on the levels of soluble transferrin receptor in the serum as EPO treatment drastically changes Tfr levels.
*Tfr (and ferritin, ftn) respond to EPO because EPO stimulates erythropoiesis which causes redistribution of iron (an increased intake into erythroid progenitors).
*This Tfr/ftn method of assaying EPO is particularly good because it will not be scewed by hydration issues which can change hematocrit levels and it may be able to detect non-EPO-based attempts to increase erythropoiesis.
*They show that there was no significant change in hematocrit levels with the treatment of rHuEpo, yet even at a very small dose (smaller than that which would induce an ergogenic response) a detectable, significant tfr/ftn ratio change was present.
*They mention that non-elite athletes with other blood disorders like anemia are not likely to yield false positives because they are not at elite levels of performance.
*They mention that physical exercise does not modify tfr/ftn levels and therefore blood samples taken at the competition site would still yield accurate results.
*"Hence, observation of concomitant changes in haematocrit and Tfr/ftn values could permit the discrimination of pathological from physiological conditions, and thus distinguish between rHuEpo abusers (or even athletes who had undergone blood transfusions) and those competing fairly."
*"This first breach in athletes' immunity to detection of their use of engineered hormones as performance enhancers is a pledge in favour of the blood matrix to detect and deter sophisticated abusers."

Main Page

Admin — Wed, 17 Mar 2010 14:12:12 GMT

Admin:

==Exam 3==
===Reading notes===
*[[Warnock's "Liddle Syndrome: Clinical and Cellular Abnormalities" 1994]]
*[[He's "Epidemiology and Prevention of Hypertension" 1997]]
*[[Hajjar's "Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases" 2003]]
*[[Meneton's "Links Between Dietary Salt Intake, Renal Salt Handling, Blood Pressure, and Cardiovascular Diseases" 2005]]
*[[Bhalla's "Mechanisms of ENaC Regulation and Clinical Implications" 2008]]
*[[Chapter 26 notes (Renal)]]

===Lecture notes===
*Renal lectures

==Exam 2==
===Reading notes===
*[[Williams' "Cystic Fibrosis: A disease caused by a single defect in salt-transporting epithelial cells" 1992]]
*[[Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993]]
*[[Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994]]
*[[Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999]]
*[[Marshall's "Gene Therapy on Trial" 2000]]
*[[Rosenberg's "Gene Therapist, Heal Thyself" 2000]]
*[[Vogel's "FDA Moves against Penn Scientist" 2000]]
*[[Couzin's "As Gelsinger Case Ends,Gene Therapy Suffers Another Blow" 2005]]
*[[Kaiser's "Death Prompts a Review of Gene Therapy Vector" 2010]]
*[[Chapter 20 notes (Heart)]]

===Lecture notes===
*[[Cystic fibrosis lectures]]
*[[Respiration lectures]]
*[[Circulatory lectures]]
*[[Cardiovascular lectures]]

==Exam 1==
===Blood===
*[[Chapter 19 notes (Cardiovascular system)]]
*[[Blood lecture notes]]
*[[Gareau's "Erythropoietin abuse in athletes"]]
*[[Eaton's "The biophysics of sickle cell hydroxyurea therapy"]]
*[[Geddis's "The root of platelet production"]]
*[[Marshall's "Clinical promise, ethical quandry" 1996]]
*[[Brunstein's "Umbilical cord blood transplantation and banking" 2006]]
*[[Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)"]]
*[[Delude's "Clot Busters!! - Discovery of thrombolytic therapy for heart attack and stroke" (2004)]]
*[[Lee's "The Tangled Webs That Neutrophils Weave" (2004)]]
*[[Walzog's "Adhesion molecules: the path to a new understanding of acute inflammation" (2000)]]

===Lymphatic / Immune===
*[[Chapter 22 notes (Lymphoid and immune systems)]]
*[[Leslie's "Mast cells show their might" 2010]]
*[[Leslie's "Fetal immune system husches attack on maternal cells" 2010]]
*[[Leslie's "Internal affairs" 2010]]
*[[Ganz's "Versatile Defensins" 2002]]
*[[Wickelgren's "Can worms tame the immune system?" 2004]]
*[[Couzin's "Wanted: pig transplants that work" 2002]]
*[[Alexander's "Chimerism and tolerance in a recipient of a deceased-donor liver transplant" 2008]]

Chapter 22 notes

Admin — Wed, 17 Mar 2010 14:11:48 GMT

Admin: moved Chapter 22 notes to Chapter 22 notes (Lymphoid and immune systems)

#REDIRECT [[Chapter 22 notes (Lymphoid and immune systems)]]

Chapter 22 notes (Lymphoid and immune systems)

Admin — Wed, 17 Mar 2010 14:11:48 GMT

Admin: moved Chapter 22 notes to Chapter 22 notes (Lymphoid and immune systems)

=An introduction to the lymphoid system and immunity=

==Anatomical barriers and defense mechanisms constitute nonspecific defense, and lymphocytes provide specific defense==
*There are lots of non-living things that can hurt us like UV light, bumps, temperatures, etc.
*There are lots of living things that can hurt us (pathogens) like viruses, bacteria, fungi, and parasites.
**Viruses are usually within cells and rupture them.
**Bacteria are usually in the ECF and produce toxic proteins.
**Parasites can burrow through entire internal organ systems.
*"The lymphoid system includes the cells, tissues, and organs responsible for defending the body against both environmental hazards, such as various pathogens, and internal threats, such as cancer cells."
*Lymphocytes respond to abnormal body cells, invading pathogens, and foreign proteins.
*The body has several nonspecific defenses which serve to block entry to the body or to attack anything that is foreign.
*Lymphocytes, however, are specific in their attacks.
*Specific defenses are considered an immune response.
*The immune system refers to not only the lymphocytes, but all the organs and tissues that are associated with specific immune response.
**These include the integumentary, cardiovascular, respiratory, digestive, and other systems.

==Lymphatic vessels, lymphocytes, lymphoid tissues, and lymphoid organs function in body defenses==
*The lymphatic system is made up of:
**lymph (which is much like ECF but with fewer proteins),
**lymphatic vessels (which run from peripheral tissues to veins),
**some lymphoid tissues and organs (found throughout the body, think tonsils, spleen, thymus, etc.),
**lymphocytes and some phagocytes and several other cell types.

===Functions of the lymphoid system===
*The primary function of the lymphoid system is to produce and distribute lymphocytes.
*Lymphocytes are primarily generated in lymphatic tissues (like the tonsils) and organs (like the spleen and thymus) but are also generated in red bone marrow.
*Red bone marrow also generates other defense-related cells like monocytes and macrophages.
*The lymphocytes are carried throughout the body via the blood, interstitial fluid, and the lymphatic system.
*The lymphatic system helps circulate interstitial fluid and thus allows for elimination of local abnormalities of interstitial fluid and keeps nutrients moving.

===Lymphatic vessels===

====Lymphatics capillaries====
*Lymphatic capillaries run through peripheral tissue, draining interstitial fluid (including proteins, viruses, bacteria, and cellular debris) through endothelial cells that overlap, like shingles.
*Lymphatic capillaries differ from cardiovascular capillaries in four ways:
#they originate as pockets as opposed to tubes,
#they have larger diamters,
#they have thinner walls,
#they have flattened or irregular outlines in sectional views.
*Lymphatic capillaries are found throughout the body:
**They are not found where there are no capillaries; for example, in the cornea.
**They are not found in the central nervous system.
**They are particularly important in the digestive tract for transporting lipids (via ''lacteals'').

====Small lymphatic vessels====
*Lymphatic capillaries turn into lymphatic vessels as they progress toward the trunk and large veins.
*These larger vessels often appear bulbous because of valves that are placed rather close together.
*The valves are much like those in veins and are important for maintaining proper flow.
*Lymphatic vessels often occur in conjunction with veins.
*In living tissue, arteries are bright red, veins are dark red (illustrated as blue), and lymphatic vessels are pale golden.
*There are usually more lymphatic vessels than veins, but they are smaller, too.

====Major lymph-collecting vessels====
*Superficial and deep lymphatics collect lymph and deliver it to the even deeper lymphatic trunks.
*Deep lymphatics accompany deep arteries and veins to muscles, organs of the neck, limbs, trunk, and to the walls of visceral organs.
*Superficial lymphatics go everywhere else.
*The lymphatic trunks empty into two large ducts: the ''thoracic duct'' which collects from the left side of the body and everything below the diaphragm, and the ''right duct'' which drains from the right side of the body above the diaphragm.
*The thoracic duct has a saclike structure called the '''cisternae chyli''' at the base.
*The thoracic duct dumps into the left subclavian vein near the left internal jugular vein.
*The right lymphatic duct dumps into the right subclavian vein.
*Blockage of a lymph vessel can cause lymphedema--swelling associated with lack of interstitial fluid buildup.
**This can result in permanent swelling if connective tissue has a chance to loose it's elasticity.
**This can lead to bad things by way of toxin buildup.

===Lymphocytes===
*Lymphocytes account for 20-30% of all leukocytes.
*Lymphocytes in circulation are only a small fraction of the total lymphocytes in the body--massing up to a kilogram!

====Types of lymphocytes====
*There are lots of types of lymphocytes:
**'''Thymus-dependent (T) cells''':
***Make up 80% of circulating lymphocytes.
***There are sub-types of T cells:
****'''Cytotoxic T cells''': attack infected cells, usually through direct contact. These are the primary cells involve din the production of ''cell-mediated immunity'' or ''cellular immunity''.
****'''Helper T cells''': stimulate and activate both T and B cells.
****'''Suppressor T cells''': inhibit activation of both T and B cells.
****'''Suppressor / inducor T cells''': ''suppress B cells'' while ''activating T cells''.
****'''Inflammatory T cells''': stimulate regional inflammation and local defenses up injury.
***Suppressor and helper T cells are considered regulatory T cells.
**'''Bone marrow-derived (B) cells''':
***B cells are the primary cells involved in ''humoral'' (liquid, antibodies occur in body fluids) ''immunity''.
***B cells make up 10-15% of lymphocytes in the blood.
***B cells can convert into plasma cells and then produce antibodies.
***Antibodies are the same thing as immunoglobulins.
***Antibodies are generally proteins, but nucleic acids, lipids, and polysaccharides can also function to activate destruction of an antigen (target).
**'''Natural killer (NK) cells''':
***These cells maintain ''immunological surveillance''.
***NK cells are the same thing as large granular lymphocytes.
***These cells attack foreign cells, infected cells, and cancer cells.

====Life span and circulation of lymphocytes====
*The ratio of B to T cells is not ubiquitous throughout the body, it differs between the blood, thymus, spleen, etc.
*T cells move faster than B cells (think: 30 minutes in the blood, 15-20 hours in a lymph node).
*Most lymphocyte live for at least 4 years, some live for 20 years. We make more as needed to maintain a proper balance.

====Lymphocyte production====
*Production of lymphocytes (lymphopoiesis) occurs in the red bone marrow, the thymus, and the peripheral lymphoid tissues.
*Hemocytoblasts (lymphocyte progenitors) are generated in the red bone marrow.
*B cells and NK cells are generated in the bone marrow.
*B cells develop through intimate contact with large stroma cells which secrete interleukin 7 to cause differentiation into B cells.
*B cells move into lymph nodes, the spleen, and other lymphoid tissues.
*The NK cells move through peripheral tissues in search of abnormal cells.
*Some lymphatic stem cells migrate (undifferentiated) to the thymus.
*In the thymus, stem cells are protected by the blood-thymus barrier.
*These stem cells divide under the control of (at least) 7 thymus hormones to generate the various kinds of T cells.
*T cells reenter the bloodstream and return to the bone marrow and also travel to peripheral tissues, including lymphoid tissues and organs, such as the spleen.
*Recall that not all T and B cells enter the blood stream or otherwise move on from the marrow or thymus.
*T cells and B cells that do move on retain the ability to divide (because they leave before their differentiation is complete) and this is crucial for proper immune response.

===Lymphoid tissues===
*Lymphoid tissues are just connective tissue with lots of lymphocytes in it.
*A '''lymphoid nodule''' or '''lymphtic nodule''' is when lots of lymphocytes are densely joined together.
*These nodules are found in connective tissue just under the epithelium in the respiratory, digestive, and urinary tracts.
**The nodules found in the respiratory tract are called '''tonsils'''.
*Note that there is not fibrous layer separating the nodes from one another.

====MALT====
*MALT = ''mucosa-associated lymphoidal tissue''.
*Lymphatic tissue of the digestive tract is called MALT.
*'''Aggregated lymphoid nodules''' = '''Peyer patches''': clusters of lymphatic nodules found on the intestinal wall.
*The vermiform (wormlike) appendix is a "blind pouch" found where the large and small intestines connect.
*The vermiform appendix is filled with fused lymphoid nodules.

====Tonsils====
*Tonsils are large lymphoidal nodules in the walls of the pharynx.
*We have five: a pair of palantine tonsils, a pair of lingual tonsils, and a single pharyngeal tonsil (also known as the adenoid).
*Tonsillitis refers to the inflammation of the lingual tonsils.

===Lymphoid organs===
*Lymphoid organs are separated from surrounding tissues by a fibrous, connective tissue.

====Lymph nodes====
*Nodes are 1-25 mm and distributed throughout the body.
*There is a dense connective tissue that surrounds them.
*Trabeculae run from the capsule to the interior of the node and are formed with collagen.
*Shaped like a kidney, the blood vessels and nerves arrive at the '''hillum''' or the indentation.
*Afferent vessels bring stuff to the node, efferent vessels take stuff away (toward the blood stream).

=====Lymph flow=====
*Lymph flows through the subscapular space where there are macrophages, dendritic cells, and a network of reticular fibers.
*Then lymph flows into the outer cortex where there are lots of B cells in germinal centers.
*Lymph then flows through the deep cortex (paracortical area) which is filled with T lymphocytes that have migrated here from the blood. (This area has blood vessels flowing through it.)
*Then lymph flows into the medulla where there are lots of medullary cords made up of B cells and plasma cells.
*Finally, the lymph flows into the efferent vessels at the hillum.

=====Lymph node function=====
*The lymph node acts as a filter, running lymph and all the debris in it past macrophages and dendritic cells.
*This allows for macrophages to phagocytize and present antigens to and allows dendritic cells to activate T cells.
*99% of lymph will be filtered.
*Lymph nodes also provide a mechanism for early warning upon infection because antigens in the interstitial fluid often get washed into the nodes and set of an immune response.
*Lymph nodes are situated at all the major junctions of the lymphatic system: from the legs to the trunk (groin), head to body (neck), etc.
**These are bigger nodes and are often called lymphatic glands.
*"Aggregations of lymph nodes also exist in the mesenteries of the gut, near the trachea and passageways leading to the lungs, and in association with the thoracic duct."
*Nodes swell upon increased proliferation of lymphocytes or macrophages caused by peripheral infection of tissue.
*Chronic or excessive enlargement of lymph nodes constitutes lymphadenopathy, a condition that may occur in response to bacterial or viral infections, endocrine disorders, or cancer.

====Clinical note: Cancer and the lymphoid system====
*Cancers spread throughout the body via the lymphatic system because lymphatic capillaries offer little resistance.
*Because of this, we can examine lymphatic vessels to find out if cancer has spread.
*Knowing if it has spread changes treatment approaches.

====Thymus====
*The thymus sits behind the heart, from the neck down to the heart.
*It is biggest (relative to the rest of the body) at about 1-2 years of age.
*It declines in size and becomes more fibrous as puberty approaches, a process called '''involution'''.
*It may be the case that older people without their thymus are more susceptible to infection.
*The thymus is divided into two lobes and the lobes are divided into lobules, which each have a cortex and a medulla.
*In the cortex, T cells are dividing and moving into the medulla.
*The T cells migrate through the medulla over 2 or 3 weeks and finally enter the medullary blood vessels.
*Reticular cells surround groups of T cells and also surround the blood vessels, thus providing a blood-thymus barrier.
*Reticular cells also generate the factors that generate stem cell division and cause T cell differentiation.
*As T cells mature, they enter the medulla where there is not blood-thymus barrier.
*They are still surrounded by reticular cells, but they can enter the blood stream directly or enter the efferent lymphatic vessels.
*The thymus produces Thymusin (a mixture of Thymusin A / B / V, thymopoietin, thymulin and others) in order to promote the development and maturation of T cells.
*note that the rest, up to the immune system stuff is being skipped because it turns out she's not really covering it very thoroughly.

==Nonspecific defenses do not discriminate between potential threats and respond the same regardless of the invader==
*Nonspecific defenses prevent the entry, deny the approach, or limit the spread of pathogens.
*There are seven nonspecific defenses.

===Physical barriers===
*To cause problems a pathogen must get in but our epithelium, even in the dark recesses of our body has mechanisms to stop this.
*These include tight junctions, multiple layers, keratin coatings, a dense and fibrous basal lamina.
*We also have secretions from sabaceous glands and hair follicles that kill microorganisms or make it harder for them to penetrate the epithelium.
*The internal epithelium are more delicate but employ mucus and acids to keep out pathogens.

===Phagocytes===
*These are the first line of defense once through the physical barriers.
*These cells "eat" up bad cells and spit out their broken down remnants.
*These include microphages (neutrophils and eosinophils), macrophages, and basophils.
*There are free and resident macrophages in almost all tissues of the body.
*Alveolar macrophages are free floating while in the liver and CNS (kupffer and neuroglia, respectively) the macrophages are fixed.
*These cells can move through the vessel wall to get to their target.
*These cells are attracted by chemotactants and adhere to their target before engulfing them.

===Immunological surveillance===
*NK cells perform immunological surveillance and destroy abnormal cells, including host cells that have become abnormal in some way.
*NK cells are not specific in their epitope, they will recognize many different types of pathogens and abnormal cells.
*NK cells are good because they respond immediately upon meeting an abnormal cell, whereas T and B cells take a bit of time to have an effect.

====NK cell activation====
*First, an NK cell bumps into a cell and recognizes that it has antigens that are not like the host cell antigens so the NK cell adheres to the target cell.
*Then the golgi is rotated to a position between the junction of the two cells and the nucleus. The golgi is also signaled to begin generating porferins and putting them in vesicles and sending them to the membrane.
*The vesicles are fused with the NK membrane such that the porferins dump in the narrow space between the NK cell and the target cell to which it is stuck.
*The porferins integrate into the target cell's membrane to generate pores large enough to allow ions, proteins, and cellular components through, thus killing the cell.
*We think NK cells might be immune to the actions of porferins because they express protectin.
*NK cells generally find and destroy cancerous cells and virus-infested cells because they present weird surface antigens.
*Cancer antigens are called '''tumor-specific antigens'''.
*However, if the cancer escapes recognition or death by NK cell '''immunological escape''' is said to have occurred and the cell can go on to proliferate, etc.
*In viruses, while the virus is replicating in the cell, antigens from the virus are often presented on the host cell's membrane surface alerting the NK cells of the problem.

===Interferons===
*Interferons are an example of a cytokine: a chemical messenger released by a cell to affect the cells nearby.
**Cytokines can also act like hormones.
*Interferons are proteins released by activated macrophages and lymphocytes and by infected tissues.
*Interferons augment the abilities of macrophages and lymphocytes to phagocytize pathogens and viral-infected cells.
*Interferons also tell cells to generate '''antiviral proteins''' which function ''inside the cell receiving the interferon signal'' to make it a harder target for viral infection.
*There are three types of interferons, each with it's own special function(s).
*Alpha interferon: Secreted by several leukocytes, attracts NK cells.
*Beta interferon: Secreted by fibrocytes, slows inflammation.
*Gamma interferon: Secreted by T cells and NK cells, increases macrophage activity.
*Most cells secrete beta interferon upon infection with a virus.

===Complement===
*Complement refers to the fact that this system complements the antibody system.
*There are 11 plasma proteins involved in the complement system.
*These proteins work together in a series for the end result of a proteinaceous tagging of pathogenic cells.

====Classical complement activation====
*Note that proteins being with "C", in this region of these notes, are complement proteins.
*The classical method begins when C1 binds to an antibody which is already bound to its target antigen, for example on a bacterial surface.
*Then C1's enzymatic properties are turned on and through a cascade of enzymatic activity, C3 is cleaved into the active form of C3b.
*This method is much faster than the alternative method.

====Alternative complement activation====
*The alternative pathway is also called the ''properdin pathway''.
*This pathway can be activated without the presence of antibody.
*This pathway is much slower than the clinical pathway.
*The alternative, or properdin, pathway begins when several complement proteins are catalyzed to interact by the presence of an antigen, for example the capsule proteins of a virus.
*The complement proteins that interact are factor P (for properdin), factor B and factor D.
*This interaction starts a cascade which, like the classical pathway, converts C3 to C3b.

====Effects of complement activation====
*Stimulation of inflammation through increased release of histamine by mast cells.
*Attraction of phagocytes.
*Increased phagocytosis by way of better pathogen marking via complement proteins.
*Destruction of target cell membrane via complement proteins C5-C9 which build pores through which the cell's life will flow.

===Inflammation===
*Inflammation results in "rubor et tubor cum calor et dalor" (redness and swelling with heat and pain), the cardinal signs of inflammation.
*Damaged cells, from physical injury or pathogenic injury, release prostaglandins, proteins, and potassium ions and the resulting changes in the interstitial environment results in inflammation.
*Inflammation has several effects:
**The injury is temporarily repaired and additional pathogens are prevented from entering the area.
**The spread of pathogens ''away'' from the area is slowed.
**The defense systems are activated to mount a response.

====The response to injury====
*Upon damage, mast cells release histamine, heparin, and prostaglandins which serve to:
**Increase blood flow to increase cell motility for phagocytes,
**Activate pain receptors to make organism aware of infection,
**Raise temperature to increase enzymatic activity, to increase phagocytic activity, and to denature foreign proteins,
**Increase vessel permeability and clotting,
**Activate the complement system through the alternative pathway,
**Increase phagocytic activity (by inducing respiratory burst),
*Once neutrophils and macrophages are on the scene they secrete cytokines that recruit even more of the same as well as eosinophils and the adaptive immune response cells.
*Cytokines also stimulate fibrocytes to start generating scar tissue.
*All this and the breakdown of surrounding tissue from released lysosomes generates '''pus'''.
*Accumulation of pus in an enclosed tissue is called an '''abscess'''.

===Fever===
*The inherent temperature of the body can be elevated by signaling to the hypothalamus through a type of cytokine called a pyrogen, which circulate through the blood.
*Pathogens, bacterial toxins, and antigen-antibody complexes can either act as pyrogens or stimulate macrophages to release pyrogens.
*A fever is considered to be the maintenance of the body temperature over 99F or 37.2C.
*Fever may inhibit some viruses and bacteria but the major benefit is from increased metabolism of cells in the body leading to increased motility of immune and phagocytic cells and increased enzymatic activity.

==Specific defenses (immunity) respond to individual threats and are either cell-mediated or antibody-mediated===
*The specific defenses are achieved by B cells and T cells.
*T cells provide cell-mediated immunity (cellular immunity) and respond to abnormal cells and intracellular pathogens.
*B cells provide antibody-mediated immunity (humoral immunity) and respond to antigens and pathogens.
*T cells don't respond to free floating antigenic material and B cells cannot respond to antigens within cells (that is, antibodies, which are generated by B cells can only identify antigens that are on the outside of cells).

===Forms of immunity===
*Innate immunity refers to the immunity granted through genetics; innate immunity is a certain set of pathogens and signals to which the body can respond, it does not change over the course of the individual's lifetime.
*Acquired immunity is not present at birth and must be acquired through exposure over time.
**Acquired immunity can be ''active'' or ''passive''.
*Active immunity is when the body produces its own antibodies against an antigen.
**Active immunity can be ''induced'' by purposefully administering an antigen to a patient or it can be ''naturally acquired'' by chance exposure from the environment.
**'''Naturally acquired active immunity''' begins at birth as a child is exposed to pathogens and the body reacts by generating antibodies and an immune response.
**'''Induced active immunity''' occurs when a vaccine is administered.
***A '''vaccine''' is a preparation of dead / inactive pathogen or just an antigen that is administered with the intention of inducing a controlled immune response.
*Passive immunity is when antibodies enter the immune system from an exongenous source.
**In '''naturally acquired passive immunity''' a mother's antibodies protect her offspring, either through the placenta or breast milk.
**In '''induced passive immunity''', antibodies are administered in order to protect a patient form an antigen.

===Properties of immunity===
*Immunity presents four characterisitcs: specificity, versatility, memory, and tolerance.

====Specificity====
*B and T cells provide specificity by their interaction with only a particular molecular structure.
*B cell antibodies do not bind to just any antigen, they bind to their specific antigen.
*T cells are not activated by just any antigen, they are only activated by their specific antigen.
*Furthermore, the response that B and T cells generate is equally specific: killing on the cells with that exact antigen, etc.

====Versatility====
*The body is able to respond to millions of different antigens, of which we're only likely to run into 10s of thousands, hence we have great immune versatility.
*This versatility is provided by the number of lymphocytes in the body and the variability in the structure of antibodies.
*We have a trillion or more lymphocytes and millions of distinct colonies of about 1000 cells.
*1000 cells is not enough to fight of an infection but when any of those cells is activated, it undergoes rapid proliferation to generate more secret ninja warriors.

====Memory====
*When a T cell population recognizes its antigen and undergoes proliferation, it generates two types of progeny: those that will go fight the infection and those that will remain dormant until ''the next time'' the antigen is encountered.
*In this way we generate "memory" about which antigens have been seen and can mount a bigger, faster response upon a second exposure.

====Tolerance====
*Tolerance is when the immune system does not react to an antigen. Most obviously, this occurs with host cells--the immune system doesn't attack host cells.
*B and T cells mature in the bone marrow and thymus (respectively) and here are killed if they react to host cell antigens.
*This can also occur if one is exposed to an antigen chronically. However, the tolerance will only last as long as the exposure continues.

===An introduction to the immune response===
*After a macrophage or other antigen presenting cell ingests and presents an antigen, T cells are activated, then B cells are activated, then T cells start attacking antigen-laden cells and B cells start generating antibodies which bind to antigen throughout the body.

