CVPR-Cardiovascular+Old+LOs

//These notes were prepared by James Rose, CO 2011. Note that lecture order and content have been substantially reorganized since these notes were written.//

Intro to the CV system Wednesday, March 12, 2008 3:17 PM


 * Intro to the CV system, 3/17/08:**


 * [Disclaimer: I am not a physicist. I think the highest undergraduate grade I got in physics was one B-minus amidst a small horde of C's and D's. Pressure, resistance and flow are where I'm weak in the following notes. So if something about them strikes you as off, even moreso than the rest of it, double-check with someone who knows what they're talking about.]


 * [Before we get into this:]
 * **Strength of contraction**, as far as I and my notes here are concerned, is the pressure generated by the contraction of a chamber of the heart (usually the left ventricle). This tends to go up when there's more blood in the chamber, because the myosin and actin filaments in the stretched wall of the chamber have been moved into a configuration that can generate more force when they contract. This relation between "preload" (how much blood is in the chamber) and the strength of the contraction is graphed by __Starling's Law__, which we'll get into later. The strength of contraction also depends, in a different way, on how much diastolic aortic pressure ("afterload") the heart is working against to pump blood out into circulation.
 * **Contractility** is the varying ability of the cardiac muscle cells to contract __independent__ of changes in preload or afterload. It depends on the levels of calcium in cardiac muscle cells and the efficiency with which that calcium can be used by contracting actin and myosin filaments, and is essentially a __chemical__, as opposed to a __physical__, variable. As such it is modified by __chemical__ means, such as the neurotransmitters of the sympathetic and parasympathetic nervous system. It is __not itself changed__ by purely physical changes such as alterations in preload or afterload, although certainly one response of the heart to those physical changes involves sympathetic or parasympathetic responses that can modify contractility.
 * Ok, now everything else should make a little more sense.
 * Describe the basic anatomy of the heart, including the arrangement and names of the chambers, the valves, and the major vessels carrying blood to and from the heart.
 * A lot of territory to cover here. The atria sit __above__ the ventricles and pump blood __down__ into them; the ventricles in turn pump blood __back in the superior direction__ out of the main arteries (pulmonary and aortic).
 * Valves between atria and ventricles: **tricuspid** (right atrium-right ventricle) and **mitral** (left atrium-left ventricle). These are sometimes called the __atrioventricular valves__.
 * These open into the ventricle on pressure from the atria but shut against pressure from the ventricles. Their main function is to prevent backflow into the atria when the ventricle contracts.
 * Valves between ventricle and main arteries: **pulmonic** (between right ventricle and main pulmonary artery) and **aortic** (between left ventricle and ascending aorta). These are sometimes called the __semilunar valves__.
 * These open into the great vessels on pressure from the ventricle but shut against pressure from the vessels. Their main function is to prevent backflow into the ventricles.
 * Recall that the coronary arteries lie almost directly above the aortic valve-- thus proper closing of the aortic valve is important for proper coronary circulation.
 * Note that valves are mechanical contrivances and their opening and closing are not controlled by the heart as such-- they are regulated by the pressure on either side of them. The left ventricle doesn't 'tell' the aortic valve to open; it opens when the pressure inside the ventricle exceeds the pressure outside in the aorta, and closes (more or less) when that's no longer the case.
 * Explanation of 'more or less' for the curious: after the pressure in the ventricle has gone down below the aortic pressure, the inertia in the outflow of blood keeps the valve open for a short time, called the reduced ejection phase. Perhaps it would be a closer approximation to say that the valves open in response to pressure gradients but close in response to flow gradients.
 * There are small muscles (papillary muscles/chordae tendinae) that connect the ventricular side of the atrioventricular valves to the walls of the ventricles. Their function is __not__ to pull the valves open (the flow of blood from the atrium should do that) but to tense as the ventricle contracts to ensure that the valve isn't inverted into the atrium (which would bollocks up the point of having a valve there in the first place).
 * Note there are no papillary muscles associated with the semilunar valves (they have to deal with less back-pressure).
 * The main inflow comes from the venae cavae (inferior and superior) and the coronary sinus into the right atrium and the pulmonary veins into the left atrium. These, as far as I know, do not have valves associated with them (thus backflow into the venous system from the atria can occur).
 * Quick note about shapes. __The right ventricle is shaped like a curved wedge__ (make a triangle and sort of step on the top and curve the edges down) or a thick crescent. It contracts by flattening the top of the triangle against the bottom. __The left ventricle is shaped more like a cone__ and can contract from all sides in towards the middle, which gives it proportionally greater contractile force than the right (which partially explains the tremendously different pressure gradients created by the same quantity of outflow from the right and the left ventricle).
 * [Couple notes on average values:]
 * __Blood volume__ for a hypothetical average person (here, specifically a hypothetical healthy young male adult) is __70 mL/kg__ body weight. Our hypothetical young gentleman is 70 kg, and thus has about 5 L of total blood volume. Small people have less, big people (even people who are just big-boned) have more.
 * __Cardiac output__ for our guy is about __80 mL/min x kg__ body weight-- thus about 5.6 L/min. Again, small people = less, svelte-challenged people = more.
 * What this means: it takes a given blood cell a little less than a minute to travel through the entire body.
 * Describe the relationship between stroke volume (SV), heart rate (HR), and cardiac output (CO), and why SV, HR, and CO for the left and right ventricles must, on average, be the same.
 * Last part first.
 * The right ventricle is pumping in the blood that's being pumped out by the left ventricle. Think about a tank of water (the blood in the lungs) with two pumps, one pumping in and the other pumping out. If the one pumping in is pumping more than the other, the tank will overflow. If the one pumping out is pumping more than the other, the tank will run dry. They need to be pumping equal volumes, on average, for this to work.
 * This is really an argument about cardiac output. But you can't change heart rate or stroke volume without affecting cardiac output (see next point).
 * **CO = SV x HR** . This makes sense. The amount of blood your heart outputs per minute is equal to the amount it puts out per stroke times the number of strokes per minute.
 * In principle, you could set up a system whereby the heart rate is higher and the stroke volume is lower on one side but the total CO is equal between sides. In principle on Mars. We ain't set up for that-- both sides contract and relax more or less at the same time, thus have the same heart rate.
 * Since cardiac output has to be the same, and heart rate has to be the same, stroke volume also has to be the same between sides.
 * Guaranteed by Dr. Wallace to be on the first exam: __the stroke volume, cardiac output, and heart rate are equal between the left and right sides of the heart__.
 * Describe why the mean pressure decreases as blood moves from the aorta to the arteries, arterioles, capillaries, venules, and veins of the systemic circulation. List typical mean pressures for each class of vessels, which class shows the greatest drop in pressure, and which vessels contribute most to the total peripheral resistance (TPR). Compare pressures in the systemic and pulmonary circulations.
 * The mean blood pressure decreases:
 * (a), because the total cross-sectional area that it needs to cover increases dramatically from the aorta to the smaller vessels; the cross-sectional area of the capillaries is 1000x greater than that of the aorta. Same flow + larger diameter = slower blood = less pressure. This is the less important of the two reasons listed here.
 * What he specifically says is that the increase in area decreases linear velocity. I'm extrapolating that decreased velocity in a vessel also decreases the pressure that vessel is under. But note that he mentions later than the velocity of the blood (dynamic pressure) is a relatively minor contributor to the overall pressure (it's dwarfed by linear pressure, which is minimally impacted by velocity). So if he asks, go with the next one.
 * (b), because the smaller the individual vessels get, the more resistance they offer to blood flow. The aorta is massive and elastic and offers relatively little resistance to flow. The arterioles are tiny and inelastic and offer a great deal of resistance to flow, thus creating a __pressure drop__ across them between the high-pressure blood entering them from the arteries and the low-pressure blood leaving them to the capillaries. This is the more important of the two reasons listed here.
 * The veins and venules don't change the pressure that much after the blood leaves the capillaries in venules, but their cross-sectional area is still bigger than their arterial counterparts. Note that this means that most of the blood in the circulation is in the venous system at any given time. The veins are sometimes called the storage or __capacitance__ vessels for this reason.
 * Mean pressure is just the pressure in a vessel, averaged over time to even out fluctuation between systole (blood pumped out of the ventricle) and diastole (no blood pumped out of the ventricle). Note that the relative lengths of systole and diastole change, so it's not just a matter of adding systolic and diastolic pressure and halving them.* Pulse pressure is just the absolute difference between the peak systolic and the low diastolic pressures.
 * *Specifically, the length of diastole changes with heart rate. The length of systole stays relatively constant.
 * [At rest, generally the mean pressure is about a third of the pulse pressure up from the diastolic pressure.]
 * **These pressures are important** (from his Figure 1):
 * Mean pressure in the aorta: 95 mm Hg (120 systolic, 80 diastolic)
 * Mean pressure __drop__ in the arteries: 95 mm Hg (130 systolic, 75 diastolic) to 85 mm Hg.
 * Notice that although the MAP stays constant from aorta to the beginning of the large arteries, the pulse pressure actually goes up. We don't need to know why, it's got math in it.
 * Mean pressure __drop__ across the arterioles: from 85 to 35 mm Hg.
 * Mean pressure __drop__ across the capillaries: from 35 to 15 mm Hg.
 * Mean pressure __drop__ across the venules and veins: from 15 to 0 mm Hg.
 * The arterioles contribute most to the total peripheral resistance-- they have the highest flow resistance of any vessel. For this reason, they also show the greatest drop in pressure.
 * Note that the arterioles are where the body can, and does, use a small amount of effort to its greatest effect. Because small changes in their diameter (they're small to begin with) can create large changes in their resistance, contracting or relaxing regional arterioles takes very little energy but produces a significant impact on blood flow in the region. We'll see this effect again later.
 * All of the above is systemic (non-pulmonary) information. The pulmonary circulation is much less pressurized (as you'd expect given its much briefer course). **The mean pressure in the pulmonary arteries is about 15 mm Hg (25 systolic, 10 diastolic), dropping to about 5 mm Hg in the pulmonary veins**.
 * Describe the functions of the conduit arteries, arterioles, capillaries, and veins.
 * Arteries: get blood to the arterioles.
 * Arterioles: get blood to the capillary beds; also constrict or relax to regulate micro- (and thus macro-) vascular blood flow.
 * Capillaries: do the gas exchange tango.
 * Veins: get blood back to the lungs and act as a blood reservoir.
 * Note that the arteries and arterioles are called the __resistance vessels__, while the venules and veins are called the __capacitance vessels__. What you get when you let physicists define your medical terms.
 * Describe how the total cross-sectional area of the systemic vascular bed changes from aorta to capillaries to venae cavae, how this influences linear velocity in each portion of the vascular bed, and how linear velocity impacts exchange between the capillary bed and the interstitial space.
 * It gets much larger from aorta to capillaries (about 1000-fold). This means that the velocity goes from very fast (200 mm3/sec in the aorta) to quite slow (0.2 mm3/sec) -- the same amount of blood is having to cover more area.
 * This slowdown is good-- it means there's enough time for gas exchange to take place in the capillaries.
 * The cross-sectional area gets smaller again from capillaries to veins. But note that the velocity is already pretty slow, and since the veins don't provide much contractile force to repressurize it, it more or less stays slow.
 * Note that this is one reason why most of the blood (64%) is in the venous system at any given time-- it's where the blood is moving more slowly. Another reason is that the veins generally have more cross-sectional area than their corresponding arteries (don't have all that smooth muscle and elastin).
 * I think what he's getting at is that (a) blood slows down after it leaves the heart and doesn't substantially speed back up until it gets to an atrium, and (b) this allows capillary gas exchange (ie. it allows a balance of hydrostatic and oncotic pressures, see "Microcirculation and Lymphatics").
 * Define the terms pulsatile pump, systole, diastole.
 * Pulsatile pump: rhythmically contracting pump, like the heart. The term's here to differentiate your heart from pumps that constantly run (like the one in your aquarium, or the aquarium of someone cool enough to own one).
 * **Systole** : contractile stage of a heart chamber or set of chambers. Usually refers to ventricular contraction, but you could also talk about atrial systole.
 * **Diastole** : relaxation (filling) stage of a heart chamber or set of chambers. Again, usually refers to ventricular relaxation.
 * Describe the difference between mean pressure, systolic pressure, diastolic pressure, and pulse pressure and give typical values for each in the aorta and the pulmonary artery.
 * Mean pressure: as mentioned, the average pressure in a vessel over time.
 * Systolic pressure: the pressure in a vessel during ventricular systole (contraction)
 * Diastolic pressure: the pressure in a vessel during ventricular diastole (relaxation).
 * Note that this generally refers to the lowest pressure obtained in a vessel (which is generally the pressure right before ventricular systole forces more blood into it). Thus aortic diastolic pressure usually means the pressure in the aorta not right after the aortic valve closes (which would put it about at the systolic pressure) but right before it opens again.
 * Pulse pressure: the difference between the diastolic and systolic pressures for a given vessel.
 * This was more or less covered above, but:
 * Aorta: mean arterial pressure 95 mm Hg (120/80), pulse pressure 40.
 * Pulmonary artery: mean arterial pressure 15 mm Hg (25/10), pulse pressure 15.
 * Describe how the heart sounds arise and when during the cardiac cycle the first (S1) and second (S2) heart sounds occur.
 * Contrary to popular belief (ie. mine before I read different), heart sounds are not directly caused by the noise of the valves closing, but by the turbulent flow rushing against the newly closed valves. Notice that it's still okay to say "The S1 heart sound is caused by the closing of the atrioventricular valves" as long as you know it's an indirect mechanism. I might make fun of you a little, though.
 * S1: occurs when the atrioventricular valves close, who'da thunk it. Since the AV valves close when the blood from the ventricle is about to come back up through the atrium, and since that happens at the beginning of systole, the S1 heart sound shows up at the beginning of systole.
 * S2: occurs when the semilunar valves (vessel valves) close. Again, these valves are design to prevent backflow from the vessels, so they'll close when the inflow into the ventricle is greater than the outflow, which should occur more or less at the beginning of diastole.

Delivery of Oxygen and Measurement of Cardiac Output Wednesday, March 12, 2008 6:01 PM


 * Delivery of Oxygen and Measurement of Cardiac Output, 3/17/08:**


 * Describe the concept of partial pressure and list the partial pressures of O2 and CO2 in atmospheric air and in alveolar air at sea level. Compare the atmospheric pressure and the partial pressures of O2 and CO2 at sea level and in Denver.
 * Partial pressure: well, you have a total //atmospheric pressure// from all of the atmospheric gases around, pressing in on you. The fraction of that pressure that comes out of a particular component of that atmosphere is the **partial pressure** of that component, and is found by multiplying the total pressure of all the gases by the fraction of the atmospheric gases that that component makes up.
 * Ie: the Earth's atmosphere is generally 79% N2, 21% O2, and 0.03% CO2. The atmospheric pressure at sea level is 760 mm Hg, or 760 torr.
 * The partial pressure of O2 at sea level is (760 x 0.21 = ) 160 mm Hg.
 * The partial pressure of CO2 at sea level is (760 x 0.03 = ) 22.8 mm Hg.
 * These can be denoted as PO2 and PCO2, respectively.
 * Higher up, there's less atmosphere above you, thus there's less atmosphere to be weighed down by gravity and press on you, thus there's less total atmospheric pressure. In Denver, the total atmospheric pressure is about 630 mm Hg. Note that its composition remains the same (79-21-0.03%).
 * In Denver, the PO2 is (630 x 0.21 = ) 132 mm Hg.
 * In Denver, the PCO2 is (630 x 0.03 = ) 18.9 mm Hg.
 * The air in the __alveoli__ needs to have the same total pressure as the atmospheric air, but has a considerably higher CO2 content (from metabolism) and H2O content (intaken air becomes saturated with water vapor); thus the partial pressures are different from atmospheric air and are denoted PAO2, PACO2, and PAH2O ("PA" for alveolar, not atmospheric. Additionally, "Pa" stands for arterial partial pressure. You'd think someone could have predicted confusion). Specifically, at sea level:
 * PAO2 = 100 mm Hg
 * PACO2 = 40 mm Hg
 * PAH2O = 47 mm Hg
 * The rest (to make up the total 760 mm Hg) is presumably nitrogen, though since we don't make use of gaseous N2 no one much talks about it.
 * Explain the relationship between O2 saturation, O2 capacity, and O2 content of blood. List typical values for the partial pressures of O2 and CO2, O2 saturation, and O2 content of arterial and venous blood. Explain why venous O2 is a useful indicator of the ratio of O2 demand to O2 delivery.
 * That's a mouthful. Here we go.
 * **O2 saturation** of blood: what percentage of hemoglobin in blood is bound to O2. Has no units, it's just a percentage.
 * **O2 content** of blood: that same percentage converted to units of O2. Has units of mL O2 per 100 mL blood-- thus notice it's actually a __concentration__.
 * **O2 capacity** of blood: how much O2 could, in principle, be bound in blood if every available hemoglobin molecule was fully bound to O2. Has units of mL O2 per 100 mL blood-- thus it's also a concentration.
 * Assuming that you have the % saturation of O2 in blood, to convert to the __content__ (ie how much O2 is that, exactly?) you need to know how much O2 would be bound at 100% saturation-- ie, the O2 capacity.
 * You can figure out the O2 capacity by multiplying the amount of O2 that binds to hemoglobin (1.34 ml O2 per gram of Hb) and the concentration of hemoglobin in the blood (generally around 15 grams Hb / 100 mL).
 * Note that for whatever reason, hemoglobin and oxygen content tends to be measured per deciliter (= 100 mL) of blood. Note also that O2 content is generally measured in mL. Damn dead old smart white men and/or dead old smart women, transsexuals, or people of color.
 * This means watch your units. He likes to trip you up in conversion from 100 mL to liters and back-- watch out for factor-of-10 mistakes.
 * Once you have the O2 capacity (which tells you how much O2 is present at 100% saturation) and the current % saturation, you can multiply one by the other to get the O2 content of blood. That is: __Saturation__ x __Capacity__ = __Content__.
 * Once you have O2 content of the arterial blood (generally about 19 mL/100 mL blood, or 95% saturated) and the O2 content of the venous blood (generally about 14 mL/100 mL blood, or 70% saturated), you can subtract the one from the other (to get about 5 mL/100 mL blood) and multiply by the total cardiac output (usually about 5 L/min) to get the rate of oxygen consumption (**VO2** ).
 * In case you didn't catch that: __at rest the difference in O2 content between arterial and venous blood is about__ **5 mL O2/100 mL** __blood__.
 * Multiplying that by the cardiac output gives you the rate of systemic oxygen consumption (given average CO of 5 L/min, = about 250 mL/min).
 * This is an application of Fick's Principle (see below).
 * **Typical values** :
 * **PO2: arterial = 100 mm Hg, mixed venous = 40 mm Hg**
 * Remember your O2-hemoglobin dissociation curves here. At 100 mm Hg (assuming a standard curve) about 95% of hemoglobin molecules should be bound to hemoglobin. At 40 mm Hg, about 70% of hemoglobin molecules should be bound to hemoglobin.
 * Left-shifting effects (methemoglobinemia, etc): more O2 bound at both 100 mm Hg and 40 mm Hg (thus less O2 delivery to tissues).
 * Right-shifting effects (exercise, low pH, etc): less O2 bound at both 100 mm Hg and 40 mm Hg (thus more O2 delivery to tissues).
 * Remember that reductions in the hemoglobin count shouldn't affect what __saturation__ percentage of hemoglobin is bound to oxygen at a given PO2, although they will decrease the oxygen __content__ of that hemoglobin.
 * **PCO2: arterial = 40 mm Hg, mixed venous = 45 mm Hg**
 * **O2 saturation: arterial 95%, venous 70%**
 * **O2 content: arterial 19 mL/100 mL blood, venous 14 mL/100 mL blood**
 * Venous O2: for the purposes of our present discussion, it can __only be measured systemically at the pulmonary artery__ ("mixed venous blood"). The reason for this is that that's the only place where the venous blood from all parts of the body (including the coronary arteries) is adequately mixed together (thus it's the only place where you can get an idea of mean O2 consumption). Since this is the blood going into the lungs to be reoxygenated, it's a good place to look to see how much oxygen the tissues have pulled out of it. If the venous O2 is high relative to normal, your ratio of O2 supply to demand is probably fine. If venous O2 is low relative to normal, the demand is probably up relative to supply.
 * Note that you can measure arterial O2 and CO2 content in any major artery and they'll be more or less the same, in contrast to venous blood where oxygen consumption varies tremendously by the tissue that's been supplied.
 * Note that you can measure the PO2 and PCO2 perfectly well in arteries going to and veins going away from a given organ if you want to look at oxygen consumption by that organ. But precisely because O2 consumption by different organs are different, you can't take venous blood from any organ as representative of oxygen consumption in the entire system.
 * Describe the equilibrium of O2 between alveolar air, plasma, the cytoplasm of red blood cells, and hemoglobin.
 * Lots of time for the O2 to equilibrate between the alveolar air (recall PAO2 = 100 mm Hg) and the plasma in the alveolar capillaries. The O2 diffuses from there into the red blood cells and thence into the hemoglobin.
 * Describe the equilibrium of CO2 between alveolar air, plasma, and bicarbonate.
 * Similarly, lots of time for it to equilibrate from the alveolar air into the capillary plasma. Once it's in the plasma, it reacts with water to form carbonic acid (H2CO3), which in turn dissociates into H+ and HCO3- (bicarbonate).
 * Describe the basis of Fick's Principle and demonstrate how it can be used to determine cardiac output.
 * Fick's Principle: early method to determine cardiac output, based on conservation-of-matter principles:
 * The amount of O2 in the blood coming out of the pulmonary veins must equal the amount of O2 in the blood going into the pulmonary arteries, plus whatever O2 is absorbed into the blood in the alveoli.
 * Note that the subject must be at steady-state for this, but can it be either a resting or an exercising steady state.
 * __Quantity__ of O2 (not the same as __content__, which is actually a concentration) in blood equals __the content times the cardiac output__ (CO). So Fick's principle can be expressed:
 * [O2]pulm. veins x CO = [O2]pulm. arteries X CO + O2 uptake in lungs
 * This means you can rearrange to figure out the CO, assuming you know everything else:
 * **CO = (O2 uptake)/([O2]pulm. veins - [O2]pulm. arteries)**
 * Ie: CO = O2 uptake divided by the difference in O2 content between pulmonary venous and pulmonary arterial blood.
 * Note, as mentioned before, that you can also solve Fick's equation to get the rate of oxygen consumption in a tissue, given that you know the O2 content going in and out and you know the total cardiac output. Note that the O2 uptake term and the term for O2 consumption - VO2 - are the same, which makes sense if you think about it a moment. The equation is outlined below.
 * Identify where samples of true mixed venous blood can be obtained.
 * As indicated, at the pulmonary artery __only__.
 * Use Fick's Principle to determine the rate of oxygen consumption by a particular tissue or organ.
 * Recall the basic concept here: the O2 content going into the tissue must equal the O2 content leaving it, plus the amount of O2 consumed by the tissue.
 * Therefore the O2 consumed by a tissue = the cardiac output times the difference in O2 content between the arterial blood entering it and the venous blood leaving it.
 * **(VO2)tissue = CO x ([O2]arterial - [O2]venous)tissue**
 * If this doesn't make sense, send Jeff Dunn a few dozen emails until it does.
 * Note this is exactly what we did earlier, albeit systemically, when looking at systemic oxygen consumption by using the difference in O2 content between pulmonary venous and arterial blood.
 * Describe how indicator dilution, thermodilution, and echocardiography techniques can be used to determine cardiac output.
 * Indicator dilution: Essentially, you stick a substance into the subject's vein or right heart and see how long it takes for all of it to pass by some arbitrary point downstream in the circulation (you detect the presumably labeled substance through some manner of ingenious device such as a radiograph). This should give you an idea of how much volume is being passed through the system: CO = q/(c x delta-t), where q = amount injected, c = concentration injected, and delta-t = amount of time is takes for all of it to pass by.
 * Thermodilution: essentially the same thing, but you use cold saline instead of labeled substances and use a temperature probe to figure out how long it takes for the colder substance to move through the vein.
 * Echocardiography: I think everyone knows what this is. Noninvasive, the cat's pajamas, etc. You can measure flow (ie. cardiac output) with it.