==T cells play a role in the initiation, maintenance, and control of the immune response==
*T cells have varied responses depending on the three types:
**Cytotoxic T cells are responsible for the cell-mediated response; they enter tissues and attack antigens.
**Helper T cells activate T and B cells; reduction in the helper T cell population is largely responsible for the loss of immunity in AIDS.
**Suppressor T cells inhibit T and B cell response in order to moderate the immune response.
*Activation of T cells rarely happens by direct lymphocyte-antigen interaction.
*Furthermore, most antigens don't even cause an immune response, only an innate immune battle.

===Antigen presentation===
*'''Antigen presentation''' to a lymphocyte only works if the antigen is presented on a cell surface in combination with a special glycoprotein called '''major histocapatibility complex proteins'''.
*These proteins are coded on ch 6 in a region called the '''major histocompatibility complex'''.
*These proteins have a distinct three-dimensional shape with a narrow groove in which an antigen can fit enough to be held by hydrogen bonds.
*There are two classes of MHC proteins: I and II.

====Class I====
*Class one proteins are constantly expressed by all nucleated cells in the body.
*As the protein is made it picks up small parts of proteins found in the cytoplasm of its generating cell.
*The protein is moved to the surface and displays it's little chunk of the proteome to any passing T cells.
*If the protein chunk it is presenting is a host protein (that is, something that T cells recognize as being host-like) then the T cell will not be activated.
*However, if a virus or bacteria has entered that cell, the chunk of protein presented by a class I MHC protein may be foreign and would therefore activate cytotoxic T cells which would kill the cell.
**Note that class I MHC proteins serve to activate cytotoxic T cell and suppressor T cells.
*In this way, MHC class I proteins scream "Hey, I'm an abnormal cell. Kill me!"
*MHC class I proteins are the reason that transplanted organs get rejected.

====Class II====
*'''Antigen presenting cells''' are certain cells responsible for activating T cell defenses against foreign cells and foreign proteins.
**These include macrophages (free and fixed) and dendritic cells.
*Note that the Langerhans cells are the same thing as dendritic cells.
*These APCs take in pathogens and antigens (macrophages through phagocytosis, dendritic cells through pinocytosis) and break up the material.
*Class II proteins are expressed on the surface of APCs '''only while they are processing antigenic material'''.
*When these MHC proteins are on the surface with an antigen, they will activate a T cell to respond.
**Note that class II MHC proteins serve to activate a Helper T cells.

===Antigen recognition===
*T cells have receptors that recognize Class I and Class II MHC proteins.
*The receptors also have binding sites for the antigen held by the MHC protein.
*If the antigen held by the MHC protein is not the antigen which that particular T cells is programmed to bind, the T cell will not be activated.
*A given T cell can either bind a class I or class II MHC protein.
*Proteins on the T cell's surface called '''cluster of differentiation''' (CD) markers determine which class the T cell receptors can bind.
**All T cells have a CD3 '''receptor complex''' on their surface.
**'''Cytotoxic T cells and Suppressor T cells''', which respond to antigens presented by '''Class I''' MHC proteins, have '''CD8''' markers on their cell membrane.
**'''Helper T cells''', which respond to antigens presented by '''Class II''' MHC proteins, have '''CD4''' markers on their cell membrane.

====Costimulation====
*CD8 or CD4 (depending on the T cell type) complexes with CD3. This complex will ultimately activate the T cell.
*However, before a T cell is activated it must be exposed to the antigen, and then make a second binding interaction with the antigen presenting cell '''at a different site'''.
*The '''different site''' is a protein that is only expressed if the APC has engulfed antigen or is infected by a virus.
*This requirement is called costimulation and is important because it confirms that the antigen is being presented as a result of phagocytic or infectious action.
*Many costimulation proteins are structurally similar to cytokines and can stimulate transcription, proliferation, and differentiation of the T cell.

===Activation of CD8 T cells===
*Recall that CD8 marked T cells respond to class I MHC proteins.
*Two different classes of CD8 T cells exist.
**One rapidly generates lots of cytotoxic T cells and lots of memory Tc cells upon activation.
**The other, rather slowly, generates a modest amount of suppressor T cells upon activation.

====Cytotoxic T cells====
*Cytotoxic T cells = Tc cells = killer T cells.
*These cells move around in injured tissue, look for their specific antigen bound to a class I MHC protein, and kill abnormal or infected cells.
*Killer T cells can kill cells in three ways:
**by releasing perforin which makes pores in the target cell thus deregulating all sorts of vital concentrations,
**by releasing lymphotoxin (a cytokine) which "kill the virally infected cells by producing holes in the cell's cell membrane." (wikipedia).
***lymphotoxin = TNF-beta.
**by activating genes in the target cell that will engage apoptosis.

====Memory Tc Cells====
*Memory Tc cells are produced during the same cell divisions that generate cytotoxic T cells but they don't fully differentiate.
*Upon second exposure to the antigen, these cells are able to ''immediately'' differentiate into cytotoxic T cells to produce a rapid karate chop to that antigen presenting cell.

====Suppressor T cells====
*Suppressor T cells secrete cytokines that inhibit the activity of cytotoxic T cells and B cells which serves to keep the immune response in control.
*The effects of suppressor T cells are not immediately incurred because their activation takes much longer than that of other T cells. Furthermore, most CD8 cells, upon activation, differentiate into killer T cells and memory Tc cells, and therefore the suppressor T cell effects build up more slowly.

===Activation of CD4 T cells====
*CD4 T cells, upon activation, undergo a series of divisions that produce helper T cells and memory Th cells.
*The memory Th cells remain in reserve.
*These helper T cells secrete cytokines in order to coordinate the specific and non-specific defenses and to stimulate cell-mediated and antibody-mediated immunities.
*Helper T cell-secreted cytokines have the following effects:
**stimulate the production of Th memory cells,
**stimulate maturation of cytotoxic T cells,
**enhance nonspecific defenses by attracting macrophages, preventing macrophages from leaving, and making them more effective,
**attracting and stimulating NK cells to the site of infection,
**promoting the activation of B cells, their division, their maturation to plasma cells, and thus antibody production.
*Remember that infected or abnormal cells present with Class I MHC proteins which are bound by CD8 T cells which become suppressor T cells and killer / memory Tc cells.
*Remember that extracellular pathogens and foreign proteins present with Class II MHC proteins (because they were eaten) which are bound by CD4 T cells which become helper T cells and memory Th cells.

===Clinical note: Graft rejection and immunosuppression===
*After transplantation, cytotoxic T cells are generated after CD8 T cells are activated by exposure to cells from the transplanted tissue presenting antigens.
*These killer T cells then destroy the implanted tissue.
*We used to use drugs that suppressed the entire immune system, like predinsone which decreases levels of circulating leukocytes.
*Now, however, we use more specific drugs like cyclosporin A which inhibits Helper T cells (thus inhibiting B cell activation and killer T cell maturation) while leaving the suppressor T cells intact (thus allowing them to damper the immune response of killer T cells).
*We even have drugs that inhibit the binding of antigen by antibodies.

==B cells respond to antigens by producing specific antibodies==
*B cells launch an attack on antigens by producing specific antibodies.

===B cell sensitization and activation===
*When a B cells binds its antigen in its membrane receptor, it prepares to go through '''sensitization'''.
*Sensitization generally occurs in one of the peripheral lymphatic tissues.
*During '''sensitization''', a B cell endocytizies it's antigen-bound receptors and then presents the antigen on it's membrane via MHC proteins.
*A Helper T cells that has been activated (that is, has interacted with an antigen presenting cell) can activate a B cell that is presenting antigen via MHC proteins.
*Helper T cell activation of a B cell occurs first via binding of the T cell to the MHC of B cell and then continues through stimulation via cytokines.
*The helper T cell stimulation leads to the generation of memory B cells, activated B cells, and plasma cells.
*When stimulated by T cell cytokins a plasma cell can generate up to 100 million antibody molecules each hour!
*On subsequent exposure, memory B cells can quickly divide and differentiate into plasma cells, thus generating antibodies much more rapidly upon second infection.
*So a helper T cell has to bind its antigen with a MHC II protein first, then the T helper cell is active and it can bind to a B cell that is presenting the same antigen and thus activate the B cell

===Antibody structure===
*There are one pair of heavy chains and one pair of light chains in antibodies, each with constant and variable segments.
*The heavy chain forms the bottom of the antibody.
*There are only 5 types of constant regions and they determine the class of the antibody, how it is secreted, and how it is distributed in the body.
*The heavy chains contain binding sites that can be used to activate the complement system.
**These are only revealed once the antigen has bound in the antigen binding site.
*Slight changes in the aa sequence generate the variable sites.
*A normal adult human has about 10 trillin B cells which generate about 100 million different antibodies.

====The antigen-antibody comples====
*The complex is held together by hydrogen bonding and other weak chemical forces.
*The epitope is also called the '''antigenic determinant site'''.
*A '''complete antigen''' is one that has an epitope that fits in each of the two antigen binding sites of the antibody.
*Most environmental antigens are complete antigens because they have multiple epitopes; most microorganisms have thousands of epitopes.
*Partial antigens are also called '''Haptens'''.
*A hapten does not normally cause an immune response. However, sometimes haptens will bind with other molecules (called carriers) and then each of them will sit down in one of the two antigen binding sites of a B cell. This can cause an immune reaction, which is bad when the carrier is actually a normal host molecule because it can lead to a reaction against host cells. This is how penicillin allergic reactions to occur.

====Classes and actions of antibodies====
*Because the class of antibody is determined by the constant chain, it does not affect the antibodies antigen binding specificity.
*IgG:
**Largest class (80% of all Abs).
**Has several subtypes.
**Provide resistance against viruses, bacteria, and bacterial toxins.
**Can cross placenta (think Anti-RhD).
*IgE:
**Sits on basophils and mast cells.
**Stimulates basophils and mast cells to release histamine and other chemicals that accelerate inflammation.
**Important in allergic response.
*IgD:
**Sits on B cells, binds antigen from extracellular fluid.
**Can be part of B cell activation.
*IgM:
**First antibodies generated, then decrease in production once IgGs are being generated.
**Form 5-membered rings and are therefore particularly affective.
**Anti-A and Anti-B (think blood type) antibodies are of type M.
*IgA:
**Travel through blood until absorbed by epithelial cells.
**Epithelial cells put two IgAs together with a '''secretory piece''' to confer water solubility..
**IgA are excreted in glandular secretions like mucus, tears, saliva, and semen.
**Because they are secreted, IgA antibodies can attack pathogens before they gain entrance to the body.
*There are seven ways that antibodies can neutralize antigens:
**Antibodies can bind to the specific locations on a virus or toxin that needs to be free for their function. Thus the antibodies binds there and '''neutralizes''' the virus or toxin.
**Antibodies can bind several different antigens and form '''immune complexes''' and cause '''precipitation''' or agglutination.
**Upon binding an antigen, an antibody may change conformations and thus recruit complement proteins.
**Antigens covered with antibodies attract eosinophils, neutrophils, and macrophages that destroy the antigen.
**Opsonization is the covering of a pathogen with antibodies and complement proteins which allow for easier phagocytosis.
**Antibodies can cause inflammation by stimulating basophils and mast cells.
**Antibodies coat many epithelials surfaces, making it more difficult for pathogens to bind and penetrate.

===Primary and secondary responses to antigen exposure===
*Both humoral and cell-mediated responses show differences in primary and secondary responses.
*The best way to understand the difference is by looking at antibody production over time.

====The primary response====
*In the primary response, the '''antibody titer''' (the highest level of antibody production) occurs at 2 weeks.
*Decline in antibody production occurs because B cells die quickly and T reg cells inhibit their action.
*IgM is produced first then IgG.
*IgG is more effective than IgM, but IgM provides a faster response.

====The secondary response====
*Memory B cells generate more and more effective antibodies at a lower threshold than primary B cells, thus the response is stronger and faster.
*Memory B cells can live for 20 years or more.
*Antibody titer levels are much higher in a secondary response.

===Summary of the immune response===

===Immune disorders===

====Allergies====
*Allergies are an inappropriate or excessive response to an antigen.
*Antigens that generate this inappropriate response are called allergens.
*The side effects of a huge immune response can be irritating: tissue damage and great inflammation.
*Type I, Immediate hypersensitivity:
**In these reactions, the body is sensitized and basophils are covered with antibodies such that secondary exposure results in basophils rapidly releasing histamine, heparin, several cytokines, prostaglandins, and other chemicals into the surrounding tissues thus destroying tissue and causing a huge inflammatory response. The attraction of other cells only amplifies the situation.
**If this kind of response occurs in the blood or airway it can be fatal.
*Anaphylaxis:
**In response to a blood-bourne antigen, mast cells may be systemically activated.
**This will cause increased capillary permeability and thus swelling, edema, and hives. Furthermore, smooth muscle of the respiratory tract will constrict potentially causing difficulty in breathing. Peripheral vessel dilation may also cause a drastic drop in blood pressure.
*Fast response with anti-histamines can reduce the effects of activated mast cells.

Chapter 19 notes

Admin — Wed, 17 Mar 2010 14:11:05 GMT

Admin: moved Chapter 19 notes to Chapter 19 notes (Cardiovascular system)

#REDIRECT [[Chapter 19 notes (Cardiovascular system)]]

Chapter 19 notes (Cardiovascular system)

Admin — Wed, 17 Mar 2010 14:11:04 GMT

Admin: moved Chapter 19 notes to Chapter 19 notes (Cardiovascular system)

=Chapter 19: An Introduction to the Cardiovascular System=
*75 trillion cells in the human body.

==Blood has several important functions and unique physical characteristics==
*There are 5 main functions of blood:
**The Transportation of Dissolved Gases, Nutrients, Hormones, and Metabolic Wastes.
**The Regulation of the pH and Ion Composition of Interstitial Fluids (via diffusions of over concentrated entities from or to the blood).
**The Restriction of Fluid Losses at Injury Sites (via enzymes and other substances that respond to breaks in the vessel walls).
**Defense against Toxins and Pathogens (via delivery of white blood cells and antibodies).
**Body temperature stabilization (via dispersion of excess heat or the conservation of heat).
*Plasma is the fluid matrix in which cells are suspended.
*The protein content of plasma makes it slightly more dense than water.

*'''Formed elements''' include RBCs (erythrocytes), WBCs (leukocytes), and platelets.
*There are five types of leukocytes, each with a specific function: neutrophils, eosinophils, basophils, lymphocytes, monocytes.
*Platelets are membrane-bound cell fragments with enzymes and "other substances" for clotting.
*Hematopoiesis = hemopoiesis = production of formed elements.
*Myeloid and lymphoid stem cells generate the formed elements.
*'''Whole blood''' is the combination of plasma and formed elements.
*Blood from any location in the body has three characteristics:
**a temperature of around 38C (100.4F),
**a viscosity 5-times that of water (because of proteins, formed elements, and water molecules all sticking together),
**a pH of about 7.35 to 7.45.
*An adult male has between 5 and 6 liters of blood (5.3-6.4 quarts); women usually have between 4 and 5 liters (difference is due to body size, not physiological).
**Dividing one's mass (kg) by 7 yields a rough estimate of liters of blood.

===Clinical note===
*A venipuncture is usually used to obtain blood because:
**superficial veins are usually easy to find,
**the walls of a vein (compared to an equally sized artery) are thinner and therefore easier to puncture,
**the blood pressure is lower in veins and therefore the puncture wound will seal more readily.
*Arterial punctures can be useful for measuring the efficiency of gas exchange at the lungs.

==Plasma, the fluid portion of blood, contains significant quantities of plasma proteins==

===The composition of plasma===
*Plasma makes up 46-63% of the volume of whole blood.
*Plasma is 92% water.
*Most of the ECF of the body is plasma and water.
*Plasma and ECF are pretty similar in composition.
*Water, ions, and small solutes can flow freely between plasma and ECF at the capillaries.
*Generally, in capillaries, more liquid and solutes are transferred from the blood to the ECF than ''vice versa''. This is possible because the lymphatic system is draining ECF from tissue, thus decreasing the amount of ECF that needs to be drained (as the cells are generating more ECF).
*The big differences between plasma and ECF are the concentrations of oxygen / carbon dioxide and the concentrations of dissolved proteins (because plasma proteins cannot diffuse across the capillary walls).

===Plasma Proteins===
*The proteins that are found in the plasma are generally large, globular proteins and therefore cannot escape the circulatory system.
*The three major proteins are albumins, globulins, and fibrinogen; these make up 99% of the plasma proteins.
*Other proteins include enzymes, hormones, and prohormones.

====Albumins====
*Albumins make up 60% of the plasma proteins.
*They are important for generating osmotic pressure.
*They transport fatty acids, thyroid hormones, some steroid hormones, and some other substances.

====Globulins====
*Globulins make up 35% of plasma proteins.
*Globulins include antibodies and transport globulins.
*Antibodies = immunoglobulins = attack foreign proteins and pathogens.
*Transport globulins transport things with low water solubility and things that might otherwise be filtered out by the kidneys.
**Hormone binding proteins, like thyroid-binding globulin or transcortin (ACTH), provide a reserve of hormones.
**Metalloproteins, like transferrin, transport metals.
**Apolipproteins carry triglycerides and other lipids.
**Steroid-binding proteins, like testosterone-binding globulin (TeBG), bind and transport steroid hormones.

====Fibrinogen====
*Fibrinogen makes up 4% of the plasma protein.
*In a blood sample, one must make sure that the fibrinogen doesn't get converted to fibrin, otherwise '''serum''' is generated and the sample is no longer a proper '''plasma''' sample.

====Other plasma proteins====
*Other proteins found in the plasma include insulin, prolactin (PRL), TSH, FSH, LH, etc.

====Clinical note====
*Plasma expanders can be used to increase blood volume temporarily.
*These are better than donated plasma because donations can be contaminated with viruses or bacteria.
*Saline can be used but it is quickly absorbed into the ECF.
*So one can add solutes that cannot diffuse into the ECF, such as lactate in ''Ringer's solution''.
*Even lactate, however, is eventually absorbed by the liver, skeletal muscles, and other tissues.
*So we could add saline with lots of albumin in it (because it cannot be absorbed through capillaries).
*The best, however, is large carbohydrate molecules in saline. Over time, these will eventually be phagocytized by phagocytes.
*Note that these only increase blood volume, they do not increase oxygen levels.

====Origins of the plasma proteins====
*The liver generates more than 90% of the plasma proteins, including all the albumins, all the fibrinogen, most globulins, and some prohormones.
**Therefore, liver problems can lead to blood problems.
*Lymphocytes generate plasma cells which generate antibodies.

==Red blood cells, formed by erythropoiesis, contain hemoglobin that can be recycled==
*RBCs are the most abundant cell in blood.
*They have hemoglobin which is a red pigment that binds oxygen.

===Abundance of RBCs===
*A single drop of blood has 260 million RBCs.
*There are approximately 25 trillion RBCs in the whole body.
*Hematocrit is the percentage of the whole blood volume made up of formed elements (which is 99.9% RBCs).
*Adult males have hematocrit of about 46% while females are about 42%; this is primarily because the androgens found in men stimulate RBCs generation.
*Hematocrit is measured via centrifugal separation of plasma, WBCs / platelets, and RBCs.
*Because RBCS outnumber all other formed elements so easily, hematocrit is often reported as the ''volume of packed red cells'' (VPRC) or the ''packed cell volume'' (PCV).
*Hematorcit levels can vary from dehydration, EPO stimulation, or other factors.
*An abnormal hematocrit level is usually not evidence enough for diagnosis, but is an indicator that more specific tests are needed.

===Structure of RBCs===
*RBCs are highly specialized and this is reflected in their shape: a biconcave disc with a thin central region and a thicker outer marigin.
*The shape of a RBC is important for three reasons:
**increased surface-area-to-volume-ratio for fast, efficient exchange of oxygen from intracellular proteins to tissue (through capillaries),
**ability to form ''rouleaux'' (stacks of RBCs) that can flow easily through capillaries that are only slightly wider than a RBC,
**ability to flex in order to fit through capillaries as narrow as 4 micrometers (half the normal diameter of a RBC).
*RBCs have few organelles (and no nucleus in mammals) and no mitochondria and therefore have low energy demands.
*The energy they do need, they generate via glycolysis of glucose absorbed from blood plasma.
*RBCs cannot generate proteins.

===Hemoglobin===
*RBCs lose any organelles not directly involved in transport of oxygen.
*Hemoglobin (Hb) makes up 95% of intracellular protein in RBCs.

====Hemoglobin structure====
*Hemoglobin is made up of four globular chains, 2 alpha and 2 beta units.
*Each chain, like myoglobin, contains a heme unit which is a non-protein pigment complex.
*Each heme group contains an iron ion which can easily bind and unbind oxygen.
*When the iron binds oxygen, the hemoglobin unit is called oxyhemoglobin. These are bright red.
*When the iron does not bind oxygen, it is called deoxyhemoglobin. These appear dark red or burgundy.

*Infants have fetal hemoglobin (hemoglobin F) which binds oxygen more readily. In this way a fetus can "steal" oxygen from it's mother's blood stream.
*Hemoglobin F can be stimulated via hydroxyurea or butyrate and thus treat blood disorders like sickle cell anemia or thalassemia.

====Hemoglobin function====
*Each RBC has about 280 million hemoglobin (Hb) proteins which each have four heme groups. Thus, each RBC can carry over 1 billion molecules of oxygen.
*98.5% of all oxygen in the blood is carried by Hb molecules inside RBCs.
*When plasma oxygen levels drop, Hb releases oxygen.
*When plasma CO2 levels increase, the alpha and beta chains of Hb bind CO2. This state is called carbaminohemoglobin.
*These binding balances shift in the capillaries and the lungs where gas exchange is occurring.
*If hematocrit levels decrease or Hb levels within RBCs decrease, not enough oxygen will be delivered to tissues--anemia.
*Anemia can present with weakness, lethargy, and confusion as muscles, organs, and the brain are all being deprived of oxygen.

===RBC formation and turnover===
*RBCs must be constantly replaced because they incur much damage in their 700 mile, 120 day lifespan.
*Phagocytes engulf and digest aging RBCs upon detection of damage.
*1% of all RBCs are produced and digested each day--that's a rate of 3 million new RBCs each second!

====Clinical note: Abnormal hemoglobin====
*Two well known genetic disorders resulting in abnormal hemoglobin are thalassemia and sickle cell anemia.
*Thalassemia results from the too-slow production of alpha or beta units, the subsequent low concentration of Hb in RBCs, fragile and short-lived RBCs, and thus problems with development and growth of systems throughout the body.
*Patients with thalassemia may require transfusions to increase components of the blood.
*Sickle cell anemia is due to a mutation in the beta chain of Hb.

====Hemoglobin conservation and recycling====
*The heme prosthetic group in hemoglobin and myoglobin is heme B.
*Macrophages and phagocytes of the liver, spleen, and bone marrow engulf deteriorating RBCs, generally (90% of the time) before they rupture (hemolyze).
*If a RBC does hemolyze, the hemoglobin will deteriorate into alpha and beta chains and be excreted via the kidneys which may lead to hemoglobinuria (red or brown urine).
*Upon damage to the kidney or vessels along the urinary tract, hematuria may occur such that fully intact RBCs are found in the urine.
*The amino-acid chains of hemoglobin are broken down into aas in the macrophages and either used in the macrophage or secreted into the blood for use by other cells.
*The heme units first have there iron molecules removed making them biliverdin (a greenish color that shows up in bruises) which gets converted into bilirubin (an orangish color) and dropped into the bloodstream where albumin transports it to the liver for excretion via bile.
**Macrophage + heme -> biliverbin -> bilirubin -> bloodstream + albumin -> liver -> bile -> out.
*If the liver cannot absorb or secrete bilirubin, the bilirubin will build up in peripheral tissues like the sclera and the skin and cause '''jaundice'''.
*Bilirubin are converted into urobilinogens and stercobilinogens by bacteria in the large intestine. Upon exposure to oxygen, these turn into urobilins and stercobilins which give urine and feces their yellow-brown, brown color.

====Iron====
*Iron released into the blood at the liver upon destruction of heme units is bound to transferrin for transport in the blood.
*Bone marrow tissue absorbs iron so that it can generate new Hb.
*Ferritin and hemosiderin are used by the liver and spleen to store excess amounts of iron.
*This recycling program of iron from digested heme to generation of new heme is quite efficient--only 1-2 mg of iron is needed in the diet while 26 mg are used each day to produce heme units. That is, only 1-2mg of the 26mg of iron generated from the breakdown of RBCs is lost each day.
*So, too little iron (which will decrease RBC production) or too much iron (which will increase irons stores in the liver and cardiac tissue) can cause health issues.

===RBC production===
*Embryonic blood cells appear in the blood stream at week three.
*For the first 8 weeks, the yolk sac is where most blood is generated.
*As other organs develop, some ESCs move into the liver, spleen, thymus, and bone marrow where they will differentiate into stem cells that generate blood cells.
*The liver and spleen are the primary organs producing blood cells for months 2-5 of development-until the bone can mature into having marrow.
*In adults, RBCs are generated ''only'' in the marrow.
*RBCs are generated in red bone marrow (myeloid tissue).
*Red bone marrow is found in the vertebrae, scapulas, ribs, sternum, pelvis, skull, and the proximal limb bones.
*Yellow marrow can be converted to red marrow upon extreme and sustained duress.

====Stages in RBC maturation====
*Hemocytoblasts can generate myeloid stem cells and lymphoid stem cells which will generate red / white blood cells and lymphocytes, respectively.
*Hemocytoblasts -> myeloid stem cells -> proerythroblasts -> erythroblasts (basophilic -> polychromatophilic -> normoblast) -> reticulocyte -> mature RBC.
*Erythroblasts actively generate hemoglobin and are named based on their size, the amount of hemoglobin presnet, and the appearance of their nucleus.
*As a reticulocyte, the cell enters circulation with 80% of its Hb generated. Though the nucleus is gone, the RNA needed to generate the last 20% of Hb is still present. After 24 hours in circulation, all the Hb has been generated and the RNA is gone.

====Regulation of Erythropoiesis====
*Generating RBCs requires that the bone marrow get enough nutrients, including vitamin B12.
*B12 comes from dairy and meat in our diet.
*The stomach generates something called ''intrinsic factor'' which is required for absorbing B12.
*When there isn't enough B12, pernicious anemia occurs.
**This can occur because of too little B12 in the diet, too little production of ''intrinsic factor'' or because of an abnormality with B12/''intrinsic factor'' absorption.
*Generating RBCs can be stimulated with erythropoietin, thyroxine, androgens, and growth hormone. Note, however that estrogen does not stimulate RBC generation.
*EPO is a glycoprotein.
*EPO is produced by the liver and kidneys.
*EPO is generated when peripheral tissues or the kidneys experience hypoxia which might occur because of:
**anemia,
**decreased blood flow to kidneys,
**decreased oxygen concentration in respired air (high altitude),
**damaged lung respiratory surfaces.
*EPO acts on the stem cells found in bone marrow to increase generation of erythroblasts from their progenitors and to increase erythroblast division.
*EPO also acts to increase RBC maturation rates, sometimes up to 30 fold faster!
*EPO arc: Kidney / peripheral tissues suffer hypoxia -> Liver / kidney produce / release EPO -> blood stream -> bone marrow -> myeloid cells generate more erythroblasts, erythroblasts divide more rapidly to make more RBCs, and RBCs mature faster.
*Using EPO to increase RBC counts in for athletes is dangerous because it puts a strain on the heart because of increased viscocity.
*'''Blood doping''' is when you take blood out of an athlete, sequester the RBCs, and then reinfuse them at a later date to increase RBC counts.
*Blood tests can be used to quickly, cheaply, and unobtrusively assess a patient's health in several ways.

==The ABO blood types and Rh system are based on antigen-antibody response==
*Antigens are usually proteins but some other organic molecules can also act as antigens.
*Our own cells have surface antigens that mark them as native, also called agglutinogens.
*RBCs have over 50 surface antigens, but three of particular importance are A, B, and Rh (D).
*These 50 antigens are integrated glycoproteins or integrated glycolipids.
*Type O: 46%, type A: 40%, type B: 10%, type AB: 4% (of US population).
*Blood plasma contains '''agglutinins''' which attack cells with foreign antigens and cause a clumping together called agglutination.
*Rh antigens are a little different in that an Rh negative patient will not have anti-Rh antigens until they have been ''sensitized'' or exposed (perhaps via pregnancy with an Rh positive child or via a transfusion).

===Cross-reactions in transfusions===
*When blood antigen types are not matched for a transfusion, the agglutinogens will cause the foreign cells to clump together which can block blood vessels in lethal areas like the lungs, heart, brain, or kidneys.
*Remember that the reaction of the recipient's plasma antigens against the donor's RBCs is more important when considering cross-reaction potential because the donation will only include a very small amount of the donor's plasma such that it's attack on the recipient's RBCs will probably not generate harmful clumping.
**This means that one must consider most carefully the antigens on the donor's RBCs.
*One unit of blood is 500ml, of which 275ml is plasma (because the plasma content has been reduced).

===Testing for transfusion compatibility===
*Before a transfusion, a compatibility test is run which identifies the antigens of the donor and then shows the results of a cross-match test.
*To identify antigens on a donor's RBCs, two separate drops are exposed to anti-A and anti-B antigens; if there is a reaction with both, the blood type is AB, if only with one, then A or B, respectively.
*Rh is also noted (but the book didn't say how this test was run, which is interesting because one wouldn't necessarily have anti-Rh antigens even if they are Rh-).
*When time permits, we try to match all 50 antigens because, though it is rare, it is possible to have a reaction to one of the other 48 antigens.
*Blood typing is inherited and therefore is used in paternity testing and in crime scene detection.
**Testing for the other 48 antigens increases accuracy and DNA testing can generate 100% surety.

==The various types of white blood cells contribute to the body's defenses==
*In a microliter of blood, there are about 5-10K WBCs and 4-6M RBCs.
*Most WBCs are found in the connective tissue or organs of the lymphoid system.
*WBCs can be identified in a smear with a Wright stain or a Giemsa stain.
**Granular leukocytes = granulocytes: neutrophils, eosinophils, and basophils with large secretion vesicles and lysosomes.
**Agranular leukocytes = agranulocytes: monocytes and lymphocytes with much smaller vesicles and lysosomes.

===WBC circulation and movement===
*WBCs mostly reside and migrate through the loose and dense connective tissue.
*The only travel through the blood stream to get where they are going.
*As they are traveling through the blood stream, they can exit upon detection of a signal indicating damage.
*There are four characteristics of circulating WBCs:
**they can exit the blood stream by adhering to the endothelial wall (margination) and squeezing through the endothelial wall (emigration or diapedesis),
**they are capable of amoeboid movement through the ECM which requires ATP and Ca++,
**they are sensitive to specific chemical stimuli which act as positive chemotaxants toward damaged tissue and other activated WBCs,
**Neutrophils, eosinophils, and monocytes are capable of phagocytizing cells and materials.
*Macrophages are just monocytes that have moved out of the blood stream and are actively phagocytic.

===Types of WBCs===
*Neutrophils, eosinophils, basophils, and monocytes are nonspecific defenses.
*Lymphocytes are specific defenses.

====Neutrophils====
*Neutrophils are also called polymorphonuclear leukocytes because the nucleus has several dense lobes.
*Neutrophils got their name from having a neutral coat that is hard to stain because it doesn't attract acidic or basic dyes.
*Neuts make up 50-70% of circulating WBCs.
*They have lysosomes with enzymes and bactericidal compounds.
*Neuts are very fast and active and generally the first on the scene of an injury.
*They can attack and digest bacteria and other cells that have been marked with complement proteins.
*Once a neutrophils has engulfed a cell, it turns on it's metabolism to high (called ''respiratory burst'') in order to generate superoxides and hydrogen perioxides (called ''defensins'').
*The phagocytized cell is then fused with the lysosomes (degranulation) and the enzymes destroy the cell by eating away it's membrane.
*Neutrophils also release leukotrienes to attrack other leukocytes to the site of attack.
*Neutrophils release prostaglandins in order to make the capillaries near the injury more permeable and therefore contribute to local inflammation.
*Neutrophils live about 10 hours in the blood stream, perhaps only 30 minutes if they are attacking a bad guy.
*Pus is a mixture of dead neutrophils, cellular debris, and other waste products.

====Eosinophils====
*Eosinophils stain easily with eosin, a red dye.
*They have a bilobed nucleus and are about the same size as a neut.
*They make up only 2-4% of circulating WBCs.
*These guys can engulf antibody laden bad guys but generally secrete nitric oxide and cytotoxic enzymes.
*They are particularly good at attacking multicellular parasites.
*Eosinophils multiply rapidly when parasitic infection occurs or allergens are detected.
*Eosinophils help reduce inflammation by neuts and mast cells at a site of infection, keeping it from spreading to adjacent tissue.

====Basophils====
*Basophils can be stained with basic dyes.
*Basophils are smaller than neuts and eosinophils.
*They make up only 1% of the WBC population.
*Basophils release their granules into the interstitial fluid.
*The granules include:
**histamine to dilate blood vessels,
**heparin to prevent blood clotting,
**chemicals to reduce inflammation started by mast cells,
**chemicals to attract eosinophils,
**chemicals to attract more basophils.

====Monocytes====
*Monocytes are the largest WBCs.
*Monocytes make up 2-8 percent of the WBC population.
*Monocytes have a kidney or oval shaped nucleus.
*Monocytes are only in the bloodstream long enough to get to their tissue, then they become a resident macrophage.
*Macrophages phagocytize aggressively.
*While phagocytizing, macrophages release factors that attract neutrophils, monocytes, other phagocytic cells, and fibrocytes.
*The fibrocytes will build scar tissue.

====Lymphocytes====
*Lymphocytes are 20-30% of the circulating WBC population.
*Lymphocytes have a large round nucleus with only a little cytoplasm surrounding it.
*Lymphocytes are circulating through the blood, peripheral tissue, and lymphatic system constantly.
*The circulating fraction is only a very small portion of all lymphocytes, however.
*There are three functional classes of lymphocytes, none of which can be distinguished with a microscope:
**T cells either attack foreign cells themselves or coordinate a response involving the other lymphocyte classes. T cells are responsible for ''cell-mediated immunity''.
**B cells are responsible for the ''humoral immunity'' (fluid immunity) of the body because as mature cells (plasma cells) they generate antibodies that attack antigens on foreign cells throughout the body.
**Natural killer cells are responsible for immune surveillance--the detection and destruction of abnormal tissue cells like those of cancers.
*Note that T cells must migrate to their target but B cells generate antibodies which can act anywhere in the body.

===The differential count and changes in WBC profiles===
*We can often tell what is going on in a body by looking at the numbers of each type of WBC in a sample.
*''penia'' means ''too little''.
*''osis'' can mean ''too many''.
*So ''leukopenia'' means there is a low count of leukocytes (WBCs) and ''lukocytosis'' means there may be too many.
*''Leukemia'' refers to having boatloads of WBCs.

===WBC Production===
*This image is pretty much all we need to know.

====Regulation of WBC production====
*The thymus secretes hormones that stimulate the production of T cells, that is, until the thymus stops working in youth.
*Therefore, in adults, it is the exposure to antigens that increases production of B and T cells.
*The non-lymphocyte WBCs are stimulated by colony-stimulating factors (CSFs).
*There are four CSFs:
**M-CSf stimulates production of monocytes.
**G-CSF stimulates the production of the granulocytes (neutrophils, eosinophils, and basophils).
**GM-CSF stimulates the production of monocytes and granulocytes.
**Multi-CSF accelerates the production of granulocytes, monocytes, platelets, and even RBCs.
*Communcation between lymphocytes and other WBCs occurs via chemicals like the CSFs and EPO.
*Some of these communicatory chemicals are approved for clinical use: like G-CSF = filgrastim = neupogen which is given to chemotherapy patients to increase their neutrophil count.

==Platelets, disc-shaped structures formed from megakaryocytes, function in the clotting process==
*Platelets are called thrombocytes in nonmammals because they are still nucleated cells.
*Platelets are important for clotting, along with plasma proteins and the cells and tissues of the blood vessels themselves.
*About 1/3 of our platelets are found in the spleen and other vascular organs while 2/3 are circulating.
*Platelets circulate for about 10 days before being phagocytized.
*Thrombocytopenia (too few platelets) generally occurs because of bleeding along the digestive tract, withing the skin, or within the CNS (and thus platelets are lost faster than made).
*Thrombocytosis (too many platelets) often results from accelerated production in response to infection, inflammation, or cancer.

===Platelet function===
*Platelets:
**release enzymes and other factors at the appropriate time to help initiate clotting,
**form a clump of platelets to plug up injuries of vessels,
**contract (via actin / myosin) to make the size of the clotted area / damaged area smaller.

===Platelet production===
*The generation of platelets (thrombocytopoiesis) is facilitated by megakaryocytes in the bone marrow.
*Megakaryocytes are large, have a large nucleus, and generate lots of proteins, enzymes, and membrane.
*Then segments of the megakaryocyte's cell body are slowly sheered off by the blood stream and thus are made platelets.
*Thrombocytopoiesis can be stimulated via:
**thrombopoietin (TBO, AKA: thrombocyte-stimulating factor) which is a peptide hormone produced in the kidneys,
**IL-6,
**multi-CSF.

==Hemostasis involves vascular spasm, platelet plug formation, and blood coagulation==
*Hemostasis literally means blood halting; it is about stopping blood loss.
*There are three, intermixed stages: vascular, platelet, coagulation.

===The vascular phase===
*The vascular phase begins first and includes the contraction of the smooth muscle that surrounds the injured vessel. This cans slow or even stop blood loss.
*Three changes in the endothelium occur during the vascular phase:
**Endothelial cells contract and expose the underlying basal lamina to the blood stream,
**Endothelial cells release chemical factors including ADP, tissue factor, prostacyclin, and endothelins.
***Endothelins stimulate smooth muscle contraction and the division of endothelial cells, smooth muscle cells, and fibrocytes.
**The endothelial cells of the vessel wall become sticky and thus stick together to help seal the break. This also helps faciliate the beginning of the platelet phase.

===The platelet phase===
*The platelet phase begins upon ''platelet adhesion'' to the sticky endothelial cells as well as collagen fibers.
*Then the platelets aggregate to form a plug which can sometimes stop blood loss if the injury is small.
*Platelet aggregation occurs within 15 seconds of an injury.
*Platelets become activated as they arrive at the site of injury and thus they release:
**ADP to stimulate platelet aggregation and secretion,
**Thromboxane A2 and serotonin to stimulate vascular spasms,
**Proteins that play a role in clotting (called ''clotting factors''),
**PDGF, a peptide hormone that promotes vessel repair, and
**calcium ions which help will aggregation and clotting.
*Because each platelet is releasing all this stuff, there is positive feedback such that this process occurs rapidly.
*Therefore, plug formation must be limited to the site of injury by several factors:
**Prostacyclin is released by endothelial cells,
**Inhibitory compounds are released by WBCs,
**Plasma enzymes break down ADP (which is stimulating aggregation) near the plug,
**Compounds (like serotonin) which, at high levels, block formation of more plug material, and
**The formation of a blood clot isolates the plug (and therefore all the factors encouraging more plug formation) from the general circulation.

===The coagulation phase===
*The coagulation phase takes about 30 seconds to sit in while the vascular and platelet take 0-15 seconds.
*In the coagulation phase, the blood clot is formed over the platelet plug via a complex series of steps that convert fibrinogen (a soluble protein circulating in the blood) into a mesh of fibrin in which other blood cells and such get stuck to form a filled mesh that will become something like a scab and effectively stop blood loss.

====Clotting factors====
*Clotting factors = procoagulants.
*Clotting factors are generally proenzymes that go through a cascade of activation in order to start the clotting process.
*Ca++ is also a clotting factor.
*Clotting occurs through two pathways; the intrinsic pathway begins in the bloodstream while the extrinsic pathway begins outside the bloodstream, in the vessel wall.
*Both pathways activate the common pathway (see diagram above) via ''factor x''.

====The extrinsic pathway====
*The extrinsic pathway starts by the release of factor III by damaged endothelial cells.
*Factor III interacts with Ca++ and other factors to activate factor x.

====The intrinsic pathway====
*The intrinsic pathway begins when proenzymes in the blood are activated by exposure to collagen (or a glass test tube).
*Then several platelet factors and clotting factors interact before they activate factor x.

====The common pathway====
*The common pathway begins when factor x is activated which forms prothrombinase.
*Prothrombinase converts prothrombin into thrombin which converts fibrinogen into fibrin.

====Interactions among the pathways====
*The extrinsic pathway is shorter and faster and produces a quick, but small amount of thrombin.
*Clotting occurs in a matter of minutes.

====Feedback control of blood clotting====
*The common pathway speeds up both the extrinsic and intrinsic pathways via positive feedback, thus making clotting a very fast process.
*Because there is such positive feedback, there are also many factors that inhibit clot formation:
**Anticoagulants found in blood plasma,
**Heparin, released by basophils and mast cells,
**Thrombomodulin released by endothelial cells which activates '''protein C''' which deactivates fibrin strands,
**Prostacyclin from the platelet phase.
*Many clinical conditions require close regulation and manipulation of clotting and anticlotting factors.

====Calcium ions, vitamin K, and blood clotting====
*Ca++ is required in all three pathways: intrinsic, extrinsic, and common.
*Vitamin K is required for the liver to generate many of the clotting factor proteins found in plasma.
*Therefore anything that messes up Ca++ or vitamin K levels can affect the patient's ability to clot.
*Vitamin K is fat soluble.
*Half our vitamin K needs are absorbed in the diet and half is generated by bacteria in the gut.

====Clot retraction====
*Within about 30 to 60 minutes, a clot has formed and platelets are pulling together to reduce residual bleeding and to make it easier for fibrocytes, smooth muscle cells, and endothelial cells to complete their repairs.

===Fibrinolysis===
*The fibrin network can be broken down via plasminogen.
*For everything to work properly, blood has to keep flowing. RBCs make about 2 circuits per minute.

Chapter 20

Admin — Wed, 17 Mar 2010 14:10:33 GMT

Admin: moved Chapter 20 to Chapter 20 notes (Heart)

#REDIRECT [[Chapter 20 notes (Heart)]]

Chapter 20 notes (Heart)

Admin — Wed, 17 Mar 2010 14:10:31 GMT

Admin: moved Chapter 20 to Chapter 20 notes (Heart)

==Chapter 20: The heart==

===An introduction to the cardiovascular system===
*There is a '''pulmonary circuit''' and a '''systemic circuit'''.
*''Efferent vessels'' = arteries = away from the heart.
*''Afferent vessels'' = veins = toward the heart.
*Capillaries = exchange vessels.
*The heart pumps 100k times per day, moving 8k liters!
*The right atrium receives blood from the systemic circuit; the left atrium receives blood from the pulmonary circuit.
*The ventricles pump at the same time and move the same volume of fluid into each circuit.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-01.jpg

===The heart is a four-chambered organ, supplied by the coronary circulation, that pumps oxygen-poor blood to the lungs and oxygen-rich blood to the rest of the body===
*The heart lies slightly to the left of center, behind the sternum.
*The inferior tip of the heart is called the '''apex'''.
*The '''mediastinum''' is the region between the two pleural cavities.
*The mediastinum holds the heart (in the pericardial sac) and the '''great vessels''' as well as the thymus, esophagus, and trachea.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-02.jpg

====The pericardium====
*The pericardial sac is like a balloon in which one's heart is depressed.
*The pericardial sac has two tissue layers:
**The '''visceral pericardium (epicardium)''' covers and adheres to the surface of the heart.
**The '''parietal pericardium''' lines the inner surface of the sac.
*Between the membranes, there is pericardial fluid which serves to reduce friction between the membranes and to protect the heart.
**'''Pericarditis''' is the reduction of pericardial fluid and thus presents with a scratching noise that can be heard via stethoscope.
**'''Cardiac tamponade''' occurs when fluid builds up in the pericardial sac (from infection or wounding, perhaps) and thus restructs the movements of the heart.
***''Tampon'' means plug in latin.

====Superficial anatomy of the heart====
*The atria have thin, muscular walls that are highly expandable.
*The atria have '''auricles''' that go limp and wrinkle after contracting blood out of the atria.
*The '''coronary sulcus''' is a deep grove that marks the boundary between the atrium and the ventricle.
*The '''anterior / posterior interventricular sulci''' are shallower depressions that mark the boundary between the left and right ventricles.
*The sulci also contain the coronary arteries / veins and substantial amounts of fat.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-03.jpg

====The heart wall====
*There are three layers to the wall of the heart:
**The '''epicardium''' is the same as the visceral pericardium and has two sub layers: the exposed mesothelium and the areolar tissue which is connected to the myocardium.
***'''Areolar''': "Areolar tissue known as areis exhibits interlacing, loosely organized fibers, abundant blood vessels, and significant empty space. Its fiber run in random directions and are mostly collagenous, but elastic and reticular fibers are also present." [http://en.wikipedia.org/wiki/Areolar]
**The '''myocardium''' contains nerves, blood vessles, and muscle tissue that intricately wraps around the great vessels, the atria, and the ventricles with a figure-eight pattern. The myocardium has multiple layers of muscle fibers.
**The '''endocardium''' is a simple squamous epithelium that covers the inside of the heart, including the valves, and is continuous with the endothelium of the vasculature.
***'''Squamous''': "In anatomy, squamous epithelium (from Latin ''squama'', "scale") is an epithelium characterised by its most superficial layer consisting of flat, scale-like cells called squamous cell". [http://en.wikipedia.org/wiki/Squamous]

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-04.jpg

=====Cardiac muscle tissue=====
*Cardiac muscle fibers are connected with intercalated discs where the membranes of adjacent muscle cells interlock and are held together by desmosomes and gap junctions.
*These junctions allow for the fast propagation of action potentials.
*Note that cardiac muscle fibers can be differentiated in histological slides by:
**their smaller size,
**their single, centrally located nucleus,
**their branching interconnections, and
**the presence of intercalated discs.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/table-20-01.jpg

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-05.jpg

====Internal anatomy and organization====
*The muscular interatrial and interventricular septums separate the atriums and the ventricles.
*The atrioventricular valves keep blood from flowing from the ventricle to the atrium.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-06.jpg

=====The right atrium=====
*The right atrium receives blood from the superior and inferior vena cava and coronary sinus.
*The superior vena cava delivers blood from the head, neck, upper limbs, and chest.
*The inferior vena cava delivers blood from the rest of the trunk, the viscera, and the lower limbs.
*The coronary sinus delivers blood from the coronary veins.
*The foramen ovale allows blood to pass from the right atrium to the left atrium until birth when it closes.
*The '''formen ovale''' is generally permanently closed by three months of age leaving only the '''fossa ovalis'''.
*When the foramen ovale doesn't close, there are serious cardiovascular problems.
*The posterior side of the right atrium has a smooth surface while the anterior side and the auricle have muscular ridges called '''pectinate muscles'''.

=====The right ventricle=====
*Blood flows from the right atrium to the right ventricle via the right '''atrioventricular valve''' which is also called the '''tricuspid valve''' because there are three cusps made of fibrous tissue.
*There are '''chordae tendinae''' that are attached to the papillary muscles inside the '''ventricle''' that keep the cusps from being forced backward into the atrium when the ventricle contracts and blood pressure increases.
*There is a band called the '''moderator band''' that connects the internal conduction system to the papillary muscles so that the papillary muscles will be contracted before the rest of the heart flexes.
*The blood in the right ventricle is pumped through the '''pulmonary valve''' (also called the '''pulmonary semilunar valve''') and into the pulmonary trunk and then into the left and right pulmonary arteries.

=====The left atrium=====
*The left atrium receives blood from the four pulmonary veins.
*Like the right atrium, the left atrium has an auricle.
*The right atrium has an atrioventricular valve, called the '''bicuspid valve''' or the '''mitral valve'''.
*Remember that you "tri (sic) to be right when remembering where the tricuspid valve is located."

=====The left ventricle=====
*The left ventricle is similar to the right ventricle:
**It has chrodae tendinae that support the atrioventricular valve (the mitral valve) to prevent backflow.
**There are large muscular ridges.
**The two ventricles hold the same volume of blood.
*The left ventricle has much thicker walls than the right ventricle, however, so that it can generate the increased pressure needed to circulate blood throughout the entire body.
*Blood leaves the left ventricle via the '''aortic semilunar valve''' (also called the '''aortic valve''') to enter the ascending aorta and then the aortic arch and the descending aorta.
*In the fetus, the pulmonary branch of the circulatory system is linked to the systemic branch through a blood vessel that later deteriorates into a fibrous ligament called the '''ligamentum arteriosum'''.

=====Structural differences between the left and right ventricles=====
*The function of the atria are almost identical and thus they look almost identical; the ventricles, however, are different because they have different duties.
*The right ventricle only has to push blood through the short pulmonary circuit which has relatively wide vessels and is therefore able to be effective which much lower pressures. Therefore, it has developed into a bellow-like compartment that compresses into the wall of the left ventricle.
**Bellows: "A bellows (AKA Bagpipe) is a device for delivering pressurized air in a controlled quantity to a controlled location. Basically, a bellows is a deformable container which has an outlet nozzle. When the volume of the bellows is decreased, the air escapes through the outlet." [http://en.wikipedia.org/wiki/Bellows ref]
*The right ventricle has a circular cross section and concentric muscular form.
*When contracting, the right ventricle both narrows its diameter and shortens the chamber and can thus generate 4-6 times as much pressure as the right ventricle.
*The contraction of the left ventricle causes it to bulge into the chamber of the right ventricle and thus helps pump blood into the pulmonary system as well.
**Sometimes, patients with damage to their right ventricle can survive because of this physiological effect.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-07.jpg

=====The heart valves=====

======The atrioventricular valves======
*Backflow of blood is also called '''regurgitation'''.

======The semilunar valves======
*The semilunar valves (those that lead from ventricles to either the systemic or pulmonary circuits) don't need supporting chordae because there is no pressure on the blood in the circuit trying to get back into the ventricle.
*When the semilunar valves close, the three flaps support each other like the three legs of a tripod.
*At the aortic valve, there are '''aortic sinuses''' (sacs) that keep the cusps of the valve from sticking to the walls of the aorta as blood is flowing outward.
*The coronary arteries originate at the aortic sinuses.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-08.jpg

*'''Valvar heart disease''' occurs when a patient's heart valves misfunction to the point that a steady flow of blood cannot be maintained.
**Often VHD develops after '''carditis''' (an inflammation of the heart tissue) which can be caused by infections.
**Rheumatic fever, an autoimmune inflammatory response to an infection is often the cause of carditis.

===STUFF MISSING!===

====The Blood Supply to the Heart====
*Blood flow to cardiac tissue can increase by 9 or 10 fold at times of greatest exertion.

http://wps.aw.com/wps/media/objects/6275/6425991/ebook/fig/big/ch20-09.jpg

=====The coronary arteries=====

===20-3 Events during a complete heartbeat constitute a cardiac cycle===

====Phases of the cardiac cycle====

====Pressure and volume changes in the cardiac cycle====

=====Atrial systole=====
*Atrial systole occurs to push blood into the ventricle to fill the 30% of the volume that wasn't already filled passively.
**Hence one can live without atrial systole.
*At the end of atrial systole, the ventricle contains all that it will hold for the current cardiac cycle: '''the end diastolic volume'''.

=====Ventricular systole=====
*During ventricular systole, both sides of the heart eject about 70-80 mL of blood: the '''stroke volume'''.
*At rest, the ratio of stroke volume to end diastolic volume is about 60%; this is called the '''ejection fraction'''.
*At the end of ventricular systole, the volume of blood remaining in the ventricle is about 40% of the original end diastolic volume and is called the '''end systolic volume'''.