Introduction to Autonomic Nervous System Thursday, March 13, 2008 2:27 PM


 * Introduction to the Autonomic Nervous System, 3/17/08:**


 * Describe the anatomical projections of the sympathetic and parasympathetic autonomic nervous system and the central control of the autonomic nervous system.
 * Recall that you've got a sympathetic chain of ganglia running down outside each side of the spinal column. Sympathetic preganglionic neurons (white rami, myelinated) come off the CNS and head to their ganglia, from which sympathetic postganglionic neurons (gray rami, unmyelinated) come off and head to the target tissue.
 * Note that you can have lots of postganglionic neurons that come off from a given sympathetic chain ganglion-- this means you can have one signal generating responses in a lot of targets.
 * Exception to having pre- and post-ganglionic neurons: the adrenal medulla, in which the preganglionic neuron acts directly on the gland tissue itself (Dr. Zahniser: "the adrenal medulla acts as a big sympathetic ganglion").
 * Recall that the sympathetic nerves, of all levels, exit the spinal column with the T1-T12 and L1-L2 spinal nerves.
 * Recall that the parasympathetic ganglia are usually located in the target tissues themselves, from which the postganglionic neurons have to go a very short way to affect their targets.
 * Notice this means one input signal tends to go to only one target.
 * Parasympathetic nerves exit the spinal column mainly by following either certain cranial nerves or some of the sacral nerves.
 * Parasympathetic neurons travel with cranial nerves III (ciliary muscles), VII (salivary/lacrimal glands), IX (also salivary glands), and X (heart, lungs, stomach, GI tract up to mid-colon), as well as with sacral nerves 2-4 (genitourinary tract, rest of colon, kidneys).
 * Hypothalamus is the most important area for integrating and controlling the autonomous nervous system.
 * Also medulla oblongata in brainstem (regulation of blood pressure and respiration).
 * Some voluntary control through cerebral cortex.
 * Describe homeostasis, flight-or-fight, and rest-and-digest with regard to sympathetic and parasympathetic activity.
 * Homeostasis: generally the body keeps a dynamic balance going between parasympathetic and sympathetic activity. By altering that balance it can quickly adjust to new conditions.
 * Note that the SNS is not essential for life, but the PNS is. The SNS is there mainly to make sure you can run for dear life when your embittered professor threatens to decapitate you with a chalkboard eraser.
 * Flight-or-fight (evidently someone thought "fight-or-flight" was too pugilistic): powered by the SNS. Acts as kind of a temporary 'booster'.
 * Generally acts all over the body, in concert. Her notes say it "discharges as a unit," which seems to me like a good way to describe it. Few local effects, lots of system-wide effects.
 * Eg.: tachycardia, increased cardiac contractility, increased peripheral resistance through vasoconstriction, increased BP, increased blood glucose, dilation of the pupil, etc.
 * Rest-and-digest: powered by the PNS. Point is to curb energy use (rest) and replenish energy stores (digest).
 * Again, from her notes: "Produces discrete, localized discharges." Like ex-governor Spitzer. Oops, that was out loud.
 * Seriously, what a freaking moron.
 * So in contrast to the SNS, the PNS has predominantly local effects.
 * Eg.: increased secretion from bronchial, lacrimal, and salivary glands, constriction of the pupil, bradycardia, increased GI motility and absorption, etc.
 * List the neurotransmitters and receptors that mediate neurotransmission at the ganglia and/or end organs in the parasympathetic and sympathetic nervous systems
 * Parasympathetic nervous system:
 * Preganglionic neurons release ACh in the ganglia.
 * ACh interacts with neuronal-type nicotinic ACh (cholinergic) receptors (or **NNRs** ) in the ganglia to effect postganglionic transmission.
 * Parasympathetic end-organ (postganglionic) neurons release ACh at their target sites.
 * ACh interacts with **muscarinic receptors** to effect parasympathetic stimulation.
 * PNS: Acetylcholine all the way through, baby.
 * Sympathetic nervous system:
 * Preganglionic neurons release __acetylcholine__ (ACh) in the ganglia/adrenal medulla.
 * ACh interacts with neuronal-type nicotinic ACh (cholinergic) receptors (or NNRs) to effect postganglionic transmission.
 * This much is similar to the parasympathetic system.
 * Postganglionic neurons mainly release __norepinephrine__ (NE) at their targets.
 * Exceptions:
 * The adrenal medulla releases mainly __epinephrine__ (EPI), directly into the blood stream.
 * Postganglionic sympathetic neurons innervating sweat glands release __ACh__.
 * Postganglionic sympathetic neurons innervating renal blood vessels release __dopamine__ (DA).
 * Generally, sympathetic end-organ (postganglionic) neurotransmitters (mainly NE and EPI) interact with **alpha- and beta-adrenergic** **receptors** in the end organs to effect sympathetic stimulation.
 * Exceptions:
 * In sweat glands: ACh interacts with muscarinic receptors instead (to increase sweat production).
 * In renal blood vessels: DA interacts with dopamine-1 receptors (DA1Rs) instead (to cause vasodilation).
 * Discuss the concept of “tone” and explain the consequences of the fact that parasympathetic tone predominates at most organs and tissues.
 * Both SNS and PNS (which is how we're calling the parasympathetic nervous system here) innervate most organs. Most important exception to this is blood vessels, which are innervated by SNS only (contraction).
 * "Tone," I think, refers to the fact that both are generally stimulating most organs at most times-- thus control over which one predominates is like a rheostat as opposed to a light switch. Increasing the sympathetic tone involves turning the rheostat towards the sympathetic side (thus increasing the relative stimulation from the sympathetic as opposed to the parasympathetic system), and vice versa.
 * Notice, however, that tone also frequently refers to the amount of SNS or PNS innervation, or the number of a given type of receptors, that an organ has. So take my definition with a grain of salt.
 * As mentioned, the PNS predominates in most organs and tissues. This intimately relates to the fact that the PNS is essential for life and the SNS isn't.
 * Note that the parasympathetic system __doesn't__ directly innervate the muscles of the blood vessels. We'll get more into this in the next lecture.
 * List and describe the responses of end organs to activation of the sympathetic and parasympathetic nervous systems.
 * Sympathetic:
 * Contracts radial iris (pupil dilation). Less importantly, it also relaxes the ciliary muscle and increases tear secretion.
 * Accelerates heart rate, increases atrial and ventricular contractility, increases AV node conduction.
 * Constricts arteries in skin, mucosa, abdominal viscera, and skeletal muscle.
 * Constricts systemic veins.
 * Slightly relaxes bronchial smooth muscle.
 * Decreases GI motility and contracts sphincters.
 * Decreases motility in urinary tract, contracts genitourinary sphincters, both relaxes and contracts the pregnant uterus, controls ejaculation.
 * Increases sweat and saliva secretion.
 * Contracts spleen capsule.
 * Metabolism:
 * Glycogenolysis in skeletal muscle and liver
 * Gluconeogenesis in liver
 * Lipolysis in fat cells
 * Increased renin release in kidney
 * Decreased insulin release in pancreas
 * Parasympathetic:
 * Contracts circular iris and ciliary muscle (pupil constriction), increases tear secretion.
 * Decreases heart rate, atrial and ventricular contractility, and AC node conduction.
 * No effect on arteries and veins.
 * Contracts bronchial smooth muscle and stimulates bronchial secretion.
 * Increase urinary motility, relaxes genitourinary sphincters, controls erection.
 * No effect on sweat, spleen, or metabolism.
 * Increases salivation.
 * Describe the general mechanisms by which most drugs alter activity in the autonomic nervous system.
 * (1) Mimicking neurotransmitter at receptors (direct agonists)
 * (2) Blocking neurotransmitter receptors (direct antagonists)
 * (3) Altering synthesis, release, or reuptake of the neurotransmitter (indirect agonists/antagonists)

Parasympathetic Nervous System Thursday, March 13, 2008 3:01 PM


 * Parasympathetic Nervous System, 3/18/08:**


 * List the steps in the synthesis, storage, release and inactivation of acetylcholine, and drugs that interface with those processes.
 * Big picture: ACh has two parts, an acetyl group and a choline group (no kidding, huh). You put the two together inside the presynaptic neuron, which makes ACh an active compound. It's stored in vesicles, gets released into the synaptic cleft, does its neurotransmitter thing, and is broken back down into an inactive choline and an acetyl group by esterases. The choline gets transported back into the presynaptic neuron, gets activated by another acetyl group, and the band plays on.
 * Note that ACh has a __quaternary amine group__, which gives it a permanent positive charge, which means it can't cross membrane barriers well-- which means that it **can't get through the BBB**.
 * Synthesis in the presynaptic neuron:
 * Pyruvate donates an acetyl group to the enzyme CoA.
 * ACh is synthesized by the further transfer of this acetyl group onto choline.
 * The choline has been transported into the neuron by choline transporters (the rate-limiting step in ACh synthesis is this uptake).
 * The acetyl transfer reaction is catalyzed by choline acetyltransferase.
 * ACh is sequestered inside vesicles to be stored until its release.
 * Vesicular acetylcholine transporter (VAChT) does this.
 * Release into the synaptic cleft:
 * Can occur spontaneously in small packages (vesicles).
 * But generally due to stimulation in the neuron:
 * Ca2+ stimulates release from vesicles into cleft.
 * This releases lots of ACh (hundreds of vesicles) at once.
 * Release is modified by cholinergic receptors on the presynaptic neuron (negative feedback mechanism).
 * If these presynaptic receptors are bound by the same NT that's being released, they're called "autoreceptors"; if they're bound by a different NT (as when epinephrine from the sympathetic system inhibits release of ACh in the heart or the GI tract), they're called "heteroreceptors."
 * Once it's in the cleft, it can be broken down by acetylcholinesterases (enzymes that break down the ester linkage between acetyl and choline) and inactivated.
 * Choline transporters reuptake the choline into the presynaptic neuron for reuse.
 * For cholinergic receptors:
 * a) List the locations of and the differences between nicotinic and muscarinic cholinergic receptors.
 * b) Describe the signal transduction mechanisms activated by stimulation of nicotinic versus muscarinic cholinergic receptors.
 * c) State the significance of presynaptic versus postsynaptic cholinergic receptors.
 * Nicotinic cholinergic receptors are __ligand-gated ion channels__. (They're also called nAChRs, for nicotinic ACh receptors.)
 * When stimulated, they allow influx of Na+ through the membrane and trigger depolarization (and thus an AP, in neurons).
 * Muscarinic cholinergic receptors are __G protein-coupled receptors__. (They're also called mAChRs, for muscarinic ACh receptors.)
 * When stimulated, they use second-messenger systems to activate various, largely calcium-concerned, effects.
 * There's two functional classes of mAChRs, and the five subtypes of receptor are split among them:
 * **M2 and M4** (evens):
 * __Inhibit adenylyl cyclase__, lowering cAMP
 * Activate K+ channels, leading to hyperpolarization
 * Inhibit voltage-gated Ca2+ channels.
 * **M1, M3, and M5** (odds):
 * __Activate phospholipase C__ (PLC), increasing intracellular Ca2+ and DAG.
 * This stimulates Ca2+-dependent nitric oxide synthase, which in turn jumps up the NO content in the cell, which (recall) tends to be anti-inflammatory and vasodilatory through increased cGMP levels.
 * Presynaptic receptors alter the release of ACh (feedback mechanisms, generally inhibitory).
 * Postsynaptic receptors can do a couple different things:
 * Nicotinic cholinergic receptors in neurons trigger action potentials.
 * M2Rs (ie M2 muscarinic cholinergic receptors) in cardiac muscle hyperpolarize the muscle cell (slow down AP conduction/generation).
 * MRs in glands: stimulate secretion.
 * MRs in smooth muscle:
 * In smooth muscle cells with pacemaker cells (like the intestine), quickens the rate of contraction.
 * In other smooth muscle cells it can either contract or relax, depending on the target organ.
 * Note that although the __smooth muscle__ of the vasculature __isn't innervated by the PNS__, the __endothelial cells__ of vessels do __have muscarinic receptors__ (mainly **M3Rs** ) in them. If stimulated, they can cause indirect vascular relaxation by NO production (NO diffuses through endothelial cells to muscle cells).
 * Locations of nicotinic vs. muscarinic cholinergic receptors:
 * Nicotinic receptors are found, within the context of this discussion, mainly in the ganglia (NNRs) and in skeletal muscle (NMRs). Muscarinic receptors are found within the target end organs themselves.
 * For muscarinic cholinergic drugs:
 * a) List the pharmacologic actions of direct acting muscarinic agonists.
 * Activate MRs at end organs-- simulate PNS activation.
 * Activate non-innervated MRs (such as those in blood vessel endothelia)-- cause vasodilation and decreased peripheral resistance.
 * Cross-react with acetylcholine's sympathetic effects-- cause sweating (recall that sweating is a sympathetic response but is caused by ACh release onto muscarinic receptors).
 * Prototypical agonist: **pilocarpine** (crosses BBB).
 * b) Describe the pharmacokinetic disposition of muscarinic agonists.
 * We don't, generally, use ACh itself (broken down too fast by acetylcholinesterases)-- use synthetic analogs of it. If you tack some methyl groups on there, can get no or slower turnover by esterases as well as a higher selectivity for muscarinic receptors.
 * Generally these, like ACh, do not cross the blood-brain barrier.
 * c) List the pharmacologic actions of muscarinic antagonists.
 * Bind and inactivate muscarinic ACh receptors, causing a limited blockade of activation of PNS system.
 * Specificity to muscarinic receptors is kind of spotty.
 * Competitive antagonists: with enough ACh put into the system, can override the antagonist activity.
 * Effects are what you'd expect with PNS depression: decreased salivary secretions, tachycardia, mydriasis (pupil dilation), slight bronchodilation, urinary retention, reduced GI motility.
 * Note also impaired sweating (thus overheating) and vasodilation ("atropine flush").
 * Prototypical antagonist: **atropine** (crosses BBB). (made from belladonna.)
 * For acetylcholinesterase inhibitors:
 * a) Describe their pharmacologic actions and why they affect muscarinic and nicotinic cholinergic transmission.
 * Block hydrolysis of acetylcholine. This means that ACh's effective lifespan in the synaptic cleft is increased.
 * They __indirectly__ activate mAChRs by preventing the removal of their stimulus.
 * They also "stimulate and then depolarization block nAChRs"-- which means that they leave ACh bound to neuronal nicotinic cholinergic receptors (which, recall, are ligand-gated ion channels), leaving the cell perpetually depolarized and unable to repolarize to send another AP.
 * Note that direct-acting nicotinic agonists (notably succinylcholine) can have this effect by binding to nicotinic receptors but being impervious to dissolution by acetylcholinesterases.
 * Prototypical AChE inhibitor: **physostigmine**.
 * b) Explain the reason why some acetylcholinesterase inhibitors are useful clinically whereas others are toxic agents.
 * Mainly because the ones that are useful are reversible and don't cross the blood-brain barrier. The ones that are irreversible and do cross the BBB are insecticides and nerve gases (think Nicholas Cage's unfortunate escape from VX gas in "The Rock").
 * Recall that acetylcholinesterase inhibition is non-specific-- it will increase the rate of ACh stimulation in the entire body.
 * [Note that although we've characterized each subtype of muscarinic receptors, as of yet we don't have selective drugs that target only particular subtypes.]

Pyruvate donates acetyl to CoA, CoA + choline + choline acetyltransferase -> ACh. Choline taken up from synapse by choline transporters (rate-limiting step) ACh sequestered by vesicular acetylcholine transporter (VAChT).

Microcirculation and Lymphatics Thursday, March 13, 2008 10:08 AM


 * Microcirculation and Lymphatics, 3/18/08:**


 * List the transmural pressure across the walls of a typical capillary in a recumbent person and use LaPlace's Law to explain why capillaries, which have thin, non-muscular walls, are not split open by such a transmural pressure.
 * __Transmural pressure__: just the difference between the pressure inside the vessel and the pressure in the interstitial space outside the vessel. This gets important when considering filtration and absorption of water in capillary beds (see below).
 * Transmural pressure in a capillary starts out, at least, at about 35 mm Hg (recall that pressure drops from 85 to 35 across the arterioles).
 * LaPlace: Transmural pressure times the inner radius of the vessel, divided by the thickness of the vessel wall, equals the tension on that wall.
 * In other words: Tension on a vessel wall is directly proportional to the **radius** of the vessel and inversely proportional to the **thickness** of the vessel wall.
 * What this means for capillaries:
 * The pressure in a capillary is about 1/3 of the pressure in the aorta (35 vs 95).
 * The thickness of the capillary is about 0.0005, or 1/2000, of that of the aorta.
 * However, the radius of the capillary is about 0.0002, or 1/5000, of the aorta's.
 * So, proportionally, the wall tension per unit of vessel wall on the capillary is (1/3) x (0.0002/0.0005) or (1/3 x 2/5) = about 1/7th of that in the aorta.
 * Remember the proportionality of tension to radius (direct) and thickness (inverse). It comes in handy later when we're looking at why aortic aneurysms tend to burst.
 * Describe how constriction or dilation of arterioles, venules, or veins would affect the flow of blood through the capillaries.
 * As mentioned, arterioles have the main effect here and regulate which capillaries are open and which are closed (note that you're not actually opening and closing the capillaries, just their access ports).
 * Venule/vein contraction doesn't do much to affect the capillaries, since constriction doesn't substantially affect their internal pressure..
 * Note a phenomenon called "**vasomotion** " in which the arterioles and venules rhythmically constrict and relax, to help microvascular blood flow and to ensure that the blood gets spread out through all available capillaries.
 * Note also that vessels called "metaarterioles" can connect arteries directly to veins, bypassing the capillary beds.
 * Describe the cellular and paracellular pathways for movement of fluids and dissolved substances from the blood into the interstitial space.
 * Lipid-soluble substances can simply diffuse through endothelial cell membranes (cellular pathway).
 * Important: both **O2** and **CO2** are lipid-soluble.
 * Lipid-insoluble substances can diffuse through spaces ("pores," a paracellular pathway) between the endothelial cells in the capillary beds. This is dependent on their size:
 * Small lipid-insoluble molecules (**water, NaCl, glucose** ) diffuse very rapidly and tend to be at equilibrium between the blood and interstitial space.
 * Medium-sized (less than 60,000 MW but bigger than "small") molecules diffuse more slowly and can take a while to reach equilibrium.
 * Large (> 60,000 MW) molecules like **albumin** generally don't diffuse at all except in the liver, where the capillary pores are extremely large.
 * Two ways of describing movement of substances here:
 * **Flow-limited** . Delivery of a substance in the blood to the interstitial space is limited only by the amount of blood you can get there.
 * This applies to lipid-solubles and small lipid-insolubles.
 * **Diffusion-limited** . Delivery of a substance in the blood to the interstitial space is limited by the rate of diffusion across the endothelium.
 * This applies to middle-weight lipid-insolubles.
 * Notice that there's also a way to transport large lipid-insoluble molecules into the interstitial space: transcytosis (effectively transport and release with membrane-bound vesicles so that the substance itself never has to get across the membrane).
 * Describe how oxygen and CO2 move between the blood and the interstitial space.
 * As mentioned, very quickly. They rapidly diffuse through membrane cells.
 * Describe the hydrostatic and oncotic forces that produce capillary filtration and absorption and how the balance of absorption and filtration determine the //net// transport of water across capillary walls.
 * **Hydrostatic force** : the capillary's blood pressure (35 at its beginning, 15 at its end).
 * High hydrostatic forces tend to force water out of the capillary (**filtration** ).
 * **Oncotic force** : the osmotic pressure exerted by the higher concentration of solute inside the capillary than in the interstitial space (remember Dr. Betz's lectures on osmotic pressure in M2M?). This concentration gradient (caused by the retention of large solutes - mainly albumin - in the vessel) doesn't change much along the length of the capillary (water diffuses very quickly, maintaining the oncotic pressure at a steady level).
 * High oncotic forces tend to force water back into the capillary (**absorption** ).
 * So across any given capillary, __the balance between how much water exits to the interstitial space due to hydrostatic pressure and how much water returns to the vessel due to oncotic pressure is the //net//__ __transport of water across the capillary walls__.
 * Note that hydrostatic force along the capillary is dependent on both venous and arteriolar pressure (ie the pressures at both ends). If the central venous pressure goes up, odds are good that the hydrostatic pressure will rise too, favoring filtration over absorption.
 * Describe how hydrostatic and oncotic pressure vary along the length of a typical capillary.
 * As mentioned, the hydrostatic goes down (resistance in the capillary means the pressure of the blood is less at the end of the capillary than is was at the beginning) as the blood progresses through the capillary.
 * Note that this means most of your filtration occurs in the first half of the capillary and most of your absorption occurs in the second half.
 * Note also that in most capillaries, more fluid is filtered than reabsorbed (whence the lymphatic system). Note that this balance varies significantly from system to system (renal has high hydrostatic pressures, intestine/lung have low) by changing the hydrostatic pressure in particular organs' capillaries (the osmotic pressure should be more or less the same everywhere you're not losing albumin).
 * Describe the forces that propel lymph from lymph capillaries to the thoracic duct.
 * Essentially lymph vessels move their contents along by being squished. They're connected to the surrounding tissue; when the tissue moves, it collapses the lymph vessel, which squirts its contents out along the lymphatic drainage system (valves keep it from going the wrong way).
 * Define edema and describe two pathophysiological conditions that can produce edema. Describe how pulmonary edema compromises CV function.
 * Recall that lymph is largely just the fluid that's filtered out of the capillary but not reabsorbed. If there's more filtered fluid at a site than can be drained into nearby lymphatic capillaries, you get **edema** : an accumulation of interstitial fluid.
 * Things that produce edema: pretty much anything that increases filtration over absorption, or blocks the proper drainage of lymph.
 * Liver disease: causes lower blood concentration of albumin, thus lowering oncotic pressure and favoring filtration.
 * Blocked lymph vessels (as when you resect the axillary lymph nodes) or increased caval pressure (which backs up the thoracic duct, which is trying to drain into the left brachiocephalic vein) impede the flow of lymph and reduce the lymphatic drainage of filtered fluid.
 * Pulmonary edema compromises CV function because it inhibits gas exchange in the alveolar capillaries-- the extra fluid is more space the O2 and CO2 have to diffuse through before reaching their targets, which decreases blood reoxygenation.

Hemodynamics I and II Thursday, March 13, 2008 11:18 AM


 * Hemodynamics I and II, 3/18/07:**


 * Describe the difference between static and dynamic pressure and identify which is most important in determining the flow of blood in the circulatory system.
 * Static pressure: aka 'lateral' pressure. As far as I can tell this is your grandma's pressure-- pressure exerted by a liquid on its confining space, even when standing still. It's the most important type of pressure in blood flow.
 * Dynamic pressure: comes out of the kinetic energy of the fluid itself. This only seems to be important in blood flow when it's moving really fast (as in the aortic root).
 * Add these together to get the total pressure. As mentioned, generally this is just the static pressure, except at the base of the aorta.
 * [Greatly increased cardiac output tends to create turbulent flow conditions, leading to those "systolic flow murmurs" we heard so much (and so little) about in hematology. Laminar flow is generally quiet; turbulent flow is noisy.]
 * Write and be able to use the equation for the relationship between pressure (P), flow (Q), and resistance (R).
 * Change in pressure through a vessel equals the rate of flow times the resistance:
 * **delta-P = QR**
 * (for mnemonic's sake, note that PQR are consecutive letters of the alphabet.)
 * Note the similarity to circuits, where the change in voltage equals the current flow times the resistance. I knew I should have studied that crap more.
 * Diagram resistors in series and in parallel and use such diagrams to represent i) the distribution of cardiac output to the various organs and ii) the arrangement of the aorta, arteries, arterioles, capillaries, venules, and veins in the systemic circulation.
 * In series: the flow goes through first one resistor, then another, etc, end on end (ie. going from aorta to artery to arteriole to capillary to venule to vein).
 * In parallel: the flow goes through a bunch of different resistors simultaneously (ie. branching off into both renal arteries from the descending aorta or from a mesenteric artery into lots of little arterioles at the same time).
 * Demonstrate how such diagrams can be used to calculate the contribution of a particular class of vessels, such as the arterioles, to the total peripheral resistance and the contribution of an organ or organ system to the total peripheral resistance.
 * Here follows an unfortunately kind of massive explanation. May be too much detail.
 * Here's how to break this down. If you're looking for how much a particular __class of vessels__ contributes to the total peripheral resistance, you want to be thinking of resistors __in series__:
 * The key here is that resistors in series **add together** to get the total resistance.
 * Because you know that delta-P = QR, R must = delta-P/Q for any given resistor. We know Q (generally assumed to be a constant 5 L/min for a nonexistent average person), and we know the mean pressure drop across various types of vessels from an earlier lecture (starts at around 100, goes to 85 in the arteries, 30 in the arterioles, 15 in the capillaries, etc).
 * This means you can figure out what R has to be for each of these classes of vessel (ie. for arterioles, the change in pressure is 85-30 = 55, divided by 5 = 11). If you add all these up, you can get the total peripheral resistance (see the diagram on page 2 of his notes), then you can divide a given class of vessel's contribution to the total resistance by the total resistance to get what percentage of the total is made up by that class of vessel.
 * Ie: if the total resistance (figured out by going through R = delta-P/Q for each class of vessel) is 20, and the resistance offered by arterioles is 11, then the percentage of the total resistance made up by the arterioles is 11/20 = 55%
 * If you're looking for how much a given organ or organ system contributes, you need to be thinking of resistors __in parallel__:
 * The key here is that resistors in parallel follow a different, **reciprocal**, relationship: 1/total resistance = 1/T1 + 1/T2 + … etc for as many parallel resistors as you've got.
 * Note that R still = delta-P/Q for any given resistor (ie. organ).
 * As he describes it, P across the organ system (evidently defined here as pretty much all arterial and venous vessels associated with the organ) is going to drop from around 100 (at the aorta) to 0 (back in the right atrium). This is, obviously, an approximation, but a handy one.
 * This means you can assume delta-P is 100 for all organ systems you're considering. The trick is that the flow, Q, is no longer constant the way it was for vessels-- different organ systems get different flows of blood. These generally need to be given.
 * Once given, you can figure out that if the flow to the brain is 0.8 L/min, since delta-P = 100, resistance across the brain = (100/0.8) = 125. If you did the same for all other given organ systems, then took the reciprocal of all those resistances and added them together, and took the reciprocal of the result, you'd get the total peripheral resistance. Notice that __for resistors in parallel, the resistance of any one resistor (ie organ) is greater than the resistance of the whole__. Don't ask me, I'm no engineer.
 * So if you're given the information that the resistance through the GI tract has increased ten-fold (example in his notes) from 100 to 1000, then you'd run through the same calculations with the new numbers and figure out how much the total peripheral resistance has increased.
 * If the total peripheral resistance changes, one or the other of cardiac output or total pressure is going to have to change also (recall delta-P = QR). Assuming cardiac output stays the same at 5 L/min, you're going to wind up with a higher mean pressure.
 * (take home here, I think: constricting arterioles to certain systems raises the mean arterial pressure, dilating them lowers it. This makes sense: more resistance, more pressure; less resistance, less pressure.)
 * Indicate how resistance varies with radius, length, and viscosity (Poiseuille’s Law).
 * **Resistance varies directly with the length of the vessel and the viscosity of the blood**.
 * Wallace mentioned that the one he particularly wanted us to know was the viscosity.
 * **Resistance varies inversely with the radius of the vessel __raised to the fourth power__**.
 * Ie.: changing the radius of the vessel (which is the element of the situation the body can realistically change, given short notice) is by far the most effective way to regulate resistance, and thus blood flow, in a given organ system.
 * Define hematocrit and give the typical hematocrit of venous blood. Sketch plots of viscosity as a function of hematocrit and as a function of vessel diameter.
 * You better already know what hematocrit is, bucko. Typical lab values are 35-45 (female), 39-49 (male), higher at high altitudes.
 * Check out his plots on pgs. 4 and 5 of the notes.
 * Viscosity vs. hematocrit is some kind of exponential curve, but within normal ranges it's more or less linear.
 * Viscosity vs. radius looks like some kind of log-base curve.
 * Essentially at very small vessel diameters the viscosity rises very quickly with diameter, but past about 0.5 mm it tapers off, and past 1 mm it doesn't change appreciably at all.
 * Viscosity tends to be lowest at the center of a vessel and highest at its edges.
 * Describe how tension in the wall of a blood vessel or heart chamber varies with transmural pressure, radius, and wall thickness (LaPlace’s Law).
 * We went through this already: higher radius = greater tension, thicker wall = less tension.
 * This is significant for aneurysms because the radius is increasing but the wall stays the same thickness-- thus the tension in the aneurysm keeps increasing as well, which causes the radius to increase more as the aneurysm progresses. This is why you don't look at an aneurysm and say, "well, it probably won't get any worse, just go on home, that'll be $500." (What you really say is, "you need surgery, come with me, that'll be $50,000.")
 * Write and use the equation describing the relationship between cardiac output, total peripheral resistance, and mean aortic pressure. Describe the relationship between stroke volume and pulse pressure
 * I'm reasonably positive we already did this. Keep in mind that the equation (delta-P = QR) can be used both systemically (mean aortic pressure is starting pressure, 0 is ending pressure in the right atrium, thus delta-P is the mean aortic pressure) with the total peripheral resistance as R and cardiac output as Q, or it can also be used locally to describe a given class of vessels (Q still = cardiac output, but delta-P and R are different) or a given organ system (delta-P still = mean aortic pressure, but Q and R are different).
 * Define compliance and describe the hemodynamic consequences of changes in the compliance of the aorta.
 * **Compliance** : essentially the __elasticity__ of the aorta. Remember, the aorta is pretty heavy with elastic fibers. What that's going to do is **decrease the systolic pressure** (walls give a little under the ventricular outflow) and **increase the diastolic pressure** (the walls' rebound creates pressure once the ventricular outflow has stopped). Essentially it's **decreasing the pulse pressure** (pulse pressure is the difference between the systolic and diastolic pressures). Note that it doesn't affect mean pressure, since it's moving both points (systolic and diastolic) towards each other equally.
 * So if you __reduce__ compliance/elasticity of the aorta, the systolic pressure will go **up**, the diastolic pressure will go **down** , the pulse pressure will **increase** , and the mean pressure will stay the same.
 * Indicate ways in which the peripheral vessels influence systolic and diastolic arterial blood pressure.
 * Elasticity/compliance of large arteries and aorta: reduces systolic blood pressure, increases diastolic pressure (see above).
 * Constriction or dilation of vessels increases or decreases the resistance across those vessels, respectively. This changes total peripheral resistance, which elevates or depresses both systolic and diastolic pressure, again respectively.
 * Determine the consequences of increased arteriolar resistance, increased venous resistance, increased arterial pressure, and increased venous pressure on pressure and flow in the peripheral vasculature.
 * __Increased arteriolar resistance__: increases peripheral pressure, decreases flow to the region with those arterioles.
 * Wallace: "this is where you have the dam." It decreases pressure after those arterioles (in capillaries and venules) but builds up pressure in front of them (in the arterioles and arteries).
 * The dam analogy is a reasonably good way to think about most vasoconstriction, regardless of location. It decreases pressure (and flow) after it and creates more pressure (and flow) behind it. Conversely, vasodilation creates more pressure (and flow) ahead of it and creates less pressure (and flow) behind it.
 * __Increased venous resistance__: not much effect. The veins are so relatively depressurized that increasing their resistance isn't going to do much.
 * __Increased arterial pressure__: not much effect (can always correct the incoming pressure to the capillaries by constricting arterioles).
 * __Increased venous pressure__: because the pressure gradient across the capillary is what drives their blood flow and dictates their fluid exchange, increased venous pressure is a big deal because it slows blood flow across capillaries and increases fluid loss (filtration) due to higher sustained hydrostatic pressure across the capillary (leading to edema).