=====Ventricular diastole=====
*The ventricle relaxes until atrial pressure is greater than ventricle pressure.
*Then the atrioventricular valves open and blood passively passes from the atria to the ventricle until atrial systole begins.

===20-4 Cardiodynamics examines the factors that affect cardiac output===
*Stroke volume is end diastolic volume (EDV) minus end systolic volume (ESV).
*Stroke volume is the most important consideration in cardiodynamics.
*Cardiac output, then is the stroke volume multiplied by the heart rate.
**Cardiac output, essentially, tells us how much blood is flowing through the circulation each minute.

====Overview: Factors affecting cardiac output====
*Heart rate and stroke volume are the two factors that can be adjusted and they are usually adjusted in concert.
*The heart rate can be changed through the autonomic nervous system or through the endocrine system.
*Stroke volume can be changed through the autonomic nervous system or through the endocrine system (which will adjust the EDV and ESV).

====Factors affecting the heart rate====
=====Autonomic nervous system=====
*The autonomic nervous system can control the heart rate from the cardioinhibitory center and cardioacceleratory center of the medulla oblongata.
*The sympathetic system will be controlled by the cardioacceleratory center which will cause the heart to beat faster and with greater contractility.
*These centers in the brain change the heart rate based on information from baroreceptors and chemoreceptors found in arteries and innervated by the cranial nerves.
*The parasympathetic and sympathetic nervous systems change the heart rate by changing ion permeability at the SA node.
**For instance, making them more permeable to K+ will mean that the cell will depolarize less quickly (because K+ will be flowing out more and Na+ will be flowing in the same as before). This can be achieved through the parasympathetic release of acetylcholine.
**The sympathetic system, on the other hand, can release norepinephrine in order to bind a channel and allow more Na+ to enter the cell, thus depolarizing the SA node at a higher frequency.
*Another way the autonomic nervous system can receive feedback is from cells of the right atrium.
**When they stretch (that is, when venous return is high) they cause increased sympathetic stimulation and thus increased heart rate.

=====Hormones=====
*Just as the sympathetic system uses norepi, hormonal release of norepi or epi can trigger an increase in heart rate.
*Epi increase not only the heart rate but also contractility.

====Factors affecting the stroke volume====
*To affect stroke volume, one must change either EDV or ESV or both.

=====The EDV=====
*The filling time, when increased can increase the EDV and ''vice versa'' when decreased.
**Filling time is directly proportional to the heart rate; increased heart rate means decreased filling time.
*The preload is the amount of stretching experienced by the ventricular muscles.
**Preload is directly proportional to the EDV; the higher the EDV the more stretch (preload).
**The more preload (stretch) the higher the force of contraction by the mycardium (because as mycardial fibers stretch, more of the sarcomere length overlaps).
**Therefore as the mycardiocytes approach optimal sarcomere stretching, they will increase contractile strength and decrease the ESV.
**So we see an increase of EDV and a decrease of ESV which means an increase of stroke volume.
**And so, this relationship of increased EDV leading to increased stroke volume is called the '''Frank-Starling principle'''.

=====The ESV=====
*There are three factors that affect the ESV: preload (as discussed in the EDV section), contractility, and afterload.

*Contractility is the force produced during contraction at a given preload.
**This is usually controlled by the autonomic nervous system and hormones but can also be manipulated with drugs and abnormal ion concentrations in the extracellular fluid.
**Things that increase contractility are said to be '''positively inotropic''' and generally work by increasing Ca+ permeability into the cells such that the force and length of contraction are increased.
**Things that decrease contractility are said to be '''negatively inotropic''' and generally work by blocking Ca++ or by depressing cardiac muscle metabolism.
**The autonomic systems can control contractility through NE, E (sympathetic, increased metabolism) and ACh (parasympathetic, hyperpolarization).
*Hormonal control of contractility:
**Anything that increases metabolism of the cells will increase contractility, including glucagon.
**Negative inotrophs are used as hypertension (high blood pressure) drugs because they can decrease heart contractility and thus decrease blood pressure.
*Afterload:
**Afterload is the amount of pressure the ventricular muscles must generate in order to open the semilunar valves.
**As afterload increases, the isovolumetric stage of ventricular systole increases and thus the duration of ventricular blood ejection decreases. This means that the ESV will decrease and stroke volume will decrease.
**Anything that increases resistance in the blood vessels will increase the afterload.
**Though reduction of ESV to zero because of afterload is rare in healthy hearts, if the heart tissue is damaged it be the case that it simply cannot reach the necessary afterload needed to pump blood; this is known as heart failure.

Chapter 20 notes (Heart)

Admin — Sun, 07 Mar 2010 22:21:41 GMT

Admin: /* 20-3 Events during a complete heartbeat constitute a cardiac cycle */

Chapter 20 notes (Heart)

Admin — Sun, 07 Mar 2010 22:04:23 GMT

Admin:

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 21:37:29 GMT

Admin: /* Electrical activation of the heart */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart.
Really, the heart? or some big vein?
*Yes, it is actually the atrium into which they dump.
*The heart must have extensive blood flow and therefore the coronary circulation is very extensive.
**The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, one can compensate by using ATP reserves, switching to anarobic energy generation, using lactic acid or one can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, thus it must always have adequate oxygen.
*Ischemia means "reduced blood flow".
*Hypoxia means "low oxygen".
*Coronary atherosclerosis means "a buildup of plaque in heart".

====Coronary atherosclerosis====
*Coronary atherosclerosis is the same thing as coronary artery disease (CAD).
*Coronary artery disease is the leading causes of death in the US, by a large margin.
*Deposition of plaque in coronary vessels leads to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't contractive.
*Ultimately, CAD leads to a failing of the heart due to low blood supply.

=====Causes of CAD=====
*Hypertrophy of the endothelial cells.
*Cholesterol deposition.
*Endothelial cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suction.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like [Delude's_"Clot_Busters!!_-_Discovery_of_thrombolytic_therapy_for_heart_attack_and_stroke"_(2004)| tPA and streptokinase].
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is extremely invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it (but only in 20% of the population).
*Inflammatory responses, perhaps cuased by infections.

=====Cowley's Newsweek article: Cardiac Contagion=====
*Contagion: "A disease spread by contact; The spread or transmission of such a disease; The spread of anything harmful, as if it were such a disease...." [http://en.wiktionary.org/wiki/contagion ref]
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*The article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.
*The authors even suggest that CAD may be somewhat contagious because if you get respiratory chlamidia, you can end up with CAD.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endothelial cells.
**As in, it generates a peptide that looks like a host peptide and thus starts an auotinflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mitochondria so that they have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice.
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First, the electrical activity spreads from the SA node over the atrium, then it reconvenes at the AV node, then it spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials through nerves travel really fast--much faster than through cardiac muscle.
*All cells of the body have a spontaneous potential difference measured in volts.
**The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials.
**In pacemaker cells it is -40 millivolts (that is, -40 inside compared to outside).
*-40 mV is the threshold in pacemaker cells.
*After an action potential, the potential drops below threshold and then starts leaking back toward threshold such that another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then polarization is maintained by slow calcium channels that open late and stay open for a longer time.
*Then a nearly neutral level of polarization is maintained as potassium channels are opened such that Ca++ is coming in and K+ is going out.
*Then repolarization is achieved through the previously mentioned potassium channels remaining open while the slow calcium channels close, thus allowing potassium to continue out of the cell driving the potential back to the negatives.
*How often this whole process occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increased permiability to potassium which drives the refractory polarization to a lower (more negative) number such that it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the Ca++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you must have functional ventricles.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excite the cardiac muscle fibers.
*The cardiac action potentials last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: fast sodium, slow chloride, and slow potassium.
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel opening.
*When channels break:
**Long-qt syndrome can be exhibited.
**The first symptom is death.
**Stimulation of the heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (the QRS wave), then the potential spreads up the ventricles (still the QRS wave), and then the ventricles relax (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve (which would cause the hypertrophy of the atrium).
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A '''junctional rhythm''' marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sympathetic stimulation.
*Temperature decreases HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 21:12:49 GMT

Admin: /* Electrical characterisitcs of the heart */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart.
Really, the heart? or some big vein?
*Yes, it is actually the atrium into which they dump.
*The heart must have extensive blood flow and therefore the coronary circulation is very extensive.
**The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, one can compensate by using ATP reserves, switching to anarobic energy generation, using lactic acid or one can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, thus it must always have adequate oxygen.
*Ischemia means "reduced blood flow".
*Hypoxia means "low oxygen".
*Coronary atherosclerosis means "a buildup of plaque in heart".

====Coronary atherosclerosis====
*Coronary atherosclerosis is the same thing as coronary artery disease (CAD).
*Coronary artery disease is the leading causes of death in the US, by a large margin.
*Deposition of plaque in coronary vessels leads to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't contractive.
*Ultimately, CAD leads to a failing of the heart due to low blood supply.

=====Causes of CAD=====
*Hypertrophy of the endothelial cells.
*Cholesterol deposition.
*Endothelial cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suction.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like [Delude's_"Clot_Busters!!_-_Discovery_of_thrombolytic_therapy_for_heart_attack_and_stroke"_(2004)| tPA and streptokinase].
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is extremely invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it (but only in 20% of the population).
*Inflammatory responses, perhaps cuased by infections.

=====Cowley's Newsweek article: Cardiac Contagion=====
*Contagion: "A disease spread by contact; The spread or transmission of such a disease; The spread of anything harmful, as if it were such a disease...." [http://en.wiktionary.org/wiki/contagion ref]
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*The article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.
*The authors even suggest that CAD may be somewhat contagious because if you get respiratory chlamidia, you can end up with CAD.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endothelial cells.
**As in, it generates a peptide that looks like a host peptide and thus starts an auotinflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mitochondria so that they have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice.
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First, the electrical activity spreads from the SA node over the atrium, then it reconvenes at the AV node, then it spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials through nerves travel really fast--much faster than through cardiac muscle.
*All cells of the body have a spontaneous potential difference measured in volts.
**The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials.
**In pacemaker cells it is -40 millivolts (that is, -40 inside compared to outside).
*-40 mV is the threshold in pacemaker cells.
*After an action potential, the potential drops below threshold and then starts leaking back toward threshold such that another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then polarization is maintained by slow calcium channels that open late and stay open for a longer time.
*Then a nearly neutral level of polarization is maintained as potassium channels are opened such that Ca++ is coming in and K+ is going out.
*Then repolarization is achieved through the previously mentioned potassium channels remaining open while the slow calcium channels close, thus allowing potassium to continue out of the cell driving the potential back to the negatives.
*How often this whole process occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increased permiability to potassium which drives the refractory polarization to a lower (more negative) number such that it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the Ca++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you must have functional ventricles.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sympathetic stimulation.
*Temperature decreases HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:51:36 GMT

Admin: /* Properties of cardiac muscle fibers */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart.
Really, the heart? or some big vein?
*Yes, it is actually the atrium into which they dump.
*The heart must have extensive blood flow and therefore the coronary circulation is very extensive.
**The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, one can compensate by using ATP reserves, switching to anarobic energy generation, using lactic acid or one can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, thus it must always have adequate oxygen.
*Ischemia means "reduced blood flow".
*Hypoxia means "low oxygen".
*Coronary atherosclerosis means "a buildup of plaque in heart".

====Coronary atherosclerosis====
*Coronary atherosclerosis is the same thing as coronary artery disease (CAD).
*Coronary artery disease is the leading causes of death in the US, by a large margin.
*Deposition of plaque in coronary vessels leads to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't contractive.
*Ultimately, CAD leads to a failing of the heart due to low blood supply.

=====Causes of CAD=====
*Hypertrophy of the endothelial cells.
*Cholesterol deposition.
*Endothelial cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suction.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like [Delude's_"Clot_Busters!!_-_Discovery_of_thrombolytic_therapy_for_heart_attack_and_stroke"_(2004)| tPA and streptokinase].
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is extremely invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it (but only in 20% of the population).
*Inflammatory responses, perhaps cuased by infections.

=====Cowley's Newsweek article: Cardiac Contagion=====
*Contagion: "A disease spread by contact; The spread or transmission of such a disease; The spread of anything harmful, as if it were such a disease...." [http://en.wiktionary.org/wiki/contagion ref]
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*The article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.
*The authors even suggest that CAD may be somewhat contagious because if you get respiratory chlamidia, you can end up with CAD.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endothelial cells.
**As in, it generates a peptide that looks like a host peptide and thus starts an auotinflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mitochondria so that they have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sympathetic stimulation.
*Temperature decreases HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:50:08 GMT

Admin: /* Blood flow of the heart */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart.
Really, the heart? or some big vein?
*Yes, it is actually the atrium into which they dump.
*The heart must have extensive blood flow and therefore the coronary circulation is very extensive.
**The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, one can compensate by using ATP reserves, switching to anarobic energy generation, using lactic acid or one can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, thus it must always have adequate oxygen.
*Ischemia means "reduced blood flow".
*Hypoxia means "low oxygen".
*Coronary atherosclerosis means "a buildup of plaque in heart".

====Coronary atherosclerosis====
*Coronary atherosclerosis is the same thing as coronary artery disease (CAD).
*Coronary artery disease is the leading causes of death in the US, by a large margin.
*Deposition of plaque in coronary vessels leads to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't contractive.
*Ultimately, CAD leads to a failing of the heart due to low blood supply.

=====Causes of CAD=====
*Hypertrophy of the endothelial cells.
*Cholesterol deposition.
*Endothelial cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suction.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like [Delude's_"Clot_Busters!!_-_Discovery_of_thrombolytic_therapy_for_heart_attack_and_stroke"_(2004)| tPA and streptokinase].
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is extremely invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it (but only in 20% of the population).
*Inflammatory responses, perhaps cuased by infections.

=====Cowley's Newsweek article: Cardiac Contagion=====
*Contagion: "A disease spread by contact; The spread or transmission of such a disease; The spread of anything harmful, as if it were such a disease...." [http://en.wiktionary.org/wiki/contagion ref]
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*The article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.
*The authors even suggest that CAD may be somewhat contagious because if you get respiratory chlamidia, you can end up with CAD.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endothelial cells.
**As in, it generates a peptide that looks like a host peptide and thus starts an auotinflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sympathetic stimulation.
*Temperature decreases HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Chapter 19 notes (Cardiovascular system)

Admin — Sun, 07 Mar 2010 20:31:49 GMT

Admin: /* The coagulation phase */

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:22:34 GMT

Admin: /* The mechanics */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*The pressure of the blood being squeezed by the ventricle closes the AV valve and opens the semilunar valve.
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles (which are on the inside of the ventricle walls).
**These do not pull the flap open, they only keep the valve from turning inside out when the ventricle begins to compress the blood such that there is force on the valve that would otherwise collapse it.

*The heart can tolerate some leaking (that is, retrograde circulation).
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to these epitopes (as we should because they are presented by bad guys), we might start attacking host cells, too.
***Strep is one of these. If it becomes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart (really, the heart? or some big vein?).
Yes, it is actually the atrium in which they dump.
*The coronary circulation is very extensive.
*The heart must have extensive blood flow.
*The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, you can use ATP reserves, you can switch to anarobic energy generation, you can use lactic acid or you can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, so you have to always give it oxygen.
*Ischemia = reduced blood flow.
*Hypoxia = low oxygen.
*Coronary atherosclerosis = buildup of plaque in heart.

====Coronary atherosclerosis====
*Coronary artery disease is a one of the leading cause of death in the US, by a lot.
*Deposition in coronary vessels leading to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't so contractive.
*Failing of the heart due to low blood supply.

=====Causes=====
*Hypertrophy of the endo cells.
*Cholesterol deposition
*Endo cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suck it out.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like tPA and streptokinase.
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is dang invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it, but only in 20% of the population!
*Inflammatory responses, perhaps cuased by infections.

=====Newsweek article: Cardiac Contagion=====
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*They article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endo cells.
**As in, it generates a paptide that looks like a host peptide and thus starts an inflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sypathetic stimulation.
*Temperature decreases temperature HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:18:09 GMT

Admin: /* Valves */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atrio-ventrical (AV) valves:
**Have thin walls.
**Are open at rest such that blood int he atria leaks into the ventricles.
**The tricuspid valve has three valves but the mitral (bicuspid) valve has only two.
What is a miter?
*The name of the mitral valve comes with reference to the miter (mitre) which was a religious headgear from long ago [http://en.wikipedia.org/wiki/Mitre ref].
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles.
**These do not pull the flap open, they only passively hold it open. Then they keep the valve from turning inside out when the chamber fills with blood.
*The pressure of the blood coming in closes the AV valve and opens the semilunar valve.

*The heart can tolerate some leaking.
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to them, we might start attacking host cells, too. Strep is one of these. If it goes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart (really, the heart? or some big vein?).
Yes, it is actually the atrium in which they dump.
*The coronary circulation is very extensive.
*The heart must have extensive blood flow.
*The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, you can use ATP reserves, you can switch to anarobic energy generation, you can use lactic acid or you can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, so you have to always give it oxygen.
*Ischemia = reduced blood flow.
*Hypoxia = low oxygen.
*Coronary atherosclerosis = buildup of plaque in heart.

====Coronary atherosclerosis====
*Coronary artery disease is a one of the leading cause of death in the US, by a lot.
*Deposition in coronary vessels leading to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't so contractive.
*Failing of the heart due to low blood supply.

=====Causes=====
*Hypertrophy of the endo cells.
*Cholesterol deposition
*Endo cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suck it out.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like tPA and streptokinase.
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is dang invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it, but only in 20% of the population!
*Inflammatory responses, perhaps cuased by infections.

=====Newsweek article: Cardiac Contagion=====
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*They article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endo cells.
**As in, it generates a paptide that looks like a host peptide and thus starts an inflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sypathetic stimulation.
*Temperature decreases temperature HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:14:43 GMT

Admin: /* Myocardium */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atro-ventrical (AV) valves:
**Allow blood that has just come back from the body
**Have thin walls.
**Are open at rest.
**The tricuspid valve has three valves but the mitral valve has only two.
What is a miter?
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles.
**These do not pull the flap open, they only passively hold it open. Then they keep the valve from turning inside out when the chamber fills with blood.
*The pressure of the blood coming in closes the AV valve and opens the semilunar valve.

*The heart can tolerate some leaking.
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to them, we might start attacking host cells, too. Strep is one of these. If it goes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart (really, the heart? or some big vein?).
Yes, it is actually the atrium in which they dump.
*The coronary circulation is very extensive.
*The heart must have extensive blood flow.
*The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, you can use ATP reserves, you can switch to anarobic energy generation, you can use lactic acid or you can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, so you have to always give it oxygen.
*Ischemia = reduced blood flow.
*Hypoxia = low oxygen.
*Coronary atherosclerosis = buildup of plaque in heart.

====Coronary atherosclerosis====
*Coronary artery disease is a one of the leading cause of death in the US, by a lot.
*Deposition in coronary vessels leading to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't so contractive.
*Failing of the heart due to low blood supply.

=====Causes=====
*Hypertrophy of the endo cells.
*Cholesterol deposition
*Endo cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suck it out.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like tPA and streptokinase.
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is dang invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it, but only in 20% of the population!
*Inflammatory responses, perhaps cuased by infections.

=====Newsweek article: Cardiac Contagion=====
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*They article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endo cells.
**As in, it generates a paptide that looks like a host peptide and thus starts an inflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sypathetic stimulation.
*Temperature decreases temperature HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:13:03 GMT

Admin: /* Pericarditis */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is caused by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for the each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atro-ventrical (AV) valves:
**Allow blood that has just come back from the body
**Have thin walls.
**Are open at rest.
**The tricuspid valve has three valves but the mitral valve has only two.
What is a miter?
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles.
**These do not pull the flap open, they only passively hold it open. Then they keep the valve from turning inside out when the chamber fills with blood.
*The pressure of the blood coming in closes the AV valve and opens the semilunar valve.

*The heart can tolerate some leaking.
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to them, we might start attacking host cells, too. Strep is one of these. If it goes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart (really, the heart? or some big vein?).
Yes, it is actually the atrium in which they dump.
*The coronary circulation is very extensive.
*The heart must have extensive blood flow.
*The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, you can use ATP reserves, you can switch to anarobic energy generation, you can use lactic acid or you can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, so you have to always give it oxygen.
*Ischemia = reduced blood flow.
*Hypoxia = low oxygen.
*Coronary atherosclerosis = buildup of plaque in heart.

====Coronary atherosclerosis====
*Coronary artery disease is a one of the leading cause of death in the US, by a lot.
*Deposition in coronary vessels leading to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't so contractive.
*Failing of the heart due to low blood supply.

=====Causes=====
*Hypertrophy of the endo cells.
*Cholesterol deposition
*Endo cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suck it out.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like tPA and streptokinase.
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is dang invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it, but only in 20% of the population!
*Inflammatory responses, perhaps cuased by infections.

=====Newsweek article: Cardiac Contagion=====
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*They article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endo cells.
**As in, it generates a paptide that looks like a host peptide and thus starts an inflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sypathetic stimulation.
*Temperature decreases temperature HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Cardiovascular lecture notes

Admin — Sun, 07 Mar 2010 20:12:25 GMT

Admin: /* Gross anatomy of the heart */

*started here on 02/10/10.

==Cardiovascular: The heart==

===Diagram of heart===
*Today will be mostly anatomy.
*There are two pumps, the right heart (pulmonary circulation) and left heart (systemic circulation).
*O2 poor = blue, rich is red.
*Arteries carry blood away from the heart, veins carry it back.
**Be careful associating this to whether or not it is carrying oxygenated blood or not.

===Heart===
*Both sides have to pump the same amount b/c it is a closed system.
*They pump about 5 liters per minute.
*The two tracts are not equal in resistance because the pulmonary (less resistance) is shorter and simpler.
*The systemic circulation is much higher resistance with lots of branching.
*Coronary arteries are important for feeding the heart.

===Gross anatomy of the heart===
*The heart is surrounded by the pericardial sac.
**It surrounds, anchors, and protects.
**The pericardial sac is much like a balloon, only it is filled with fluid, not air.
**The sac is also attached to the major vessels.
**There are three layers to the pericardium:
***The outer layer is the fibrous layer which is what anchors the sac to the diaphragm and vessels.
***The next layer is the serous layer (two layers, because of a folding over) with fluid in between the two layers.
***Visceral layer of the serous layer is inner-most and fused to the heart.

====Pericarditis====
*Inflammation of the pericardial membrane, often from a bacterial infection.
*Diagnosis comes through cardiac tapenae. This is called by excess fluid build up.
*Problems:
**Initially, there is excess fluid buildup. This can usually be removed by direct needle aspiration because it will otherwise inhibit proper beating.
**Secondary problems include a decrease in the amount of fluid which generates more friction which leads to adhesions and thus inhibits heart activity.

====Myocardial tissue====

=====Myocardium=====
*Myocardium is composed of muscle cells built on a connective tissue network.
*The cardiac muscle cells are arranged such that they would have maximum efficiency at pumping blood.
*Intercalated discs allow for the each heart muscle to interdigitize with the next heart muscle cell.
**This is key for proper contraction.
**All along the intercalations are desomosomes and tight junctions that link the cells.
*Gap junctions allow for communication between cells.
**These allow ions to flow between cells for cell-cell communication.

=====Endocardium=====
*The endocardial layer lines the whole inside of the heart and is contiguous with the endothelial cells of the vessels.
*Ventricles do the major pumping.
*There are two sets of valves:
**Those that connect the atria to the ventricles.
**Those that connect the ventricles to the vessels.
**Note that the muscle layer of the left wall (the systemic pump) is bigger than the wall of the right wall (pulmonary pump).

=====Valves=====
*The valves open and close in response to pressure changes.
*They are made of a fibrous material (same as that which runs through the rest of the heart to give it structure).
*Atro-ventrical (AV) valves:
**Allow blood that has just come back from the body
**Have thin walls.
**Are open at rest.
**The tricuspid valve has three valves but the mitral valve has only two.
What is a miter?
*Semi-lunar (SL) valves:
**Are closed at rest. This makes sense because blood in the vessels have a back force that will close the semi-lunar valves.

===The mechanics===
*AV valves have long fibrous strings (chordae tendeneae) which are connected to the papillary muscles.
**These do not pull the flap open, they only passively hold it open. Then they keep the valve from turning inside out when the chamber fills with blood.
*The pressure of the blood coming in closes the AV valve and opens the semilunar valve.

*The heart can tolerate some leaking.
**Severe leaking is a problem because the heart has to keep pumping stronger or faster or both to maintain circulation which can lead to heart failure.

*Molecular mimicry:
**There are organisms that have epitopes that are very similar to self-epitopes. So when we generate an immune response to them, we might start attacking host cells, too. Strep is one of these. If it goes systemic it can generate rheumatic fever (damage to the heart valves) which is thought to occur because of molecular mimicry and the immune system attacking cells of the heart.

===Blood flow of the heart===
*There are two arteries coming off the aorta artery; these start the coronary circulation.
*Then there are veins that run back from the cardiac tissue and feed into the heart (really, the heart? or some big vein?).
Yes, it is actually the atrium in which they dump.
*The coronary circulation is very extensive.
*The heart must have extensive blood flow.
*The heart is 1/200th of the body's weight but it has 1/20th of the blood supply.
*Why do we need all this blood flow to the heart?
**If you start depleting blood flow from skeletal muscles, you can use ATP reserves, you can switch to anarobic energy generation, you can use lactic acid or you can just stop using it.
**You cannot switch to glycogen metabolism in the heart and it never stops beating, so you have to always give it oxygen.
*Ischemia = reduced blood flow.
*Hypoxia = low oxygen.
*Coronary atherosclerosis = buildup of plaque in heart.

====Coronary atherosclerosis====
*Coronary artery disease is a one of the leading cause of death in the US, by a lot.
*Deposition in coronary vessels leading to a lowering of cardiac blood circulation.
**Occlusion of the vessel deprives the heart of the oxygen.
**In a myocardial infarction, if mycardiocytes die, they are replaced with fibrous scar tissue which isn't so contractive.
*Failing of the heart due to low blood supply.

=====Causes=====
*Hypertrophy of the endo cells.
*Cholesterol deposition
*Endo cells separate and form gaps which causes platelet aggregation.

=====What can you do about it?=====
*You can do a balloon angioplasty to remove circulatory blockage.
**This is an older procedure, it can be an outpatient procedure.
**This pushes all the plaque out of the vessel.
**The problem still exists, however, because the plaque is still there.

*You can ablate plaque with lasers.

*You can pull it out with spinning knives and suck it out.
**This and the laser can damage the vessel, so be careful.

*Stents can be placed to hold the vessel open.
**There are many generations of these.
**There is a great need for these.
**These are now coated with things that inhibit clotting and platelet aggregation.
**We often treat with clot busters like tPA and streptokinase.
**Removal of the clot can generate emboli which can cause problems, too.

*If nothing else works, we have to do coronary bypass surgery.
**In this surgery, they replace the coronary vessels with vessels from another part of the body (usually from the leg).
**It is possible to use other vessels because the coronary flow is not a high pressure flow.
**It is dang invasive to get to and work on the heart.

=====What causes plaque formation?=====
*High cholesterol contributes to it, but only in 20% of the population!
*Inflammatory responses, perhaps cuased by infections.

=====Newsweek article: Cardiac Contagion=====
*There are several types of chlamidya, including respiratory.
*The only way to know if you have respiratory chlamidia is assaying for antibodies.
*They studied rabbits because they don't get CAD.
*They infected rabbits with respiratory disease and they got CAD.
*Clamidia survive in macrophages.
*They article suggests that while a macrophage is attacking the plaque formation, it transfers the chlamidia into the cells lining the vessel thus starting an inflammatory response.

=====Science articles=====
*They talk about the correlation of chlamidia and gum disease with CAD. It may be that this correlation is not causation.
*It could also be that chlamidia can start a molecular mimicry problem that attacks the endo cells.
**As in, it generates a paptide that looks like a host peptide and thus starts an inflammatory response.

===Properties of cardiac muscle fibers===
*Shorter and fatter than skeletal muscle.
*Anchored to fibrous network in myocardium.
*Do not function as individual units but as a functional syncytium.
*The ventricles form one functional syncytium, the atria form another.
*Remember that the coordination is generated from good cell-cell communication between the gap junctions and the interdigitation.
*Cardiac muscle is very rich in mt so that htey have a constant source of ATP.

===Electrical characterisitcs of the heart===
*The heart can beat with no intervation.
*If the heart is otherwise healthy, you can cut the nerves and heart will keep on beating.
*If you take it out of the body (and maintain the temperature) it will start beating faster. The innervation actually slows down the heart beat.
*Thus, when you take the heart out, you put it on ice. What? No!
*The stimulus for beating comes from the pacemaker cell.
*There are multiple cells that can do this, but the one that fires first wins. The others can take over if need be.
*These are found in the SA node.
*The autonomic nervous system feeds into the node to control the rhymicity of the cell.
*The parasympathetic system slows the heart rate whereas the sympathetic nervous system increases the heart rate.
*Normally the parasympathetic system dominates.
*First the electrical activity spreads over the atrium, then reconvenes at the AV node, then spreads down to the tip of the heart via the Purkinje fibers.

====Pacemaker cells====
*Action potentials in nerves happen really fast, much faster than in cardiac muscle.
*All cells have a spontaneous potential difference measured in volts. The outside of the cell is always greater in charge, so the inside is always negative.
*Each tissue type has different resting potentials. In pacemaker cells it is -40 volts (that is, -4o inside compared to outside).
*-40 is the threshold in pacemaker cells.
*After a potential, the potential drops below threshold and then starts leaking back toward threshold, then another action potential is fired.
*The '''depolarization drift''' comes from the flow of ions through the desmosomes.
*Upon reaching threshold, Ca++ channels (voltage sensitive) open up and Ca++ rushes into the pacemaker cells. This happens very quickly and drives the potential inside the pacemaker cell well into the positive range.
*Then repolarization is achieved through potassium channels which allow potassium to rush out of the cell driving the potential back to the negatives.
*How often this occurs determines how often the heart beats.
*Normal heart beat is about 70 bpm (3 billion action potentials in 70 years).

====Regulation of pacemaker activity====
*The autorythmicity is about 90-100.
*Neurotransmitters slow the heart rate (those from the parasympathetic system).
*These NTs cause an increase permiability to potassium which drives the refractory polarization to a lower (more negative) number and then it will take a longer time for enough Na+ to leak in to reach threshold.
*The sympathic system affects both the CA++ channels (makes them faster) and the repolarization.... we'll come back to it.

====Alternate pacemakers====
*If you lose all the cells in the SA node, the AV node can take over.
*You can survive without the atria working but you have to have the ventricles working.
*There are ventricle pacemakers that can take over if you lose the AV node, too, but they are pretty slow (30 bpm) so you're in trouble.
If the SA node is lost, do the atria still contract?
Our study group doesn't think so. Think back to the loss of the p wave.

*We'll finish the heart next week.

*stopped here on 02/10/10.
*started here on 02/15/10.

===Electrical activation of the heart===
*The action potentials that are generated at the SA node travel along the conduction system and excited the cardiac muscle fibers.
*The cardiac aps last hundreds of times longer than a typical nerve action potential.
*Contractile fibers have resting membrane potentials of about -90mV.
*In skeletal muscle, you can get tetanus by stimulating the muscle even at the height of the contraction.
*But in cardiac muscle, tetanus doesn't occur because you cannot restimulate during contraction because the refractory period lasts the entire time of the contraction period.

====The specifics of contraction====
*Three types of channels: sodium, then ...?
*There is a spike from -90 to +20, then a plateau, then a repolarization.
*Sodium is moving into the cells, calcium is moving in, and potassium is moving out.
*The sodium channel / movement is extremely rapid.
*The potassium channel closes almost simultaneously with the sodium channel.
*Long-qt syndrome, the first symptom is death. Stimulation of heart is arrested because of a sodium channel gain of function or a potassium channel loss of function.

====EKG or ECG====
*We're looking at the waves of electrical activity caused by all the firing.
*There are three waves: P, QRS, and T.
*We're not measuring contractions in the heart, we're measuring electrical activity.
*First the SA node fires, the potential is carried across the atria (the P wave), then to the AV node and down the bundle branches (some complex wave called the QRS wave), then the potential spreads up the ventricles (the QRS wave), and then relaxation of the ventricles (the T wave).
*When the P wave is larger (wider) than a standard, then the atrial muscle area is larger than normal.
**This is likely to be caused by a leaky mitral valve.
*An absent P wave can occur when the SA node has failed and the pace makers in the AV node have taken over.
*When the R wave is larger than normal, the ventricles are larger than normal.
**The primary cause of an enlarged R wave is hypertrophy because the ventricles are having to pump harder and are thus growing in size.
*A junctional rhythm marks the loss of the SA node. You can tell because the P wave is completely gone and there are fewer heart beats (because the AV node generates fewer beats per minute than the SA node).
*A heart block pattern is indicated by P waves not being conducted through the AV node.
**This will result in more P waves than QRS complexes.
**This indicates that the pacemakers aren't working and there is some blockage of the electrical signal from getting beyond the AV node.
*Ventricular fibrillation:
**Here the electrical activity makes no sense.
**This occurs because multiple pacemakers are firing.
**Often seen in MIs.

===Mechanical activity of the heart===
*Overview:
**Atria fill with blood via the veins.
**Blood begins to flow into the ventricles and this is completed by an atrial contraction.
**Ventricles contract forcing the AV valves to shut and the semilunar valves to open and expulsion of blood into the artery.
**Ventricles relax, pressure goes down and the semi-lunar valve closes preventing backflow of blood.
*When we talk about systole and diastole (contraction and relaxation) we are talking about ventricles.
*Find circular figure in book, go over it.
*Figure of ''everything''.

====Cardiac output====
*The cardiac output (CO) is a measure of the amount of blood pumped out of one side of the heart in one minute.
**Remember, however, that both ventricles have to pump the same volume of blood.
*CO = heart rate x stroke volumen
*Normal: 6000ml / minu = 75 beats / min x 80 ml / beat.
*This can be increased 3 fold upon need.
*Both heart rate and stroke volume are the function of several different parameters.

=====Stroke volume=====
*Remember that there is about 50ml left in the left ventricle at the end of the stroke.
*At rest, you pump out of the ventricle 60% of the blood that was in the ventricle at the end of relaxation.
*SV = end diastolic volume - end systolic volume.
*End systolic volume is the volume of blood left in the ventricle after the contraction.
*End diastolic volume is the amount of blood in the ventricle after diastole (relaxation).
*Frank-Starling law of the heart:
**There is a proportional relationship between the diastolic volume of the heart and the stroke volume."
**That is, the heart will pump whatever it receives within limits.

*Preload:
**Myocytes are set up such that they can always pump whatever they get.
**They are normally sitting relaxed at a length shorter than their optimal contraction length, such that when you add more blood, they are stretched '''toward''' their optimal contraction position.
**So, a healthy heart can pump all that it is given (within normal bounds).
**Things that can increase preload:
***The speed of the venus return can increase cardiact output.
***An increase blood volume.
***Increase in heart rate.
***Cellular hypertrophy: each cardiomyocyte generates more contractile proteins when there is extra strain on the cells. Note that myocytes do not divide!
****Occurs in athletes, when there are blockages, and when you have heart defects like a messed up valve.

*End systolic volume (contractility):
**Can be increased by more sympathetic stimulation.
***Epi, norepi: these increase calcium entry into cells which allow for increased cross-bridge formation and thus generate more contractility.
**Can be increased through chemicals and hormones.
***Glucagon and thyroxine increase contractility over a very long time period.
***Acidosis, increased extracellular K+, and calcium channel blockers can all decrease contractility of the heart.
****Calcium channel blockers are used to decrease blood pressure.
**Parasympathetic can decrease contractility and heart rate.
***Acetylcholine decreases contractility by increase parasympathetic signaling.

*Afterload
**This is the pressure against which the ventricles must push to open the semilunar valves and to push 60% of the blood volume into the aorta.
**This can be affected by hypertension, blood volume, and blockages in the vessels.

====Neural regulation of heart rate====
*The cardiac center of the medulla oblongata receives input from several parts and yields output to the heart which can increase or decrease the heart rate.
*The inputs:
**The higher brain centers: getting upset, etc.
**The sensory receptors: proprioceptors, chemoreceptors (oxygen detectors, especially), and baroreceptors.
***Baroreceptors monitor blood pressure. Baroreceptors become resistant to low pressure signals, however, over time
*The outputs:
**The spontaneous depolarization at the SA and AV node can be increased or decreased.
**You can have increased contractility which will increase stroke volume.

*Both contractility and heart rate have to be increased at the same time or you'll have a back up in the circuit.
*At rest, the parasympathetic system is the most important because it brings the heart rate down.
*Effect of NTs on pacemaker cells:
**Parasympathetic: makes cells more permeable to K+ which increases hyperpolarization.
**Sympathetic: opens Ca++ channels which increases the Ca++ and reduces repolarization. This means that it is easier to reach threshold.

===Hormones===
*Epinepherine and thyroxine increase heart rate and contractility.
*Epinepherine as a hormone:
**Causes vasodilation of skeletal muscle, so that you can run away from the bad guy!
**Causes vasoconstriction in internal organs and skin, which shunts blood to the heart and brain and skeletal muscles.
**Causes increased glycogenolysis in liver and muscle, which generates more energy sources for the brain and heart.
**Causes increased lypolysis in adipose tissue.

*Thyroxine
**Effects are slow; work on a weekly or monthly period.
**Over a long period of time can increase heart rate.
**Increases metabolism and body temperature.
**Increase oxygenation of blood by increasing breathing rate and RBC production.
**Increases lipid turnover to liberate lipids which can be converted to energy.
**Increases protein synthesis.
**Stimulates GH secretion.

===Heart rate, physical changes===
*Age
**Fetal is much higher.
*Gender (25 yos with ideal weight):
**Women faster than men, fetus much faster than women.
*Exercise increases HR b/c of sypathetic stimulation.
*Temperature decreases temperature HR by slowing rate of depolarization of pacemaker cells.

===Cardiac output and energy consumption===
*We want the heart to use as little energy (oxygen consumption) as possible to pump blood.

*stopped here on 02/15/10.
*started here on 02/17/10.

*Read through the CF papers on our own because she'll be talking about the ethics.
**They are long, skip the methods and the histology.
**You really need to read the introduction and the discussion, and have a look at the results.

===Heart - diseases and treatments===

====Terms====
*Tachycardia is a fast heart rate, over 100 beats per minute.
**Above 170, it is hard for the heart to fill between beats.
*Bradycardia: slow heart rate, lower than 60 beats / minute.
*Congestive heart failure is the inability to generate a normal cardiac output.
**Most common is left side failure.
**Causes include MI (with damage), hypertension,

====Congestive heart failure====
*Adema often arises.
*Pulmonary congestion occurs if the left side fails because there is a backup in the lungs.

====MI====
*1.5 million in US.
*1/3 die immediately, of those that do survive, 1/2 die within a year.
*If patient survives initial lack of oxygen, the risk of reperfusion injury is high.
**This is not confined to heart, can also occur with kidney diseases.
**When blood is limited for a bit of time and then it flows back in, an inflammatory response is raised.
**Lymphocytes and other inflammatory cells are attracted to the area.
**Cytokines and other chemicals are released.
**The chemicals are cytotoxic (particularly in the heart) and therefore cause further tissue damage.
**Cardiac contractility is depressed.

====Treatments for heart problems====
*Ventricular defibrillators
*Pacemakers
*Nitroglycerine - vasodilator of coronary vessels.
*Cholesterol lower agents
*Beta blockers - block sympathetic nervous system - slow HR and force of contraction.
*Ca+ channel blockers - mainly on vessels, reduces resistance by opening vessels
*ACE inhibitors - reduce cardiac afterload
*Diuretics - remove excess water
*Digitalis (a drug) - slows HR, conserves energy.
**Used as a poison in the old days.

=====Ventricular defibrillators=====
*Devices which shock the heart in case of ventricular fibrillation.
*Used if likely that damaged heart will go into uncontrolled electrical activity.
*Shock the hear tot stTop all electrical activity to it can "reset".
*First used in the 80s.
*Early defibrillators couldn't distinguish between arrhythmia from a rapid heartbeat coming from exercise.
*Current versions are much smaller.

====Heart failure====
*100k people in heart failure each year.
*2.2k donor hearts.
*Shortage.

=====Article: New directions in cardiac transplantation=====
*Summary of > 30 years of clinical practical and some of the new directions that are contributing to ...
*Read the first half of the article.
*They studied the mortality in the 90 days post-op and showed that transplants mortality rates are decreasing.
*They also addressed who are good candidates for hearts:
**In the first two decades of heart transplants we didn't consider people with high age, diabetes, kidney or liver disease, HIV, or hepatitis.
*Ethical issues:
**Who should get the heart and who shouldn't? Age, weight?
**Should incurable illnesses be transplanted?
**Should elderly patients get young hearts because it will likely outlast the recipient.
*Interesting scientific notes:
**Introduced the idea of using a ventricular assist device, which has increased survival both by keeping the patient alive until a donor is found and aiding in survival after transplantation.
**In infants, you don't have to match the ABO blood groups because they have low levels of anti-A and anti-B antibodies. They also have an incompetent complement system.

====Artificial hearts====
*An early approach cut away some of the skeletal muscle and put in a pacemaker cell. But skeletal muscle is not meant to be flexed over and over.
*In 1982, Jarvik made the first artificial heart.
**It was attached to the atria and there was basically just ventricular.
**Barney Clark was the first patient. He was a dentist. He lived 112 days.
**Another patient lived 2 years, in a hospital room hooked up to a loud machine.
**Problems included blood clots and infections.
**This was actually banned in 1990.

====The next generation of artificial hearts====
*Now we use left ventricle assist device.
**80% of heart failures are in the LV, hence it assists the LV.
*These are connected to the bottom of the ventricle and pump the blood up into the aorta.
*The grapefruit sized machine is anchored just below the diaphragm.
*Now there is lots of external stuff.
*There is still a risk of infection.
*Blood clotting is controlled by using pig tissues instead of artificial tissues.
*Biggest problem with the HeartMate is the size.
*So the next, next generation has a 10K rpm rotor that pushes blood into the aorta constantly.
**But with this, you have damage to blood cells and vessels and therefore clotting.
**This will generate no beat and we thought this would be an issue but it isn't.
**The internal / external interface is still a problem for infections and such. We're working on electrical field transfer of power.
**One pt. has made a transatlantic trip and lived 2 years.

**In January of 2010, the HeartMate II was approved for long-term treatment of heart failure.
**It is a rotor pump.
**< 1 lb.
**1.5 x 2.5 inches, so it can be used on children.

====Theoretical combination therapy====
*Assist devices along with other therapies.
**Sometimes the heart can repair itself to the point that the LVAD can be removed.
*Other therapies may include:
**Beta agonists like clenbuterol which would cause the cardiac cells to hypertrophy (through increases stimulation by the sympathetic system).
**Agents that stimulate coronary vessel re-growth.
*The goal is to allow the heart to repair itself.

====Space aged vision====
*The whole thing weighs two pounds and is completely self contained.
*Blood clots are still an issue.
*Powered through a transcutaneous energy transmission system.
*First recipient lived for 5 months and died of a stroke.

====Indianapolis Star, 2004====
*This is about a totally artificial heart.
*FDA approved artificial hearts as a temporary measure for heart failure patients.
*Some patients have serious bleeding problems and 22% had infections.

*moved on to [[Circulatory lectures]] on 02/17/10.

Couzin's "As Gelsinger Case Ends,Gene Therapy Suffers Another Blow" 2005

Admin — Sun, 07 Mar 2010 19:55:34 GMT

Admin:

===Introduction===
*18 year old (Gelsinger) died in a gene therapy experiment
*In another trial for gene therapy a child developed leukemia from severe combined immunodeficiency (X-SCID)
**However 17 children have been succesfuuly treated for SCID using gene therapy
**Speculated that cells with the oncogene insertion proliferated more readily in young children (causing leukemia)

Vogel's "FDA Moves against Penn Scientist" 2000

Admin — Sun, 07 Mar 2010 19:54:33 GMT

Admin:

*The FDA has started proceedings that will end in a ruling as to whether Dr. James Wilson will be able to continue clinical trials of gene therapy.
*Wilson lead the University of Pennsylvania's clinical trial on gene therapy in which 18 year old [http://en.wikipedia.org/wiki/Jesse_Gelsinger Jesse Gelsinger] died after treatment.
*The FDA's harshest penalty for a researcher is that of '''disqualification''' which bars them from receiving drugs for administration to patients--effectively arresting their ability to perform clinical trials.
*The FDA sent letters two Wilson and two collaborators (Raper of Penn and Batshaw of the Children's National Medical Center) that listed the claims being brought against them, which include:
**"repeatedly or deliberately violating regulations governing the proper conduct of clinical trials",
**enrolling ineligible patients in the trial,
**not halting the trial upon evidence of severe side effects,
**not informing participants that a similar drug had severely sickened monkeys.
*Wilson has 30 days to respond to the letter from the FDA, at which point they will review his response and make a final decision on his disqualification.
*One quoted researcher says this is a drastic step while another says that harsh and critical regulation by the FDA will ultimately strengthen gene therapy research.
*In class, we learned about [[Cystic fibrosis lectures#Jesse_Gelsinger_case| the outcome]].

Rosenberg's "Gene Therapist, Heal Thyself" 2000

Admin — Sun, 07 Mar 2010 19:50:33 GMT

Admin:

*As a giant physician in medicine once reminded his students, "if what you're doing isn't working, try something else."
*And so it is with gene therapy; '''over a decade of promise and clinical trials has not resulted in a single unequivocal case of therapeutic efficacy by the year 2000'''.
*The authors express their concern over repeated promises of a "golden age" of gene therapy even in the light of the [http://en.wikipedia.org/wiki/Gene_therapy#Problems_and_ethics Gelsinger tradgedy]--the death of a gene therapy patient.
*It is improper for scientists to insert themselves into the "culture and discord" of the field (that is, the politics, the rhetoric) because it can lead to improper decisions that are bad for patients, for science, and for society.
*The authors even go so far as to compare scientists who "insert themselves into the culture and discord" to viruses!
*Bone marrow transplants and chemotherapies for cancers have become important therapeutics and their development came at the price of some lives, too.
**However, the scientists who developed these therapeutics maintained wide support of their science by '''promising little and delivering much--the opposite of gene therapy, thus far'''.
*We must have self-critical scientists to run these studies.
**They must be scientists who will ask of themselves whether they or their family members would join their study.
**They must honestly asses the benefit-to-cost ratio.
**They must attend to good communication with study participants, proper timeliness, proper safety, honest assessment of result legitimacy, and proper discussion / disclosure of untoward results.
***Untoward: "unfavourable, adverse, or disadvantageous; Unruly, troublesome; Unseemly, improper" [http://en.wiktionary.org/wiki/untoward ref]
**The authors call the members of the [http://www.asgt.org/ American Society for Gene Therapy] to "pledge themselves to sound, disciplined science in the public interest and eschew uncritical winner-take-all gambles."
*The authors call for higher legislation of conflict-of-interest issues which seem to be common in gene-therapy trials.
**They mention both personal conflict-of-interest (i.e. an investigator has stock in a company that is helping to fund their clinical trial) and institutional conflict-of-interest (i.e. a university is invested in a company that is running clinical trials through investigators at the university).
*Perhaps, if gene therapy scientists heed the old dictum (think "if what you're doing isn't working, try something else"), we can bring gene therapy to fruition and save some lives.

Marshall's "Gene Therapy on Trial" 2000

Admin — Sun, 07 Mar 2010 19:44:10 GMT

Admin:

*Dusty Miller wants to find gene therapy for CF after death of Penn volunteer
**says we lack a good vector
**There is a general fear that nobody will do gene therapy reseach for a while because of the "crackdown" and recent negative media coverage
*FDA cracking down hard on gene therapy trials
**shut down all trials at Penn after death
**warning letter to St. Elizabeth Medical Center in Boston
*Two lessons learned by Penn accident:
**every vector has it’s limits
**the nature of human clinical trials is dangerous

'''Design By Committee'''
*Penn’s Insitute for Bioethics defends trial by saying "they had the best intentions"
*Jesse Gelsinger had an [http://en.wikipedia.com/Ornithine_transcarbamylase_deficiency enzyme deficiency]
**occurs when the X chromosome is missing or defective, producing to little of the liver enzyme OTC (ornithine transcarbamylase)
**OTC is needed to remove ammonia from the blood
**Most people die in infancy but if kept to a strict diet, can live a normal life.
*Purpose of the study was to use the adenovirus vector to inject OTC into Jesse’s liver.
*Adenovirus Vector Pros:
**it was the only one that worked “rapidly enough”
**most vectors take 3-6 weeks, adenovirus starts to work in 24 hours.
*Adenovirus Vector Cons:
**gene expression with this vector has a limited duration
**could possibly lead to need for liver transplat
*Initial patients would have almost no chance of benefitting:
**vector can only be given once
**patients develop an immune response to the vector

'''A meeting of experts decided to use adults rather than children'''
*"it’s wrong to do non-therapeutic research on someone who can’t consent."
*Toxicity trial in primates gave a level of toxicity they thought was comparable to humans
*Their plan was to start with a dose that was 5% of what caused maximum toxicity in primates
**5 three-fold increases after the initial 5% does
**FDA agreed and gave them the "green light" in 1997
*17 patients were injected this way, all experienced minor symptoms but nothing severe.
*Gelsinger was the 18th patient.

'''Surprising Toxicity'''
*Trying to figure out why Gelsinger’s toxicity was so much more severe than other patients
*his RBC precursors had been wiped out in his bone marrow
*concluded it was due to a pre-existing parvovirus
*also had high IL-6 which contributes to inflammation
**1993 California gene therapy study showed a similar immune response when adenovirus was injected into CF patients.
**1995 study in North Carolina also showed inflammation in CF patients using adenovirus because the vector stimulated nerve fibers in the epithelium causing an inflammatory response.
***said it was a capsid protein problem
***caused by the outer shell of the vector
*reached the target cells very late in the process
**Coxsackie adenovirus receptor (CAR): is much more prevalent in mouse livers
**CAR is needed for uptake of vector.

'''A Mortal Blow for Adenovirus:'''
*want to try and engineer the vector to not be so dangerous.
*high doses will always be necessary

Main Page

Admin — Sun, 07 Mar 2010 19:37:34 GMT

Admin: /* Reading notes */

==Exam 2==
===Reading notes===
*[[Williams' "Cystic Fibrosis: A disease caused by a single defect in salt-transporting epithelial cells" 1992]]
*[[Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993]]
*[[Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994]]
*[[Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999]]
*[[Marshall's "Gene Therapy on Trial" 2000]]
*[[Rosenberg's "Gene Therapist, Heal Thyself" 2000]]
*[[Vogel's "FDA Moves against Penn Scientist" 2000]]
*[[Couzin's "As Gelsinger Case Ends,Gene Therapy Suffers Another Blow" 2005]]
*[[Kaiser's "Death Prompts a Review of Gene Therapy Vector" 2010]]
*[[Chapter 20]]

===Lecture notes===
*[[Cystic fibrosis lectures]]
*[[Respiration lectures]]
*[[Circulatory lectures]]
*[[Cardiovascular lectures]]

==Exam 1==
===Blood===
*[[Chapter 19 notes]]
*[[Blood lecture notes]]
*[[Gareau's "Erythropoietin abuse in athletes"]]
*[[Eaton's "The biophysics of sickle cell hydroxyurea therapy"]]
*[[Geddis's "The root of platelet production"]]
*[[Marshall's "Clinical promise, ethical quandry" 1996]]
*[[Brunstein's "Umbilical cord blood transplantation and banking" 2006]]
*[[Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)"]]
*[[Delude's "Clot Busters!! - Discovery of thrombolytic therapy for heart attack and stroke" (2004)]]
*[[Lee's "The Tangled Webs That Neutrophils Weave" (2004)]]
*[[Walzog's "Adhesion molecules: the path to a new understanding of acute inflammation" (2000)]]

===Lymphatic / Immune===
*[[Chapter 22 notes]]
*[[Leslie's "Mast cells show their might" 2010]]
*[[Leslie's "Fetal immune system husches attack on maternal cells" 2010]]
*[[Leslie's "Internal affairs" 2010]]
*[[Ganz's "Versatile Defensins" 2002]]
*[[Wickelgren's "Can worms tame the immune system?" 2004]]
*[[Couzin's "Wanted: pig transplants that work" 2002]]
*[[Alexander's "Chimerism and tolerance in a recipient of a deceased-donor liver transplant" 2008]]

Marchall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999

Admin — Sun, 07 Mar 2010 19:37:22 GMT

Admin: moved Marchall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999 to Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999: Spelled the author's name incorrectly.