Adrenergic Neurotransmission Saturday, March 15, 2008 9:06 AM


 * Adrenergic Neurotransmission, 3/19/08:**


 * [Ok. He doesn't seem to have any LOs specifically about the normal mechanisms of adrenergic receptors. We really need to discuss what these different types of receptors are and how they work first, it'll make the rest of this much easier.]
 * Synthesis of **catecholamines** (dopamine, norepinephrine, epinephrine):
 * __Tyrosine__ is taken up into the neuron by a Na+-driven active pump.
 * Tyrosine is effectively hydroxyl-phenylalanine (aromatic amino acid).
 * Tyrosine is converted to __dopamine__ by tyrosine hydroxylase (__rate-limiting step__)
 * This sticks another hydroxyl group on tyrosine, making dihydroxy-phenylalanine (DOPA).
 * DOPA is converted to dopamine by taking off the carboxyl group (thus converting it definitely from an amino acid to a catecholamine) by L-aromatic amino acid decarboxylase.
 * If it's a dopaminic neuron, the process ends here and DA is taken up into vesicles to be stored.
 * Otherwise, the DA is further acted upon by dopamine beta-hydroxylase to form __norepipnephrine__.
 * This sticks yet another hydroxyl group on dopamine, at the first carbon off the aromatic ring. Note that the only difference between dopamine and norepinephrine is a hydroxyl group.
 * If it's a norepinephrine neuron, the process ends here and NE is taken up into vesicles to be stored.
 * Otherwise, the NE is acted upon to add a methyl group to the amine group (changing from a primary to secondary amine), forming __epinephrine__.
 * EPI is taken up into vesicles to be stored.
 * [Catecholamines are monoamines (biologically synthesized amines) with hydroxyl groups on their phenyl groups. Not a catecholamine but still a monoamine and still active in the SNS: seratonin (it's a indolamine).]
 * Once synthesized and stored, can be released upon stimulation.
 * Termination step of catecholamines:
 * Reuptake receptors: for example NET (NE transporters).
 * After reuptake, can either be restored in vesicles or inactivated by monoamine oxidases.
 * Keep in mind: the amount of stored catecholamine in a neuron depends on a balance between storage and breakdown of its NTs. If you inhibit the breakdown (as with MAOIs), there's more NT stored. If you inhibit storage enzymes (as with reserpine), there's less NT stored.
 * Types of receptors:
 * French discusses this in terms of which types of receptors are mainly stimulated by which adrenergic NTs or drugs. The three he mentions are epinephrine (EPI), norepinephrine (NE), and **isoproterenol**, which is an epinephrine analog that mainly works on beta receptors.
 * __Alpha-1 adrenergic receptors__: Bind preferentially to EPI; failing that, they'll bind to NE. They only minimally bind to isoproterenol.
 * __Alpha-2 adrenergic receptors__: Bind preferentially to either EPI or NE, depending on tissue. Don't bind to isoproterenol.
 * __Beta-1 adrenergic receptors__: Bind preferentially to isoproterenol. If none's available, they’ll bind EPI or NE with roughly equal, but lesser, affinity.
 * __Beta-2 adrenergic receptors__: Bind preferentially to isoproterenol; failing that, they'll bind to EPI. They only minimally bind to NE.
 * Ie.:
 * EPI binds to alpha-1, beta-1, and beta-2 receptors.
 * NE binds to alpha-1 and beta-1 receptors.
 * Isoproterenol binds to beta-1 and beta-2 receptors.
 * Mechanisms of adrenergic receptors:
 * All are G-protein coupled.
 * Alpha-1: increase PLC, increases calcium content (generally constricts, increases total peripheral resistance).
 * Alpha-2: generally on pre-synaptic neurons, autoreceptor, negative feedback. Less important here.
 * Beta-1: increase adenylyl cyclase, increases cAMP content, increased protein kinase activity, __more__ calcium content.
 * In heart: this causes greater contractility.
 * Beta-2: increase adenylyl cyclase, increases cAMP content, increased protein kinase activity, __less__ calcium content.
 * This causes relaxation- in lungs, blood vessels, uterus, etc.
 * [General notes about sympathetic drugs:]
 * Either agonists or antagonists.
 * Agonists can be direct (bind directly to the receptor and activate it) or can be indirect (increase activity of sympathetic stimulation without binding to the receptors, mainly by inhibiting reuptake of sympathetic neurotransmitters).
 * Note that the termination step of sympathetic neurotransmission involves reuptake of the sympathetic NTs-- as opposed to parasympathetic transmission termination, which involves inactivating ACh by hydrolyzing it.
 * Thus the indirect agonists often involve increasing effective release and duration of sympathetic NTs by inhibiting the termination step.
 * Antagonists can also be direct (bind directly to the receptor and prevent it from activating) or can be indirect (ie a "sympatholytic").
 * Sympatholytics: "lyse" the activity of the sympathetic nervous system. Don't act directly on the receptor, but inhibit the synthesis, release or duration of action of sympathetic NTs.
 * Generally effects are too widespread to be useful-- limited clinical use due to side effects.
 * Dr. French: "the best site for drug action is at the receptor" (direct ant/agonists).
 * Describe the elements of adrenergic neurotransmission (neurotransmitter synthesis, storage, release, inactivation and interaction with receptors) that represent targets for adrenergic and anti-adrenergic drug action.
 * Stimulation or inhibition of neurotransmitter synthesis, storage, release: __less clinical utility__ as drug targets-- small degree of selectivity (affect system-wide NTs, leading to widespread systemic side effects).
 * Inhibition of neurotransmitter metabolism: __some clinical utility__ as drug targets-- mainly inhibiting NT metabolism by monoamine oxidases, MAOs, or catechol-O-methyl transferases, COMTs, in CNS, despite limited selectivity. Allows more storage and release of NT-- thus greater effect on stimulation.
 * MAOs target endogenous NTs.
 * COMTs target exogenous catecholamines.
 * Inhibition of neurotransmitter reuptake: __moderate clinical utility__ as drug targets, particularly in CNS disorders. Produces a longer-lasting effect after stimulation.
 * Can be targeted to particular NT uptake systems.
 * Stimulation or inhibition of neurotransmitter receptors: __greatest clinical utility__ as drug targets, since they can be targeted to particular adrenergic receptor subtypes (alpha-1, beta-1, etc) found in specific tissues and/or having specific effects.
 * Compare and contrast the modes of drug action with respect to selectivity of action and clinical utility.
 * See above.
 * For adrenergic agonists, distinguish the different mechanisms whereby direct-acting, indirect acting, and mixed-acting agents work.
 * **Direct-acting adrenergic agents** : drug binds directly to target adrenergic receptors and mimics the action of the endogenous neurotransmitter.
 * **Indirect-acting adrenergic agents** : drug has an effect on the endogenous NT processing (reuptake, metabolism) that results in increased amounts of the NT at the receptor.
 * Most common indirect mechanism is to increase storage/release of NT.
 * Others: inhibit reuptake, block catabolism, increase synthesis.
 * **Mixed-acting agents** : About what you'd expect, a mix of direct and indirect action.
 * For anti-adrenergic agents, describe the logic behind the various sympatholytic strategies.
 * I think the idea here is to inhibit various steps of the catecholamine synthesis pathway. If you inhibit a step early on, you're going to inhibit all the other catecholamines further down the line.
 * List subtype (alpha-1, alpha-2, beta-1, beta-2) specific receptor agonists and antagonists and therapeutic indications for the use of each (as per the bolded drugs from the drug lists on pages 20 and 21)
 * Agonists:
 * NE (alpha and beta-1)
 * EPI (alpha, beta-1, beta-2)
 * Pseudoephedrine (alpha, beta-1, beta-2, plus CNS)
 * Isoproterenol (beta-1, beta-2)
 * Phenylephrine (alpha)
 * Dopamine (alpha, beta-1, DA-1 receptors)
 * Clonidine (alpha-2)
 * Antagonists:
 * Phentolamine (blocks alpha)
 * Prazosin (blocks alpha-1)
 * Atenolol (blocks beta-1)
 * Metoprolol (blocks beta-1)
 * Labetalol (blocks alpha-1, beta-1, beta-2)
 * List the gross distribution of adrenergic receptor subtypes on the following organ systems and describe the physiologic responses that result from activation or blockade of these receptors or of synaptic activity: heart, blood vessels, lungs, kidney
 * Heart: largely beta-1 receptors (lesser beta-2 and alpha-1 activity). Beta-1 receptor activation: increased heart rate in the SA node, increased conduction across the AV node, increased contractility in the cardiac muscles.
 * Blood vessels: alpha-1, beta-1, and beta-2 receptors.
 * Beta-1 activation produces constriction in blood vessels.
 * Lungs: beta-2 (bronchodilation of bronchial smooth muscle) and alpha-1 (constriction of bronchial blood vessels)
 * Kidneys: beta-1 receptors in renin release system.
 * For each organ system above, specifically: a) describe the spectrum of effect seen following sympathetic activation (flight or fight response); b) describe the concept of autonomic nervous system "tone" and the consequences of parasympathetic tone predominating at most organs and tissues, the exception being sympathetic control of blood vessels; and c) describe the baroreceptor reflex, its effect on heart rate, and its role in mediating indirect cardiovascular actions of adrenergic agonists and antagonists
 * [p. 19 of notes]
 * (c) You know about the baroreceptor reflex ("Regulation of Cardiac Output"). If hypertensive medications are given, baroreceptors get triggered to kick up the heart rate in compensation (tachycardia). Similarly, raising a chronically low blood pressure can trigger bradycardia.
 * Describe the relationship of adrenergic drug structure to their pharmacokinetics with regards to absorption, distribution, and duration of action
 * Absorption: oral drugs are subject to first-pass metabolism. So if they're going to be effective, often they need to have their structures modified to resist first-pass esterases.
 * Distribution: mainly, "can it get through the BBB?"
 * Main factor that determines this is the presence of absence of hydroxyl groups on the phenyl ring (absence = can get through BBB better).
 * Elimination/duration of action: if metabolized quickly, need to either give them on a continuous drip or modify the structures to get around metabolism.
 * Relate the physiologic responses produced by the receptor actions of adrenergic agonists and antagonists to their adverse affects and toxicities
 * This follows, more or less, from the receptor action. Ie: increased alpha-1 receptor stimulation (causes vasoconstriction) can cause big elevations in blood pressure which can bust arteries (cerebral/pulmonary hemorrhage).
 * For the bolded drugs from the drug list on pages 20 and 21, describe their: a) mechanism and site of action (receptors and effector organs involved); b) pharmacokinetic factors (when clinically relevant): central vs. peripheral activity, organ of elimination, duration of action (short vs. long); c) major clinical uses; d) most common and most severe side effects (treatment of overdose/toxicity)/Significant contraindications
 * Look up in French's notes.
 * [Organ effects: determined by which receptors are activated __and also__ which receptors predominate in that particular organ system.
 * Recall that the vascular system is the only organ system in which the predominant tone is provided by the sympathetic nervous system.
 * [Note that EPI in pharmacological doses have effects on alpha-1 receptors in the vasculature higher than that on the beta-1 receptors in the heart or beta-2 receptors in the vasculature-- thus get peripheral vasoconstriction.]
 * [Inactivation:]
 * Catechols: have hydroxyl groups on the phenyl ring.
 * COMT: target the hydroxyl groups on the phenyl ring.
 * MAO: targets the monoamine ring; protected from MAO activity by methyl groups on the alpha carbon.

Conducting Pathways and the Cardiac Action Potential Saturday, March 15, 2008 9:18 AM


 * Cardiac Pathways and the Cardiac Action Potential, 3/19/08:**


 * Beginning in the sinoatrial (SA) node, describe the anatomy and function of the cardiac structures responsible for generation and spread of cardiac depolarization. Indicate the normal sequence of the spread of depolarization through the conducting pathways of the heart. Explain the importance of the atrioventricular (AV) node normally being the only electrical pathway between the atria and the ventricles.
 * Ok. First thing to understand is that APs are being conducted in the heart __not__ by traditional neurons but by specialized myocardial cells that conduct an electrical impulse by means of gap junctions between adjacent cells. These specialized myocardial cells are called conduction pathway cells and have lost most of their contractile proteins (actin, myosin, etc; see next lecture).
 * This tends to be distinct from neuronal APs in a variety of ways. One is that many cells in the conducting pathways are capable of spontaneous AP generation. The SA node is the fastest generator of APs and thus tends to set the pace for everyone else.
 * Imagine a bunch of people walking together. One guy wants to amble, another wants to skip, another wants to jog, another wants to sprint. Whichever one wants to go fastest forces the rest to go at his pace. But if you take out every one but the slowest ambler, he'll still keep ambling along, albeit a lot more slowly than he would if someone was there to whip his ass into shape and make him run.
 * The SA node is the sprinter-- it sets the pace. But if the SA node was disconnected from the rest, the AV node would still keep generating APs, just more slowly. And if the AV node was disconnected, the bundle of His would keep going, and if the bundle of His were disconnected, the Purkinje fibers would just amble right along. This is different from neurons, who can sit around quietly receiving no APs at all and never get it into their brains to make one themselves.
 * Specifically:
 * SA node generates about **100** APs per minute by itself, normally pared down to **60-80** by parasympathetic influence.
 * AV node and the bundle of His generate about **40-60** APs/min.
 * Purkinje fibers generate about **20-45** APs/min.
 * As far as conduction speed goes, Dr. Wallace suggests thinking about myocardial conduction pathways as __unmyelinated neurons__-- their **diameter** is the most important factor in their conduction speed, since with increased diameter you get less internal resistance.
 * This means that small cells - like in the AV node - will conduct more slowly, and large cells - like in the Purkinje fibers - will conduct more rapidly.
 * Another important difference is in the structure of the AP itself. We'll get to this a little farther down.
 * SA node: located in right atrial wall, near where the superior vena cava drains.
 * APs arise from the SA node and travel in two directions: one to the left atrium through **Bachmann's bundle**, one to the AV node through the **internodal bundle**.
 * It takes about **30 milliseconds (msec)** for impulses from the SA node to reach the AV node.
 * AV node: located on the right side of the interventricular septum, near where the coronary sinus drains.
 * Conduction of the SA node's AP through the AV node is slow-- it takes about **130 msec** due to the small size, relative depolarization (see below for rationale), and few sodium channels of the AV cells.
 * So: the SA's AP takes **a total of 160 msec** to propagate to and through the AV node. This is to allow the atria time to contract before the ventricles do.
 * It's important that the AV node is the only electrical point of connection between the atria and the ventricles (the rest is insulated by connective tissue). This means that there's only one pathway to coordinate atrial-ventricular contractions, which makes it more easily regulated but also makes it easier to screw up (all you need is a problem with one conduction pathway).
 * From the AV node, the AP is conducted to the **bundle of His** (do women have a **bundle of Hers** ?), which splits into **left and right bundle branches**.
 * The bundle branches connect to a network of fine intramuscular fibers called the **Purkinje fibers** which conduct APs quite rapidly (largest-diameter cells in the heart). These more or less start at the bottom (apex) of the heart and go up into the top (base).
 * So the conduction pathway all together looks like: SA node to atria (which contract) and the AV node, down the interventricular septum to the apex, then out through the ventricular walls and up the outer walls to the base.
 * Note that this means the bottom part of the ventricles are going to contract first and the top parts a little later. This makes sense when you think about the fact that the ventricles are trying to squeeze blood out of their tops.
 * Note also that the papillary muscles receive impulses ahead of the rest of the ventricle, allowing them time to tense before the ventricle contracts.
 * Draw a timeline that compares the time course of the spread of depolarization through the conducting pathways, and the time course of atrial and ventricular systole.
 * I think we more or less covered this. Normally there's about a 160 msec time delay between SA node AP generation (atrial systole) and AV node AP conduction (ventricular systole). The entire AP takes about 300 msec to go all the way through the heart (note that contraction follows, and is not synchronous with, the progress of the AP-- it takes a finite amount of time for contraction to occur).
 * Sketch typical "fast" and "slow" cardiac action potentials, labeling both the voltage and time axes accurately, and describe the cells in which each type of action potential is found.
 * Basically in a "fast" cardiac AP (found outside the SA and AV nodes, in the Purkinje fibers/myocardial walls), the incoming AP spikes a depolarization of the membrane like a neuronal AP, then has a brief, small dip towards repolarization, then a long, sloping plateau that's slowly repolarizing, then a fast repolarization, at which point it stays more or less polarized until the next AP comes along.
 * Depolarization: phase 0.
 * Small dip: phase 1.
 * Plateau: phase 2.
 * Notice that the width of the plateau is responsible for the relatively sustained contraction (~250 msec) of the muscle cell.
 * Repolarization: phase 3.
 * Polarized state: phase 4.
 * In a "slow" cardiac AP (found primarily in SA and AV node cells), the cell never gets quite as polarized as the "fast" AP cells. It slowly and steadily depolarizes until it reaches a certain threshold, at which point it depolarizes more rapidly (though still more slowly and incompletely than "fast" APs), peaks, and repolarizes again, at which point it begins to slowly depolarize again.
 * Steady depolarization state: phase 4.
 * Faster depolarization: phase 0.
 * Repolarization: phase 3.
 * Describe the properties of the ion channels that underlie "fast" and "slow" cardiac action potentials.
 * If you need to go back and review Betz's lectures on membrane depolarization, do so.
 * Sodium channels (INa): responsible for phase 0 depolarization in fast APs.
 * Calcium channels (ICa): responsible for phase 2 plateau in fast APs (offset K+ efflux).
 * Potassium channels: there's a variety of them, unfortunately.
 * IKto: responsible for small initial repolarization (phase 1) in fast APs.
 * IKr: "rapid" **delayed rectifier** channels. Open quickly during plateau (phase 2) and contribute to repolarization (phase 3) of fast APs.
 * IKs: "slow" **delayed rectifier** channels. Open very slowly during plateau (phase 2) and contribute to repolarization (phase 3) of fast APs.
 * IK1: Open at resting depolarization (phase 4) of fast APs, __shuts off__ during the rest of the cycle. Essentially it maintains the especially polarized resting state of "fast" AP myocardial cells. Also called the "anomalous inward rectifier" channels.
 * IKACh: Activated by acetylcholine (ie. is a parasympathetic effect):
 * In fast AP cells: shortens plateau (shortens myocyte contraction).
 * In slow AP cells: slows down steady depolarization (delays effective AP generation rate, thus slows heart rate, which is what you'd expect from PNS stimulation, ya?).
 * Slow APs are funny. No, really. The current that causes them to steadily and slowly depolarize (phase 4) is called the "funny" current or If (alternately Ih). This seems to be mainly due to 'slow' If Na+ channels (as opposed to 'fast' INa Na+ channels, which are quite rapid).
 * Note there are very few INa channels as such in the slow-AP myocytes. Thus the more rapid (but still fairly slow) depolarization (phase 0) is caused more or less exclusively by ICa channels.
 * The repolarization in slow-AP myocardial cells is triggered and sustained by IKr channels (slow-AP cells have few IKs or IK1 channels).
 * Describe the significance of the unusual voltage dependence of the IK1 channels in myocardial cells having “fast” action potentials and the Ih [or If] channels in cells having “slow” action potentials.
 * As mentioned, the IK1 channels essentially maintain a highly polarized (near EK) membrane potential in the __resting__ (ie polarized) fast-AP cells but don't contribute anything to the development of the AP itself once it's started (ie depolarized). They're phase-4 only, polarization-triggered; this sets them apart from the other IK channels, which are triggered by depolarization.
 * Also as mentioned, the If channels are responsible for pacemaker activity in slow-AP cells (though recall that the actual depolarization itself is driven by ICa).
 * Define absolute refractory period, relative refractory period, and safety factor.
 * Absolute refractory period: the period in which a conducting cell cannot propagate another AP. Generally dependent on INa channels, at least in fast-AP cells.
 * Relative refractory period: the period in which a conducting cell can only transmit another AP if given a stimulus that's considerably stronger than that normally required. Also dependent on INa channels.
 * Absolute: lasts from the beginning of phase 0 (depolarization) to about halfway through phase 3 (repolarization).
 * Relative: lasts from halfway through phase 3 (repolarization) to the end of phase 3 (approaching a steady polarized state).
 * Safety factor: the fact that you have more ion channels than you need to trigger an AP, particularly in the SA and AV nodes. This allows some channels to be damaged without significantly affecting heart rate.
 * Describe how cell injury, resulting in a less negative resting potential, alters action potential propagation through the conducting pathway.
 * This gets tricky. I asked him about it.
 * You'd think that the less negative resting potential would mean that there's a shorter period for the If to cover before it reaches depolarization threshold. But it turns out that a more depolarized (less negative) resting potential inactivates some calcium (and sodium) channels, which essentially means that the ability of the cell to reach depolarization threshold is __diminished__ rather than enhanced. So with depolarizing damage, the cells generate and/or conduct action potentials more slowly.
 * This is also why the AV node conducts slowly: the resting depolarization of the cells means that calcium channels are relatively inactivated, causing a delay in reaching threshold.
 * Notice that we've seen that pacemaker cells can also be __hyper__polarized (as with ACh acting through IKACh channels) to slow down AP generation. This is due to the fact that the hyperpolarization means it takes If longer to reach depolarization threshold.
 * Dr. Wallace: if you mess with pacemaker cells' resting potentials at all - more negative or less negative - you're going to slow down their rate of AP generation.
 * Describe what accounts for the slow conduction velocity in the atrioventricular (AV) node and the importance of slow propagation for cardiac function.
 * As mentioned: small cells (diameter is related to speed of conduction), relative depolarization of those cells (see above LO), and slow-AP generation/propagation (few INa channels).
 * Slow propagation, also as mentioned, allows the atria to finish contracting before the ventricles begin to contract.
 * Discuss the mechanism and significance of overdrive suppression. Describe circumstances under which an ectopic pacemaker might arise in the AV node or in the Purkinje fiber system.
 * __Overdrive suppression__ is a fancy term for the sprinter/ambler thing. Basically if a pacemaker cell is getting AP signals at a faster rate than it would naturally generate them, it effectively conducts the APs it receives rather than generating new ones-- it acts as a conductor rather than a pacemaker. If you cause the incoming AP signals to stop, it will resume its natural pacemaker activity.
 * __Ectopic pacemaker__ is a fancy term for what I just described-- if you block the SA node from conducting to the AV node, the AV node will take over generating APs for the bundle of His/Purkinje fibers. That is, the AV node will act as the ectopic (meaning "out of place") pacemaker for the rest of the heart. If you block the AV node and the bundle of His from conducting to the Purkinje fibers, then they'll take over and become the ectopic pacemakers for the myocytes of the ventricular walls.

Properties of Myocardial Cells Saturday, March 15, 2008 10:48 AM


 * Properties of Myocardial Cells, 3/19/08:**


 * Describe the roles of ATP, calcium, actin, myosin, tropomyosin, and the troponin complex in the generation of force in striated muscle.
 * Once again, this is best understood by going back to the M2M notes on muscle contractions. Briefly:
 * Calcium influx binds to troponin, which causes tropomyosin to move, uncovering the myosin-binding sites on actin. Myosin binds ATP, hydrolyzes it to ADP + Pi (in the process "cocking" the myosin head), and binds (with ADP) to the actin. Once bound, the myosin head releases its "cocked" position to create the "power stroke," contracting the myosin along the actin filament. Fresh ATP displaces the ADP, causes dissociation of myosin from actin and beginning the cycle again.
 * Compare and contrast excitation-contraction coupling in skeletal and cardiac muscle, Include the “dihydropyridine-receptor” L-type calcium channel, the ryanodine receptor calcium channel, the sarcoplasmic reticulum calcium pump, the plasma membrane calcium pump, and the plasma membrane sodium-calcium exchanger.
 * Skeletal: APs travel down the surface of myocytes into T-tubules, where they activate dihydropyridine receptors (DHPRs), which allow a bit of extracellular Ca++ into the cells but also, and more importantly, pull open the ryanodine receptors (RyRs) on the surface of the sarcoplasmic reticulum, allowing stored intracellular Ca++ to flood out into the cytoplasm.
 * Cardiac: DHPRs are stimulated in the same way. However, the DHPRs are not mechanically connected to the RyRs in cardiac cells-- the RyRs have to be triggered by the small influx of extracellular Ca++ that comes along with DHPR activation.
 * What this means: you can remove extracellular calcium from skeletal muscle with no effect on its contractility. But if you remove extracellular calcium from cardiac muscle, it won't contract at all. Similarly, changes in the concentration of extracellular calcium in cardiac muscle will change the amount of intracellular calcium released through RyR receptors and thus the degree of contraction.
 * Both of them seem to resolve their Ca++ concentrations after contraction in the same way, through two pumps and an exchanger channel:
 * ATP-dependent sarcoplasmic-endoplasmic reticulum calcium pump (**SERCA** ): pumps Ca++ back into the SR for release in the next contraction.
 * ATP-dependent plasma membrane calcium pump (**PMCa** ): pumps Ca++ out into the extracellular space.
 * Plasma membrane sodium-calcium exchanger (**NCX** ): exchanges three Na+ ions for one Ca++ ion. After contraction (diastole) this lets Na+ into the cell and throws Ca++ out; during contraction (systole) this lets Ca++ into the cell and throws Na+ out.
 * Define preload, afterload, and contractility.
 * **Preload** : the degree to which the cardiac muscle in a chamber is stretched before it contracts. Usually used to refer to how much the ventricle is filled during diastole. Often a reflection of central venous pressure (which dictates rate of atrial filling).
 * **Afterload** : effectively the aortic pressure against which ventricular systole has to eject blood.
 * **Contractility** : The ability of a heart to contract at a given preload (filling) and afterload.
 * Shorthand: "how fast can the ventricles contract if everything else stays constant?" Affected by a variety of chemical factors, generally phosphorylation-related. More on this in "Regulation of Cardiac Output" and I covered it a bit more in my notes on the first lecture ("Intro to the CV system").
 * Diagram the Frank-Starling Law of the Heart on a plot of pressure versus volume and use the diagram to compare and contrast the effects of preload and contractility on the force produced by myocardial cells when they contract.
 * It's a curve that says, "more pre-loaded volume, more pressure generated by contraction up to a certain point (the 'ascending limb' of the curve). After that, more volume means less pressure generated (the 'descending limb' of the curve). See pg. 6 of his notes for the diagram.
 * Note that the descending limb is almost never actually reached (by the time you get that much preload you're either an Olympic athlete or dead), so colloquially what "Starling" means is that you get more pressure generated with more preload.
 * Note that 'pressure' here can also mean stroke volume, cardiac output, or tension, while 'preload' can also mean end diastolic volume or central venous pressure. All of these factors are related and you'll see five Starling graphs with five different labels on the axes. Don't let it throw you.
 * Notice Starling curves **do not** plot afterload.
 * Notice Starling curves **do not** plot contractility, although different contractility levels change the placement of the curve (see below).
 * Higher contractility raises the curve (more pressure at the same pre-load volume); lower contractility lowers it (less pressure at the same pre-load volume).
 * This whole Starling concept actually turns out to be insanely useful. So work on it if you don't get it.

Regulation of Cardiac Output Monday, March 17, 2008 6:53 PM


 * Regulation of Cardiac Output, 3/19/08** :


 * [This is relatively dense information but is extremely useful, so pay attention.]


 * Describe the chronotropic (rate) and inotropic (contractility) effects produced by activation of the sympathetic input to the heart, and describe the mechanisms that produce these effects.
 * [Interesting side split: sympathetic fibers on the left side of the heart have more inotropic effects, while those on the right side of the heart have more chronotropic effects.]
 * Chronotropic effects of sympathetic cardiac stimulation: **increases heart rate**.
 * Inhibits ACh release (ACh = PNS stimulation, see below).
 * Norepinephrine + beta-1 adrenergic receptors activates **adenylyl cyclase**, which raises **cAMP** levels, which potentiates ICa, IK, and If currents. In the case of ICa, it does this through a protein kinase, cAMP-dependent protein kinase or **PKA** , that phosphorylates the ICa ion channels.
 * Broken down:
 * Potentiated ICa and IK channels increase the amplitude and shorten the duration of cardiac APs, allowing greater heart rate.
 * Potentiated ICa and If channels accelerate the steady depolarization in pacemaker myocytes, which also kicks up the heart rate.
 * Inotropic effects of sympathetic cardiac stimulation: **increases contractility**.
 * Mainly due to kinase-mediated phosphorylation of various enzymes and ion channels, secondary to increased cAMP due to adenylyl cyclase activation after NE binds to beta-1 receptors, as described above in ICa:
 * (1) As mentioned, ICa channels are PO4'd and potentiated.
 * (2) The heads of myosin molecules are also phosphorylated, which increases the rate of myosin-actin crosslink formation-- which in turn means the muscle will shorten faster and more strongly.
 * (3) Troponin is phosphorylated, which decreases its affinity for calcium, which speeds cardiac relaxation (and thus cardiac filling).
 * (4) **Phospholamban** is also phosphorylated and potentiated. Phospholamban is an enzyme that regulates Ca++ reuptake into the SR (by the SERCA pump), so making it work faster has two effects:
 * (1) it allows more Ca++ to be stored in the SR, which allows more Ca++ to be released (causing a stronger contraction) when the next signal comes; and
 * (2) it removes Ca++ from the cytoplasm faster, which means the muscle relaxes faster, which means it has more filling time before its next contraction.
 * Name four proteins within myocardial cells that are phosphorylated in response to sympathetic stimulation. Describe how phosphorylation of each of the proteins contributes to increased contractility.
 * As mentioned above:
 * ICa (increases the strength of contraction and the heart rate)
 * Myosin (heads) (increases the speed of contraction)
 * Troponin (speeds relaxation)
 * Phospholamban (increases strength of contraction, speeds relaxation)
 * Describe the chronotropic and inotropic effects produced by activation of the parasympathetic input to the heart, and the molecular mechanisms that mediate the changes.
 * [Again with the side split: left PNS fibers go to the AV node, right PNS fibers go to the SA node.]
 * Chronotropic effects of parasympathetic cardiac stimulation: **decreases heart rate**.
 * __Activates IKACh receptors__ (see "Conducting Pathways"), countering the If current and slowing the depolarization to AP threshold in pacemaker cells.
 * __Inhibits adenylyl cyclase activation__, lowering cAMP levels within the cell. This reduces potentiation of ICa and If channels (counter-effect to the sympathetic effect on these channels listed above).
 * Also inhibits norepinephrine release (blocking sympathetic stimulation).
 * Inotropic effects of parasympathetic cardiac stimulation: **decreases contractility**.
 * Due to inhibition of NE release (as mentioned) and inhibition of adenylyl cyclase activity (thus also cAMP levels and phosphorylation of the four PKA target proteins) as mentioned above.
 * Note that cAMP levels affect both chronotropy and inotropy, so reducing them (by inactivating adenylyl cyclase) affects both pathways.
 * List the typical intrinsic heart rate and resting heart rate in an average healthy young adult, and describe the factors that determine each of these rates.
 * Intrinsic = 100 beats per minute. Comes about because of innate properties of the SA pacemaker cells, which reach their steady depolarization thresholds (through If) about that rapidly.
 * Resting = 60-80 beats per minute. Come about because of parasympathetic innervation of the SA pacemaker cells (by the vagus nerve)-- as mentioned above, ACh release causes IKACh activation, which decreases the rate of depolarization in those cells.
 * Describe the response of arterial and medullary chemoreceptors to a decrease in PaO2, an increase PaCO2, and a fall in blood pH. Describe the cardiovascular consequences of the responses.
 * First off: the arterial chemoreceptors respond the same to all of those stimuli because all of those stimuli indicate more or less the same thing (O2:CO2 imbalance towards CO2).
 * Responses:
 * [Increase in ventilation (breath rate, get in more O2 and get out more CO2).]
 * Relevant: stimulates cardioinhibitory and vasoconstrictor regions in the medulla.
 * Effects:
 * Decreases heart rate, constricts arterioles and venules, particularly in skeletal muscle.
 * This means __cardiac output is going down and peripheral resistance is going up__.
 * Recall that delta-P = Q x R. If Q (cardiac output) goes down about the same amount that R (peripheral resistance) goes up, __the systemic blood pressure isn't going to change__. This is exactly what happens.
 * What decreased cardiac output and increased peripheral resistance do is to allow more time for gas exchange to take place in capillary beds (slowing down blood flow, effectively).
 * This allows greater perfusion of tissues to correct the presumed O2 deficit, without raising the systemic blood pressure.
 * The preference for vasoconstriction in skeletal muscle means that more blood (thus more O2) winds up shunted to the brain and heart.
 * Describe how changes in blood volume influence cardiac output.
 * What we're talking about here is the preload. Greater blood volume, greater preload in the ventricles, which means that (by Starling) you'll generally have a greater pressure generated by the ventricle upon contraction, which means that you wind up with more cardiac output.
 * Describe the short- and long-term effects of the renin-angiotensin-aldosterone system, vasopressin, and atrial natriuretic peptide on blood volume and blood pressure. Identify the source of vasopressin and ANP.
 * **RAA system** : renal vasoconstriction and low blood flow to the kidney tubules causes renin release, which causes (through RAA axis) increased retention of Na+, causing a higher blood volume, and thus a higher blood pressure and cardiac output (Starling's law, no change in contractility).
 * **Vasopressin** (aka antidiuretic hormone or ADH): causes increased rate of H2O reabsorption in the kidney tubules, thus increased blood volume, thus higher blood pressure and cardiac output.
 * Vasopressin is synthesized in the hypothalamus and released from the posterior pituitary.
 * **Atrial natriuretic peptide** (aka ANP): vasodilation of the kidney tubules, thus decreased retention of Na+, thus a lower blood volume, thus a lower blood pressure and cardiac output.
 * ANP is synthesized by the myocardial cells of the atria (thus the name) and are released by atrial stretch receptors that sense atrial overfilling. Note this is a mechanical process (increased preload) triggering a chemical signal (ANP) to effect a mechanical change (decreased preload).
 * [Note also that the kidneys are the main source of epinephrine, which acts in beta-1 receptors in the heart to kick up contractility.]
 * [Reasonably important distinction: increases in blood volume don't change contractility, they just increase the strength of the contraction (ie the pressure generated by contraction). Recall that contractility is a chemically mediated (as by EPI) change in the ability of cardiac muscle fibers to contract at the same preload and afterload-- sort of "contractile strength in a vacuum" (except the heart would probably blow up in a vacuum).
 * Describe how the baroreceptor reflex acts to maintain a constant mean arterial pressure.
 * **Baroreceptors** : pressure sensors, mainly in the aortic arch and carotid sinus. These fire in response to pressure; at about 100 mm Hg (aortic) or 50 mm Hg (carotid sinus)mean arterial pressure (MAP), they're firing at a "normal" rate (faster during systole, slower as diastole progresses, following the aortic pressure curve).
 * If MAP goes up __quickly__, the baroreceptors start firing more quickly; this serves as a signal to the medulla to stimulate the depressor area and inhibit the pressor area.
 * SNS stimulation decreased; PNS stimulation increased.
 * Heart rate is reduced, contractility is reduced, increased vasodilation (less R).
 * (since delta-P = QR, by decreasing Q and R you should decrease MAP.)
 * If the MAP goes down __quickly__, they start firing more slowly; this signals the medulla to stimulate the pressor area and inhibit the depressor area.
 * PNS stimulation decreased; SNS stimulation increased.
 * Heart rate goes up, as does contractility; increased vasoconstriction (more R).
 * (by increasing Q and R you should increase MAP).
 * The reason I say "quickly" is that baroreceptors show __adaptation__: over time they can adapt to incremental changes in MAP to accustom themselves to a new arterial "set point." What this means is that the nervous system control of the blood pressure (which is what you're talking about with baroreceptors) is good at regulating short-term changes, but not so good at long-term changes. That's why you have the endocrine pressure mediators (see last LO).
 * [His notes make the interesting and useful observation that the factors that influence cardiac output, pressure, and distribution can be broken down as follows:]
 * Neural input mainly controls contractility and short-term blood pressure.
 * Renal (endocrine) input mainly controls blood volume and long-term blood pressure.
 * Intrinsic mechanisms (see "Regulation of the Vasculature") mainly control blood distribution throughout local tissues.

Phosphorylated: · ICa, IK, If · Myosin heads · Troponin · Phospholamban

Tools of the Trade in Cardiology Tuesday, March 18, 2008 9:37 AM


 * Tools of the Trade in Cardiology, 3/20/08:**


 * [This seemed more or less straightforward. Some notes below, but don't look for too much.]
 * CHEST X-RAY:
 * a) identify major cardiovascular structures
 * You want to look at his slide 4, preferably on the powerpoint (doesn't print well).
 * Recall that the heart is rotated-- right side is more anterior, left side is more posterior. This means that a heart that 'bulges' in a lateral X-ray in one or the other direction is likely to be caused by a problem in a structure of that side.
 * b) list the kinds of cardiovascular abnormalities in these structures
 * So he wants us to list the possible cardiovascular abnormalities.. in the heart?
 * c) outline the role in diagnosis of cardiovascular disorders
 * Diagnosis. Who needs it?
 * ECHOCARDIOGRAM:
 * a) identify the principles of echocardiography
 * Ultrasound sent into body, strikes objects, and reflects to transducer.
 * Can look at blood flow and pressure gradients with Doppler.
 * Blue = away from transducer; red = towards transducer.
 * Can use "M-mode" for echocardiogram - sort of a geological approach looking at various layers underneath a transducer placed on the chest over the heart.
 * Can be used to look at sizes of structures with more accuracy.
 * Note also esophageal ultrasound, in which the patient swallows the transducer to get it close to the heart in the esophagus.
 * b) list the kinds of abnormalities which can be assessed by echocardiography
 * Regurgitation-- backwards flow across heart valves (look with Doppler).
 * If you put a little air in saline and shake it up real good to get some microbubbles (less than 10 microns), you can inject it into the venous system and look for them going through the heart-- they should stay on the right side. If they go to the left side, odds are good that you've got some kind of septal defect. Can assess with basic ol' 2-D four-chamber views.
 * Note you also see some negative contrast from blood coming across the defect from the left heart into the right.
 * Can assess the size and shape of heart valves to look at stenosis.
 * See also his slide 15, I think, titled "Information Obtained from Echocardiography."
 * MYOCARDIAL ISCHEMIA AND INFARCTION:
 * a) describe the kinds of stress tests used in detecting ischemia
 * Stress test-- look for oxygen supply/demand mismatch. Use exercise or something else that makes the heart work harder (more O2 demand), then look at blood pressure and EKG or perfusion/echocardiogram for abnormalities.
 * Most common is treadmill (a la Jay and Silent Bob: "Fly, fat-ass, fly!").
 * This is good in identifying left-main or 3-vessel coronary artery disease in middle-aged men. Not so sensitive outside its comfort zone.
 * It's also cheap (stick a guy on a treadmill and make him run).
 * Can also use pharmacologic stress test (adenosine, dobutamine) that exercise the heart without the patient having to physically exercise.
 * Imaging during stress test: usually used if baseline EKG is abnormal, if the patient's on digoxin, or if you have wonky cardiac conduction not due to ischemia (wolff-parkinson-white).
 * This increases sensitivity dramatically (so might use this for non-middle-aged men), as well as giving you a good localization of the problem. It's good for pre-operative cardiac risk assessment.
 * Can use nuclear perfusion imaging to compare flow at rest and during exercise. If flow during exercise has a weaker signal, good sign that there's a problem (such as temporary ischemia). If flow during both rest and exercise has a place with no signal, that's indicative of a fixed MI (dead portion of heart).
 * Can use thallium-201 (need to use image immediately)
 * Can also use Cardiolite (technetium-99m-sestamibi) (stays in blood for a while, can watch its progress over time)
 * Can also use echocardiogram-- left ventricle should be contracting more vigorously during exercise. If part of the heart stops contracting as much or at all, indicative of a lack of oxygen to that part.
 * b) list the diagnostic tests used in detecting infarction
 * Look at ECG.
 * Look at BP (goes up transiently but then goes down with exercise-- heart can't keep generating adequate pressure)
 * Look at heart rate (if you get to 85% of maximal heart rate without getting abnormal, it's ok; if you run into an abnormality before that, that's bad; if you don't get to 85% but haven't seen an abnormality yet, that's inconclusive)
 * Calcification of coronary arteries is a marker for coronary atherosclerosis-- detect with CT scans, get a 'calcium score'.
 * Can also use combination of angiography and CT scans to locate narrowing point of arteries. Run a catheter up into vasculature, look at pressure + O2 content, inject contrast, etc.
 * c) describe techniques used in patients with ischemia or infarct to locate and treat coronary lesions

Regulation of the Vasculature

Tuesday, March 18, 2008 10:09 AM


 * Regulation of the Vasculature, 3/20/08:**


 * Describe the similarities and differences in structure and function between striated muscle and vascular smooth muscle.
 * Vascular smooth muscle (similarities):
 * Develops tension through sliding filament mechanism.
 * Phosphorylation of myosin heads (see "Regulation of Cardiac Output") controls rate of myosin-acting bond cycling.
 * Has calcium and potassium channels (ICa and IK).
 * Removes its intracellular calcium with the same three pumps (SERCA, PMCa, NCX)-- see "Properties of Myocardial Cells."
 * Vascular smooth muscle (differences):
 * Generally not AP-directed (__graded change in membrane potential produces graded change in tension__, as opposed to all-or-nothing AP contraction).
 * No fast Na+ channels; when APs are present, it's through Ca++ influx.
 * Contract more slowly than striated muscle but can maintain a high degree of tension for some time with low ATP consumption.
 * Has no t-tubules.
 * Doesn't have obvious sarcomeres.
 * Has cells that are connected electrically by gap junctions (similar to cardiac, but not skeletal, striated muscle).
 * Has no troponin or tropomyosin (has calmodulin + myosin light chain kinase instead).
 * (calmodulin binds to calcium, activating MLCK to bind myosin to actin and contract; MLC phosphatase releases them for the next cycle.)
 * Identify two voltage-activated ion channels that play a pivotal role in regulating contraction of vascular smooth muscle. Describe factors that regulate the activity of these channels.
 * Before we get into this, remember **your adrenergic receptor types** :
 * Alpha-1 adrenergic receptors trigger PLC activation, releasing DAG, which activates protein kinase C. (also involved with IP3 signaling.) Tend to bind norepinephrine.
 * Beta-2 adrenergic receptors trigger adenylyl cyclase activation, generating more cAMP. Tend to bind (at physiological doses) epinephrine.
 * Slow calcium channels: ICa(s)
 * cAMP and cGMP activate kinases which __in__activate the ICa channels (note contrast to sympathetic cAMP kinase activity in the heart), which causes a decrease in Ca++ influx and hence a decrease in contractile tone.
 * The protein kinases that __inactivate__ calcium channels in vascular smooth muscle are **PKA** (cAMP) and **PKG** (cGMP); a protein kinase in vascular smooth muscle that __potentiates__ calcium channels is **PKC** (stimulated by diacylglycerides, which are stimulated by alpha-1 adrenergic receptors and angiotensin II).
 * Note on possible confusion: PKA (cAMP-stimulated) inactivates calcium channels in smooth vascular muscle, but potentiates them in cardiac muscle.
 * ANP and NO raise cGMP levels. EPI raises cAMP levels (binds to beta-2 adrenergic receptors, more on this below).
 * Delayed rectifier potassium channels: IKr and IKs
 * So basically what you've got is synergistic effects with the ones just described. Recall that calcium and potassium channels carry opposing currents.
 * Increases in cAMP/cGMP __activate__ IK channels, hyperpolarizing the cells and causing voltage-gated calcium channels to close (thus complementing the Ca++ channel inactivation by PKA and/or PKG), resulting in more vasodilation. Increases in DAG/PKC activity do the reverse (more vasoconstriction).
 * Note a difference here between cardiac and vascular smooth muscle.
 * In the heart, the IK channels are co-activated along with the ICa channels in order to facilitate faster cardiac cycling (heart rate).
 * In vascular smooth muscle, because the two channels are simply opposed and there's not the whole complicated phase-2 plateau dance going on between them, stimulating ICa channels is going to tend to decrease IK channel activity and vice versa.
 * Note also that calcium pump activity tends to change with cAMP/cGMP levels as well. ICa potentiation inhibits the plasma membrane (PMCa, not SERCA) calcium pumps, ICa inhibition potentiates them.
 * Essentially, in vascular smooth muscle:
 * Alpha-1 stim: increased ICa, decreased IK and PMCa pumps.
 * Thus constriction.
 * Beta-2 stim: decreased ICa, increased IK and PMCa pumps.
 * Thus dilation.
 * So:
 * Stimulation of alpha-1 adrenergic receptors (as by **NE** ) causes increased PKC, which potentiates calcium channels and inhibits potassium channels and calcium pumps, causing contraction.
 * Note that **angiotensin II** increases PLC levels, doing the same thing.
 * Stimulation of **beta-2 adrenergic receptors** (as by **EPI** ) causes increased cAMP, which (in vascular smooth muscle) inhibits calcium channels and potentiates potassium channels and calcium pumps, causing inhibition.
 * Note also that ANP creates more cGMP, which has the same effect.
 * Describe how vascular endothelial cells contribute to vascular tone and resistance.
 * So there's a bunch of native effects that the endothelium can bring about on the nearby smooth muscle under certain conditions. Generally these are involved with either constriction (in which case they're called **endothelial-derived contracting factors** ) or dilation (in which case they're called **endothelial-derived relaxing factors** ).
 * Prostaglandins are produced by the endothelium-- they can be either EDCFs or EDRFs.
 * We've already mentioned NO as a vasodilator produced in the endothelium. Other EDRFs: adenosine, H+, CO2, potassium (more on these under "Coronary and Skeletal Muscle Circulation").
 * Potent EDCFs: **endothelins**.
 * Describe sympathetic and parasympathetic innervation of the vasculature and the distribution of alpha-adrenergic, beta1-adrenergic, beta2-adrenergic, and muscarinic acetylcholine receptors.
 * Alpha-adrenergic receptor stimulation: constricts vascular smooth muscle.
 * Found in arteries, arterioles, and veins.
 * Beta-adrenergic receptor stimulation: relaxes vascular smooth muscle.
 * Found in arteries and arterioles, particularly in striated muscle (cardiac and skeletal).
 * Muscarinic ACh receptor stimulation: indirectly relaxes vascular smooth muscle.
 * Found in the endothelial cells (not the smooth muscle cells) of the vasculature.
 * Compare the role of cAMP-induced phosphorylation in cardiac muscle contraction with that of cAMP- and cGMP-mediated phosphorylation in vascular smooth muscle contraction.
 * cAMP-induced phosphorylation in __cardiac__ muscle (through protein kinase A) __potentiates__ calcium channels, causing an increase in Ca++ and thus in AP generation.
 * cAMP- and cGMP-induced phosphorylation in __vascular__ smooth muscle (through protein kinases A and G respectively) __inactivates__ calcium channels, causing the muscle surrounding them to relax and dilate.
 * **So note a couple of differences between cardiac and vascular smooth muscle sympathetic stimulation.**
 * In heart muscle: sympathetic stimulation, mainly through **beta-1** receptors, increases the level of cAMP in the cell. This phosphorylates and __potentiates__ ICa channels (among other effects), causing __increased__ calcium influx and chronotropic/inotropic effects.
 * In vascular smooth muscle: sympathetic stimulation, through **beta-2** receptors, increases the level of cAMP in the cell. This phosphorylates and __inhibits__ ICa channels (among other effects), causing __decreased__ calcium influx and thus decreased contraction (leading to vasodilation).
 * Note this can also come about through nitric oxide-induced buildup of cGMP.
 * **Alpha-1** receptor stimulation in vascular smooth muscle doesn't change cAMP levels, but causes dephosphorylation of ICa channels, __potentiating__ them again and increasing calcium influx (leading to vasoconstriction).
 * Compare and contrast the cardiovascular effects of norepinephrine, a low concentration of epinephrine, and a high concentration of epinephrine.
 * NE effects: activates alpha-adrenergic receptors, produces vasoconstriction.
 * Low concentration of EPI: preferentially activates beta-2 adrenergic receptors, increases cAMP levels, produces vasodilation.
 * High concentration of EPI: activates both alpha- and beta-2 adrenergic receptors, nullifying the beta-2 adrenergic vasodilation effect. Dr. French says that at pharmacological doses, EPI actually preferentially binds alpha-1 adrenergic receptors.
 * [Discussion of the consequences of this double effect can be found under "Coronary and Skeletal Muscle Circulation."]
 * Note that both NE and EPI can bind to beta-1 receptors in the heart, as well.
 * Describe the molecular mechanism by which ACh causes dilation of blood vessels. Explain why this is referred to as a "paracrine" mechanism.
 * As mentioned, ACh causes NO release in the endothelial cells near the vascular smooth muscle, which diffuse into the muscle and raise cGMP levels, causing dilation.
 * This is called "paracrine" because it's a mechanism that arises in the endothelia but has an action in a nearby tissue (muscle).
 * Describe myogenic autoregulation and its consequences.
 * Myogenic autoregulation: responses of vascular smooth muscle (not endothelial cells) to changes in blood flow, independent of endocrine or neural input.
 * This is actually pretty cool. So if I cut off Rhett's leg (thus making it independent of autonomic nervous and endocrine control) and vary the amount of flow that I pump through his blood vessels, the vessels will still constrict or dilate to maintain a constant flow rate. This is evidently important in sudden changes in CV pressure such as large postural changes (like lying down after Rhett clubs me with his leg and wanders off to find a spare surgeon).
 * Note three mechanisms of autoregulation in the vasculature:
 * (1) myogenic autoregulation
 * (2) endothelial autoregulation (EDCFs or EDRFs)
 * (3) metabolic vasodilation (get to this later, but essentially the byproducts of metabolism increase vasodilation-- see "Coronary and Skeletal Muscle Circulation" and "Regulation of O2 During Exercise")
 * Describe the cardiovascular consequences of changing from a recumbent (lying down) to a standing position.
 * You get up. Gravity now sucks at the blood going to your head, decreasing its pressure. The baroreceptors in the carotid sinus ("Regulation of Cardiac Output") freak out and trigger sympathetic responses to jack up your heart rate and contractility and increase your peripheral resistance, all in order to get your blood pressure up.
 * You'll maintain the higher blood pressure as long as you're upright.
 * Wonder if this is why you're not supposed to eat standing up-- you have sympathetic stimulation that's telling your GI tract not to digest.
 * Note that __decreases__ in blood pressure upright are not normal (orthostatic hypotension) and are frequently indicative of low-volume status.
 * Also see some effects in the lung capillaries -- the flow through the ones at the top of your lungs goes down, the flow through the ones at the bottom of your lungs goes up. See "Special Circulations."

Cardiac Pump I Tuesday, March 18, 2008 4:12 PM


 * Cardiac Pump I, 3/20/08:**


 * Lots of diagrams in this one. Go read his notes. Note that I consider his closed-curve afterload diagram to be misleading (doesn't show the increase in systolic pressure before ejection that you would expect in increased-afterload situations).
 * Sketch a plot of left ventricular pressure as a function of time and label the following phases of the cardiac cycle: atrial systole, isovolumic contraction, rapid ejection, reduced ejection, isovolumic relaxation, rapid ventricular filling, and reduced ventricular filling (diastasis). On the same plot sketch the changes that occur in left atrial pressure and aortic pressure.
 * Atrial systole is the pressure bump at the beginning.
 * Isovolumic contraction: after mitral valve closes but before aortic valve opens.
 * Rapid ejection: the first (ascending) part of the pressure curve, after the aortic valve opens.
 * Reduced ejection: the second (descending) part of the pressure curve, before the aortic valve closes. Note that the ventricular pressure can actually fall below the aortic pressure in this phase and still show limited ejection (see below for reasons why).
 * Isovolumic relaxation: after aortic valve closes but before mitral valve opens.
 * Rapid ventricular filling happens right after the mitral valve opens; reduced ventricular filling (diastasis) happens after that up under atrial systole.
 * Get three waves in the atrial pressure. Note that these also correspond to waves in the venous pressure (since the atrium backs up into the venous circulation):
 * //a// wave occurs during atrial contraction.
 * //c// wave occurs during ventricular contraction (the mitral valve bulges backwards into the atrium, increasing pressure).
 * //v// wave is slower and occurs during atrial filling, releasing when the mitral valve opens and unimpeded flow to the ventricle is restored.
 * Aortic pressure starts, when the aortic valve opens, at its lowest (diastolic) pressure, follows the pressure curve around to when the aortic valve closes, has a small "blip" upwards (incisura or dicrotic notch), and then slowly declines until the next ventricular systole.
 * Sketch the relationship between the time course of changes in left ventricular pressure during the cardiac cycle and i) the volume of the left ventricle, ii) the waves of the ECG, and iii) the first and second heart sounds.
 * P wave (EKG) comes first, followed by atrial systole, followed by the QRS complex and the first heart sound as the mitral valve closes. The T wave follows, followed by relaxation of the ventricle and the second heart sound as the aortic valve closes.
 * Sketching this helps. It's in First Aid, I think.
 * Compare the contribution of atrial systole to ventricular filling under normal conditions at rest, as heart rate increases, and under pathophysiological conditions.
 * At rest: not much contribution. The rapid filling of the ventricle through the open AV valve should suffice fine without the small additional push from the atrial contraction.
 * With an increased heart rate: more significant contribution. The ventricle is undergoing systole more rapidly and is having less time to fill, so the additional push from atrial systole can be important.
 * With hypertensive heart disease or with a stenotic AV valve: also significant. With hypertensive disease (my speculation here), the increased aortic pressure means that the ventricle needs all the preload it can get in order to push its pressure high enough to eject a good fraction of its volume into the pressurized aorta. With stenotic AV valves (also my speculation), ventricular filling is limited because passive flow from the atria to the ventricle is impaired, requiring help from atrial systole.
 * Explain why, during the reduced ejection phase of ventricular systole, the hydrostatic pressure in the aorta can exceed that in the left ventricle and yet the flow of blood from the ventricle to the aorta continues.
 * Simple explanation: inertia.
 * Slightly less simple explanation: pressure exerts force. Force is an accelerant. Accelerants affect the rate at which velocities change-- thus a negative pressure will produce a negative rate of change in velocity but will take a certain amount of time to actually bring the velocity down to zero. Thus ejection continues despite the wrong direction of the pressure gradient because that pressure gradient takes time to reverse the velocity of the blood flow.
 * Describe how heart sounds and heart murmurs are produced.
 * Turbulent blood flow.
 * Explain why the second heart sound “splits” when the patient takes a deep breath.
 * Inhalation = decreases intrathoracic pressure (which, recall, is what causes air to come into the lungs in the first place). This depressurizes the right atrium relative to its intake veins, which increases right atrial flow. This means that the right ventricle gets more preload, which increases its cardiac output for the stroke (see Starling curve). Since the cardiac output will be slightly increased for the right ventricle as opposed to the left, the pulmonary valve will close slightly after the aortic valve (more outflow from the right ventricle than the left), causing a "splitting" of the S2 heart sound.