#REDIRECT [[Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999]]

Marshall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999

Admin — Sun, 07 Mar 2010 19:37:22 GMT

'''University of Pennsylvania’s Institute for Human Gene Therapy'''
*18 year old (Jesse Gelsinger) participating in gene therapy study for an unspecified enzyme deficiency
*died 4 days after injection of a genetically altered virus into his liver
*first patient to die in the study
*highlighted a central problem: the difficulty of transferring genes to human cells and getting them expressed

'''Meeting with NIH'''
*Chief of Penn’s clincical team (James Wilson) appeared at a special meeting called by the NIH to discuss what went wrong in the case.
**Penn team admitted they weren’t sure.

'''Details about Gelsinger’s Treatment'''
*injected vector: a crippled from of adenovirus combined with a gene to control Gelsinger’s ammonia metabolism.
*he was given the highest dose of anyone in the trial
*invaded the target (liver) but also other unintended organs
**For completeness: liver, spleen, lung, thyroid, heart, kidney, testicles, brain, pancreas, lymph nodes, bone marrow, bladder, small intestine, muscle, skin.
*this activated an innate immune response and a systemic inflammatory response.
**death due to lungs filling with fluid, could not oxygenate blood properly.
*only 1% of transferred genes were taken up by target cells.
**animal studies have shown to be much more effective
**not sure why transfer isn’t as efficient in humans

'''New findings about patient'''
*Gelsinger’s bone marrow was severely depleted of erythroid precursor blood cells
**This suggested an undetected genetic condition or parvovirus
**'''''the only patients who have ever had a similar immune response to this therapy were patients with CF, although they did not make any mention of Gelsinger having CF'''''

The article concluded with comments about the FDA suggesting that NIH improve monitoring of gene therapy.

Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994

Admin — Sun, 07 Mar 2010 19:30:13 GMT

Admin: /* Introduction */

===Abstract===
*They administered a recombinant adenovirus vector (AdCFTR) containing the normal human CFTR cDNA into the nasal and bronchial epithelium of 4 individuals with CF.
*They found the vector expresses the CFTR cDNA in the respiratory epithelium in vivo.
*At 2x109 pfu there was no recombination, complementation, shedding of the vector, or rise in antibody titres. Although, there was a transient and systemic pulmonary syndrome observed (possibly mediated by IL-6)
*They saw no long term effects

===Introduction===
*CF is a common lethal hereditary disorder caused by a mutation on CFTR on chromosome 7
*The disorder is characterized by airway and gastrointestinal disease, the lung manifestations dominate
*The pathogenesis is clearly linked to the lack of CFTR in the respiratory epithelia
*Symptoms in first decade:
**Thick mucus, colonization with infectious bacteria, and chronic airway inflammation
*One approach to prevent respiratory manifestations of CFTR is gene therapy (talked about in abstract)
*Gene therapy must be carried out ''in vivo'', cannot be done ''ex vivo''

====I also decided to add in the notes I took in class just for completeness====
*One of the four human gene therapy trials approved and initiated at the same time
*Based on the results of this trial, the others were halted
*Used CF patients who were in remarkably good health
*Did multiple dosing to find effecting concentration

====Results in the human study:====
*Treatment evoked an immune response
*Inflammation accompanied the immune response
*Results are short lived-- at most 6 weeks
*Because of the immune response, will not be able to do multiple dosing
*Very inefficient transfer of gene of interest-- will do nothing to correct the defect
*"Correction of the CF phenotype of the airway epithelium might be achieved with this strategy"
*"To maintain chronic expression, adenovirus vectors will probably have to be administered repeatedly"
**This is not possible with an immune response

Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994

Admin — Sun, 07 Mar 2010 19:23:13 GMT

Admin: /* Abstract */

===Abstract===
*They administered a recombinant adenovirus vector (AdCFTR) containing the normal human CFTR cDNA into the nasal and bronchial epithelium of 4 individuals with CF.
*They found the vector expresses the CFTR cDNA in the respiratory epithelium in vivo.
*At 2x109 pfu there was no recombination, complementation, shedding of the vector, or rise in antibody titres. Although, there was a transient and systemic pulmonary syndrome observed (possibly mediated by IL-6)
*They saw no long term effects

===Introduction===
* CF is a common lethal hereditary disorder caused by a mutation on CFTR on chromosome 7
* The disorder is characterized by airway and gastrointestinal disease, the lung manifestations dominate
* The pathogenesis is clearly linked to the lack of CFTR in the respiratory epithelia
* Symptoms in first decade:
** Thick mucus, colonization with infectious bacteria, and chronic airway inflammation
* One approach to prevent respiratory manifestations of CFTR is gene therapy (talked about in abstract)
* Gene therapy must be carried out in vivo, cannot be done ex vitro

====I also decided to add in the notes I took in class just for completeness====
* One of the four human gene therapy trials approved and initiated at the same time
* Based on the results of this trial, the others were halted
* Used CF patients who were in remarkably good health
* Did multiple dosing to find effecting concentration

====Results in the human study:====
* Treatment evoked an immune response
* Inflammation accompanied the immune response
* Results are short lived- at most 6 weeks
* Because of the immune response, will not be able to do multiple dosing
* Very inefficient transfer of gene of interest- will do nothing to correct the defect
* "Correction of the CF phenotype of the airway epithelium might be achieved with this strategy"
* "To maintain chronic expression, adenovirus vectors will probably have to be administered repeatedly"
** This is not possible with an immune response

Main Page

Admin — Sun, 07 Mar 2010 19:21:46 GMT

Admin: /* Reading notes */

==Exam 2==
===Reading notes===
*[[Williams' "Cystic Fibrosis: A disease caused by a single defect in salt-transporting epithelial cells" 1992]]
*[[Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993]]
*[[Crystal's "Administration of an adenovirus containing the human CFTR cDNA to the respiratory tract of individuals with cystic fibrosis" 1994]]
*[[Marchall's "Gene Therapy Death Prompts Review of Adenovirus Vector" 1999]]
*[[Marshall's "Gene Therapy on Trial" 2000]]
*[[Rosenberg's "Gene Therapist, Heal Thyself" 2000]]
*[[Vogel's "FDA Moves against Penn Scientist" 2000]]
*[[Couzin's "As Gelsinger Case Ends,Gene Therapy Suffers Another Blow" 2005]]
*[[Kaiser's "Death Prompts a Review of Gene Therapy Vector" 2010]]
*[[Chapter 20]]

===Lecture notes===
*[[Cystic fibrosis lectures]]
*[[Respiration lectures]]
*[[Circulatory lectures]]
*[[Cardiovascular lectures]]

==Exam 1==
===Blood===
*[[Chapter 19 notes]]
*[[Blood lecture notes]]
*[[Gareau's "Erythropoietin abuse in athletes"]]
*[[Eaton's "The biophysics of sickle cell hydroxyurea therapy"]]
*[[Geddis's "The root of platelet production"]]
*[[Marshall's "Clinical promise, ethical quandry" 1996]]
*[[Brunstein's "Umbilical cord blood transplantation and banking" 2006]]
*[[Kvietys' "Neutrophil diapedesis: paracellular or transcellular? (2001)"]]
*[[Delude's "Clot Busters!! - Discovery of thrombolytic therapy for heart attack and stroke" (2004)]]
*[[Lee's "The Tangled Webs That Neutrophils Weave" (2004)]]
*[[Walzog's "Adhesion molecules: the path to a new understanding of acute inflammation" (2000)]]

===Lymphatic / Immune===
*[[Chapter 22 notes]]
*[[Leslie's "Mast cells show their might" 2010]]
*[[Leslie's "Fetal immune system husches attack on maternal cells" 2010]]
*[[Leslie's "Internal affairs" 2010]]
*[[Ganz's "Versatile Defensins" 2002]]
*[[Wickelgren's "Can worms tame the immune system?" 2004]]
*[[Couzin's "Wanted: pig transplants that work" 2002]]
*[[Alexander's "Chimerism and tolerance in a recipient of a deceased-donor liver transplant" 2008]]

Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993

Admin — Sun, 07 Mar 2010 19:19:31 GMT

Admin:

===Abstract===
*Prepared a pre-clinical study of gene transfer into the lungs of baboons.
**Recombinant adenovirus vectors containing expression cassettes for human cystic fibrosis transmembrane conductance regulator (CFTR) and Escherichia coli ~-galactosidase (lacZ) were instilled through a bronchoscope into limited regions of lung in 14 baboons
*Results of toxicity studies were found using clinical laboratory tests, chest radiographs, and necropsy tests were used
**These were used to detect adverse effects
*** The only adverse effect noted was a mononuclear cell inflammatory response within the alveolar compartment of animals receiving doses of virus that were required to induce detectable gene expression.
**Minimal inflammation was seen and 107 and 108 pfu (plaque forming units) per ml (infectious units per volume) but perivascular lymphocytic and histocytic infiltrate was seen at 109 and 1010 pfu.
***Intensity of inflammation increased between 4 and 21 days
**** At its greatest intensity, there was diffuse alveolar wall damage with intra-alveolar edema (the airways were relatively spared)
**Chest radiographs revealed alveolar infiltrates, but only in regions of lung having the greatest intensity inflammation
* Concluded that adenovirus-mediated gene transfer into the lungs of baboons is associated with development of alveolar inflammation at high doses of virus

===Introduction===
*Adenovirus-base vectors have certain properties that make them attractive vehicles for human gene therapy
**Ability to transfer genetic material efficiently into lung epithelial cells
***Led them to be chosen for the first trials for human gene therapy for cystic fibrosis
*Success of trial will be determined by the level and duration of transgene expression and safety
**Performed studies on baboons in order to prepare for human trial

Simon's "Adenovirus-Mediated Transfer of the CFfR Gene to Lung of non-human primates: toxicity study" 1993

Admin — Sun, 07 Mar 2010 19:11:22 GMT

Admin: moved Simon's "Adenovirus-Mediated Transfer of the CFfR Gene to Lung of non-human primates: toxicity study" 1993 to Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993: Misspelled the gene in the title.

#REDIRECT [[Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993]]

Simon's "Adenovirus-Mediated Transfer of the CFTR Gene to Lung of non-human primates: toxicity study" 1993

Admin — Sun, 07 Mar 2010 19:11:22 GMT

===Abstract===
*Prepared a pre-clinical study of gene transfer into the lungs of baboons.
**Recombinant adenovirus vectors containing expression cassettes for human cystic fibrosis transmembrane conductance regulator (CFTR) and Escherichia coli ~-galactosidase (lacZ) were instilled through a bronchoscope into limited regions of lung in 14 baboons
*Results of toxicity studies were found using clinical laboratory tests, chest radiographs, and necropsy tests were used
**These were used to detect adverse effects
*** The only adverse effect noted was a mononuclear cell inflammatory response within the alveolar compartment of animals receiving doses of virus that were required to induce detectable gene expression.
**Minimal inflammation was seen and 107 and 108 pfu (plaque forming units) per ml (infectious units per volume) but perivascular lymphocytic and histocytic infiltrate was seen at 109 and 1010
***Intensity of inflammation increased between 4 and 21 days
**** At its greatest intensity, there was diffuse alveolar wall damage with intra-alveolar edema (the airways were relatively spared)
**Chest radiographs revealed alveolar infiltrates, but only in regions of lung having the greatest intensity inflammation
* Concluded that adenovirus-mediated gene transfer into the lungs of baboons is associated with development of alveolar inflammation at high doses of virus

===Introduction===
*Adenovirus-base vectors have certain properties that make them attractive vehicles for human gene therapy
**Ability to transfer genetic material efficiently into lung epithelial cells
***Led them to be chosen for the first trials for human gene therapy for cystic fibrosis
*Success of trial will be determined by the level and duration of transgene expression and safety
**Performed studies on baboons in order to prepare for human trial

Respiration lecture notes

Admin — Wed, 03 Mar 2010 21:39:34 GMT

Admin:

*started here on 02/24/10.

==Respiration==
*Respiration requires some stuff:
**We'll talk about convection system (that is, ventilation and cirulation).
**We'll also talk about mechanisms for gas transport int he blood.

===Respiratory functions===
*We're going to talk about ventilation in general and which muscles of the chest wall are used.
*We'll tlak about negative pressure that pulls the air into the lungs.
*We're going to think about ...

===More requirements for respiration===
*We have to have a way for the air to flow. Ventilation perfusion coupling.
**We'll look at some problems of this, too.
*We'll look at the CNS's involvement in respiration and circulation.
*Oxygen level is important, but CO2 is the primary regulator of respiration.

===Non-respiratory functions===

====Filter and moisten air====

====Facilitate olfaction by transporting airborne molecules====

====Defense against airborne pathogens - mucocilliary elevator====

====Sound production====

====Trap small emboli in pulmonary circulation where they are dissolved====

====Blood reservoir for left ventricle====
*Lungs contain 500 ml of blood.
*Two beats can be supplied if pulmonary artery is clamped.

====Biochemical reactions====
*ACE converts angiotensin I to antiotensin II.
*Some prostaglandins are removed at the lungs.

===Organization of the respiratory system===
*Can be divided into upper (down to the pharynx) and lower (everything lower).
*We could also look at the system in terms of function instead of structure.
**The transition of function (from conducting zone to respiratory zone) occurs when alveoli start to occur.
*The tubes branch significantly. There are about 16 divisions before there are any alveoli.
*There is also a change in type of cells found.
**We transition from columnar at the top to squamous at the bottom.
**We see a change from more to less (going down) of goblet cells because of the elevator.
**We see a decrease in cartilage because we have less and less structure.
**Elasticity goes the entire length. They are important for recoil in the chest wall and the alveoli.

====The mucocilliary elevator====
*Goblet cells are releasing mucus on surface.
*Cillia are beating upward.
*As we get to the lower region, the size of pathogens is important because the smaller they are the deeper they can get and the better they can get across the endothelial cells when they land.

====Nose====
*The air enters through the external nairs.
*There is mucus secretion and tears coming through ducts, these help to trap crap.
*Air passes through conchae around the turbanates (an outcropping of bone). This generates turbulance to facilitate smell and moistening.
*We have sinuses (four of them) which connect to the nose through the medemus (?).
**When this connection is blocked, pressure can build up.

====Palate====
*Separates nose to mouse.
*Hard and soft palate.
*Cleft can occur which is bad. Usually happens where bones come together in top of mouth.
**Can happen in hard or soft palate or both.

====Nasopharynx====
*This is in common with digestive and respiration tracts.
*There are three regions but we won't dwell on them.
*Nasal connection is called the internal nares.
**This is the location of the adenoid.
**This is also where the opening to the ear occurs and it is important for good sound conductance and balance.

====Oropharynx and laryngopharynx====

====Larynx functions====
*This structure is trying to keep the airway open.
*Behind it is the esophagus.
*Epiglottis sits on the top with some cartilage that allows the epiglottis to cover the glottis (a slit-like opening).
*The vocal cords are on either side of the glottis.
*There is upward movement that helps to close off the glottis.

====Anatomy of larynx====
*The thyroid cartilage forms the adams apple.

====Tracheal cartilages====
*Begins at the base of the larynx.
*You can feel the cartilage rings with connective tissue in between.
*The rings are c shaped with the open part in the back.
*There is a muscle and a ligament on the back which are responsible for changing the diameter to change resistance.
*The esophagus is posterior to the trachea.

====Primary bronchi====
*Our first bifurcation occurs.
*The right and left are not equal.
*The angle of division are not equal.
*The right has a short bronchial tube and left has a straighter angle.
*This is a problem when kids breath something. Most likely it is in the right bronchial tube because the angle isn't as great.
*At the bifurction, the cartilage extends into the airway a little (think shelf).
**This is covered by endothelium and is very sensitive.
**This causes the coughing when you inhale something.

====Hilus====
*The hilus is the midline of the lung (theres one on the kidneys, too).
*This is the location where the major structures enter the organ (think veins, lymphatics, bronchii).
*The whole thing is held together by a mesh-work of connective tissue.

====Lungs====
*The right lobe is larger than left because the heart is taking up space on left side.
*You can see the fissure that helps separate the middle lobes from the upper lobes.
**Note that on the left there are only two lobes.
**Right has a middle lobe.

====Lung lobes====
*The lobes are divided into segments.
*The segments are able to be isolated by surrounding connective tissue.
**They can be removed for something like lung cancer or what-not.
*The reason for these sections is that the the lymphatics, respiratory, and circulation all branch together such that all the sections separate systems.

====Lobules====
*Sections can be divided.
*Can be the size of a penny to an eraser.
*Respiration occurs at the level of the alveoli which are at the base of the lobules.
*Artery, vein, and lymphatics all supply each lobule and each alveoli.

===Smooth muscle control===
*The cartilage is gone, recall, so we rely on the muscle to keep the airway open.
*Therefore we can change the dilation.
*The sympathetic will open airways to reduce resistance and the parasympathetic will do the opposite.
*Histamine will also restrict to increase resistance.
*This is all further compounded by the fact that we need airpressure from the outside to help hold it open.

===Alveolar organization===
*There are capillaries that pass through avleolar, which means that we can get oxygen from either capillary.
*There are several cell types at this point: type 1 cells and type 2 cells.
**Type 1 are long and thin, these do gas exchange.
**Type 2 are important for generating surfactant.
*There are also macrophages in this space to help with protection.
*Neighboring alveoli have pores that connect them; we do not know the function.
**Might help to maintain stability; for example, gas may be able to move between alveoli.
*Surface area is very important:
**It increases significantly as we develop (3 to 75 square meters).
**Yet the number of alveoli stays about the same.

===Gas exchange===
*We have to oxygen and co2 across the respiratory membrane.
*We have to diffuse across the epithelial cell and the basement membrane that holds them together, then the interstitial space (not much), then the basal membrane, then the endothelial cells.
*So, there are 10 different diffusion steps that have to occur.
*If the wall is too wide, the time to cross will take too long and we're less likely to oxygenate the blood.
**We only have about 7/10ths of a second before the opportunity is lost.

====Respiratory membrane====
*The membrane works well when everything is functional.
*It is important that there is a difference in partial pressure (especially for O diffusion).
*Distance is small, which is good and key.
*Oxygen and Co2 and Co are lipid soluble so we don't have to have transporters but we do have to have a moist surface for efficient exchange.
**So we have to keep solublility issues in our minds.
*Large surface area is important.
*There must be good stability at the air=water interchange.
*Coordination of flow is important.
*The blood cell membrane must be thin with the blood cell close to the cell wall.

====10 stems to transport====
*Notice that there are D1-d10 steps.
*Amazing it works at all, really.
*So we go from water-air place to type 1, to interstitial, to endothelial cell, through plasma, through blood cell, onto Hb.

===Air replacement===
*We don't replace all of our air with each breath.
*Even after 16th breaths, there are still some of the original air molecules before total replacement.

===Integration of two processes (respiration and circulation)===

====External respiration====
*Involves:
**Ventilation (breathing)
**Diffusion over capillaries
**Exchange of CO2 and O with Hb.

====Respiratory laws====
*There are four laws.

=====Dalton's law=====
*This is looking at the gas mixture itself.
*There is some total pressure, added to by each individual gas, which is a percentage of the total--the partial pressure.
*Remember that the partial pressure is only calculated from the free molecules of gas.

=====Henry's law=====
*Takes dalton one step further.
*Here we look at solubility issues.
*This law is important to respiratory process because we need to think about getting the gas dissolved in the liquid interface on the surface of alveoli.
*There is a different solub coeff for different liquieds

=====Graham's law=====
*The rate of diffusion is driven by difference in partial pressure of the gasses.
*There are solublility issues, too, but overall, it's the difference in pp.
*Oxygen gets used up so there is an inward gradient while co2 has an exit gradient because we're generating it.

=====Fick's law=====
*Ties everything together.
*The gradient the pp difference, the greater the rate of diffusion.
*The greater the permeability of the membrane the better the diffusion.
*The more surface are the more diffusion.
*The larger the molecule the lower the diffusion.
*The thicker the membrane the less diffusion.

====Balance====
*We have to have blood and gas flow balance.
*Incoming air is not always equally distributed because of mucus or disease or whatever.
*Therefore, there will be differences in concentration of oxygen in these different areas.
*This can generate hypoxia in a certain area, which will cause vasoconstriction (constriction?).

====Ventilation perfusion coupling====
*This is how pps of O and CO2 change vasodilation.
*Let's say there's a blockage and a reduction of air coming into a certain lobule.
*So CO2 goes up, O goes down.
*The arterioles will restrict because there's no reason to go there because there is no oxygen.
*On the other hand, you can open the vessels where there is more oxygen.
*So this all balances the air with the blood.

====Never perfect perfusion balance====
*Gravity has an effect.
*Circulation at the topof the lungs isn't as well as the bottom of the lungs.
*So there is more perfusion at the bottom than at the top.

===Normal and abnormal respiration===

====Tissue structure on perfusion, etc====
*A normal lung has nice, open, alveoli.
*With pneumonia, you start to lose openness of alveoli.
*In emphasema, you have coelescing of the alveoli.

====Pneumonia====
*There is an impedance in the alveoli of the sick lung.
*This causes there to be much lower venous return in terms of saturation. So flow hasn't changed but there is a decrease of oxygen returned to the body because one lung is sucking at diffusion.

====Collapsed lung====
*Edges are sticky, can't inflate.
*Now the circulation does change along with this problem.
*So circulation will be decreased to bad lung and it will be increased in the good lung such that we can offset the loss of oxygen.
*So, this person actually gets more oxygen returned than the penumonic lung patient.

====Surfactant and surface forces====
*We want the alveoli to be open, even while we exhale.
*The liquid on the inner interface interact differently as the surface becomes smaller.
*They then become part of the subphase and the surfactant keeps the alveoli from collapsing.
**More on this next time.

====Compliance====
*This is an indication of how well the lung is inflating relative to the pressure differences we're imposing.
*If it is highly compliant it won't expand as we expect.
*This can be affected by:
**Connective tissue of lung (elastic versus structural)
**amount of surfactant
**missed third
*Historesis is the difference between lung volume during inspiration and expiration.
**This won't occur if the lung is filled with saline.
**So looking at the volumes under some pleural pressure can tell us something about the tissue.
*Normal physiology will give a nice, steady change of volume relative to pressure.
*In emphasema, it will be high in compliance. There will be a huge volume change relative to pressure. That is, it is very easy to inflate. It is easy to inhale. the problem is that it is hard to deflate. They make the last little 'hewh'.
*In low compliance, it is easy to exhale but hard to inhale. These people tend to develop a barrel chest under the struggle to inflate lungs.

====Pleural sac====
*The lungs are in the pleural sac.
*The pleural space is fluid filled.
*The parietal membrane is right underneath the chest wall.
*The visceral membrane follows the ung proper, including folds.

====Musculature====
*Diagraphm is main.
**Contraction means it is coming downward and inhaling.
**Relaxation causes a dome and exhaling.
*intercostal are between ribs and helps with expansion and reflexion.
*The sternocleidomastoid muscles are also able to help lift he rib cage.

====Expriation====
*Generally passive.
*In active exercise, we can use muscles that make the chest smaller.
**REctus abdominus = pulling ndown.
**Intercostal pull ribs downward.
**External oblique muscle pull chest inward.

====Quiet breathing====
*Normal shallow breathing = glutnant.
*Hyperpnia is the use of excessory muscles.

====Pressures of pleural sac====
*REcall that this is fluid filled.
*This is an area of lower pressure than atmospheric pressure (negative pressure).
*The transpulmonary pressure is that between the lung tissue and the pleural sac.
*We're not normally looking at much pressure change differences, usually just 1-2-3 mmHg changes.
*But when we really exercise hard, we can see big changes like -30 mmHg and +100 mmHg. This may not be a good idea.

====Pressure changes associated with ventilation====
*When normally inhaling, we decrease the pressure in the pleural space because the space gets larger because of muscle movement.
*So the pressure tissue across the pulmonary space will increase (that is the transpulmonary pressure).
*The negative pressure pulls on the lung tissue which causes it to inflate.
*Then the pressure in the alveoli will drop below atmospheric pressure.
*Air enters lung until reaching atmostpheric pressure.
*So then intrapelural pressure decreases and transpulmonary pressure increases and the lung exhales.

====Chest wall breach====
*When the pleural space is equal to the atmospheric pressure.
*This can happen from gunshot wound or tear.
*The lung will collapse.
*So we have to close the tear and reinflate the lung.

*stopped here on 02/24/10.
*started here on 03/01/10.

*We're going to talk about control points for rates and volumes issues.
*We're also going to talk about surfactant.

===Respiratory Rates and volumes===
*In order to meet the chaning needs, there has to be a way to balance the production with the need.
*So we can change how often we breath and how much volume occurs during each breath.
*The respiratory curve defines the volumes and how they are linked.
*In a normal inhale-exhale, we move the tidal volume: how much we move with each breath.
*With excersize we have to accomadate more volume so we do this with reserve volume (both on the respiratory size and expiratory side).
*Our total inspiratory capacity includes the inspiratory reserve and the tidal volume.
*The numbers on the slide are averages.
*Our total expiratory volume is the expiratory volume and re residual volume.
*The vital capacity is the total amount of room that could be moved in and out.
**There is always some that cannot be moved: residual volume. It is in an unusable area.
**In a forensic lab, you could test to see if an infant was stillborn or not by testing the floating capacity of the lung because if the baby ever took a breath, the residual volume will be filled with air.