Cardiac Pump II Tuesday, March 18, 2008 5:48 PM


 * Cardiac Pump II, 3/20/08:**


 * Define ejection fraction and describe how to calculate it.
 * **Ejection fraction** : the fraction of the blood in the ventricle at the end of diastole that is ejected during the following systole.
 * The ejection fraction is equal to the stroke volume (how much blood was expelled from the ventricle) divided by the end diastolic volume (how much blood was present in the ventricle at the end of diastole).
 * Ie: EF = SV/EDV.
 * Note that SV is just EDV - ESV (end-diastolic volume minus end-systolic volume).
 * List typical values for stroke volume, cardiac output, and ejection fraction for the right and left ventricles of a healthy young adult male.
 * Typical SV of left ventricle: EDV = 130 mL, ESV = 50 mL, so SV = 80 mL.
 * Typical SV of right ventricle: has to be more or less the same as the left, so 80 mL.
 * Typical EF of left ventricle: 80/130 = 0.62.
 * Typical EF of right ventricle: 80/160 = 0.5 (EDV for right ventricle is 160).
 * Typical cardiac output: same on both sides. Equals stroke volume (80 mL) times heart rate (around 70) = typically around 5.6 L/min.
 * Yes, I know we've been working with 5 L/min as standard up to now.
 * Sketch a plot of left ventricular pressure as a function of left ventricular volume during the cardiac cycle. Label the period of rapid and reduced ventricular filling, isovolumic contraction, rapid and reduced ejection, isovolumic relaxation, end-systolic volume, end-diastolic volume, and stroke volume.
 * These are the characteristic "**closed curves** "-- they look like misshapen boxes or polygons.
 * It will help to be looking at these while you read this.
 * Normal cardiac conditions:
 * Upward-sloping bottom side: filling of left ventricle during diastole.
 * Bottom right corner: mitral valve closes.
 * Right-sided vertical line: isovolumetric contraction (building pressure).
 * Upper right corner: aortic valve opens.
 * Curving top side: expulsion of volume from ventricle.
 * Upper left corner: aortic valve closes.
 * Left-sided vertical line: isovolumetric relaxation (releasing pressure).
 * Bottom left corner: mitral valve opens.
 * The heart runs counterclockwise through this cyclic graph.
 * In terms of his terminology:
 * Bottom side: rapid filling first (brief), reduced filling second (long). There's a small bump in pressure at the end where the atrium contracts.
 * Top side: rapid ejection first, reduced ejection second.
 * End systolic volume is the volume at the bottom of the left vertical line (where mitral valve opens).
 * End diastolic volume is the volume at the bottom of the right vertical line (where mitral valve closes).
 * Stroke volume: the horizontal area between the EDV (bottom right corner) and the following ESV (bottom left corner).
 * Note you can find the aortic pressure (afterload) by looking at the top right corner (where the aortic valve opens)
 * Note that preload is EDV, thus it's at the bottom right corner (where the mitral valve closes).
 * Describe how preload and afterload are represented on a plot of left ventricular pressure versus left ventricular volume.
 * Increased preload:
 * The ventricle will end up, more or less, at the same ESV (bottom left corner doesn't move), but the starting EDV will go up (bottom right corner shifted right). This means that the pressure generated will go up (Starling curves). So the ventricle will reach the aortic pressure faster, and raise the maximum pressure achieved, while having enough time to pump the extra preloaded blood out. Thus the bottom right corner shifts right and the pressure curve across the top gets higher, but the left corners don't move.
 * This means that the stroke volume has gone up.
 * Note that his lecture doesn't agree with his notes (lecture says a small increase in ESV results from increased preload, notes say it doesn't). Probably doesn't matter much.
 * Notice also that this is relatively steady-state-- assuming ESV doesn't change, increased preload is going to maintain the same curve for all subsequent heart strokes until the preload changes again (increased blood in, increased blood out). This is in contrast to afterload (see below).
 * Essentially, increased preload stretches the closed-curve to the right (left side doesn't change).
 * Increased afterload:
 * The ventricle isn't generating more pressure (contractility and preload haven't changed), but it will take a longer build in pressure (generated by isovolumetric contraction) to get the aortic valve to open (since the pressure in the aorta is higher) and release volume. This is going to shift the top right corner and top side of the curve sharply higher and - since the duration of contraction hasn't changed - it will not eject as much blood, ending at a higher ESV (both left corners shift to the right).
 * This means that the stroke volume has gone down.
 * Notice that the stroke __after__ that is going to face the same afterload, but will now have an increased preload (EDV) due to the increased beginning ESV and the same ventricular filling. This will increase the strength of the ventricle's contraction, allowing it to keep the same ESV at the end of its stroke (left corners stay the same as the previous stroke) as well as keeping its increased maximum pressure and EDV (bottom right corner shifted right, top side higher).
 * This is essentially why, with an increased afterload, you don't keep your low stroke volume forever-- the increased preload compensates, to maintain cardiac output. But you do it at a higher systolic pressure.
 * Essentially, increased afterload shifts the entire closed-curve to the right (and makes it higher).
 * Use a plot of pressure versus volume for the left ventricle to illustrate the effects of an increase in preload, afterload, or contractility.
 * We just did preload and afterload.
 * Contractility:
 * You're not changing preload - so the EDV shouldn't change much - but the heart should beat more strongly (higher top side) and should eject more of its volume (ESV shifts left). More or less: bottom right corner doesn't move much, left corners shift left.
 * This means that the stroke volume has gone up.
 * Note that the stroke __after__ that- since the preload situation hasn't changed - is going to go back to the same stroke volume, since the EDV is going to be comparatively smaller. The lower EDV (lower preload) is going to result in a lower pressure being generated, which counteracts the increased contractility.
 * This seems pretty useless, but only until you think that contractility is generally coupled with something else-- like a higher heart rate. Higher heart rate = decrease in EDV (less filling time). Normally this would decrease the pressure generated per heartbeat-- but if you also increase the contractility, the drop in pressure along the Starling curve is compensated for by the rise in contractility, allowing a more rapid heartbeat at the same stroke volume.
 * Essentially, increased contractility shifts the entire closed-curve left (and makes it higher).
 * [In a person actively exercising:]
 * What we mentioned a minute ago. Heart rate goes up, __de__creasing preload (less ventricular filling time), but the sympathetic activity also increases the contractility (inotropic change), making the same amount of pressure available at a lower preload volume and maintaining stroke volume, thus allowing cardiac output to increase faster.
 * Another way of thinking about this: CO = HR x SV, right? If you increase HR, in the absence of increased contractility, the preload goes down, which decreases the SV (Starling) and limits the increase of the CO. But if you increase contractility along with HR, then with increased HR, SV can stay constant or even go up, allowing cardiac output to rise faster.
 * Indicate on a plot of left ventricular pressure vs. volume the changes associated with loss of systolic function.
 * Loss of systolic function: similar to a loss of contractility. Top side gets lower, left side shifts right (increased EDV with decreased stroke volume-- decreased ejection fraction).
 * Describe the causes and consequences of diastolic dysfunction.
 * AV (mitral/tricuspid) valve stenosis: causes impaired filling.
 * Inability of heart to relax properly: also causes impaired filling. The most common cause of this is aging-- as damaged myocytes are replaced by fibroblasts, the heart gradually loses both its contractile ability and (germane to this discussion) its elasticity.
 * Chronic hypertension: causes hypertrophy in the ventricular muscles without a corresponding increase in the volume they encompass, causing less volume to be available for filling.
 * Consequences: well, you've got less blood to eject out into the circulation. That's generally thought of as a bad thing.

Special Circulations Wednesday, March 19, 2008 11:31 AM


 * Special Circulation, 3/21/08:**


 * Describe the properties and function of arteriovenous shunts in the cutaneous vasculature of “non-hairy” skin.
 * Here we're talking mainly about shunts in acral areas and the face, particularly the lips, ears, and nose.
 * AV shunts bypass capillary beds; they seem to be there mainly for thermoregulation.
 * AV shunts show no myogenic autoregulation ("Regulation of the Vasculature"). However, they do show extensive regulation by endocrine and neuronal mechanisms.
 * They are densely innervated by sympathetic fibers; generally they become dilated (thus more blood flow and erythema) when sympathetic signals are __inhibited__ and become constricted (thus less blood flow and pallor) when sympathetic signals are __stimulated__.
 * Temperature regulation:
 * Cold: sympathetic fibers stimulated. Blood flow through AV shunts stops (no more heat loss).
 * Warmth: sympathetic fibers inhibited. Blood flow through AV shunts increases (accelerate heat loss).
 * Note that the temperature regulation can override the sympathetic stimulation (which is why you get red during exercise despite the fact that your sympathetic nerves are firing like crazy).
 * Describe the principle factors that regulate cerebral blood flow.
 * Since the brain in encased in a rigid structure, its blood inflow must always equal the outflow (total volume of blood and fluid must stay the same).
 * The rate of cerebral blood flow doesn't vary much in contrast to the rest of the body: it averages about 800 mL/min for your average brain.
 * Relatively weak influence of autonomic nervous stimulation on cerebral vessels (no sympathetic innervation, slight parasympathetic innervation), although recall that there are baroreceptors in the carotid sinus that regulate the heart by sympathetic or parasympathetic stimulation. The steadiness of the cerebral flow is maintained mainly by myogenic autoregulation.
 * Most important regulator of cerebral blood flow: the partial pressure of CO2 in the arteries (PaCO2). __A small increase in CO2 results in a large amount of vasodilation__ (perhaps due to pH changes in the extracellular area).
 * Under normal, constant PaCO2 (40 mm Hg), the cerebral blood flow can be held fairly constant under a wide range of mean arterial pressures by myogenic autoregulation.
 * Under elevated, constant PaCO2 (70-80 mm Hg), the autoregulatory capabilities of the cerebral vessels are lost, and the cerebral blood flow begins to vary in direct proportion to the mean arterial pressure.
 * PaO2 also regulates to some extent, but only after it gets very low (less than 50 mm Hg)- also causes vasodilation and increased flow.
 * Describe the CNS ischemic response and explain how it might be triggered by head trauma (Cushing’s Reflex).
 * (continuation of prior LO) If the CO2 levels are high, and the mean arterial pressure becomes low (below 60 mm Hg), the brain begins to become ischemic (= condition in which an organ is hypoxic and accumulating metabolites).
 * This provokes the **CNS ischemic response** : an extremely strong stimulation of the sympathetic nervous system in an effort to increase cerebral blood flow.
 * The result is to increase resistance to other locations-- with a sufficiently strong CNS ischemic response, you can get __complete cessation of blood flow__ to almost all other sites of the body (excepting the coronary arteries, which are necessary to maintain blood flow to the brain).
 * **Cushing's reflex** : head trauma causes intracranial swelling, compressing cerebral vessels and dramatically lowering the blood pressure in cerebral arteries, thus triggering a CNS ischemic response even in the absence of elevated PaCO2.
 * List typical values for the mean, systolic, and diastolic pressures in the pulmonary circulation of a healthy young adult.
 * Recall: __systemic circulation__ is what goes out the left ventricle and comes in the right atrium. __Pulmonary circulation__ is what goes out the right ventricle and comes in the left atrium.
 * Note the lung tissue itself gets __both__ pulmonary perfusion and systemic perfusion (the latter from the bronchial arteries coming off the thoracic aorta). What we're talking about here is the pulmonary vasculature.
 * Systolic: 25 mm Hg (see "Intro to the CV system")
 * Diastolic: 10 mm Hg
 * Mean: 15 mm Hg
 * Recall P = QR; for the systemic and pulmonary circulation, both sides have to have the same Q, but both P and R are lower in pulmonary circulation and higher in systemic circulation.
 * [Interesting: the mean hydrostatic pressure across pulmonary capillaries (about 10 mm Hg) is lower than that in systemic capillaries. The oncotic pressure, however, is the same (about 25 mm Hg). Thus pulmonary capillaries, under standard conditions, favor net absorption over filtration. Makes sense-- you really don't want fluid around the alveolar capillaries inhibiting blood flow.]
 * Note that the pressure in the pulmonary vein is about 5 mm Hg
 * [Can approximate left atrial pressure, and thus can approximate left ventricular preload, by looking at __pulmonary arterial wedge pressure__ by sticking a Swan-Gans catheter up through the right heart and into the pulmonary artery. Note that despite the name, you're measuring __pulmonary venous pressure__ (occluding artery and allowing venous blood to wash back against the catheter sensor).]
 * [Not in his LOs but interesting and he did spend some time on it in class:]
 * Visualize the lung as a big square. There's capillaries at all heights of the square, but the afferent and efferent vessels are coming in at the middle (hilum). Blood going to the capillaries at the top (apex) is going to have to climb against gravity to get there; blood going to the capillaries at the bottom (base) is going to pick up speed and pressure on its way as gravity helps it along.
 * The pressure going into capillaries at the top of the lung is therefore lower than the pressure going into capillaries in the middle of the lung, which is also lower than the pressure going into capillaries at the bottom of the lung. However, the pressure drop across all capillaries in the lungs should be about the same (10 mm Hg).
 * Note that this means pulmonary capillaries at the base, or __Zone III__, of the upright lung will be relatively more dilated (and potentially edemic) than those at the apex, due to the effects of gravity and the corresponding hydrostatic pressure increase.
 * Under hypovolemic/low pulmonary pressure conditions, the capillaries at the apex of the lung can cease to have any blood flow at all (not enough pressure to overcome gravity effects and climb up to the apex, or __Zone I__, of the lung).]
 * Note that on positive pressure ventilation, the pressure in the alveoli suddenly goes up (normally it's in equilibrium with atmospheric pressure, thus 0). The pressure in alveoli (which are surrounding the capillaries) can collapse the vessels if alveolar pressure exceeds fluid pressure in a capillary. Note that, since vessels at the apex of a lung are going to have lower pressure than vessels at the base, the apical (Zone I)vessels are going to be affected more (closed) than the base vessels (Zone III). The capillaries in the middle (Zone II) are going to have intermittent flow but less than the base vessels.
 * [Increasing pulmonary arterial pressure is generally neutralized by increasing the number of capillaries that are open and the degree to which they're open, thus increasing cross-sectional area and total resistance. Increasing pulmonary venous pressure tends to have more of an effect, like increasing systemic venous pressure.]
 * [Note that some of the deoxygenated blood from the bronchial veins drains directly into the pulmonary veins and hence the left ventricle. This has two fairly miniscule effects: one, the CO of the left ventricle is slightly higher than the CO of the right ventricle, and two, the partial pressure of oxygen in the aorta is slightly less than the partial pressure of oxygen in the alveoli. Ignore on exams, but it's cool.]
 * Compare and contrast the neural and intrinsic regulation of the systemic and pulmonary vasculature.
 * Neural regulation: similar in systemic and pulmonary systems but there just __aren't that many autonomic receptors in the pulmonary vasculature__. Generally the regulation of pulmonary flow is passive (not a lot of muscle or innervation).
 * Intrinsic regulation:
 * Passive regulation more or less looks like this: as flow goes up, more vessels are recruited to accommodate it, increasing peripheral resistance not by constricting vessels but just by recruiting more of them.
 * In the pulmonary system, the vessel response to hypoxia is **backwards** from systemic intrinsic response to hypoxia-- the pulmonary vessels __constrict__ in hypoxic areas (as opposed to dilating in systemic vessels). This shunts blood flow to the better-ventilated alveoli (perhaps those that aren't damaged) and away from the less well-ventilated alveoli (which may not be able to uptake oxygen any more). This is reinforced by a local vasoconstrictive effect of low pH (as occurs in hypoxia).
 * Note the difference between cerebral vessels and pulmonary vessels-- in cerebral vessels, hypoxia (high CO2, low O2) causes vasodilation. In pulmonary vessels, hypoxia causes vasoconstriction.
 * Note this means that if the entire lung is hypoxic you're in trouble. Pulmonary resistance (and pressure) goes up across the entire lung, which can increase pulmonary filtration and cause edema.
 * Compare and contrast the responses of the pulmonary and systemic vasculature to hypoxia.
 * Mentioned above.

Cerebral blood flow should stay more or less constant.

Most important regulator of cerebral flow = PaCO2.

With normal PaCO2, cerebral pressure steady. With raised PaCO2, cerebral pressure rises linearly with MAP.

Coronary and Skeletal Muscle Circulation Wednesday, March 19, 2008 2:09 PM


 * Coronary and Skeletal Muscle Circulation, 3/21/08:**


 * Explain why a sample of true mixed venous blood can only be obtained from the pulmonary artery, and not from the venae cavae or right atrium.
 * Well, the thing to remember is that you're looking at venous blood coming from a bunch of different types of organ systems, some of which use more blood oxygen than others. To get an average, you want them all to be thoroughly mixed together. The caval channels won't work, as you're leaving out all the blood from the other vena cava when you draw from one. Dr. Wallace maintained in lecture that the coronary sinus and some of the right ventricular coronary drainage drains into the right ventricle. I don't know about the right coronary drainage, but the coronary sinus (which mainly drains the left ventricular coronary supply) drains into the right atrium, not the ventricle. I think his point is that you want all the venous blood mixed together in one place-- whether or not all the venous blood (aside from some bronchial venous blood as mentioned in last lecture) winds up in the right atrium or not, it's safe to say that the blood won't be adequately mixed until it's ejected out of the ventricle into the artery.
 * Ok, his notes also say that the coronary sinus and right ventricular drainage go to the right atrium. So I'm not sure what he was getting at in lecture.
 * Describe when during the cardiac cycle the majority of coronary blood flow to the left ventricle occurs and explain why this is the case.
 * Explanation given here: the pressure in the ventricular walls generated by contraction shuts off the coronary vessels within the walls. This is particularly marked in the left ventricle, in which the strength of the contraction can actually force blood back out of the coronary arteries (negative flow).
 * Alternate/additional explanation: Recall from anatomy that the coronary arteries are mainly filled by backflow against the closed aortic valve (the openings of the coronaries are almost directly above the aortic valve in the ascending aorta). Thus during systole, the flow to the coronary arteries drops dramatically (pressurized systolic blood being forced out into the aorta, only a small amount of which goes into the coronary arteries); however, during diastole, the flow to the coronaries goes up (diastolic pressure forces blood back against the closing aortic valve, draining directly into the coronary arteries). Ask me, this combines well with the given explanation to make sense out of the filling curves we're given in his notes.
 * Note that this means that if you have something that causes a rapid decline in pressure or duration of diastole, can spell trouble for the coronary circulation.
 * Name the primary energy source that cardiac muscle uses to produce ATP under normal circumstances.
 * Under normal conditions, the heart mainly (65%) uses oxidation of fatty acids to generate ATP.
 * Note that this is buffered by __phosphocreatine__, a kind of ATP-backup system which can quickly regenerate ATP from ADP.
 * Describe the consequences of the reliance of myocardial cells on aerobic metabolism.
 * A heart deprived of oxygen will begin to malfunction immediately due to having only a fraction of its normal amount of ATP. In 20-40 minutes, the myocytes will deplete their stash of phosphocreatine (see above) and undergo necrosis (ie. myocardial infarction).
 * Note that the cells of the heart have no way to metabolize lactate (anaerobic product); thus under anaerobic conditions __lactate__ will accumulate, lowering pH, which in turn further decreases the ability of the cardiac cells to metabolize.
 * Note that anaerobic metabolites trigger chemoreceptors in the heart, causing pain triggers in the left chest and shoulder (angina).
 * Name the three major determinants of myocardial oxygen consumption.
 * Increased heart rate (and CO)
 * Pressure developed during systole
 * Contractility (force/speed of contraction)
 * Describe how the oxygen delivery to ventricular myocardium is increased when ventricular oxygen demand increases.
 * Note that the cardiac myocytes are __already operating at near peak extraction of O2__ from blood-- thus under conditions of stress they can't just kick up their O2 extraction rates. **If the cardiac muscles need more O2, they have to increase their blood flow**.
 * Recall that the difference in O2 content between the arterial and venous blood systemically is about 5 mL O2 / 100 mL blood (from 19 to 14, see "Delivery of Oxygen and Measurement of Cardiac Output").
 * In the coronary vessels, the difference is more or less constant at 12 mL O2 / 100 mL blood (from 19 to 7). This is the most the cardiac muscles can extract and they extract this amount all the time, in contrast to skeletal muscle, which is capable of extracting 100% of the oxygen from blood during exercise but which usually operates at a much lower efficiency.
 * There's a correspondingly linear relationship between the rate of oxygen consumption by myocardial tissue (driven by the abovementioned three factors) and the blood flow through the coronary arteries.
 * This seems to be mostly mediated by adenosine release (see below).
 * In general, the neural and endocrine effects on coronary vessels is relatively minimal.
 * [When it happens, sympathetic stimulation seems to largely activate beta-2 receptors in small coronary arteries, dilating them and increasing coronary perfusion. Note, by contrast, that the coronary arteries are not extensively innervated by parasympathetic fibers.]
 * Compare and contrast increased pressure work and increased volume work and compare the oxygen demands they produce in the ventricular myocardium.
 * Stroke work: mean arterial pressure times the stroke volume (SW = MAP x SV). For total work, need to also include heart rate (total work = MAP x SV x HR).
 * Put another way, ventricular stroke work is determined by the volume of output, the pressure which it has to reach to be ejected (the afterload or mean arterial pressure), and the rate at which it's contracting. So this can be broken down:
 * Increased **volume work** : effectively, greater preload, which means the heart generates more pressure when beating (Starling curve, also the preload pressure vs volume closed-curve). This does, in fact, involve increased pressure, but it's a change in pressure due to a change in stroke volume. This tends to be lighter work for the heart (less myocardial O2 consumption), possibly because you're relying on intrinsic mechanical factors to increase the force generated.
 * Increased **pressure work** : effectively, greater afterload, which means the heart needs to generate more isovolumetric pressure to eject blood against aortic pressure. This tends to be harder work for the heart (more myocardial O2 consumption).
 * Maybe another way of saying this is that in volume work, the ratio of pressure built up to volume of blood ejected stays relatively stable (more pressure, more blood ejected). In pressure work, the ratio goes up (more pressure, less blood ejected). So per mL of blood, the heart is having to work harder (and use more O2) to eject it. Just my thoughts.
 * Interestingly, this is why it's more dangerous to shovel snow than jog. (I would still, albeit barely, rather shovel snow.) Lots of muscle use stimulates increased aortic pressure, which makes your heart do pressure work and work harder. Less active muscle use (jogging) stimulates increased cardiac output but not aortic pressure, thus making your heart do volume work and work easier. See "Regulation of O2 Delivery During Exercise."
 * Describe the cardiovascular consequences of stenosis of the aortic valve.
 * This relates to what we're just talking about. Stenosis of the aortic valve is going to create an effective high afterload (the ventricle has to build to a higher pressure to release blood into the aorta), making the heart perpetually work harder doing pressure work.
 * However, this disease is especially craptastic because the coronaries (which under a 'normal' elevated afterload would at least get increased filling from the heightened diastolic pressure) are getting filled at a normal or slightly decreased rate (diastolic pressure in the aorta is normal to low since blood can't get out the stenosed valve well, and may be draining back into the ventricle when it does). This means the heart is burning O2 faster but can't get enough blood to itself to keep up the pace.
 * Describe two mechanisms mediating autoregulation of the coronary circulation.
 * Myogenic autoregulation: innate properties of the vascular smooth muscle, causing it to dilate under high pressure and constrict under low pressure.
 * Chemical autoregulation: mainly through the metabolite **adenosine** (breakdown product of ATP). Cardiac muscle is generating adenosine all the time (since it's also using ATP all the time in regular metabolism). Normally adenosine is washed out of the cardiac muscle/vessels at some rate by coronary blood flow. Under conditions of low coronary supply, the concentration of adenosine goes up due to a decrease in its clearance, and the increased supply of adenosine acts as a __vasodilator__ to increase coronary blood flow.
 * Describe the distribution of adrenergic receptors on skeletal muscle vessels and the effect of norepinephrine and epinephrine on skeletal vascular resistance.
 * Skeletal muscle vessels:
 * Beta-2 adrenergic receptors (stimulation causes vasodilation) predominate in small arteries.
 * Alpha adrenergic receptors (stimulation causes vasoconstriction) predominate in arterioles.
 * **During exercise** (this is important):
 * Norepinephrine and epinephrine are released first due to sympathetic stimulation.
 * Recall that NE is going to cause vasoconstriction, while EPI tends towards vasodilation in cardiac and skeletal muscle. The NE effect dominates at first, causing an increase in peripheral resistance and decreased blood flow in skeletal muscle.
 * As exercise goes on (doesn't generally take too long), the active muscles (but not the passive ones) start to fill up with anaerobic metabolic products which lower their pH (K+/H+ ions, lactate, adenosine, CO2). These produce a vasodilatory effect that overrides NE's vasoconstriction (helped along by EPI's underlying vasodilation tone in small arteries) and increases blood flow. Once the metabolites are gone (presumably after exercise), vasodilation ebbs.
 * Compare and contrast autoregulation in coronary and skeletal muscle resistance vessels.
 * Both coronary and skeletal vessels show myogenic and chemical autoregulation, but coronary vessels seem to chemoregulate (vasodilate) predominantly with adenosine, while skeletal muscle vessels seem to do it by a variety of pH-lowering factors (as described in the previous LO), including but not limited to adenosine.
 * [Notice the blood flow to resting muscle is fairly low (about 10% of capillaries) due to a predominant sympathetic tone (recall that sympathetic innervation is much more significant in skeletal muscle than cardiac muscle). However, that still comprises about 20% of normal blood flow, since a large amount of perfused body mass is skeletal muscle.]

Regulation of O2 Delivery During Exercise Wednesday, March 19, 2008 4:50 PM


 * Regulation of O2 Delivery During Exercise, 3/21/08:**


 * Describe the cardiovascular changes that account for the 25-fold increase in skeletal muscle blood flow during strenuous exercise.
 * (1) A roughly 30% __increase in mean arterial pressure__, due to increased cardiac output and intermittent compression in skeletal muscle arteries during activity. Also there's an __increase in central venous pressure__, which shunts more blood from capacitance to resistance vessels and jumps up BP as well. This is why snow-shoveling makes your heart work harder than jogging (more active muscles = higher aortic pressure).
 * Notice that here the purpose of the 'capacitance' part of the capacitance vessels is revealed: by constricting the veins, can produce a large increase in the amount of blood in active circulation through the arteries. But you don't need or want that large volume there all the time, so normally it's held in reserve in the venous system until it's needed and venoconstriction kicks in.
 * (2) A roughly 20-fold reduction in arterial resistance due to vasodilation in active skeletal muscle.
 * This is just delta-P = QR, or Q = delta-P/R. Delta-P is going up, R is going down in the muscles-- thus increased blood flow to those muscles.
 * Describe how local, intrinsic mechanisms contribute to the regulation of skeletal muscle vascular resistance during exercise and identify three factors that mediate exercise-induced vasodilation.
 * This was largely covered in "Coronary and Skeletal Muscle Circulation." Metabolic byproducts accumulate during exercise, overriding NE influence and producing arteriolar vasodilation.
 * Three factors (ie, metabolites or results of metabolites) that mediate vasodilation in skeletal muscle during exercise:
 * K+ ions
 * Adenosine (recall this is also the major factor that increases vasodilation and blood flow in coronary arteries)
 * H+ ions, or a decrease in pH
 * Identify the major factor limiting overall muscular performance during strenuous exercise.
 * As far as I can tell, he's talking about heart rate, which can increase up to about 180 beats per minute. Stroke volume changes relatively little for most people (10% for slobs, 35% in moderately fit people, can go up to 200% in Olympic runners).
 * Stroke volume doesn't go up much because it's working against the fact that preload is decreasing with elevated heart rate, so you start with less blood in the ventricle. This is offset by the sympathetic increase in contractility (thus making the ejection fraction go up) but it's a limited influence on CO.
 * Notice that __heart rate__, not __stroke volume__, tends to be the major factor driving CO during exercise.
 * [Notice also that the efficiency of oxygen extraction from blood in __skeletal__ muscle (thus VO2 in that muscle) also goes up about 3-fold with exercise, which also contributes to muscular performance. But Wallace says that cardiac output - and thus heart rate - is more important.]
 * Describe how exercise elicits an increase in cardiac output from a completely denervated heart.
 * Recall that the primary means of CO increase in exercise is generally a rise in heart rate. In a denervated rate the means of accomplishing that increase - sympathetic stimulation - is removed, so the main factor driving CO becomes stroke volume, probably due to increased central venous pressure and thus increased preload.
 * The heart rate does actually go up a bit, but it's because you're removing the vagal parasympathetic inhibition of the natural SA rhythm of 100 beats/minute. You can also get humoral epinephrine stimulation of beta-1 receptors in the heart due to EPI release into the bloodstream from the kidneys.
 * Describe how the balance of filtration and absorption changes in active and inactive tissues during strenuous exercise.
 * Active muscles: vasodilation causes a greater hydrostatic pressure differential across the capillary, favoring filtration-- so you see sustained interstitial pressure during exercise. Note that all the compression in active muscles moves the lymph more rapidly on its way and keeps the increased filtration from turning into edema.
 * Inactive muscles: vasoconstriction causes a lower hydrostatic pressure differential across the capillary, favoring absorption (less liquid loss).
 * Describe the cardiovascular changes that occur as a result of endurance training.
 * Endurance training: doesn't involve increasing arterial pressure much, but does involve increasing cardiac output. Results:
 * Lower resting heart rate and greater resting stroke volume (note these counter each other), probably due to an increase in ventricular volume (see next LO).
 * Increased myocardial contractility (the cause of the increased stroke volume) and thus increased ejection fraction.
 * Lower peripheral resistance due to the formation of additional capillaries in skeletal muscle.
 * Note that maximum heart rate doesn't change with exercise.
 * Compare the structural changes that occur in the myocardium as a result of endurance vs. strength training.
 * In the myocardium itself:
 * Endurance training causes an increase in ventricular __volume__ without causing a corresponding increase in ventricular __thickness__ (hypertrophy).
 * Strength training causes an increase in ventricular __thickness__ (hypertrophy) without a corresponding increase in ventricular __volume__.
 * Note that hypertrophy doesn't increase the number of capillaries in the myocardium, and thus the capillary density in the heart actually decreases with strength training, making it more difficult to supply the myocardium with enough O2.
 * Note also that ventricular hypertrophy from strength training is dwarfed by the hypertrophy generated by chronic hypertension.
 * Describe the cardiovascular changes produced by anticipation of exercise and the changes that occur as exercise becomes more and more strenuous.
 * Anticipation of exercise increases sympathetic tone (more SNS, less PNS stimulation).
 * Increased heart rate and contractility, peripheral vasoconstriction; both of these lead to increased mean arterial pressure.
 * Skin vasculature decreases due to SNS stimulation.
 * Exercise begins:
 * Vasoconstriction of splanchnic/renal circulation.
 * Blood flow to the heart increases (adenosine-driven).
 * Blood flow to the brain remains constant (assuming a reasonably normal PaCO2)
 * Skin blood flow increases as temperature goes up, to cool down.
 * Exercise continues:
 * Vasodilation and increased blood flow in skeletal muscle (metabolite-driven)
 * Increased venoconstriction to move blood into the arterial system.
 * Skin blood flow decreases again, since the blood is needed for other organs.
 * Note that you can get a really absurdly high blood flow rate to the skeletal muscle under conditions of severe exercise (upwards of 20 L/min).