===Respiratory minute ventilation===
*This is defined as how much air is moved per minute.
*It is a function of how frequently we're breathing and the volume of each ventilation.
*It is generally about 500 ml at 6 times per minute which is about 6 liters of air per minute.
*It goes beyond this, however, because we wonder how much air actually gets to the alveoli. This is important because that is hte only location where we can exchange air.

===Alveolar ventilation===
*So alveoloar ventilation is this idea of how much air gets to the alveoli.
*We include in this calculation any part of th elungs that can exchange, which begins at the respiratory bronchioles and includes everything deep to that.
*If you hold the minute ventilation constant and then increase dead space, you won't be able to keep exchanging well.
What?
*There is a dynamic balance between our rate of ventilation and the tidal volume.
*We can put this dynamic into numbers, too, and generate some equations:
**Tidal volume - dead space ventiation x frequence = ?
**This tells us how much is able to get to the alveoli and therefore is available for breathing.

*We wonder if there is an upper limit to all these things.
**We cannot exceed the oxygen levels of the partial pressure of oxygen in the environment's air.
**We can see that at lower oxygen levels, it will take a longer amount of time to reach the normal concentration of oxygen in the body.

===Oxygen transport===
*So we're thinking about the idea of oxygen and carbon dioxide transport.
*Plasma is not a good place for oxygen to disolve so 98% of it is bound to Hb.
*If you wanted to support a person simply on dissolved oxygen, you'd have o increase cardiac throughput by 17 fold!
*Iron is the binding site of the oxygen in Hb. The iron is surrounded by four heme groups.
*so we have the possibility for one RBC to transport over 1000 molecules of oxygen. On average, it works out to be about 3.8 oxygens perl Hb.
*Oxygen binds to Hb in a cooperative manner: when one binds, the second and subsequent bind more and more easily.
**The opposite is true, also.
**The significance is that in a situation in which we really need oxygen, this increases our ability to carry oxygen.
*There are several ways we can affect Hb levels.
**We can increase RBC.
**We can increase Hb in a given RBC.
*In an anemic situation, we have decreased RBC counts and therefore Hb will only be 10% of the volume and we'll only transport 13.4 ml of oxygen to the alveoli. Normally, hb is 15% and we deliver 20.1 ml. With extra RBCs we have 30% and 26ish mls.

===Carbon dioxide transport===
*About 7% of Co2 is dissolved in blood.
*About 23% of it is combined with proteins.
*And most of it is transported as HCO3-.
*In RBCs we have carbonic anhydrase which is a completely reversible enzyme so it can generate HC3- and co2 (and subsequently Ho2 and something).
**It is the water and something that will drive pH changes and thus cause regulation.
*Bicarbonate is freely diffusable so it can go and dissolve in plasma. However, if we're going to let the negative molecule into the plasma, we have to take one into the tissue (Cl-). This is called the chloride shift.
*Hb can also bind CO2 and upon doing so it will favor release of oxygen.
*So bicarbonate goes into the RBC exchanged for Chloride. Then Caronic anhydrase converts HCO3 into H20 and CO2. CO2 then gets released via the alveoli.

===Hemoglobin saturation curves===
*Saturation occurs based on partial pressure.
*As the curve rises, it represents the oxygen that we use during exercise and normal ventilation. And near the bottom, the curve represents the oxygen that never gets releases from Hb (which is common).
*Note the sigmoidal binding curve.
*CARbon monoxide binds very well to Hb and is very difficult to reverse which is bad because it binds much more readily than oxygen. Oxygen must be at very high partial pressures to overcome carbon monoxide (poisoning).

*Things that can affect oxygen binding include temperature and pH.
*With changes in aa pK values, we see a conformational change in Hb such that oxygen can bind well.
*We see that oxygen binds more readily at the same partial pressure. With increased temperature, saturation occurs at a higher partial pressure of oxygen.
**This makes sense because if you have a situation in which the core temp is dropping, you want to be sure the tissue stays alive as long as possible so you want to be stingy.
**And if you have fever or are working hard, the metabolism of the tissue is going up so you want to be sure you have oxygen for the tissues to use.

===Bohr effect===
*We can think about pH and CO2 and how they change the binding of oxygen.
*The bohr effect has to do with pH's effect on binding.
*Alkiline conditions will generate increased prevalance to bind at a given partial pressure.
**That is, as acidity goes up, oxygen deliver will go up. As acidity goes down, oxygen deliver goes down.

===Hb as a buffer===
*Hb is a good buffer.
*This makes sense because it binds and releases H+.

===Adult / fetal Hb===
*The partial pressure in the maternal blood after having passed through tissue that took some of it will be even lower than the environmental partial pressure, so the fetal blood has a higher affinity such that it can still take the blood from the mom's blood.
*2,3 biphosphoglycerate is generated by RBCs as part of normal glycolysis. It causes Oxygen to be dumped off of Hb.
*As you increase DPG (a right shift), one increases oxygen delivery because.
**We can increase DPG by an increase in pH, by some hormonal influence.
**DPG can be used as a marker for blood banks to determine how fresh and capable the blood is.

===Haldane effect===
*Looks at CO2 levels as they affect oxygen binding.
*As CO2 rises, Hb will be less saturated with oxygen and vice versa.
*As CO2 goes up, the carbonic anhydrase reaction will generate ... and this will cause a shift to the right.
===Control of respiration===
*There are many things that occur to control ventilation so we need to think about changing blood flow and oxygen delivery.
*So we know we can change vaso-diamter chaning both in the periphery and in the lungs.
*There are many factors that affect all thsi: Hb, NO, and vasodilators.
*NO binds to the (somethign) portion of Hb and stimulates Hb to unload oxygen. It is also a vasodilator. This means that NO increases oxygen deliver in peripheral tissues but in the lung it facilitates the uptake of oxygen (because it increases blood flow through the lung).

===Respiraotry centers of the brain===
*The voluntary centers are in the cerebral cortex but are only good for a period of time because involuntary (pons and medulla) are more imnportant.
*The voluntary centers will only work as long as CO2 levels are low or normal. As soon as CO2 goes up, it over-rides voluntary choice.

===Respiratory centers in the pons and medulla===
*They are in the brain stem.
*The medulla is the major location of control. It has a location for inspiration and expiration (IRG, VRG).
*The pons has two different areas: pneumotaxic and apneustic areas.
**These are not necessary for life but it does help with fine tuning of rate and depth of respiration.

===Medulla===
*The dorsal respiratory group is primarily inspiratory.
**We inhale for 2-3 seconds and then shut fthe pathway off and let the passive time take over for exhalation.
*During exercise we induce force respiration and we start to rely on the extra space and volume.
*Ventral respiratory group is the one that is active in forced breathing.
**This center can stimulate inhalation or exhalation depending on the situation.
**Basically, the VRG boosts the rate one way or the other.

===Quiet breathing===
*The respiratory center turns on and off; primarily we're working only with the DRG.

===Forced breathing===
*The VRG kicks in and we see an impact on depth and rate.
*This will activate the accessory breathing muscles and expand the chest cavity and thus draw on the reserve volume.

===Respiratory centers and reflex controls===
*The apneustic center provides a continual level to the DRG (which regulates normal in and out cycle).
*The pnuemotatctc center turns off the DRG and thus limits the duration of the inhalation.
*The penumotactic center also helps regulate the apneustic center.

===SIDS===
*One of the things we think happens is that the respiratory centers become disrupted in some way (though we don't know how). Then normal ventilation is affected and the baby dies.

===Sensory input modifies...===
*There are chemoreceptors in the body that are sensitive to co2, ph, or o2, (in that order) and can then feed back to (respiratory centers).
*There are also baroreceptors that will sense changes in blood pressure (caused by changes in vasoconstriction).
*So we have stretch receptors, too, that respond to changes in lung volume.
*There is the brewer-reflex. There are sensors that sense how stretched the lungs are and feed backs to the respiratory centers in order to control inhalation.
**Babies don't have a fully calcified set of ribs so they can sometimes overinhale and rip their lungs on the bones.
*We also have sensors for irritants which can causes us to hold our breath, or lock out larynx (jumping into cold water; be careful with cold drinks in heat), bronchial tree.
*Somehting.

===Influence of cranial nerve===
*Number 10 is in the aorta and senses changes in the aorta.

===Receptors monitoring the CSF===
*The receptors in the CNS respond to changes as a result of ventilation while thos ein the perphery change because of changes in metabolism.
**So as CO2 levels change, the cells of the CSF in the spinal cord have carbonic anhydrase as well. So then CO2 levels change the pH of cerebral spinal fluid and thus can be used as a way to change respiratory rate and depth.

===CNS chemoreceptor responses to partial pressure of co2===

===Baroreceptor reflexes===
*When BP falls, respiration rate goes up and ''vice versa''.
**This goes along quite nicely with needing to balance flow to demand.

===Hering-breuer relfexes===
*This has to do with over expansion of the lungs.

===Protective reflexes===
*The epithelium of the respiratory system and especially the korina (split in bronchials) have these receptors.
*This will turn off breathing so that you don't increase the irritant and in fact it increases the desire to breath out: sneezing.
*Apnea = lacking or suspending ventilation.
What's the opposite?
**Apnea can be used to balance out delivery of gasses.

===The cerebral cortex and respiratory centers===
*STrong emotions can activate the autonomic nervous system which can affect the airways and the diameter of the vessels, and thus can affect balance so as to change respiration.
*Anticipation is an involuntary summing up in the mind of how many motor units are needed. In parallel, our brain calculates how much breathing is required.

===Changes of respiration over time===
*Before birth, we have a little blood running through the pulmonary vessels to supply the lungs with blood but very decreased.
*During deliver, the fetal co2 levels will begin to rise. This will feed back on ventilation centers and cause an autostimulation of those receptors in order to cause breathing.
*At the very least, it make take a combination of CO2 and some tactile stimulation.
*So we think about lungs being able to be ventilated in babies. We have to overcome the surface tension that wants to keep the lung in a collapses position and we do so with the release of surfactant (a massive release, indeed).
*We also have to redirect blood flow (closing foramen valve).
*Add all this up and the lung should fully inflate.
*As we age, the chest wall becomes less elastic. There is a drop in performance rate of the lung.
**It seems that if you quit, as long as you're not really old, you start to recoup some of the good properties.

===3 affects of aging===
*When elastisticity goes down we have decreased performance.
*Arthritis can cause decreased movement of the chest and therefore a decrease in perforamnce.
*Some other disease.

*skipped something.

===Surfactant===
*We really started to understand this as a result of people studying Hyaline Membrane Disease (IRDS).
**This is when alveoli become clogged with dead tissue that resulted from strained breathing.
What is hysteresis?
*What is surfactant?
**He studied lipids of surfactnat for PhD.
**It's hard to find the proteins, easy to get lipids.
**There are two groups of proteins.
**We're tyring to decrease surface tensions.
**As the surface gets smaller, some of the molecules on the surface will go inward and the tension will become inward. So the aveiolus will want to collapse.
*The surfactant also helps with trapping of debris and thus eject it via the escalator.
*Note that you can take samples of amniotic fluid, look at the proteins, and determine whether an infant will be able to survive of its own. The ratio of lecithin to sphingomyelin must be greater than 2. You can increase sphingomyeling by giving glucocorticoids to the mother.
*80% of surfactant is phospholipid, 10% neutral lipids, and 10% proteins.
*If you look at th ephospholipids, 60% is in the form of DPPC. This lipid carries the property that lets the surface act the way it does.
*The second most important will be phosphlytoinositol.

*stopped here on 03/01/10.
*started here on 03/03/10.

*The DPPC is the major contributor to the reduction of surface tension.
*Phosphatidyl inositol makes up about 5-7% of the reduction of surface tension.

*There are two groups of proteins, either hydrophilic or hydrophobic.
*So while the lipids are important, the proteins were identified in the early eighties.
**The lipids have been around and known since the 50s.

===Hydrophilic surfactant proteins===
*SPA and SPD are hydrophillic.
**They are both glycosylated and in the aqueous (water soluble) phase.
**Both involved in defense through the activation of macrophages.
**So this is one of the ways we can take care of bacteria that get below the elevator.
**It is not odd to find macrophages at the air-water boundary.
*There are 28 types of cells in the lung.
*SPA is also involved in antiviral activity and surfactant cycling and secretion.
**It works closely with synthesis and secretion of miller bodies which is where something is located.
*SPB and SPC
**The spreading of the surfactant on the alveolar pocket is important and that's what B and C do.

===Lamellar bodies and tubular myelin===
*We're seeing a type II cell and a lamellar body inside.
**This is really a package of tubular myelin.
**The surfactant is on the tubular myelin.

*Respiratory distress in infants:
**One of the problems is that we're trying to open lungs without surfactant.
**This causes cellular and tissue damage because they are rubbed against each other.
**This can cause the tissue to become disfunctional.
**This can even tear the lung and cause lung collapse.

*continued on to [[Cystic fibrosis lectures]] on 03/03/10.

Respiration

Admin — Wed, 03 Mar 2010 21:30:22 GMT

Admin: moved Respiration to Respiration lectures

#REDIRECT [[Respiration lectures]]

Respiration lecture notes

Admin — Wed, 03 Mar 2010 21:30:21 GMT

Admin: moved Respiration to Respiration lectures

*started here on 02/24/10.

==Respiration==
*Respiration requires some stuff:
**We'll talk about convection system (that is, ventilation and cirulation).
**We'll also talk about mechanisms for gas transport int he blood.

===Respiratory functions===
*We're going to talk about ventilation in general and which muscles of the chest wall are used.
*We'll tlak about negative pressure that pulls the air into the lungs.
*We're going to think about ...

===More requirements for respiration===
*We have to have a way for the air to flow. Ventilation perfusion coupling.
**We'll look at some problems of this, too.
*We'll look at the CNS's involvement in respiration and circulation.
*Oxygen level is important, but CO2 is the primary regulator of respiration.

===Non-respiratory functions===

====Filter and moisten air====

====Facilitate olfaction by transporting airborne molecules====

====Defense against airborne pathogens - mucocilliary elevator====

====Sound production====

====Trap small emboli in pulmonary circulation where they are dissolved====

====Blood reservoir for left ventricle====
*Lungs contain 500 ml of blood.
*Two beats can be supplied if pulmonary artery is clamped.

====Biochemical reactions====
*ACE converts angiotensin I to antiotensin II.
*Some prostaglandins are removed at the lungs.

===Organization of the respiratory system===
*Can be divided into upper (down to the pharynx) and lower (everything lower).
*We could also look at the system in terms of function instead of structure.
**The transition of function (from conducting zone to respiratory zone) occurs when alveoli start to occur.
*The tubes branch significantly. There are about 16 divisions before there are any alveoli.
*There is also a change in type of cells found.
**We transition from columnar at the top to squamous at the bottom.
**We see a change from more to less (going down) of goblet cells because of the elevator.
**We see a decrease in cartilage because we have less and less structure.
**Elasticity goes the entire length. They are important for recoil in the chest wall and the alveoli.

====The mucocilliary elevator====
*Goblet cells are releasing mucus on surface.
*Cillia are beating upward.
*As we get to the lower region, the size of pathogens is important because the smaller they are the deeper they can get and the better they can get across the endothelial cells when they land.

====Nose====
*The air enters through the external nairs.
*There is mucus secretion and tears coming through ducts, these help to trap crap.
*Air passes through conchae around the turbanates (an outcropping of bone). This generates turbulance to facilitate smell and moistening.
*We have sinuses (four of them) which connect to the nose through the medemus (?).
**When this connection is blocked, pressure can build up.

====Palate====
*Separates nose to mouse.
*Hard and soft palate.
*Cleft can occur which is bad. Usually happens where bones come together in top of mouth.
**Can happen in hard or soft palate or both.

====Nasopharynx====
*This is in common with digestive and respiration tracts.
*There are three regions but we won't dwell on them.
*Nasal connection is called the internal nares.
**This is the location of the adenoid.
**This is also where the opening to the ear occurs and it is important for good sound conductance and balance.

====Oropharynx and laryngopharynx====

====Larynx functions====
*This structure is trying to keep the airway open.
*Behind it is the esophagus.
*Epiglottis sits on the top with some cartilage that allows the epiglottis to cover the glottis (a slit-like opening).
*The vocal cords are on either side of the glottis.
*There is upward movement that helps to close off the glottis.

====Anatomy of larynx====
*The thyroid cartilage forms the adams apple.

====Tracheal cartilages====
*Begins at the base of the larynx.
*You can feel the cartilage rings with connective tissue in between.
*The rings are c shaped with the open part in the back.
*There is a muscle and a ligament on the back which are responsible for changing the diameter to change resistance.
*The esophagus is posterior to the trachea.

====Primary bronchi====
*Our first bifurcation occurs.
*The right and left are not equal.
*The angle of division are not equal.
*The right has a short bronchial tube and left has a straighter angle.
*This is a problem when kids breath something. Most likely it is in the right bronchial tube because the angle isn't as great.
*At the bifurction, the cartilage extends into the airway a little (think shelf).
**This is covered by endothelium and is very sensitive.
**This causes the coughing when you inhale something.

====Hilus====
*The hilus is the midline of the lung (theres one on the kidneys, too).
*This is the location where the major structures enter the organ (think veins, lymphatics, bronchii).
*The whole thing is held together by a mesh-work of connective tissue.

====Lungs====
*The right lobe is larger than left because the heart is taking up space on left side.
*You can see the fissure that helps separate the middle lobes from the upper lobes.
**Note that on the left there are only two lobes.
**Right has a middle lobe.

====Lung lobes====
*The lobes are divided into segments.
*The segments are able to be isolated by surrounding connective tissue.
**They can be removed for something like lung cancer or what-not.
*The reason for these sections is that the the lymphatics, respiratory, and circulation all branch together such that all the sections separate systems.

====Lobules====
*Sections can be divided.
*Can be the size of a penny to an eraser.
*Respiration occurs at the level of the alveoli which are at the base of the lobules.
*Artery, vein, and lymphatics all supply each lobule and each alveoli.

===Smooth muscle control===
*The cartilage is gone, recall, so we rely on the muscle to keep the airway open.
*Therefore we can change the dilation.
*The sympathetic will open airways to reduce resistance and the parasympathetic will do the opposite.
*Histamine will also restrict to increase resistance.
*This is all further compounded by the fact that we need airpressure from the outside to help hold it open.

===Alveolar organization===
*There are capillaries that pass through avleolar, which means that we can get oxygen from either capillary.
*There are several cell types at this point: type 1 cells and type 2 cells.
**Type 1 are long and thin, these do gas exchange.
**Type 2 are important for generating surfactant.
*There are also macrophages in this space to help with protection.
*Neighboring alveoli have pores that connect them; we do not know the function.
**Might help to maintain stability; for example, gas may be able to move between alveoli.
*Surface area is very important:
**It increases significantly as we develop (3 to 75 square meters).
**Yet the number of alveoli stays about the same.

===Gas exchange===
*We have to oxygen and co2 across the respiratory membrane.
*We have to diffuse across the epithelial cell and the basement membrane that holds them together, then the interstitial space (not much), then the basal membrane, then the endothelial cells.
*So, there are 10 different diffusion steps that have to occur.
*If the wall is too wide, the time to cross will take too long and we're less likely to oxygenate the blood.
**We only have about 7/10ths of a second before the opportunity is lost.

====Respiratory membrane====
*The membrane works well when everything is functional.
*It is important that there is a difference in partial pressure (especially for O diffusion).
*Distance is small, which is good and key.
*Oxygen and Co2 and Co are lipid soluble so we don't have to have transporters but we do have to have a moist surface for efficient exchange.
**So we have to keep solublility issues in our minds.
*Large surface area is important.
*There must be good stability at the air=water interchange.
*Coordination of flow is important.
*The blood cell membrane must be thin with the blood cell close to the cell wall.

====10 stems to transport====
*Notice that there are D1-d10 steps.
*Amazing it works at all, really.
*So we go from water-air place to type 1, to interstitial, to endothelial cell, through plasma, through blood cell, onto Hb.

===Air replacement===
*We don't replace all of our air with each breath.
*Even after 16th breaths, there are still some of the original air molecules before total replacement.

===Integration of two processes (respiration and circulation)===

====External respiration====
*Involves:
**Ventilation (breathing)
**Diffusion over capillaries
**Exchange of CO2 and O with Hb.

====Respiratory laws====
*There are four laws.

=====Dalton's law=====
*This is looking at the gas mixture itself.
*There is some total pressure, added to by each individual gas, which is a percentage of the total--the partial pressure.
*Remember that the partial pressure is only calculated from the free molecules of gas.

=====Henry's law=====
*Takes dalton one step further.
*Here we look at solubility issues.
*This law is important to respiratory process because we need to think about getting the gas dissolved in the liquid interface on the surface of alveoli.
*There is a different solub coeff for different liquieds

=====Graham's law=====
*The rate of diffusion is driven by difference in partial pressure of the gasses.
*There are solublility issues, too, but overall, it's the difference in pp.
*Oxygen gets used up so there is an inward gradient while co2 has an exit gradient because we're generating it.

=====Fick's law=====
*Ties everything together.
*The gradient the pp difference, the greater the rate of diffusion.
*The greater the permeability of the membrane the better the diffusion.
*The more surface are the more diffusion.
*The larger the molecule the lower the diffusion.
*The thicker the membrane the less diffusion.

====Balance====
*We have to have blood and gas flow balance.
*Incoming air is not always equally distributed because of mucus or disease or whatever.
*Therefore, there will be differences in concentration of oxygen in these different areas.
*This can generate hypoxia in a certain area, which will cause vasoconstriction (constriction?).

====Ventilation perfusion coupling====
*This is how pps of O and CO2 change vasodilation.
*Let's say there's a blockage and a reduction of air coming into a certain lobule.
*So CO2 goes up, O goes down.
*The arterioles will restrict because there's no reason to go there because there is no oxygen.
*On the other hand, you can open the vessels where there is more oxygen.
*So this all balances the air with the blood.

====Never perfect perfusion balance====
*Gravity has an effect.
*Circulation at the topof the lungs isn't as well as the bottom of the lungs.
*So there is more perfusion at the bottom than at the top.

===Normal and abnormal respiration===

====Tissue structure on perfusion, etc====
*A normal lung has nice, open, alveoli.
*With pneumonia, you start to lose openness of alveoli.
*In emphasema, you have coelescing of the alveoli.

====Pneumonia====
*There is an impedance in the alveoli of the sick lung.
*This causes there to be much lower venous return in terms of saturation. So flow hasn't changed but there is a decrease of oxygen returned to the body because one lung is sucking at diffusion.

====Collapsed lung====
*Edges are sticky, can't inflate.
*Now the circulation does change along with this problem.
*So circulation will be decreased to bad lung and it will be increased in the good lung such that we can offset the loss of oxygen.
*So, this person actually gets more oxygen returned than the penumonic lung patient.

====Surfactant and surface forces====
*We want the alveoli to be open, even while we exhale.
*The liquid on the inner interface interact differently as the surface becomes smaller.
*They then become part of the subphase and the surfactant keeps the alveoli from collapsing.
**More on this next time.

====Compliance====
*This is an indication of how well the lung is inflating relative to the pressure differences we're imposing.
*If it is highly compliant it won't expand as we expect.
*This can be affected by:
**Connective tissue of lung (elastic versus structural)
**amount of surfactant
**missed third
*Historesis is the difference between lung volume during inspiration and expiration.
**This won't occur if the lung is filled with saline.
**So looking at the volumes under some pleural pressure can tell us something about the tissue.
*Normal physiology will give a nice, steady change of volume relative to pressure.
*In emphasema, it will be high in compliance. There will be a huge volume change relative to pressure. That is, it is very easy to inflate. It is easy to inhale. the problem is that it is hard to deflate. They make the last little 'hewh'.
*In low compliance, it is easy to exhale but hard to inhale. These people tend to develop a barrel chest under the struggle to inflate lungs.

====Pleural sac====
*The lungs are in the pleural sac.
*The pleural space is fluid filled.
*The parietal membrane is right underneath the chest wall.
*The visceral membrane follows the ung proper, including folds.

====Musculature====
*Diagraphm is main.
**Contraction means it is coming downward and inhaling.
**Relaxation causes a dome and exhaling.
*intercostal are between ribs and helps with expansion and reflexion.
*The sternocleidomastoid muscles are also able to help lift he rib cage.

====Expriation====
*Generally passive.
*In active exercise, we can use muscles that make the chest smaller.
**REctus abdominus = pulling ndown.
**Intercostal pull ribs downward.
**External oblique muscle pull chest inward.

====Quiet breathing====
*Normal shallow breathing = glutnant.
*Hyperpnia is the use of excessory muscles.

====Pressures of pleural sac====
*REcall that this is fluid filled.
*This is an area of lower pressure than atmospheric pressure (negative pressure).
*The transpulmonary pressure is that between the lung tissue and the pleural sac.
*We're not normally looking at much pressure change differences, usually just 1-2-3 mmHg changes.
*But when we really exercise hard, we can see big changes like -30 mmHg and +100 mmHg. This may not be a good idea.

====Pressure changes associated with ventilation====
*When normally inhaling, we decrease the pressure in the pleural space because the space gets larger because of muscle movement.
*So the pressure tissue across the pulmonary space will increase (that is the transpulmonary pressure).
*The negative pressure pulls on the lung tissue which causes it to inflate.
*Then the pressure in the alveoli will drop below atmospheric pressure.
*Air enters lung until reaching atmostpheric pressure.
*So then intrapelural pressure decreases and transpulmonary pressure increases and the lung exhales.

====Chest wall breach====
*When the pleural space is equal to the atmospheric pressure.
*This can happen from gunshot wound or tear.
*The lung will collapse.
*So we have to close the tear and reinflate the lung.

*stopped here on 02/24/10.
*started here on 03/01/10.

*We're going to talk about control points for rates and volumes issues.
*We're also going to talk about surfactant.