Origin of the EKG

Thursday, March 20, 2008 11:34 AM


 * Origin of the EKG, 3/24/08:**

Elektrokardiogramm). Same difference.]
 * [Note: he calls it ECG (electrocardiogram). I call it EKG (from the German
 * Describe the P, QRS, and T waves of the ECG, the electrical events that produce them, and how the waves correspond to events in the cardiac cycle.
 * P wave: small bump that precedes the big QRS complex. Not to be confused with the T wave, a larger bump that follows the QRS complex. Produced by the depolarization of the atria and occurs right before atrial contraction.
 * QRS complex: slight down-big up-slightly bigger down set of three waves. The R wave is the big dog since it represents depolarization running down the ventricles. The Q wave is small and represents the depolarization going from left to right through the interventricular septum. The S wave is small and represents the depolarization spreading up the outside of the heart from the apex towards the base. The QRS complex, all together, immediately precedes ventricular contraction.
 * T wave: as mentioned, a large bump in the same direction* as the R wave, caused by repolarization of the ventrticles. Occurs before the relaxation of the ventricles.
 * *You might think this is kind of weird, since you would expect depolarization and repolarization to look like waves in opposite directions. But repolarization (thus relaxation) actually begins from the parts of the ventricle that contracted (thus depolarized) last. So although it's an opposed signal to R, it's also running in the opposite direction, which is why they both show up in the same direction.
 * Note that you don't usually see a repolarization wave for the atria. This is because it's buried underneath the QRS complex.
 * Identify the P-R interval on an ECG trace, identify how long it typically lasts, and describe what the P-R interval measures.
 * P-R: from the P wave (atrial contraction) to the R wave (ventricular contraction).
 * Generally lasts about 160 msec, as you would expect (we know it takes 160 msec for an AP to travel from the SA to the AV nodes through the internodal bundle).
 * Measures the conduction velocity of rate of AP propagation between the nodes.
 * Identify the Q-T interval on an ECG trace and describe the electrical events to which it corresponds.
 * Q-T interval: from the beginning of the Q wave to the end of the T wave-- this represents the length of the entire ventricular contraction and relaxation.
 * Note that you can't accurately measure the length of the entire atrial contraction and relaxation from an EKG trace, since the relaxation (repolarization) in buried in the QRS complex.
 * Identify the S-T segment on an ECG trace and describe the electrical events to which it corresponds.
 * The flat bit on the EKG trace between the end of the S wave and the beginning of the T wave. If you think about it for a minute, it should become apparent that there's no net electrical activity occurring there, which corresponds to the plateau or phase 2 of the ventricular fibers' AP during their sustained contraction.
 * Describe how currents flowing between neighboring regions of the myocardium produce electric signals that can be recorded with surface electrodes.
 * Couple things from his notes:
 * (1) "Current must flow in closed loops; therefore any current flowing longitudinally along an axon [or conducting pathways cells] and then out across the membrane (depolarizing that region [and causing an AP]) __must flow back to its site of origin through the extracellular space__. Since the solution in the extracellular space has a finite, albeit low, resistance, this flow of current back to the origin will create a voltage drop in the extracellular solution that can be recorded with a sensitive voltmeter." (emphasis added)
 * (2) "In the case of the ECG… such recordings can be made from the surface of the body [and don't have to be directly on the heart] because the heart is composed of a great many cells that are active synchronously. Thus, all their individual currents combine to produce voltage changes that are large enough to be detected with electrodes far away from the heart on the surface of the body."
 * Explain why a standard ECG trace does not have waves that correspond to the spread of depolarization through the conducting pathways of the heart.
 * The EKG electrodes measure amplitude of current. The magnitude of current in the heart is proportional to the __number of cells involved__ in any given current; this means that the conducting pathway cells (which are dwarfed in number by the contractile cells in the atria and ventricles) won't show up hardly at all on the EKG trace.
 * You can get around this by sticking an electrode directly into the heart near the tricuspid valve. Don't try it at home.

Diagnostic Features of the EKG Saturday, March 22, 2008 1:01 PM


 * Diagnostic Features of the EKG, 3/24/08:**


 * Describe the anatomy and function of the cardiac structures responsible for generation and spread of cardiac depolarization which produce the normal heart beat.
 * See "Conduction Pathways and the Cardiac Action Potential."
 * List the components of the normal EKG; understand their functional actions.
 * See "Origin of the EKG."
 * Describe the electrode leads which comprise the conventional 12-lead EKG and how they can be used to define the axis (direction) of cardiac depolarization.
 * Limb leads (all are positive to negative):
 * I: left arm to right arm
 * II: left leg to right arm
 * III: left leg to left arm
 * Unipolar leads:
 * AVL: left arm to a mix of the others
 * AVR: right arm to a mix of the others
 * AVF: left leg to a mix of the others
 * Precordial leads:
 * V1 through V6 describe a descending jagged line from the right sternal border around the 4th rib to the left mid-axillary line around the 7th rib.
 * [Extremely useful thing that no one mentioned until later: ]
 * II, III, AVF: primarily measure activity on the inferior surface of the heart.
 * AVL, V5, V6: primarily measure activity on the left side of the heart.
 * AVR, V1: primarily measure activity on the right side of the heart.
 * V2, V3, V4: primarily measure activity on the anterior surface of the heart.
 * A lead will record positive voltage deflection if the wave of depolarization is approaching it, and a negative deflection if the wave is receding from it.
 * This allows you to compare the traces from a variety of leads around the heart and figure out more or less exactly where the AP is traveling at any given time.
 * Ie:
 * Say the AP is traveling to the left and down (from the AV node to the heart's apex). Then:
 * If I'm a lead on the right side of the heart, I'm going to record a negative spike.
 * If I'm a lead on the left side, I'm going to record a positive spike when the same event happens.
 * If I'm a lead below the center line of the heart, I'm going to record a positive spike when the AP is traveling towards me (going from right to center) and then a negative spike when the AP is traveling away from me (going from center to left).
 * This allows us to infer from the electrode readouts the direction the AP is going (example more or less pulled from his notes).
 * Describe the EKG changes produced by:
 * a) Ventricular Hypertrophy:
 * Recall that the more cells contract, the greater the amplitude of the current recorded by the EKG electrodes. With ventricular hypertrophy, the amplitude of all of the QRS waves associated with the ventricle on the side of the affected ventricle are going to be bigger.
 * Ie:
 * If you have left ventricular hypertrophy, the leads on the left side of the heart will record increased positive voltage and the leads on the right side of the heart will record increased negative voltage. Vice versa with right ventricular hypertrophy.
 * Note that you can see abnormalities in the ST segment and the T wave as well. Etiology unknown (possible ischemia?).
 * b) Myocardial Ischemia:
 * Tends to be most apparent when it occurs in subendocardial layers in the walls of the ventricle (the furthest from direct blood supply from either coronaries or endocardial blood vessels). This means it's inside the ventricle, not on the surface. A current is created inside the wall of the ventricle by this ischemia.
 * During ischemia (usually with exercise or other reasons for elevated myocardial O2 consumption), the ST segment is **depressed** (ie. lowered, not shortened).
 * Note that there's __no reciprocal ST segment elevation in other leads__ in ischemia.
 * c) Myocardial Infarction:
 * Transmural infarcts (the dead tissue goes all the way through the wall of the ventricle):
 * See an abnormal, exaggerated Q wave (the EKG is seeing 'through' the electrically dead tissue to record current propagating away from it on the other side of the ventricle). It seems to me that if you see a big negative wave (not a little one but a reasonably large one) before the R wave, or if there is no R wave and just a big negative wave, you're looking at a potential MI.
 * See an **elevated** (raised, not elongated) ST segment in particular leads, while in the leads on the other side, you'll see a ST depression.
 * These reciprocal changes (EKG looks asymmetrical from opposite sides) are predictive of MI vs. pericarditis (see next point).
 * Sometimes see a T wave inversion.
 * Non-transmural infarcts are called subendocardial (Dr. Weil: "areas of ischemia gone bad") infarcts and are harder to detect (no Q wave exaggeration, no ST elevation)-- need to use blood tests and symptomatic evaluation.
 * d) Cardiac Injury:
 * During injury, the ST segment is **elevated** (ie. raised, not lengthened). Opposite from ischemia.
 * Note that local cardiac injury causes local ST segment elevation. Pericarditis causes epicardial injury across a large surface of the heart, causing ST segment elevation across a large number of different leads.
 * Describe the changes in the EKG produced by conduction block of the right or the left purkinje bundles (right and left bundle branch blocks).
 * You're going to see a widening of the QRS complex (takes longer for the AP to spread through the ventricle) in both cases. You'll also see an altered polarity in the later part of the QRS, but it's different for each side, useful for differentiating them:
 * Right bundle branch block: The left ventricle contracts before the right; thus you have a R wave in which the late R wave is positive in right-sided leads.
 * Left bundle branch block: The right ventricle contracts before the left; thus you have a R wave in which the late R wave is positive in left-sided leads.

Arrhythmias Saturday, March 22, 2008 1:47 PM


 * Arrhythmias, 3/24/08:**

), or with no regular PR interval at all due to an absence of SA/AV communication (third degree). Depending on the severity, can require no treatment or a pacemaker.]
 * Describe the normal temporal relationship of atrial and ventricular contraction, its functional implications.
 * Recall: Atria contract first, 30 msec conduction to AV node, 130 msec delay through AV node, ventricles contract second.
 * This allows the atria to finish contracting before the ventricles do (allow proper filling and avoid unnecessary stress on the AV valves).
 * Differentiate the EKG features of sinus, atrial, junctional (nodal) and ventricular rhythms
 * Arrhythmias are named for where they originate-- "sinus rhythms" originate in the sinus, etc.
 * [This seems like a misnomer to me. "Sinus rhythm" should properly refer to a normal EKG rhythm set by the sinoatrial node, while "sinus arrhythmia" should refer to abnormalities in that pattern. Off my soapbox now.]
 * **Sinus rhythms** :
 * Show relatively normal EKG patterns, but the regular rate at which they occur may be slow (sinus bradycardia, can show narrow QRS complexes) or fast (sinus tachycardia).
 * **Atrial rhythms** :
 * Premature atrial contractions: the atria intermittently contract early and are followed by a correspondingly early ventricular contraction.
 * This shows up as an occasional premature P wave followed by a normal QRS complex. The premature P wave is often widened and has an abnormal shape.
 * Atrial (supraventricular) tachycardia: seem to be more or less a regular, recurring pattern of premature atrial contractions, creating tachycardia driven by the atria.
 * Shows up as abnormal P waves (can be part negative, part positive, or can be more subtle) but normal QRS in tachycardia.
 * **Junctional rhythms** :
 * Seems to happen when the AV node takes over as the pacemaker of the heart.
 * As such you don't often see P waves (they're buried within the QRS complexes because the atria are contracting after the ventricles have started to contract). When you do see them, they're often in the wrong place and **inverted** because they're progressing upwards from the AV node as opposed to downward from the SA node.
 * The QRS complexes are often narrowed as well.
 * **Ventricular rhythms** :
 * Premature ventricular contractions: the ventricles contract without a preceding P wave stimulation (QRS complexes arise in ventricular myocardium).
 * This shows up as isolated instances of an absence of P waves with widened/abnormal QRS complexes.
 * If this is a repeating pattern, that's called ventricular tachycardia, and is not a good thing (frequent lead-in to sudden death).
 * List the clinical manifestations and main treatments of each.
 * Abnormal sinus rhythms:
 * __Sinus bradycardia__ manifests as a resting slow heart rate, and can result in syncope (fainting) during intense stimulation of the parasympathetic innervation of the heart ('vasovagal reflex'). Can treat this with **atropine** (recall atropine is a parasympathetic [ACh] antagonist) or, more rarely, a beta-agonist (but watch out for increased calcium content in the heart, particularly if your patient is on digoxin).
 * Common in athletes. May require no treatment.
 * Can be due to an inferior wall infarction (increases parasympathetic tone in heart).
 * In elderly patients can require a pacemaker if it provokes chronic fatigue or dizziness.
 * __Sinus tachycardia__ manifests as an abnormally fast heart rate usually brought on by exercise or stress. Increases the oxygen demand in the heart.
 * Usually requires no treatment, although CAD patients may have problems getting enough O2 to their myocardium and thus manifest angina. Can treat with beta-blockers.
 * Note that sinus tachycardia is a frequent symptom of hyperthyroidism.
 * Atrial rhythms:
 * Occasional __premature atrial contractions__: manifest as abnormal 'skipped-beat' or 'premature-beat' rhythms, usually noticed at rest.
 * He mentions nothing about treatment, probably because they're not much of a problem.
 * __Supraventricular tachycardia__: very high heart rate with hypotension (not enough filling time to maintain stroke volume), fainting, or chest pain.
 * This is a regularly occurring abnormal rhythm and as such needs to be treated. Can use maneuvers that increase vagal activity (ie. massage of carotid sinus), administration of adenosine, or electrical cardioversion (see below).
 * Note that atrial tachycardias often arise from re-entrant arrhythmias (see "Molecular Mechanisms of Arrhythmias") from a small circuit area near the AV node. If you take this area out (with "focal radio-frequency ablation," which no-shit involves using radio waves to burn tissue), can resolve the issue (roughly 95% permanent cure rate).
 * Junctional rhythms:
 * He mentions nothing about treatment or manifestations.
 * Ventricular rhythms:
 * The occasional premature ventricular contraction can occur in normal subjects.
 * If an occasional PVC, probably no treatment required (can treat with beta-blockers or lidocaine except in cardiomyopathic subjects).
 * Ventricular tachycardia can present as shortness of breath and rapid heart rate, like atrial fibrillation, and arise from acute MIs or heart failure (things that cause extensive damage or scarring of the ventricle, leading to a large enough abnormal pathway to get, usually, a recurring single re-entrant pathway).
 * Treatment is electrical defibrillation followed by pacemaker implantation.
 * [**AV blocks** entail delays of the conducting pathway in the internodal branch, sometimes due to structural heart disease or cholinergic activation through digitalis overtreatment. They show up as widened PR intervals (first degree), or with widening PR intervals and occasional non-conducted P waves (second degree/Mobitz type 1/Wenckebach,
 * List the causes, clinical manifestations, and treatment of atrial fibrillation
 * Most common important arrhythmia. Can occur with normal aging or with just about anything else wrong with the heart:
 * Aging, post-operative patients, NI (non-infarcted) patients, heart disease, hyperthyroidism.
 * Also fibrosis in heart chambers, atrial dilation, sympathetic activity, and thyrotoxicosis.
 * Can also occur due to over-stimulation by catecholamines.
 * Shows up as an irregular, usually **rapid** heart rate. The EKG shows normal QRS complexes punctuating a wavy, irregular baseline with no clear P waves.
 * Can start to lose ventricular contractility, and develop atrial thrombi, if left untreated. The lack of ventricular contractility seems to be due to the constant elevated heart rate (also note that without working atrial systole, the ventricle doesn't benefit from its small preload 'kick' right before ventricular systole).
 * Treatment:
 * Oral anticoagulants: aspirin, coumadin.
 * Chronotropic agents: digitalis, beta-blockers (type II), calcium-channel blockers (IV)--"rate control" agents, preferred over electrical defib.
 * Electrical defibrillation (see below). Makes maintaining the sinus rhythm afterwards harder due to the need for more toxic drugs, so usually reserved for acutely vulnerable patients.
 * [Notice __atrial flutter__ is similar but shows a regular 'saw-tooth' pattern between QRS complexes instead of the absence of any regularity in atrial fibrillation. Possibly due to single re-entrant circuit as opposed to multiple re-entrant paths, see "Molecular Mechanisms of Arrhythmias." Note that controlling atrial flutter with rate control agents is more difficult, thus it's more common to use RF ablation or electrical defibrillation.]
 * List the causes, clinical manifestations, and treatment of ventricular tachycardia
 * Causes: acute MIs, heart disease (cardiomyopathy), ventricular dilation or fibrosis.
 * Note that ventricular fibrillation can also be provoked by electrical shock during the ST segment due to the creation of a continuous (re-entrant) electrical circuit in the ventricle.
 * The ST segment is therefore called the __vulnerable period__. This is the reason why cardioversion (see below) is timed to coincide with QRS complexes and not ST segments.
 * Problem with applying voltage in ST segment: some parts of the heart are polarized, others aren't; some are in refractory period, some aren't. Thus there's a potential for creating a re-entrant rhythm and making v-tach/fib.
 * Note that agents that lengthen the ST segment (like some anti-arrhythmic drugs) can also increase the risk of v-tach, as can inherited conditions causing lengthened QT segments.
 * Clinical manifestations: shortness of breath, tachycardia.
 * Treatment: Cardioversion followed by pacemaker implantation (pacemaker will automatically administer a shock if the heart's EKGs are starting to look bad).
 * Can also use 'rhythm control' agents (mainly lidocaine and amiodarone) but they can have proarrhythmic effects.
 * Distinguish cardioversion vs. defibrillation
 * Cardioversion: you're taking an existing, but abnormal, cardiac rhythm and using an electrical shock __during the QRS complex__ to convert it back to a normal sinus rhythm.
 * Defibrillation: there's no cardiac rhythm at all to make use of. You're just going to have to zap them more or less at random, since there's no recognizable QRS complex to align with.

Exercise Training and Angiogenesis Saturday, March 22, 2008 3:01 PM


 * Describe the ways in which exercise augments delivery of oxygen to exercising muscle, including contributions of lungs, heart, blood vessels, and tissue structure.
 * Lungs: rate of ventilation increases to get rid of CO2 and uptake fresh O2. Also recruitment of lung capillaries is increased to accommodate greater cardiac flow through them.
 * Mild exercise: 1-to-1 increase in ventilation to metabolic rate. PCO2 remains at resting levels. This is called hyperpnea.
 * More strenuous exercise: past a certain 'anaerobic threshold' in the metabolic rate, anaerobic metabolism takes over, generating lactic acid, which triggers an exponential increase in ventilation relative to metabolic rate. PCO2 begins to drop due to much-increased ventilation-- this is called hyperventilation.
 * Blood vessels: accumulation of metabolites induces vasodilation and blood flow in exercise.
 * Heart: sympathetic stimulation (triggered by vasodilation and baroreceptors) induces greater contractility and heart rate and thus raises cardiac output.
 * Tissue: Muscles increase O2 extraction in their capillaries, generally triggered by a drop in tissue PO2.
 * Describe the reasons that increased heart rate augments blood flow in exercise, but not at rest.
 * At rest: greater heart rate leads to decreased filling time.
 * By contrast, exercise causes increased venoconstriction, leading to an increase in ventricular filling that counteracts that decreased preload.
 * List the sources and nature of fuels used for energy generation in exercise.
 * Muscle ATP, phosphocreatine, glycogen.
 * Describe the role of hormonal responses in support of metabolic and functional features of exercise.
 * Angiotensin causes systemic vasoconstriction. By the selective inhibition of this effect in exercising muscles, can effectively divert blood there from non-exercising areas.
 * Increased blood flow in exercising areas causes an increase in shear forces on arteriole endothelia, causing release of nitric oxide, which locally overrides the vasoconstrictive effects of angiotensin.
 * Describe the factors responsible for increased skeletal muscle vascularity produced by exercise training.
 * Increased blood flow during exercise stimulates nitric oxide production in endothelial cells. In addition to being a vasodilator, NO also stimulates __angiogenesis__ (increasing the number and density of capillaries in the muscle) and __arteriogenesis__ (increasing the number and diameter of conduit arteries).
 * Notice that angiogenesis in the heart can encourage coronary collateral formation, which means that if you do a bunch of exercise training, it's possible to have multiple large coronary blockages and still only feel slightly faint. This happened to my ex-prizefighter Hebrew professor at LSU.
 * Note also that tissue hypoxia produces HIF-1 alpha (hypoxia-inducible factor, recall from M2M's description of Von Hippel-Lindau disease), which triggers both erythropoietin (produces more red cells and angiogenesis) and vascular endothelial growth factor (increased NO production, arteriogenesis).
 * Recall that VHL disease involves a Hif-1 alpha that's always turned on, making a fertile ground for tumors to breed with all the angio/arteriogenesis going on.

Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs Saturday, March 22, 2008 6:16 PM


 * Molecular Mechanisms of Arrhythmias & Antiarrhythmic Drugs, 3/25/08:**


 * [A concept I found helpful in thinking about this: every myocyte can conduct. Every myocyte also has one other talent. The pacing cells can pace but can't contract. The contractile cells can contract but can't pace. But regardless, every myocyte can spread a signal to every other myocyte given a sufficiently strong signal and a lack of an absolute refractory period. The heart is a muscle, a pacemaker, and a nerve all bundled into one. Thus if you start getting an abnormal signal arising from a place it shouldn't, it can propagate to every other corner of the heart in short order. This is one reason why ectopic pacemakers happen-- you get a circuit established in some ordinarily non-pacing, contractile part of the heart that begins to act like a pacemaker and can spread its irregular signal to all the other parts.]
 * Describe the gene defects and molecular basis of long-QT syndrome
 * Genetic defects in cardiac ion channels:
 * IKs (LQT1)
 * IKr (LQT2)
 * INa (LTQ3)
 * [Autosomal dominant form: Romano-Ward syndrome]
 * [Autosomal recessive form: Jervell-Lange-Nielson syndrome (homozygous = deafness as well, heterozygous = asymptomatic)]
 * Molecular basis:
 * LQT1 and LQT2 (potassium channels): activation of channels is impaired, leading to slower termination of phase-2 plateau.
 * LQT3 (sodium channel): __in__activation of channels is impaired, also prolonging the phase-2 plateau. (Perhaps more to the point - see below - potentiated Na+ channels will shorten the absolute refractory period.)
 * List the cardiac ion channels and the phases of the slow and fast responses that are targeted by the various antiarrhythmic drugs
 * Class I antiarrhythmics: block Na+ channels (some cross-reaction with Ca++ channels)
 * Slow the rising phase (0) in both fast and pacing (slow) responses, thus slowing conduction velocity and decreasing the signal size (making the current less likely to spread backwards through damaged heart regions). They also prolong the absolute refractory period (which depends on inactivation of INa channels).
 * Class II: beta-blockers, block beta-adrenergic receptors, slowing If, ICa, and IK.
 * Note that these are the only drugs we have that are proven to reduce the rate of sudden cardiac death.
 * Class III: block K+ channels (slow fast phases 2-3, prolong absolute refractory period due to prolonged depolarization's inactivation of INa channels)
 * Class IV: block L-type Ca++ channels (shorten fast phase 2, slow upswing of pacing phase 0)
 * Slow and reduce APs in pacing cells.
 * [Helpful from his notes: "Fundamentally, there are 2 types of problems: (1) inappropriate impulse generation in SA node or elsewhere (ectopic focus), and (2) disturbed impulse conduction in nodes, conduction cells (Purkinje cells) or myocytes." (assuming here he means myocytes as contractile cardiac muscle cells.)]
 * Describe the cellular mechanism of triggered (early and delayed) afterdepolarizations
 * Afterdepolarizations (ADPs) are a subclass of the first type of problem as listed above (inappropriate impulse generation).
 * His notes: "the mechanism of triggered afterdepolarizations is not completely understood."
 * That said:
 * Elevated cellular calcium content causes high Na+/Ca++ exchange.
 * Recall that the NCX1 exchanger exchanges **3** Na+ for every **1** Ca++ and depends on their concentration gradients-- thus if it's on for long, it'll make the inside of the cell positive.
 * This is a problem because it usually happens during mid-phase 3 (early ADPs) or early phase 4 (late ADPs), creating a depolarization that triggers another AP during the relative refractory period or after the refractory period but earlier than it should happen in normal pacing.
 * So essentially triggered ADPs are abnormal depolarizations that occur after a regular depolarization, often **due to high intracellular calcium content** . They can start sinusoidal depolarization-repolarization cycles in which a short depolarization is followed by a short repolarization, etc (see his Figure 1, the 75% curve). This in turn can lead to ectopic pacing, ventricular arrhythmias and ventricular fibrillation.
 * Note a couple more notes on the ADP phenomenon in "French's Review for Unit I, Part II." Essentially he says that intracellular calcium content tends to trigger late afterdepolarizations, while elongated ST segments tend to trigger early afterdepolarizations.
 * Describe how a re-entrant, or circus, arrhythmia originates
 * Essentially what happens is this. You have an area of the heart (which, effectively, is one big mostly contractile neuron) that no longer conducts an AP along the pathway it normally uses (due to, say, damage to INa channels). That makes it vulnerable to an AP traveling in the other direction, coming up from the areas distal to it-- it may not be able to transmit an AP in the right direction anymore, but it can still transmit it in the wrong one if it gets a much stronger retrograde signal (ie. a signal from more cells with a higher phase 0 peak) than the one it's supposed to get in the normal direction.
 * This effectively creates a loop: the damaged area of the heart transmits an AP in the retrograde direction, back to the normal cells at the start of the damaged area; if those cells have gotten past their absolute refractory phase, they can keep the signal going back down to the end of the damaged area again, which can depolarize again in turn, etc, etc.
 * Two requirements for this to happen:
 * One, the normal conducting pathway in the damaged area of the heart must be blocked. Makes sense, otherwise those cells would be in their refractory periods when the retrograde signals were coming back up.
 * Two, the time it takes to complete the loop must be greater than the refractory period. This also makes sense, otherwise the retrograde signal coming back up the damaged area would run into refractory cells and stop (thus unable to make the loop which is the cause of re-entrant arrhythmias).
 * Notice (germane to "Arrhythmias") that this can break down a couple of ways:
 * One re-entrant path: generally a regular loop running in the heart-- effectively a pacer in an area of the heart that's not run by the normal conducting pathway. As such it will interfere with the normal conductance in a reasonably predictable manner, as in atrial flutter.
 * Multiple re-entrant paths: there are several loops running in the heart at the same time but with different periodicities. Thus we have irregular, fairly unpredictable interference in the normal conductance depending on where all these loops intersect, as in atrial fibrillation.
 * Note that single re-entrant paths can be more easily ablated with RF.
 * Describe the basis of use-dependent block of Na+ channels by class I antiarrhythmic drugs
 * Actually this is kind of like anti-cancer drugs. The sodium-blocker class I and the calcium-blocker class IV drugs will preferentially affect sodium channels in membranes that are firing more quickly or are abnormally depolarized-- thus a kind of built-in selectivity.
 * This selectivity is called 'use-dependent block' of ion channels and results from the fact that the drug preferentially affects channels that are open and in use.
 * Note that this blocks sodium channels in cardiac cells exactly like local anesthetic blocks sodium channels in neuronal cells. It's therefore not a coincidence that one of the Class I sodium blockers, lidocaine, is also an anesthetic.
 * Describe how class I antiarrhythmics increase Na+ channel refractory period, whether or not they prolong phase 2 of the fast response
 * Recall that the refractory period - while we sometimes do a quick measurement of it by the part of phase 3 the cardiac AP is in - is actually determined by the reactivation of Na+ channels that have been inactivated after the phase 0 depolarization.
 * Although class I's need to bind to active Na+ channels to block them, they like to stick around inside __inactive__ Na+ channels, __stabilizing__ them in the inactive form and thereby __prolonging__ the refractory period.
 * [Note that various kinds of sodium channel blockers exhibit varying degrees of slowed upstroke, and can either lengthen or shorten the phase 2 plateau. The evident reason that Ia and Ic drugs prolong phase 2 is that they have a lot of IK-blocking activity as well as INa inactivation.]
 * Describe how B adrenergic receptor blockers help suppress arrhythmias
 * Recall the effects of beta-1 stimulation in cardiac cells: increased IK, If, and ICa currents. Beta-blockers, then, reduce all those currents.
 * The functional effects of this are to slow down depolarization in pacing cells (If), to reduce the speed of the phase 0 upstroke in those cells (ICa), and to slow the phase 3 repolarization (IK).
 * This decreases the pacing activity (automaticity) of pacing cells (SA and AV, through If and ICa) and keep sodium channels inactivated for longer, thus increasing the ARP as well.
 * Describe how class III drugs increase refractory period
 * Class III's prolong the plateau phase (phase 2), mainly by blocking K+ channels. This lengthened depolarized phase 2, in turn, keeps INa channels inactivated (INa channels are voltage-dependent), which increases the refractory period.
 * Note that some Class III's, notably amiodarone, also prolong the RP by blocking Na+ channels (cross-activity with Class I).
 * Describe how increasing refractory period may help suppress re-entrant arrhythmias
 * We've more or less talked around this already. Re-entrant arrhythmias are dependent on the length of the refractory period being less than the time it takes for the current to make the re-entry loop (otherwise the loop runs into the RP and dies out). By prolonging the RP, it's possible to stop the loop.
 * Note that decreasing conduction velocity (as in Class I drugs) can shoot itself in the foot here by both increasing ARP (good) but also slowing conduction time, allowing more time for the cells at the beginning of the circuit to get through their ARPs (bad). But note that conduction velocity is determined by signal strength (extent of depolarization), which is inhibited by class I's, and with less signal strength you may inhibit the strength of the signal stimulating the damaged part of the heart in the wrong direction, thus shutting down the loop.
 * Describe how some antiarrhythmic drugs can suppress arrhythmias by decreasing cardiac automaticity
 * Recall that cardiac automaticity is largely determined by If. Accordingly, the drugs that target If will affect automaticity (which allows them to target arrhythmias which originate from pacemaking problems as opposed to re-entrant currents).
 * That would be Class II drugs, or beta-blockers.
 * Class IV drugs slow APs in pacing cells, which also gives them some decreased-automaticity effect.
 * Note that some Class III drugs, notably amiodarone, decrease the rate of If depolarization in pacing cells by inactivating sodium channels, thus having more or less the same effect on automaticity as beta-blockers.
 * Describe how adenosine can help suppress cardiac arrhythmias
 * Note that adenosine is __not__ a beta-blocker (doesn’t bind to beta-1 adrenergic receptors), but it acts in much the same way: increase K+ flow, decrease Ca++ flow, and inhibit If channels.
 * What it actually does is to activate a Gi protein that inhibits adenylyl cyclase and PKA activation.
 * Note that it also **activates KACh channels** in the same way as acetylcholine, thus further slowing down pacing cells.
 * Note also that adenosine has a half-life of about 10 seconds- very short duration.
 * [Note on pharmacokinetics:]
 * Big variation in anti-arrhythmics. Be careful.
 * Esmolal (beta-blocker): about a 10-minute half life.
 * Amiodarone (class III): about a 13-100 **day** half-life.

Heart Failure I and II Monday, March 24, 2008 9:13 PM


 * Heart Failure I and II, 3/26/08:**


 * [Dr. Weil: heart failure is a combination of flow-forward problems - decreased blood flow and cardiac output- and flow-backwards problems - increased venous pressure, both systemically and in the lungs.]
 * [Let's talk about ventricular hypertrophy for a minute. In athletes it's a good thing, within reason. In heart disease it's a very bad thing.]
 * Mechanical stress on a heart leads to hypertrophy of the muscle, leading to a gain in muscle strength.
 * But mechanical stress plus all the neurohumoral responses to heart failure is bad. The reason is that chronic angiotensin, aldosterone, and norepinephrine exposure is toxic to the heart. This damages the thickened wall, leading to a loss of ability to stretch and expand chamber volume during diastole.
 * [Note that many heart failure patients will die of sudden cardiac death following ventricular arrhythmias, which is why we stick implantable defibrillators and/or heart transplants in them before that point.]
 * Concerning Heart Failure, LIST:
 * a) causes:
 * Hypertension
 * Coronary artery disease
 * Diabetes
 * Valvular heart disease (rheumatic/congenital)
 * Cardiomyopathy (primary myocardial disease)
 * Renal failure
 * [MIs, cardiac tampenade]
 * Basically anything that reduces ventricular systolic function (ie. ejection) or decreases diastolic function (ie. filling). Or both (like hypertension).
 * b) hemodynamics: any or all of the following--
 * Depressed cardiac contractility (**lowered and flattened Starling curve** ).
 * This means that a large rise in preload is necessary to improve the stroke volume.
 * You need the stroke volume to maintain tissue perfusion.
 * But the rise in preload - since there's a problem with forward flow from the left ventricle - means that blood backs up into the lungs.
 * This impairs gas exchange, which decreases available O2, which increases the tissues' demand for blood and oxygen. (it also triggers alveolar receptors to stimulate a higher respiration rate.)
 * This means that more stroke volume is needed. (the tissues also increase their efficiency of oxygen extraction from hemoglobin.)
 * Etc.
 * Diastolic dysfunction (restricted filling due to hypertrophy or fibrosis) with a normal ejection fraction and contractility.
 * Increased pulmonary pressure
 * Decreased cardiac output
 * Increased vasoconstriction
 * Increased heart rate (attempt to compensate for low stroke volume)
 * Increased activation of RAA (renin-angiotensin-aldosterone) axis and vasopressins
 * c) symptoms:
 * **Breathlessness** : 3 types-
 * Dyspnea on exertion
 * Orthpnea (dyspnea lying down) - results from edema from the fluid accumulating in the lungs when lying flat.
 * Paroxysmal Nocturnal Dyspnea
 * This is a delayed dyspnea that often wakes its subject up after lying down to sleep. It's due to absorption from the fluid in the legs over several hours, which increases pulmonary venous pressure and results in edema in the lungs.
 * **Peripheral edema** (edema generally in legs when upright, in lungs when flat)
 * [Note difference between pulmonary //congestion// and pulmonary //edema// -- congestion means you have fluid in the space between the alveoli and the capillaries (limiting gas exchange); edema means you have fluid in the alveoli themselves, at which point gas exchange is . The mixing of air and fluid in the alveoli produces foam, which further inhibits air flow.This leads to a sharp decrease in oxygenation, leading to a enormous upswing in sympathetic stimulation, causing lots of peripheral vasoconstriction. The peripheral vasoconstriction leads to greater blood load in the lungs, causing more edema, causing more shortness of breath, causing more sympathetic stimulation. Etc. An unpleasant process.]
 * **Fatigue and wasting** (generally ascribed to decreased blood flow/hypoxia)
 * [can think of all of this as: problems with flow backwards from the left heart (edema, both lung and peripheral) or flow forwards from the left heart (fatigue due to peripheral hypoxia).]
 * d) signs:
 * Depending on the type/stage of heart failure, on the echocardiogram:
 * Can show up as a normally sized ventricular chamber with mostly normal diastolic filling but with a decreased systolic wall motion (ie. a decreased contractility or ejection fraction).
 * Can also show up as a stiff or smaller ventricular chamber with restricted diastolic filling but normal systolic function and ejection fraction.
 * Note that the second type often leads to the first, as in chronic hypertension or aortic stenosis: you get concentric hypertrophy from working against the effective afterload, but then you get dilation and weakened contractility from fluid overload and constant activation of compensation mechanisms (see below).
 * Natriuretic peptides (peptides that increase sodium excretion) are increased in heart failure. Specifically, look for brain natriuretic peptide, which is evidently a good marker for heart failure. Note that brain natriuretic peptide is actually made in the __ventricle__ as a response to stretch. Don't ask me, I just work here.
 * Note that heart failure, itself, has no diagnostic pattern on an EKG, although you can see signs of the underlying dysfunction (ventricular hypertrophy, MI).
 * Rales in lungs (caused by tendency of edematous alveoli to collapse in on themselves when not filled with air and to pop open during inspiration.
 * Jugular venous distention
 * 3rd heart sound (gallop rhythm)
 * Enlarged heart silhouette on chest x-ray, as well as enlarged pulmonary vessels.
 * e) diagnostic approaches:
 * Echocardiogram
 * Chest X-ray
 * Physical exam
 * History
 * Natriuretic peptide levels (particular BNP)
 * Describe the pathophysiologic mechanisms of:
 * a) dyspnea on exertion: increased systemic/cardiac VO2 can't be met due to impaired cardiac output; edema around the alveolar capillaries further reduces oxygen exchange in the lungs
 * Note that the real cause of dyspnea on exertion is the fact that your heart is already compensating and kicking up its heart rate and preload when you're sitting around at rest. When you're under exertion, your body doesn't have a lot left that it can do to improve those things-- thus dyspnea.
 * Patients can get a 'wheezing' breath pattern due to edemic constriction of the small vessels and alveoli.
 * b) orthopnea and paroxysmal nocturnal dyspnea:
 * Orthopnea: Redistribution of venous blood causing a rapid accumulation of edematous fluid in the capillaries of the lungs.
 * Paroxysmal nocturnal dyspnea: Gradual reabsorption of peripheral edema as the patient lies flat leads to an increase in blood volume, leading to an increase in edema/congestion in the lungs. Tends to wake patients up several hours after lying down.
 * c) pulmonary edema: backup of blood into lungs, causing fluid accumulation, as mentioned.
 * d) leg edema: rise in peripheral venous pressure due to pulmonary hypertension causes fluid accumulation, as mentioned.
 * e) fatigue: increased systemic hypoxia.
 * f) renal insufficiency: decreased cardiac output leads to increased peripheral vasoconstriction in an effort to preserve systemic pressure; increased renal resistance means decreased blood flow to kidneys = renal insufficiency.
 * Outline compensatory mechanisms responsible for maintenance of blood pressure in heart failure
 * Two broad categories:
 * (1) Sympathetic activation
 * (2) Hormonal responses
 * Sympathetic activation is generally triggered by baroreceptors that notice the decreased mean arterial pressure. This triggers sympathetic stimulation, which increases contractility and heart rate and causes peripheral vasoconstriction to increase central blood flow and systemic blood pressure.
 * Hormonal compensation is triggered by renal insufficiency and causes release of renin and vasopressin. Vasopressin increases blood volume; renin triggers activation of angiotensin I from angiotensin II, causing vasoconstriction, and aldosterone, causing sodium retention and also increasing blood volume.
 * List the mechanisms responsible for the self-worsening (auto-progression) of heart failure
 * The same as the compensatory mechanisms. That's the problem.
 * Lots of sympathetic stimulation and increased blood volume over a long period of time can cause ventricular hypertrophy and myocardial damage/fibrosis, as well as downregulation of adrenergic receptors.
 * Note that aldosterone in particular causes fibrosis in cardiac cells.
 * In addition, increased blood volume makes the peripheral and pulmonary edema problems a lot worse-- you have more blood in your circulation but you still can't move much of it, which means it'll wind up in your venous system and raise your CVP (thus creating more edema).
 * Describe the factors which lead to, and the consequences of, altered cardiac structure in heart failure
 * Ventricular hypertrophy results from increased mechanical stress on the ventricle. This can be caused by increased afterload, aortic valve stenosis, chronic aldosterone, vasopressin, or angiotensin II activation, or chronic sympathetic stimulation.
 * Note you can also get ventricular fibrosis through chronic RAA/pressor activation (evidently activate cytokines and fibroblasts in the heart itself).
 * The end result of all this is both a defect in systolic function (through replacement of functional heart muscle with dysfunctional structures) and a defect in diastolic filling (due to either reduced elasticity or reduced ventricular volume).
 * Describe the ways in which each of the following can point to the diagnosis of heart failure:
 * a) history: dyspnea of our three types (exertional, ortho, paroxysmal nocturnal), leg edema, fatigue.
 * b) physical exam: rales in lungs, edema, gallop rhythm, jugular venous distension.
 * c) chest x-ray: heart enlargement, lung congestion
 * d) radionuclide imaging: reduced ejection fraction
 * e) blood tests: increased brain/atrial natriuretic peptides
 * f) EKG: no change per se, but look for underlying disorder (ventricular hypertrophy, myocardial infarct)
 * g) echocardiogram: again, enlarged ventricle or reduced contraction.
 * Explain what is meant by diastolic heart failure or diastolic dysfunction
 * Again, a problem with filling during diastole, usually caused by a decrease in ventricular volume (with ventricular wall enlargement) or reduced elasticity due to damage and/or fibrosis.
 * List the various categories of treatment used to improve SYMPTOMS of heart failure
 * Inotropes (correct failing systolic function)
 * Diuretics (correct overly high blood volume)
 * Vasodilators (correct overly high peripheral resistance)
 * List treatments that improve SYMPTOMS in heart failure.
 * [repeat of last LO? I've listed example agents here.]
 * Inotropic: digitalis (reduces symptoms, leaves long-term survival unchanged)
 * Diuretics: furosemide (dramatically lower pulmonary pressures, but don't correct cardiac function)
 * Vasodilators: ACE inhibitors and nitrates (ACE inhibitors also correct overly active blood volume retention)-- reduce preload on the heart by reducing peripheral vascular resistance.
 * List treatments that improve SURVIVAL in heart failure
 * ACE inhibitors (inhibit both angio and aldosterone - target vasoconstriction and fluid overload)
 * Ex. lysinopril
 * Angiotensin receptor blockers (substitute for ACE inhibitors - target vasoconstriction and fluid overload)
 * Aldosterone receptor blockers (aldosterone only - target fluid overload)
 * Ex. spironolactone
 * All of these block cardiac remodeling/fibrosis due to angio II and/or aldosterone over-activation.
 * Note also that ACE degrades bradykinin (slight pro-inflammatory vasodilator)-- ACE inhibitors can create a backup of bradykinin and, infrequently, result in a chronic cough, but the buildup of bradykinin can also help relieve vasoconstriction and may promote angiogenesis through nitric oxide release.
 * Beta blockers (may worsen short-term symptoms due to decreased contractility, but help long-term survival-- more on this under "Heart Failure Therapeutics")
 * Define strategies which may prevent development of heart failure
 * Administer ACE inhibitors (also, potentially, beta-blockers) before initial (compensated) heart failure gets worse.

Valvular Heart Disease Tuesday, March 25, 2008 2:43 PM


 * Valvular Heart Disease, 3/26/08:**


 * Describe the ventricular anatomic and hemodynamic responses to aortic valvular stenosis and regurgitation, ie. pressure and flow overloads
 * Aortic valvular stenosis: "pressure overload"-- effectively your ventricle has to build up lots of extra pressure in order to eject blood into the aorta. This necessitates more muscle mass in the ventricle, which thickens ("concentric hypertrophy"). Due to the reduced ejection fraction, a number of compensatory mechanisms pop up (baroreceptor understimulation provokes increased sympathetic stimulation, decreased renal blood flow causes RAA axis and vasopressin activation). Recall (from "Coronary and Skeletal Muscle Circulation") that aortic stenosis is particularly unpleasant because (a) the heart is doing pressure work and increasing its oxygen consumption, but (b) the coronary circulation gets decreased flow due to decreased diastolic pressure, which undersupplies the heart muscle that's being worked. Note a high systolic pressure in aortic stenosis, at least until decompensation takes over and both blood pressures tank.
 * Aortic valvular regurgitation: "flow overload"-- effectively the aortic blood flows back into the ventricle, overloading it with fluid, thus the name. The ventricle undergoes compensatory remodeling, but instead of thickening, the muscle fibers mostly elongate, creating an increased chamber volume (a pattern called "eccentric hypertrophy") to accommodate the flow from the aortic without backing up into the left atrium. However, because the ventricle is accommodating so much of the aortic backflow, the diastolic aortic pressure drops, creating an increased pulse pressure and decreasing coronary flow (thus O2 supply to the heart). Also stroke volume tends to go up. Note that the heart deals with flow overload better than pressure overload.
 * [Note that both stenosis and regurgitation show thickened, rigid valve leaflets. The difference is that in stenosis the leaflets are partially fused, whereas in regurgitation the leaflets are retracted or perforated. Note you can have mild stenosis and mild regurgitation at the same time, but not severe stenosis and severe regurgitation at the same time.]
 * [Note that "regurgitation" = "insufficiency."]
 * Review the CAUSES, HEMODYNAMIC EFFECTS, SYMPTOMS AND SIGNS of:
 * a) aortic stenosis and regurgitation:
 * Causes:
 * aortic stenosis:
 * calcification due to aging
 * scarring due to rheumatic valve disease
 * bicuspid aortic valve
 * aortic regurgitation:
 * aortic __leaflet__ disease:
 * bicuspid aortic valve (normally it's tricuspid)
 * rheumatic disease
 * endocarditis
 * aortic __root__ disease:
 * aortic aneurysm/dissection
 * marfan's syndrome
 * syphilis
 * mitral stenosis:
 * rheumatic heart disease
 * mitral regurgitation:
 * heart failure (ventricular over-dilation)
 * infarct of papillary muscle
 * endocarditis
 * leaflet prolapse (which is also what happens from infarct of papillary muscle)
 * Hemodynamic effects:
 * aortic stenosis/regurgitation: see above.
 * mitral stenosis: increased atrial pressure, particularly during atrial systole, and can back flow up through the pulmonary circulation, resulting in pulmonary hypertension. Causes atrial hypertrophy and right ventricular hypertrophy. Note a high incidence of **atrial fibrillation** due to stretched conducting fibers and high potential for re-entrant circuits-- thus also a high risk for thrombus formation in the absence of coordinated atrial systole.
 * mitral regurgitation: backflow of blood during ventricular systole into the left atrium. Gets a reduction of the amount of blood that's actually ejected into the aorta, as well as higher ventricular preload (the regurgitated blood serves as part of the preload in the next diastole). The ventricular contractions increase in pressure (Starling) to compensate. Notice that over years this compensation doesn't play out so well.
 * Symptoms:
 * aortic stenosis: generally develops symptoms only late in course.
 * dyspnea on exertion
 * syncope (fainting) on exertion (classic finding-- can't get enough blood to the brain during exertion)
 * angina
 * aortic regurgitation: generally develops symptoms only late in course.
 * Similar to symptoms of heart failure (dyspnea, fatigue, edema)
 * mitral stenosis:
 * dyspnea
 * cough
 * atrial fibrillation
 * pulmonary edema
 * elevated jugular venous pressure
 * peripheral edema
 * mitral regurgitation:
 * shortness of breath
 * later right heart failure and peripheral edema
 * Signs:
 * aortic stenosis:
 * Look for a __low__ pulse pressure after the left ventricle has started to fail.
 * Get a __systolic__ murmur.
 * on echocardiogram:
 * abnormal aortic valve structure/area
 * ventricular hypertrophy
 * dilated aorta (from high ejection pressure)
 * increased pressure gradient across the aortic valve
 * on x-ray: small, muscular heart with aortic dilation
 * on EKG: left ventricular hypertrophy
 * aortic regurgitation:
 * Look for low aortic diastolic pressure, large stroke volume, and __high__ pulse pressure.
 * Get a __diastolic__ murmur with __systolic__ murmur accompanying it.
 * on echocardiogram:
 * valve incompetence (leakage) and regurgitation
 * dilated or hypertrophic left ventricle
 * chest x-ray: left ventricular enlargement, aortic dilation
 * on EKG: left ventricular hypertrophy
 * mitral stenosis:
 * __Diastolic__ murmur, heard only when patient is in the left lateral decubitus position.
 * Opening snap of mitral valve, loud S1 heart sound
 * on chest x-ray:
 * enlarged left atrium
 * pulmonary artery enlargement
 * "Kerley B lines" (enlarged pulmonary lymph vessels)
 * on ekg: left atrial enlargement, right ventricular hypertrophy
 * widened P wave
 * on echocardiogram:
 * abnormal mitral valve/area
 * increased pulmonary pressure
 * mitral regurgitation:
 * __Systolic__ murmur.
 * on chest x-ray:
 * enlarged cardiac silhouette (left atrial enlargement)
 * pulmonary congestion
 * on echocardiogram:
 * regurgitant flow
 * left ventricular dilation
 * Describe the use of diagnostic tools in the identification and quantification of these abnormalities
 * As above.
 * Review the natural history (behavior over time) of each of these abnormalities and timing and nature of therapeutic intervention
 * Aortic stenosis: can develop and stick around a long time before becoming symptomatic. When it does become symptomatic, survival drops like a brick. So if you can time an intervention before that, that would be good.
 * The thing is that normally the patient's body compensates for the stenosis by raising contractility. The mitral valve, as long as it stays intact, prevents mitral regurgitation and pulmonary hypertension. When this starts to fail, no good.
 * Aortic regurgitation: Generally well tolerated; only develop symptoms of heart failure after years. The idea is to replace the valve before it fails, but pinning that time down is tricky.
 * Mitral stenosis: Mostly found in women (4:1). Generally not operated on- often use a balloon to pop open the stenotic valve. Generally patients can get right-sided, not left-sided, heart failure.
 * Mitral regurgitation: Fix with either valvuloplasty and valve replacement.
 * Describe the kinds of valve abnormalities produced by valve infection (endocarditis)
 * According to her notes: Mitral stenosis, aortic regurgitation, mitral regurgitation, aortic stenosis.
 * Note that a result of endocarditis is __vegetation__, fibrotic growths on the valves. Can cause regurgitation; can also break off and embolize.

Heart Sounds and Murmurs Wednesday, March 26, 2008 8:04 AM


 * Heart Sounds and Murmurs, 3/26/08:**


 * Describe the origins of: a) first and second heart sounds; third and fourth heart sounds (aka S3 and S4 [gallops]); c) their relationship to the cardiac cycle (pressures and EKG)
 * S1 and S2: closing of AV and semilunar valves respectively.
 * S1: near beginning of systole, ventricular pressure starting to rise
 * S2: end of systole, ventricular pressure already coming down
 * S3: sound during mitral opening (beginning of ventricular diastole)-- ventricular pressure quite low (at end of isovolumic contraction).
 * S3 in atrial stenosis: bad sign (ventricle is failing or has failed)
 * S4: sound during atrial systole (near the end of ventricular diastole)-- ventricular pressure a bit higher (near end of diastolic filling) but not yet in volumic contraction.
 * Note S3 and S4 are low-pitched sounds, as opposed to S1 and S2. Listen at the apex (left-sided) or tricuspid area (right-sided).
 * [Note that you can get an "opening snap" between S2 and S3 as the mitral valve opens, and an "ejection click" between S1 and S2 as the aortic valve opens.]
 * ["Gallop rhythm"-- heart rate over 100 or so, means S3 and S4 can't be separated out from each other.]
 * Describe the characteristics of ejection (stenosis) and regurgitant (insufficiency) murmurs
 * [Systolic murmur: gets louder, then softer, during systole. Pansystolic murmur: stays roughly constant throughout systole.]
 * Regurgitant murmurs-- can be localized systolic or can be pansystolic, or diastolic.
 * Aortic regurgitation: often both diastolic and systolic (systolic from increased blood output due to increased stroke volume, diastolic due to turbulent filling).
 * Ejection murmurs-- generally crescendo-decrescendo.
 * Note aortic stenosis can radiate into the carotid arteries.
 * Note aortic stenosis tends to peak later in systole as the valve gets more stenotic.
 * Describe maneuvers and stethoscope locations for hearing murmurs of the aortic, mitral, pulmonic and tricuspid valves
 * During a rapid heart rate in which there's some trouble in distinguishing S1 from S2, take the patient's carotid pulse-- it should be before S2 and after S1.
 * Mitral: apex (easiest to hear when patient is put into left lateral decubitus position)
 * Aortic: right second intercostal space
 * Pulmonic: left second intercostal space. Note that this is normally the only place you can hear the pulmonic valve closing (and thus also the only place you can hear S2 splitting).
 * Tricuspid: left fourth intercostal space
 * When listening for heart sounds:
 * Tell patient to exhale completely and hold it.
 * Left lateral decubitus
 * Sit up, lean forward
 * With exercise or cough
 * Placing stethoscope over epigastrium when the heart has been 'pulled down' can work well.
 * If PR interval is long, the first heart sound is relatively soft - mitral valve is already mostly closed before ventricle contracts. If PR interval is short, vice versa.
 * Describe the differences between physiologic (normal) and pathologic murmurs
 * Pathologic murmurs:
 * Continuous murmurs
 * Diastolic murmurs
 * Murmurs accompanied by a thrill (palpable murmur)
 * Systolic murmurs that extend past the S2 sound

French's Review for unit I Thursday, March 27, 2008 8:57 AM


 * French's Review for Unit I, 3/27/08:**

Note digoxin is the only drug we use long-term to raise cardiac output in heart failure. Recall that it improves symptoms but doesn't improve mortality (watch for increased calcium content creating afterdepolarizations, leading to TdP and v-fib). Note that dig is considered an AV blocker because it increases vagal tone. As far as rate control is concerned, adenosine can be considered a pharmacological acetylcholine substitute (acts on the same Gi protein that ACh does).

NE: activates alpha-1, increases preload and afterload through veno/vasoconstriction. Note it also activates beta-1 receptors in the kidneys to increase release of renin. Note angio II is about 40 times more powerful a vasoconstrictor than norepinephrine. It's also a mitogen, which triggers cardiac remodeling.

Note inotropes in heart failure 'are a bridge to transplantation' -- they actually slightly worsen mortality by increasing AV node conduction speed, which can predispose to arrhythmias.

French: for __uses__ of drugs, should primarily be aware of cardiovascular uses. But you should also know the __side effects__ in other organ systems. Should follow from receptor subtype distribution among organs.

Note that there's very little parasympathetic innervation in the ventricles, but a fair bit in the atria.

Recall predominant tone is parasympathetic except in blood vessels, particularly resistance vessels. Thus parasympathetic antagonists (like atropine) should have systemic effects vary with the extent of parasympathetic tone in various organ systems (ie., it would have no effect in resistance vessels, but a large and immediate effect on salivary glands).

Note at pharmaceutical doses, epinephrine's effect on blood vessels is primarily vasoconstriction (vs physiological doses). But in bladder, etc, effect is dilatory (no alpha-1 receptors, just beta-2s).

Note alpha-1 beta-1 beta-2 blockers (ie labetalol) can be useful in heart failure-- get the survival benefits of blocking beta-1 heart stimulation as well as the symptomatic benefits of blocking alpha-1 vasoconstriction (lower fluid overload).