===Respiratory Rates and volumes===
*In order to meet the chaning needs, there has to be a way to balance the production with the need.
*So we can change how often we breath and how much volume occurs during each breath.
*The respiratory curve defines the volumes and how they are linked.
*In a normal inhale-exhale, we move the tidal volume: how much we move with each breath.
*With excersize we have to accomadate more volume so we do this with reserve volume (both on the respiratory size and expiratory side).
*Our total inspiratory capacity includes the inspiratory reserve and the tidal volume.
*The numbers on the slide are averages.
*Our total expiratory volume is the expiratory volume and re residual volume.
*The vital capacity is the total amount of room that could be moved in and out.
**There is always some that cannot be moved: residual volume. It is in an unusable area.
**In a forensic lab, you could test to see if an infant was stillborn or not by testing the floating capacity of the lung because if the baby ever took a breath, the residual volume will be filled with air.

===Respiratory minute ventilation===
*This is defined as how much air is moved per minute.
*It is a function of how frequently we're breathing and the volume of each ventilation.
*It is generally about 500 ml at 6 times per minute which is about 6 liters of air per minute.
*It goes beyond this, however, because we wonder how much air actually gets to the alveoli. This is important because that is hte only location where we can exchange air.

===Alveolar ventilation===
*So alveoloar ventilation is this idea of how much air gets to the alveoli.
*We include in this calculation any part of th elungs that can exchange, which begins at the respiratory bronchioles and includes everything deep to that.
*If you hold the minute ventilation constant and then increase dead space, you won't be able to keep exchanging well.
What?
*There is a dynamic balance between our rate of ventilation and the tidal volume.
*We can put this dynamic into numbers, too, and generate some equations:
**Tidal volume - dead space ventiation x frequence = ?
**This tells us how much is able to get to the alveoli and therefore is available for breathing.

*We wonder if there is an upper limit to all these things.
**We cannot exceed the oxygen levels of the partial pressure of oxygen in the environment's air.
**We can see that at lower oxygen levels, it will take a longer amount of time to reach the normal concentration of oxygen in the body.

===Oxygen transport===
*So we're thinking about the idea of oxygen and carbon dioxide transport.
*Plasma is not a good place for oxygen to disolve so 98% of it is bound to Hb.
*If you wanted to support a person simply on dissolved oxygen, you'd have o increase cardiac throughput by 17 fold!
*Iron is the binding site of the oxygen in Hb. The iron is surrounded by four heme groups.
*so we have the possibility for one RBC to transport over 1000 molecules of oxygen. On average, it works out to be about 3.8 oxygens perl Hb.
*Oxygen binds to Hb in a cooperative manner: when one binds, the second and subsequent bind more and more easily.
**The opposite is true, also.
**The significance is that in a situation in which we really need oxygen, this increases our ability to carry oxygen.
*There are several ways we can affect Hb levels.
**We can increase RBC.
**We can increase Hb in a given RBC.
*In an anemic situation, we have decreased RBC counts and therefore Hb will only be 10% of the volume and we'll only transport 13.4 ml of oxygen to the alveoli. Normally, hb is 15% and we deliver 20.1 ml. With extra RBCs we have 30% and 26ish mls.

===Carbon dioxide transport===
*About 7% of Co2 is dissolved in blood.
*About 23% of it is combined with proteins.
*And most of it is transported as HCO3-.
*In RBCs we have carbonic anhydrase which is a completely reversible enzyme so it can generate HC3- and co2 (and subsequently Ho2 and something).
**It is the water and something that will drive pH changes and thus cause regulation.
*Bicarbonate is freely diffusable so it can go and dissolve in plasma. However, if we're going to let the negative molecule into the plasma, we have to take one into the tissue (Cl-). This is called the chloride shift.
*Hb can also bind CO2 and upon doing so it will favor release of oxygen.
*So bicarbonate goes into the RBC exchanged for Chloride. Then Caronic anhydrase converts HCO3 into H20 and CO2. CO2 then gets released via the alveoli.

===Hemoglobin saturation curves===
*Saturation occurs based on partial pressure.
*As the curve rises, it represents the oxygen that we use during exercise and normal ventilation. And near the bottom, the curve represents the oxygen that never gets releases from Hb (which is common).
*Note the sigmoidal binding curve.
*CARbon monoxide binds very well to Hb and is very difficult to reverse which is bad because it binds much more readily than oxygen. Oxygen must be at very high partial pressures to overcome carbon monoxide (poisoning).

*Things that can affect oxygen binding include temperature and pH.
*With changes in aa pK values, we see a conformational change in Hb such that oxygen can bind well.
*We see that oxygen binds more readily at the same partial pressure. With increased temperature, saturation occurs at a higher partial pressure of oxygen.
**This makes sense because if you have a situation in which the core temp is dropping, you want to be sure the tissue stays alive as long as possible so you want to be stingy.
**And if you have fever or are working hard, the metabolism of the tissue is going up so you want to be sure you have oxygen for the tissues to use.

===Bohr effect===
*We can think about pH and CO2 and how they change the binding of oxygen.
*The bohr effect has to do with pH's effect on binding.
*Alkiline conditions will generate increased prevalance to bind at a given partial pressure.
**That is, as acidity goes up, oxygen deliver will go up. As acidity goes down, oxygen deliver goes down.

===Hb as a buffer===
*Hb is a good buffer.
*This makes sense because it binds and releases H+.

===Adult / fetal Hb===
*The partial pressure in the maternal blood after having passed through tissue that took some of it will be even lower than the environmental partial pressure, so the fetal blood has a higher affinity such that it can still take the blood from the mom's blood.
*2,3 biphosphoglycerate is generated by RBCs as part of normal glycolysis. It causes Oxygen to be dumped off of Hb.
*As you increase DPG (a right shift), one increases oxygen delivery because.
**We can increase DPG by an increase in pH, by some hormonal influence.
**DPG can be used as a marker for blood banks to determine how fresh and capable the blood is.

===Haldane effect===
*Looks at CO2 levels as they affect oxygen binding.
*As CO2 rises, Hb will be less saturated with oxygen and vice versa.
*As CO2 goes up, the carbonic anhydrase reaction will generate ... and this will cause a shift to the right.
===Control of respiration===
*There are many things that occur to control ventilation so we need to think about changing blood flow and oxygen delivery.
*So we know we can change vaso-diamter chaning both in the periphery and in the lungs.
*There are many factors that affect all thsi: Hb, NO, and vasodilators.
*NO binds to the (somethign) portion of Hb and stimulates Hb to unload oxygen. It is also a vasodilator. This means that NO increases oxygen deliver in peripheral tissues but in the lung it facilitates the uptake of oxygen (because it increases blood flow through the lung).

===Respiraotry centers of the brain===
*The voluntary centers are in the cerebral cortex but are only good for a period of time because involuntary (pons and medulla) are more imnportant.
*The voluntary centers will only work as long as CO2 levels are low or normal. As soon as CO2 goes up, it over-rides voluntary choice.

===Respiratory centers in the pons and medulla===
*They are in the brain stem.
*The medulla is the major location of control. It has a location for inspiration and expiration (IRG, VRG).
*The pons has two different areas: pneumotaxic and apneustic areas.
**These are not necessary for life but it does help with fine tuning of rate and depth of respiration.

===Medulla===
*The dorsal respiratory group is primarily inspiratory.
**We inhale for 2-3 seconds and then shut fthe pathway off and let the passive time take over for exhalation.
*During exercise we induce force respiration and we start to rely on the extra space and volume.
*Ventral respiratory group is the one that is active in forced breathing.
**This center can stimulate inhalation or exhalation depending on the situation.
**Basically, the VRG boosts the rate one way or the other.

===Quiet breathing===
*The respiratory center turns on and off; primarily we're working only with the DRG.

===Forced breathing===
*The VRG kicks in and we see an impact on depth and rate.
*This will activate the accessory breathing muscles and expand the chest cavity and thus draw on the reserve volume.

===Respiratory centers and reflex controls===
*The apneustic center provides a continual level to the DRG (which regulates normal in and out cycle).
*The pnuemotatctc center turns off the DRG and thus limits the duration of the inhalation.
*The penumotactic center also helps regulate the apneustic center.

===SIDS===
*One of the things we think happens is that the respiratory centers become disrupted in some way (though we don't know how). Then normal ventilation is affected and the baby dies.

===Sensory input modifies...===
*There are chemoreceptors in the body that are sensitive to co2, ph, or o2, (in that order) and can then feed back to (respiratory centers).
*There are also baroreceptors that will sense changes in blood pressure (caused by changes in vasoconstriction).
*So we have stretch receptors, too, that respond to changes in lung volume.
*There is the brewer-reflex. There are sensors that sense how stretched the lungs are and feed backs to the respiratory centers in order to control inhalation.
**Babies don't have a fully calcified set of ribs so they can sometimes overinhale and rip their lungs on the bones.
*We also have sensors for irritants which can causes us to hold our breath, or lock out larynx (jumping into cold water; be careful with cold drinks in heat), bronchial tree.
*Somehting.

===Influence of cranial nerve===
*Number 10 is in the aorta and senses changes in the aorta.

===Receptors monitoring the CSF===
*The receptors in the CNS respond to changes as a result of ventilation while thos ein the perphery change because of changes in metabolism.
**So as CO2 levels change, the cells of the CSF in the spinal cord have carbonic anhydrase as well. So then CO2 levels change the pH of cerebral spinal fluid and thus can be used as a way to change respiratory rate and depth.

===CNS chemoreceptor responses to partial pressure of co2===

===Baroreceptor reflexes===
*When BP falls, respiration rate goes up and ''vice versa''.
**This goes along quite nicely with needing to balance flow to demand.

===Hering-breuer relfexes===
*This has to do with over expansion of the lungs.

===Protective reflexes===
*The epithelium of the respiratory system and especially the korina (split in bronchials) have these receptors.
*This will turn off breathing so that you don't increase the irritant and in fact it increases the desire to breath out: sneezing.
*Apnea = lacking or suspending ventilation.
What's the opposite?
**Apnea can be used to balance out delivery of gasses.

===The cerebral cortex and respiratory centers===
*STrong emotions can activate the autonomic nervous system which can affect the airways and the diameter of the vessels, and thus can affect balance so as to change respiration.
*Anticipation is an involuntary summing up in the mind of how many motor units are needed. In parallel, our brain calculates how much breathing is required.

===Changes of respiration over time===
*Before birth, we have a little blood running through the pulmonary vessels to supply the lungs with blood but very decreased.
*During deliver, the fetal co2 levels will begin to rise. This will feed back on ventilation centers and cause an autostimulation of those receptors in order to cause breathing.
*At the very least, it make take a combination of CO2 and some tactile stimulation.
*So we think about lungs being able to be ventilated in babies. We have to overcome the surface tension that wants to keep the lung in a collapses position and we do so with the release of surfactant (a massive release, indeed).
*We also have to redirect blood flow (closing foramen valve).
*Add all this up and the lung should fully inflate.
*As we age, the chest wall becomes less elastic. There is a drop in performance rate of the lung.
**It seems that if you quit, as long as you're not really old, you start to recoup some of the good properties.

===3 affects of aging===
*When elastisticity goes down we have decreased performance.
*Arthritis can cause decreased movement of the chest and therefore a decrease in perforamnce.
*Some other disease.

*skipped something.

===Surfactant===
*We really started to understand this as a result of people studying Hyaline Membrane Disease (IRDS).
**This is when alveoli become clogged with dead tissue that resulted from strained breathing.
What is hysteresis?
*What is surfactant?
**He studied lipids of surfactnat for PhD.
**It's hard to find the proteins, easy to get lipids.
**There are two groups of proteins.
**We're tyring to decrease surface tensions.
**As the surface gets smaller, some of the molecules on the surface will go inward and the tension will become inward. So the aveiolus will want to collapse.
*The surfactant also helps with trapping of debris and thus eject it via the escalator.
*Note that you can take samples of amniotic fluid, look at the proteins, and determine whether an infant will be able to survive of its own. The ratio of lecithin to sphingomyelin must be greater than 2. You can increase sphingomyeling by giving glucocorticoids to the mother.
*80% of surfactant is phospholipid, 10% neutral lipids, and 10% proteins.
*If you look at th ephospholipids, 60% is in the form of DPPC. This lipid carries the property that lets the surface act the way it does.
*The second most important will be phosphlytoinositol.

*stopped here on 03/01/10.

Circulatory lecture notes

Admin — Mon, 22 Feb 2010 22:38:02 GMT

Admin:

*started here on 02/17/10.

==Vasculature==
*We will not cover all the circulatory routes.
**pages 748-767.

===Circulation===
*Arteries away, veins to; capillaries in between.
*Capillaries are site of exchange because of permeability and thin wall.

===Vasculature - control mechanisms===
*All vessels except capillaries have:
**smooth muscle cells so they can undergo constriction or dilation
**innervation that can control the constriction / dilation.
*Veins, in general, have much larger diameters.
*The artery has some layers.
**Throughout these layers are elastic fibers.
**The endothelial cells that line the inside of the artery are bunched up so they can expand outward and then spring back forward.
*Veins have some layers
**These include the outer and inner layers of smooth muscle.
**There are no elastic fibers.
*All three arteries, veins, and capillaries have:
**An endothelial layer, a basement membrane (on which the endothelial layer sits).
*Arteries and veins both have:
**Smooth muscle (except that arteries have larger layers of smooth muscle).
*Only arteries have:
**Two elastic layers between the smooth muscle and the basement membrane.
**These are important for handling pressure.
*Only the veins have:
**One way valves.
*In the arteriole, the smooth muscle layer has become very thing.
*Veins progress from capillaries as small venules, medium sized venuoles, and veins.

*When you have an increased stroke volume, it is handled by the expansion of the arteries.
**As you lose expansion ability, then the whole system pressure is increased, including backward pressure. This will cause problems with the afterload.

*Blood pressure measurement:
**Close off artery.
**Release pressure until you hear a sound, this is systolic pressure.
**Release more until you hear nothing, this is the diastolic pressure.

====Arterial system====
*Nature of the wall changes:
**Elasticity decreases, muscle decreases.
*Next level is known as the muscular or distributing arteries.
**These can change how much blood gets to the muscles.
**Uses vasoconstriction / dilation.

=====Fluid dynamics=====
*Resistance to flow is inversely proportional to the radius raised to the fourth power.
*Flow is proportional to the pressure divided by the resistance.
*Flow is proportional to the pressure times the resistance raised to the fourth power.
*Take home: change the radius a little, change the resistance and flow a lot (in opposite directions).

=====Arterioles=====
*Smalles of these is a single smooth muscle cells surrounding the endothelial lining of the vessel.
*Not much bigger than the capillary, but can still change diameter.
*There are both neuronal control and small molecule control that can change arteriole flow.
*This is where diameter changes will help to direct blood away from the skin if cold.

*There are arteriole systems that can bypass the capillaries. When closed it will increase the pressure in the capillaries.

====Capillaries====
*Very thin wall, with a basement membrane.
*Very small diameter.
*Not all capillaries are the same.
*Water, O2, Co2 just diffuse.
*There are intercellular clefts and pinocytic vesicles which can be used to move stuff across the membrane.
*You can move things across the endothelial membranes.
*You can move stuff through fenestrations; these are ares of membrane that do not have cytoplasm behind them that are adjacent to the endothelial cells. Think of them as a window into the extracellular space.
*Some capillaries don't let much through, like those in the brain.
*Some capillaries let lots thorugh, like the kidney and the intestinal tract.
**There will be more endo and exo cytosis.
**There will be fenestrations.
*There are some like the liver, bone, and lymphoid capillaries that have to move stuff.

====Venous system====
*While there is smooth muscle, there is much less control.
*There are thinner walls.
*There is less pressure.
*61% of the blood in an at rest, healthy person, is found in the systemic venous system.
**Only 18% in systemic arterial system.

*We'll finish vasculature next time.

*stopped here on 02/17/10.
*started here on 02/22/10.

===Physiology of circulation===

====Control mechanisms====
*These are the key to physiology.

=====General control=====
*Pressure causes movement.
*ARterial blood pressure is what we measure.
*Hydrostatic pressure is in the capillary beds.
*Venous pressure rarely matters.
*Resistance is the force that opposes movement.
**Vascular resistance is a function of vessel length and diameter.
***As we gain weight, there is longer length and therefore more resistance.
**Viscocity of the blood can aslo affect resistance.
***The number of RBCs, the amount of protein, etc. can affect viscosity.
**Lastly, turbulence can change resistance.
***This only becomes an isusue when we're talking about disease states and are therefore not smooth on the inside (because of plaque, for example).
*The capillaries account for much more total cross-sectional area than the aorta.
*The blood pressure is highest closest to the heart.
*The velocity of the blood is inversely proportional to the cross-sectional area.
*Cardiac output is MABP / R (mean alteriol blood pressure over resistance).
**The MABP is not just the average of systolic and diastolic.
**It is the diastolic + 1/3rd of the difference between systolic and diastolic pressures.
*So, if the cardiac output rises to to increased stroke volume or HV, then the BP also rises.

====Blood flow in capillaries====
*By the time the blood gets to the capillaries the blood pressure is very low.
*This is important b/c they are so thin they cannot take high pressure (like the 120 mm/hg as in the heart).
*They are meant for exchange, not pressure.
*There are two opposing forces: hydrostolic pressure (blood pressure) and osmotic pressure.
**The hydrostolic blood pressure wants to force fluid forward and / or outward.
**The osmotic pressure keeps fluid in the veseel, however, because of the concentration of proteins in the blood.
*Fluid can move out because of the thin walls.
*On the arteriole end of the capillariy, the blood pressure is greater than the contradicting osmotic force so fluid is lost.
*Then, on the venous system, this is reversed such that fluid is gained back.
*Blood loses 24 ish liters and gains 20, the other four go through the lymphatic system.
*What happens when these are unbalanced? Edema!
**So if BP increases beyond the counter force of osmotic pressure, you get peripheral adema: swelling of the ankles, etc.
**You can also decrease the amount of blood protein content (in something like liver disease) and thus have decreased osmotic force and therefore the bp is more effective at forcing fluids out and edema occurs.
**If you have increased permeability of capillaries (because of infections, inflammation, etc.). This is more localized.
**You can also increase the extracellular fluid of the blood which will increase osmotic pressure and result in higher blood volume and thus extra pressure because of the increased volume. So we're looking for the shift one way or the other: edema or ...
**You can also block the lymph vessels. This will result in edema in the area. This will result in higher returns at the venous side, but not enough to relieve the edema.

====Extremes====
*A drastic decrease in volume and thus bp decrease and thus hydrostatic pressure decreases. Therefore, there is less pressure pushing things out of the blood stream and the patient will retain fluids, which is good!
*In dehydration, the patient has lost fluids through sweating (let's say). So they have the same number of plasma proteins and so the BCOP (blood coloital osmotic pressure) increases and therefore less fluid is lost to the intracellular area.

====Veins====
*Veins are low pressure.
*They need some help to move blood back to heart.
*We have to auxillary pumps: respiratory pump, muscular pump.
*Muscular pump:
**Veins have one-way valve.
**When muscle flexes, it squeezes the vein and muscle can only go toward heart because of valves.
*Respiratory pump
**During inspiration, the diaphragm is moving and the skeletal muscles are contracting.
**These keep the blood moving.

====Homeostatic control of blood pressure====
*BP is dependent on resistance and cardiac output and blood volume.
*Cardiac output = blood pressure / peripheral resistance.
*So blood pressure = cardiac output * peripheral resistance.
*Remember that CO is controlled by stroke volume and heart rate.
*Blood viscocity does not change on an acute basis, really.
**You can add RBCs or water (via salt).
*You don't change blood vessel length in acute situations.
*You can, however, change blood vessel diameter acutely.
**Recall that the resistance is inversely proportional to the fourth power of the radius.

=====Regulation of peripheral resistance=====
*Important for temp regulation.
*Important for shunting toward GI tract after a meal.
*Important for stress and danger, getting blood to the heart, brain, and skeletal muscle.
*Peripheral resistance can be regulated in three ways: autoregulation, neuronal regulation, and endocrine regulation.

======Autoregulation======
*These are mechanisms that the vessel itself generates.
*Warming a vessel will dilate it, cooling it will vasoconstrict.
*Endothelium is released in low flow situations to constrict.
**NO is the opposite, it causes dilations in response to high blood flow.
*Inflammatory chemicals, which are likely to come from blood that is inside the vessels (like histamine). These can change the permeability of the vessels.
*Metabolic processes can generate both dilators and constrictors.
**Lactic acid is a dilator which makes sense because the muscles need to get that lactic acid out of there and to get oxygen to the muscle.
**K+ and H+ also cause dilation. These, too, make sense because they are like acids and metabolic processes generate acids which means there is work going on and that oxygen is needed.
**Prostaglandins are vasoconstrictors.
*Response to oxygen:
**In the systemic system, vessels will dilate if there is low oxygen to increase blood flow. In the pulmonary circulation if there is low blood flow, they will constrict to increase ? Wait, what?

======Neural controls======
*The cardiovascular center in the brain stem both positively and negatively affects cardiac output.
*This exact same area can also control the cardiovascular system.
*There are lots of receptors yielding input for the neural control system:
**Baroreceptors, higher brain centers, chemoreceptors, and propriocenters.
*The major affect on peripheral constriction is the ....
*Smooth muscle and peripheral tissue are being vasoconstricting:
**Most veins.
*The sympathetic system vasoconstrics only the veins, the periphery, and the ... not the heart or brain.

*Baroreceptors:
**Found in carotid arteries, in the aorta, in many of the major vessels.
**They sense the blood pressure.
**If bp goes up, there is feedback to the cardiovascular center which causes vasodilation of the vessels. This makes sense because dilating will decrease blood pressure. The heart rate and contractile force can also be decreased in order to decrease bp.
**If bp goes down, the cardiac output center can constrict blood vessls and increase heart rate / contractile force. This is done by
***stimulating the vasomotor centers which are trying to constrict the vessels
***stimulating the cardioacceleratory centers
***inhibiting the cardiovascular control function to allow the heart rate to increase.
**Some baroreceptors are set up to allow for individual responses to bp changes.
***For example, the carotid sinus reflex controls bp to the brain, even while the rest of the body is going for a fast run or what not.
***The aortic reflex is systemic.
***The atrial (right heart) reflex response to venous blood return (venous BP) and thus makes the heart pump faster and with more contractility to avoid a backlog of blood.
**These are all short term and only meant for acute changes.

*Chemoreceptors:
**Sense changes to gasses and pH in blood and cerebrospinal fluid.
**When stimulated, they cause vasoconstriction.
**Chemoreceptors have systemic effects, including the pulmonary branc, not just local.

*Higher brain centers:
**Anxiety, fear, temperature, exercise can all change either vasodilation or cardiac output.

*Hormonal control:
**The endocrine controls act directly on vascular smooth muscle or on the vasomotor area.
**There is lots of overlap of neural and endo control because the two systems use similar molecules.
**Neural control didn't change blood volume but endocrine system can.
**Adrenal medulary hormones:
***Epi, norepi: vasoconstrictive, except for skeletal and cardiac muscle.
***ADH, AVP: produced by hypothalamus, released by posterior pit, released in response to decreased blood volume or increases osmotic concentration. If levels are high enough, it will cause vasoconstriction. It stimulates the kidney to retain water.
***Renin-angiotensisn-aldosterone axis: when blood volume falls, renin is released which increases angiotensin II. Angiotensin II is vasoconstrictive and causes the release of aldosterone (long lasting steroid) and ADH (fast acting protein) which increase salt and water retention by the kidney. Aldosterone and ADH work on calcium and sodium channels (though I don't know which one is which). ADH also yields thirst.
***EPO: causes increase in RBC, which increases viscocity, so we must consider this when thinking about how to regulate BP.
***ANF (atrial naturetic factor / peptide): this is the exact opposite of ADH. It is a peptide hormone. This hormone is released by the cardiac atria upon increased pressure (particularly vatrial return). The immediate affect is vasodilation. Long term, ANH causes the kidneys to excrete salt and water.
***Alcohol: immediate depresses vasomotor center which promotes vasodilation and gives you a flushed look. It also inhibits ADH and thus makes you have to go the bathroom.

*Illustration of changes in blood pumping rate and where all the blood gets directed and in what amounts.

=====Exercise=====
*Muscle activity is increased so blood gets moved there.
*Breathing rate has increased to get more oxygen but also increased venous return because the respiratory return is going fast.
*There is increased venous return is increased.
*Frank Starling's principle is in effect: more blood comes in, more blood gets pumped.
*Missed the last point.

=====Blood loss=====
*In the short term, the baroreceptors will cause peripheral vasoconstriction and increase the heart rate.
*The stress of losing blood stimulates the sympathetic nervous system which increases vasomotor tone and increases vaosconstriction.
*Epi and norepi will be released t increase CO and vasoconcstritno.
*ADH will be released which iwll cause vasoconstriction.
*Now for the longer term:
**Aldosterone will get become active and cause retention of fluid via salte and water of kidney.
**Thirst will go up because of ADH.
**EPO will be released to increase RBCs.

====Circulatory shock=====
*Shock is when you cannot maintain normal flow through the system.
*Hypovolemic shock is a low blood volume, caused by vomiting, diahhrea, blood loss, etc.
*Vascular shock: an infection or reaction is causing dilation in vasculature such that blood pressure is low.
*Cardiogenic shock: the heart isn't pumping well.
*Orthostatic intolerance: under zero G force, body fluids shift to upper body, activate baroreceptors which trigger fluid loss because they think there is too much bp. When back to normal G force, blood rushes to lower limbs and is inadequate at the brain because the body has shed blood volume.

====Alterations in blood pressure====
*Hypotension: a chronic low blood pressure. CAn be caused by:
**starvation (low protein in blood)
**Addison's disease (inadequate adrenal cortex funcion)
**Hypothyroidism (runing the metabolism too much)
**Orthostatic hypotension.
*Circulatory shock: talked about it already.
**Something about old people.
*Hypertension
**Acute: fever, exercise, fear
**Chronic: affects 28% of adult Americans
***Over 50 is about 55%.

*done with cardiovascular system.
*We'll do CF next.

*stopped here on 02/22/10.