Pathology of Valvular Heart Disease Wednesday, March 26, 2008 8:08 AM


 * Pathology of Valvular Heart Disease, 3/27/08:**


 * [Notes: ]
 * Rheumatic valvular disease is much less common in developed countries.
 * Remember that hypertrophy of the ventricle can easily mess with either the placement of the valves or (for the mitral valve) the chordae tendinae, which can cause regurgitation or prolapse. An area ratio of 1.6:1 between the valve ring and the cusps is normal-- any decrease in that ratio will cause regurgitation. Can be caused either by decrease in effective area of cusps (due to scarring, etc) or an increase in are of the valve ring (due to ventricular remodeling and hypertrophy).
 * In pulmonary edema you see eosinophilic material within alveolar spaces.
 * List each of the valvular pathologies discussed in class categorized as non-rheumatic or rheumatic and stenotic or regurgitant/incompetent.
 * Non-rheumatic:
 * Aortic stenosis
 * Aortic regurgitation
 * Mitral regurgitation
 * Rheumatic:
 * Autoimmune pathogenesis (rheum. fever, cross rxn: type II immunopathology)
 * Briefly describe, verbally and in writing, 2 different underlying causes for aortic stenosis and their ultimate consequences on cardiac function.
 * Aging: fibrosis and calcification of tricuspid (normal) aortic valve over time. Extremely common over 70, somewhat common over 50.
 * Congenital deformation: fibrosis and calcification of a bicuspid aortic valve.
 * Note that calcification focuses particularly at the coronary artery openings.
 * Note can also get fusion of commissures after the inflammation of an infection.
 * Aortic stenosis: as extensively discussed earlier, leads to low cardiac output and left ventricular hypertrophy (mainly concentric).
 * Due to ventricular hypertrophy, there's an increased risk for arrhythmias and ischemia/MIs (stretched-out conduction pathways, low cardiac perfusion due to low capillary density).
 * Briefly describe verbally and in writing a "floppy mitral valve" and its consequences on cardiac function.
 * "Floppy mitral valve" = "mitral valve prolapse."
 * Fairly common (2.5-5.0% prevalence)
 * Larger mitral cusps with elongated ("waisted"-- have a thin part in their middles) chordae tendinae.
 * Possibly has something to do with connective tissue defect.
 * The present wisdom is that this doesn't really increase your risk for much of anything.
 * Describe in writing the basic sequence of events that are thought to occur during acute rheumatic fever and chronic rheumatic heart disease.
 * Acute: infection with Group A beta-hemolytic //Streptococcus pharyngitis//.
 * Type II cross-reaction with glycoproteins in the heart valve leaflets.
 * Symptoms begin 2-3 weeks after infection with //Strep pharyngitis//.
 * Cause pancarditis (inflammation in any/all layers of the heart) with formation of granulomas:
 * Valvulitis
 * Result in edema, particularly in the left-sided valves (under greater pressure).
 * Endocarditis
 * Occurs at the lines of closure of the valves and on the chordae tendinae, with fibrin deposits.
 * Fibrinous pericarditis or myocarditis
 * In most people, this clears up with complete resolution.
 * In others (stats?), this results in fibrosis (scarring) and thickening of valve leaflets. Also can get fusion of valvular commissures. This can lead to valvular stenosis and/or regurgitation.
 * Chronic: Effectively these are the people in whom acute infection leaves fibrotic scarring/fusion.
 * Generally present more than 10 years after the //Strep// infection.
 * Present with about what you'd think: complications of valve disease
 * (heart failure, infective endocarditis, thromboemboli, arrhythmias)
 * Generally __mitral valve__ damage (stenosis, regurgitation) is more common in chronic rheumatic heart disease than aortic valve damage.
 * Verbally explain how chronic rheumatic heart disease, if left untreated, will lead to heart failure, and what the pathologic changes of heart failure are.
 * As mentioned, you get thickening, fibrosis, and fusion of valve cusps, leaflets, and chordae tendinae, leading to valvular stenosis/regurgitation.
 * Leads to heart failure in a variety of ways depending on where the damaged valve is (see "Valvular Heart Disease"). Remember that it mostly results in mitral problems, often stenosis (left atrial hypertrophy and fibrillation, embolisms, right-heart failure due to backup of pulmonary vessels).
 * Explain the difference between acute infective, sub-acute infective, and non-infective endocarditis.
 * Infective endocarditis: inflammation of the valves or endocardium due to infection by microorganisms (no surprises there).
 * Note danger: inflammation in heart can expose collagen, promoting thrombus formation (the heart is a bad place to get clots).
 * Infection splits: __more virulent__ organisms can infect healthy, normal valves, while __less virulent__ organisms can only infect abnormal valves.
 * Reason for this: turbulent/high-velocity blood flow 'denudes' (strips?) the endothelial surface of the valve and allows platelets, fibrin, and presumably microorganism deposition.
 * In a nutshell, that's the difference between acute and subacute-- acute is caused by more virulent invading organisms on normal heart surfaces, subacute is caused by less virulent organisms, or normal commensal bacteria, getting onto damaged heart surfaces or regular surfaces in immune-compromised hosts.
 * Noninfective endocarditis: inflammation of the valves of endocardium for other reasons (also no surprises there).
 * Non-bacterial thrombotic endocarditis: sterile (no bacteria) fibrinous vegetations along valve closure lines.
 * Associated with endocardial trauma, hypercoagulative states, wasting (cachexia), uremia (kidney failure), metastatic malignancy.
 * Note that a noninfective endocarditis can still easily become infected due to inflammation and fibrosis providing abundant places for microorganisms to live.
 * Libman Sacks endocarditis
 * Sterile vegetations, seen in lupus patients (autoimmune).
 * What is the definition of vegetations?
 * Growths in the heart or on the valves. Composed of fibrin, red blood cells, inflammatory cells (macrophages), or microorganisms.

Heart Failure Therapeutics I and II Thursday, March 27, 2008 9:03 AM


 * Heart Failure Therapeutics I and II, 3/28/08:**


 * [Note that in certain conditions, such as chronic hypertension and aortic stenosis, heart failure can involve both diastolic and systolic dysfunction-- the heart develops left ventricular hypertrophy, then progresses to ventricular dilation and loss of contractility. This is in some contrast to the model advanced before, where heart failure split into either systolic or diastolic modes.]
 * [Note that women are less likely to get heart failure until menopause, at which point the incidence evens out.]
 * [Note that coronary heart disease is by far the most common starting point for heart failure in the US. Stop eating that damn cheeseburger, Cole.]
 * [Note that normally you have parasympathetic tone in your heart. With CHF, you get a more sympathetic tone, at least until the sympathetic receptors start desensitizing on you.]
 * Note also, germane to our earlier discussion about lots of NE being bad for you, that higher [NE] directly correlates to decreased survival.
 * [Note that you're looking at a bunch of different CHF syndromic drug targets: heart, blood vessels, and kidneys. Various drugs target various ones:]
 * Heart: inotropes, beta-blockers, ACE inhibitors
 * Blood vessels: vasodilators, ACE inhibitors
 * Kidney: diuretics, vasodilators, ACE inhibitors
 * Note that ACE inhibitors apply to all three target areas. No surprise that we use them here so much.
 * Understand that both the progression and treatment of congestive heart failure occurs in stages. Understand that there is generally no cure, per se, for congestive heart failure. The main therapeutic goal is to slow to as great an extent possible the rate of progression of this highly prevalent disease.
 * Ok.
 * Class I: relatively asymptomatic until rigorously exercised.
 * Can start Class I folks on ACE inhibitors.
 * Class II and III are more or less as you'd expect, more and more severe. The treatment and medications are more or less the same, just with different gradations. Their goal is to reduce, probably not eliminate, the chance that your guy is going to die of CHF complications in the next X years, and to make those X years better than they'd otherwise be.
 * Understand the principles of intracellular calcium handling in cardiomyocytes. In this context, understand how cardiac glycosides modulate increased myocardial contractility via blocking the Na+/K+/ATPase thereby affecting [Ca++]i. Understand that by completely different pathways, both beta-AR and alpha-AR stimulation also increases [Ca++]i. In essence, understand the fundamental basis of inotropic activity.
 * Ok.
 * Digitalis more or less = digoxin more or less = digitoxin, for the purposes of our discussion. Digoxin has another hydroxyl group on one of its rings, which impacts its pharmacokinetics vs. digitoxin as mentioned below.
 * Use dig: for treating CHF with atrial fibrillation or treating CHF with S3 heart sound. Generally the point here is to fix systolic failure with an option on conduction; dig isn't going to do much for you if you've got a problem with diastolic filling.
 * Fundamental basis of inotropic activity: more intracellular calcium, stronger stroke.
 * Beta-1 AR stimulation: increased ICa channel activation through Gs-elevated cAMP. Remember that it also phosphorylates phospholamban, resulting in increased SERCA2 activity to increase Ca++ reuptake (means stronger contractions and faster recovery).
 * [Recall that troponin and myosin are also PO4'd by beta-1 stimulation.]
 * Alpha-1 AR stimulation (not previously covered in the heart, less important): Gq activation triggers IP3 (increasing calcium release from the SR).
 * Alpha-2 AR stimulation (not previously covered in the heart, less important): Gi activation lowers cAMP to decrease ICa channel activation.
 * **Digitalis** : __inhibits Na+/K+ pump by binding to its K+ binding site, causing accumulation of intracellular Na+. This triggers increased activity of the NCX1 exchanger to try and get rid of the excess sodium, thus resulting in more intracellular calcium__. Another way of looking at it is that they trigger decreased activity of the NCX1 exchanger during systole, resulting in less efflux of calcium, thus resulting in more intracellular calcium. Either way, [Ca++]i goes up.
 * Understand that cardiac glycosides have many effects, but that the net effect is generally to ameliorate the symptoms of CHF thereby reducing central adrenergic drive.
 * Ok.
 * [Shift closed-curves (pressure vs volume) to the left (in CHF they’re shifted right).]
 * [Shift Starling curves up and to the left (in CHF they're shifted down and right).]
 * [His main point here seems to be that dig essentially can decrease the overactive sympathetic stimulation of the heart/body by decreasing one of the main symptoms (forward cardiac failure) of CHF over time.]
 * Understand that the electrophysiological effects of cardiac glycosides are both the basis of their usefulness in treating supraventricular arrhythmias and are also the basis for their proarrhythmic effects (PVC’s, nodal block).
 * Ok.
 * I'm not sure this is the best way to phrase this LO. When I asked him about it, he said that their usefulness derives mostly from their long-term suppression of sympathetic tone as just mentioned, allowing parasympathetic tone to dominate and thus increasing muscarinic ACh receptor actions to slow down AV and SA node conduction. That's not really an electrophysiological effect in the same way that it's a proarrhythmic, unless you want to stretch "electrophysiological effect" to include indirect suppression of sympathetic nervous stimulation due to intropic effects."
 * In any case, French mentioned that there's also a direct effect of digitalis on vagal tone-- maybe just from increasing cardiac output so as to tell the baroreceptors to tell the medulla to start stimulating more ACh release and less NE release.
 * As I said, you get your antiarrhythmic effects - reduced conduction velocity at the SA node (use for atrial flutter/fib) and the AV node (use for supraventricular tachycardia, but watch out for AV block) - from a combination of suppression of sympathetic responses over time and induction of parasympathetic responses in the short term.
 * Proarrhythmic effects are caused by an accentuation of normal ebb-and-flow of calcium levels between the cytoplasm and the SR-- evidently the SR is kind of an unstable storage vessel, and the more it's storing, the more the cytosolic concentration of calcium fluctuates. Since digitalis acts by increasing intracellular calcium, and all that calcium has to go somewhere, generally it goes into the SR. Evidently the fluctuations in intracellular calcium due to SR storage instability can get large enough to cause **delayed afterdepolarizations** in phase 4-- thus leading to PVCs and all the unpleasantness involved in ventricular arrhythmias.
 * Note that this is a different afterdepolarization mechanism than we've seen before, in which the NCX1 exchanger works overtime during conditions of high intracellular calcium and makes the cell depolarize due to an increase in sodium. Might still apply to dig patients even through they have increased intracellular sodium as well. Not sure.
 * His notes on effects:
 * Decreased AV node conduction velocity (saw that already)
 * __Increased__ Purkinje fiber conduction velocity (due to increased depolarization from intracellular calcium levels)
 * __Decreased__ ARP in ventricular muscle
 * Note it causes T wave inversion, long PR segs, and short QT intervals on EKGs.
 * [Note digitalis also stimulates sympathetic activation in the heart.]
 * Understand the role (limited) of non cardiac glycoside positive inotropic agents (PDE I's, beta-AR agonists) in the treatment of chronic CHF.
 * Effectively these make the heart beat stronger than digitalis. Thus they're generally last-ditch agents, only used in situations where digitalis has already failed (recall that digitalis itself is usually used only when other therapies like ACE inhibitors and diuretics aren't predicted to be able to correct systolic failure).
 * __Beta-ARs__: a host of problems. Very poor oral availability and short half-life. Desensitization of receptors in the heart after a few days. You still get catecholamine toxicity and vascular remodeling. Increase the heart's VO2 more than they increase cardiac output, potentiating cardiac ischemia. Pro-arrhythmic thus increased risk of sudden death.
 * __PDE inhibitors__: generally better drugs, but still increase mortality. Raise cAMP levels without stimulating sympathetic receptors; thus can be used in conjunction with beta-blockers to maintain cAMP levels (inotropy) while blocking over-binding effects of endogenous norepinephrine on beta receptors. Don't seem to raise the heart's VO2 more than cardiac output.
 * [Understand the basis of the usefulness of diuretics in the treatment of CHF.]
 * Not actually a LO, I just read the next one wrong and I think my answer is clever so I'm loath to delete it.
 * Basically: reduce preload by relieving the relentless volume of blood squeezed into the heart as catalyzed by all the peripheral vasoconstriction that accompanies CHF. Reducing preload reduces the stress on the ventricle, which can't eject or can't fill or both normally anyway, and more importantly for symptoms, it also takes a lot of the volume from out of the pulmonary circulation, which improves the dyspnea and orthopnea.
 * "But," you protest, "by reducing preload, doesn't Starling predict that we're damaging their stroke volume? Gadzooks, Rose, these patients need every iota of cardiac output they can get. What were you smoking?" Aha- but in patients with CHF, their Starling curves (which, recall, tend to get lower and flatter with loss of contractility) are pretty damn low and flat. The flatness means that you can move a considerable distance along the horizontal axis (preload) without significantly affecting placement on the vertical axis (stroke volume)-- which in turn means that you can vasodilate a CHF patient to some extent before having to worry about impinging on stroke volume.
 * However, you do have a point. Past a certain preload, more diuretic use is going to affect stroke volume and end you up in the malpractice dock.
 * Note that with diuretic AND an inotropic agent (like dig) you can avoid the reduction in stroke volume and let you use more diuretic.
 * But watch out for potassium/magnesium wasting in diuretics when you're co-administering digoxin.
 * Understand the basis of the usefulness of vasodilators (including ACE inhibitors) in the treatment of CHF.
 * According to Dr. Port, these are the most important drugs in treating heart failure.
 * Note that vasodilators can target arteries (reduce afterload, thus the pressure required to be generated in the ventricles), veins (reduce preload), or both.
 * Venodilator: nitroglycerin, isosorbide dinitrate (ISDN)
 * Arterial dilator: minoxidil, hydralazine
 * Vasodilators, in general, reduce the amount of blood in the heart and lungs by increasing the amount of blood in the peripheral circulation. You can see how they'd work well with the diuretics, as above.
 * ACE inhibitors: as mentioned elsewhere, useful on lots of different levels. Reduce cardiac remodeling, reduce preload, reduce vasoconstriction, bake cupcakes, make thousands of Julienne fries.
 * Watch out-- __ACE inhibitors increase serum K+__ (inhibit K+/Na+ exchanger to dump serum sodium).
 * To beat this point to death, ACE inhibitors also prevent the breakdown of bradykinin, a vasodilator which also increases tPA action (thus preventing clots).
 * Understand the basis of the usefulness of beta-blockers in the treatment of CHF.
 * Beta-blockers without negative inotropic effects can be used for a couple of reasons-- one is that they allow the receptors to recover from the bombardment of stimulation that makes up such an endearing part of CHF (that is, the beta-blockers allow resensitization of the beta-1 receptors). The other is, as mentioned earlier, that they block catecholamine toxicity (which leads to fibrosis and further systolic and diastolic failure) by preventing their binding.
 * "without negative inotropic effects:" what I mean here is that beta receptors actually have some effect to increase cAMP all of the time, whether or not they're being stimulated. Some beta-blockers decrease this normal 'tone' of cAMP levels (thus actual negative inotropic effects), some just block the receptor's further stimulation without affecting its normal cAMP tone. These latter ones are the ones you want to use in CHF.
 * Describe digoxin-related toxicities and their treatment.
 * Digoxin (digitalis): very narrow therapeutic window. Lower doses tend to cause less increased mortality than higher doses. Note that there are lots of things that affect effective digitalis concentrations, so you need to watch these concentrations very closely when administering.
 * Recall that you inhibit the Na+/K+ pump-- digitalis binds to the K+ binding site, thus it competes with K+ and has been dosed for normal-K+ individuals. When you have a situation in which a person has a low serum level of K+ (as when they're taking many diuretics), you can get digitalis toxicity. Note that low levels of K+ also cause higher levels of intracellular Na+, thus also intracellular Ca++ (recall NCX1).
 * ACE inhibitors increase serum potassium, which will similarly decrease the effect of digoxin.
 * Recall that Ca++ blockers (ie. diltiazem) and beta-blockers (ie. metoprolol) also slow AV conduction and can cause AV block when used in conjunction with digoxin.
 * Watch out for antibiotics and arrhythmic drugs, all of which have the potential to screw with dig levels or effects.
 * Dig toxicity manifests as:
 * Anorexia, nausea, vomiting, headache, fatigue; also cognitive and sensory impairment.
 * Ventricular arrhythmias; also varying degrees of AV block due to overly slowed AV node conduction.
 * Can cure dig toxicity with antibodies against digoxin (DigiBind). Can, carefully, use potassium infusions in hypokalemic patients.
 * [Note that digitoxin has a half-life of 7 days on average. This is why we don't really use it much-- it takes too long to get to a steady-state concentration. It has to be metabolized by the liver before it can be excreted, as opposed to digoxin, which can be excreted unchanged by the kidneys and has a half-life of about 1.7 days.]

French's Review for Unit I, Pt. II Friday, March 28, 2008 12:03 PM


 * French's Review for Unit I, Pt. II**

Don't generally treat chronic arrhythmias with drugs except for atrial fibrillation. (for AF, usually use amiodarone and lidocaine)

Best channels to target to affect refractory period in nodal cells: potassium channels.

Different causes of different afterdepolarizations: · Prolonging the ST segment: early afterdepolarization -- torsades de pointes, sudden death. · Digoxin: calcium-dependent, delayed afterdepolarization-- PVCs, v-tach.

Recall that drugs that alter sodium conduction - like class I and class III's amiodarone - affect conduction speed and thus can be proarrhythmic.

Rate vs rhythm control: Rate control is used in origination arrhythmias that begin above the AV node, by increasing the __vagal tone of the heart__. Drugs used for this: class II, class IV, digoxin (which is why dig is used in CHF patients with atrial fibrillation), adenosine. Also vagal maneuvers. None of these are particularly toxic except for digoxin. Rhythm control is used to control conduction disorders in the ventricles, by adjusting their conduction speed. Drugs used for this: I, III (amiodarone). As mentioned, these can be dangerous. Ib drugs (ie. lidocaine) are helpful because they have sodium-blocking, but no potassium-blocking activities-- thus less cross-reactivity with SA/AV cells (recall that conducting cells aren't regulated by fast Na+ channels).

Digoxin: French: low serum potassium predisposes to arrhythmias. Dig predisposes to arrhythmias. In combination this can be bad. Potassium-losing diuretics: thiazide (some K+ wasting) or loop (lots of K+ wasting) Potassium-sparing diuretics: aldosterone antagonists/ACE inhibitors

Definitely know the structure of the catecholamine molecule, there'll be a question on it. hydroxylation of the phenyl ring make these drugs less able to get into the CNS-- dehydroxylated = more able to get into the CNS.

Endothelial Function Tuesday, April 01, 2008 8:01 AM

(Aka "Why We Love Nitric Oxide")
 * Endothelial Function, 4/1/08:**


 * List the substances released by the normal endothelium and their functions.
 * Mostly, here, **nitric oxide** . Does all kinds of good stuff:
 * (1) __Tightens endothelial barrier__ (prevents edema, also important in atherosclerosis)
 * (2) __Vasodilation__ (diffuses into smooth muscle, stimulates cGMP production)
 * (3) __Anti-proliferative__ in smooth muscle cells
 * Lilly says this is important in preventing the muscle cells from growing out into the lumen. I interpret this to mean that it's important in the effect, described later, of eccentric vs. concentric hypertrophy of vasculature with sustained vasodilation-- concentric hypertrophy does, in fact, involve the muscles growing into the lumen and occurs primarily in NO-deprived vasculature.
 * (4) __Anti-platelet binding__ (suppresses platelet-endothelium binding sites)
 * (5) __Anti-inflammatory__ (suppresses leukocyte-endothelium binding sites)
 * Mentioned in passing: another vasodilator (prostacyclin, or PGI2) and a vasoconstrictor, **endothelin** (which kind of acts in opposition to NO-- not only vasoconstricts, but also promotes smooth muscle proliferation and encourages platelet and leukocyte binding and activation).
 * I think it's probably best to think of the endothelium as having 'tone' of its own-- it's situated in between constriction and dilation, platelet aggregation and disaggregation, etc. Important point: normally the dilated, non-aggregating tone is dominant. When the endothelium gets damaged, it tends to shift more towards the constrictive, thrombotic side.
 * Also mentioned in passing: the endothelium, if damaged, can secrete cytokines that attract leukocytes. This is one mechanism of atherosclerotic plaque genesis (see below).
 * List the factors which stimulate, and decrease, endothelial generation of nitric oxide.
 * NO production:
 * Stimulated mainly by increased blood flow (as in vasodilation during exercise), which generates increased shear stress on the endothelial surface to stimulate NO production.
 * Note that this seems to be mainly an acute phenomenon. Chronically increased shear stress can damage an endothelium and induce dysfunction, leading to thrombosis and ischemic injury.
 * Hypoxia also triggers NO production.
 * Muscarinic receptor agonists, as we've seen, can trigger it as well. The ligands listed here are __acetylcholine__ and __bradykinin__.
 * Factors that decrease NO generation: the reverse of any of the above, obviously. Also anything that decreases L-arginine levels or eNOS activation (see next LO).
 * Describe the pathways leading to the generation, actions, and degradation of nitric oxide.
 * NO generation:
 * L-arginine is converted to nitric oxide by a variety of NO synthase (NOS) enzymes. The one important in endothelia is endothelial NOS, or eNOS.
 * NO degradation:
 * NO is very very transient and degrades very quickly (on the order of .001 seconds)
 * The main factors that degrade NO are oxidants- superoxide (O2-), hydrogen peroxide (H2O2), and hydroxyl radical (OH*).
 * Another way to think about this is that NO is a ubiquitous vascular antioxidant.
 * NO actions:
 * As mentioned, tightens endothelial barrier, suppresses endothelial adherence sites for platelets and white cells, vasodilates, anti-proliferative in muscle cells. It dilates through cGMP production and binds to the appropriate sites to prevent binding of platelets and leukocytes. Unless I'm missing something, neither Weil nor Lilly go into the molecular mechanisms of anti-proliferative effects and endothelial tightening.
 * NO is responsible for a lot of the 'good' vascular remodeling that goes on-- that is, remodeled widening of the lumen during sustained vasodilation/NO release.
 * Note the converse-- without functioning NO, the lumen gets narrower. In either case, the vascular walls are getting thicker (evidently independently of NO), so without NO, vessels can get a sort of concentric hypertrophy of their own.
 * List the specific actions of nitric oxide which maintain normal vascular structure and function.
 * This seems redundant. All the stuff I just talked about.
 * Describe the role of and mechanism by which endothelial dysfunction promotes atherosclerosis.
 * Notice we go over all this again in part I of "Lipids, Lipoproteins, and Atherosclerosis."
 * (0) Endothelium gets damaged by inflammation or oxidants: hypertension, diabetes, smoking.
 * (1) NO isn't being generated from the endothelium.
 * (2) The endothelium isn't as tight a barrier as before; thus some LDL cholesterol winds up stuck underneath the endothelium. It gets oxidized in the tunica, and triggers a release of cytokines that attract white cells to the site.
 * (3) The white cells' binding sites aren't being blocked, so a monocyte binds to the site where the LDL entered and squeezes into where the LDL got stuck.
 * (4) The monocyte (now actually a macrophage) begins to engulf the LDL, turning into a pro-inflammatory 'foam cell.' These foam cells eat enough LDL that they get trapped in the tunica.
 * (5) The LDL molecules and foam cells accumulate into a 'plaque' pushing up from under the endothelial layer, which can partially occlude the lumen if it goes on long enough.
 * (6) The foam cells are responsible for generating a lot of matrix metalloproteinases (remember these? bad news in inflammation), which can degrade the surface of the endothelium above the plaque. This can lead to plaque rupture, and spilling out the foam cells and LDL into the bloodstream-- the Family Platter of emboli and thrombogenesis.
 * [stable angina: plague without a lot of inflammation, thus not a lot of metalloproteinases.]
 * [unstable angina: plague with lots of metalloproteinases, thus plaque can rupture at any time, posing a thrombus risk however big the plaque is.]
 * Describe the action of statins on nitric oxide generation.
 * Statins, in addition to their blockade of LDL, inhibit an agent called geranylgeranyl-PP (seriously?), which has the evident result of __increasing NO production__.

Anticoagulant, Antiplatelet, &c. Drugs Tuesday, April 01, 2008 8:46 AM


 * Anticoagulant, Antiplatelet, &c. Drugs, 4/1/08:**

> **Anticoagulants** : Heparin/low MW heparins [enoxaparin, dalteparin], warfarin > **Thrombolytic agents** : Urokinase, streptokinase/anistreplase, tissue plasminogen activator and variants > **Antiplatelet agents** : Aspirin, clopidrogel, dipyridamole, abciximab/epifibatide/tirofiban //With special emphasis on their use in the following cardiovascular conditions:// Venous thromboembolic disorders Acute myocardial infarction Atrial fibrillation Percutaneous coronary interventions (pre-, peri-, post-) Secondary prevention of myocardial infarction Unstable angina/Acute coronary syndrome
 * Describe the general mechanisms of coagulation, fibrinolysis, and platelet function with special emphasis on the sites and targets for pharmacotherapeutic interventions in disorders of hemostasis.
 * Coagulation:
 * French seems to focus mainly on the common pathway, so let's stick with that. Factor X is activated to Xa (by extrinsic VIIa + tissue factor or intrinsic IXa + VIII), which with Factor V activates prothrombin (II) to thrombin (IIa), which in turn cleaves fibrinogen (I) to form fibrin (Ia). (Fibrin is subsequently cross-linked by XIIIa to harden the plug.)
 * Notice that Proteins C and S inhibit Factors V and VIII.
 * Note intrinsic pathway is triggered by contact with glass, as in glass test tubes.
 * Targets for drug interventions:
 * Unfractionated heparin (with ATIII): Factors Xa, IIa (also, less importantly, XIIa, XIa, and IXa)
 * Low-molecular weight heparin (with ATIII): Factor Xa
 * Warfarin: Factors II, VII, IX, X; Proteins C and S.
 * Lepirudin (leech compound): IIa.
 * Platelet function:
 * Platelet binds with glycoprotein Ib to exposed collagen in the damaged endothelium.
 * Once bound ('activated'), the platelet expresses glycoproteins IIb and IIIa and releases thromboxane A (TXA) and adenosine diphosphate (ADP) that bind to and activate other platelets.
 * When the other platelets are bound by TXA or ADP, they also express gp IIb/IIIa.
 * The two platelets' exposed gp IIb/IIIa sites are bound together with fibrinogen to cause platelet aggregation.
 * The fibrinogen is cleaved through the clotting cascade by thrombin (IIa) to tightly bind the platelets together.
 * The second platelet also releases TXA and ADP, causing a third platelet to become activated, etc.
 * Fibrinolysis:
 * Once platelet plug (thrombus) is formed, start ramping up anti-fibrin factors (fibrinolytics). These primarily work through **plasmin**, the cleaved form of plasminogen, that breaks apart fibrin into degradation products.
 * Agents that increase plasmin production:
 * Tissue plasminogen activator (**tPA** )
 * Streptokinase
 * Etc (see discussion below)
 * Keep in mind that increasing systemic fibrinolytic activity can have pro-bleeding side effects, particularly in the cranium.
 * For the following categories of drugs utilized in the treatment of disorders of hemostasis:
 * Describe their mechanism of action and pharmacokinetics
 * List their uses, adverse reactions (plus treatment of overdosage if applicable), and drug-drug interactions
 * Explain the relative advantages and disadvantages of drugs in each category
 * [French: "A healthy endothelium is non-thrombogenic."]
 * [Some indications from lecture:]
 * Atrial fibrillation: use anticoagulants (warfarin)
 * Acute coronary syndrome: anti-platelets (chewed aspirin) and anticoagulants
 * MIs: fibrinolytic agents (streptokinase, tPA, etc)
 * Percutaneous interventions: IV anti-platelets
 * Peripheral vascular disease (venous thromboembolic): anti-coagulants (warfarin)
 * Ischemic heart disease: anti-platelets
 * (Notice that in his notes he describes DVTs, which sound like venous thromboembolic disorders to me, as treatable with fibrinolytics.)
 * Anticoagulants:
 * Unfractionated heparin:
 * MOA: Combines with circulating antithrombin III, to increase about 1000x the rate at which ATIII inactivates **IIa** and **Xa** . (and others, but don't worry about them so much-- thus saith French)
 * Onset: Minutes
 * Test to monitor: aPTT
 * Pharmacokinetics: Given subcutaneously or IV. (large, highly-charged molecules; **don't cross** the BBB or **placental barrier** .)
 * Adverse drug reactions: Bleeding, also hypersensitivity reactions. The big one is **thrombocytopenia**.
 * Can be mild-- platelet count goes down (but stays above 100,000) because heparin seems to have a slight pro-aggregating effect on platelets.
 * Can be severe-- autoimmune, complement-mediated destruction of platelets called **heparin-induced thrombocytopenia** (HIT).
 * The result is both a shortage of platelets and a reactive hypercoagulable state.
 * Problem here is that you can get thrombosis, or DIC, from an __anticoagulant__. Not fun.
 * Can use **lepirudin**, a direct IIa inhibitor, in place of heparin in HIT.
 * Overdose treatment: **protamine** -- positively-charged molecule that binds to heparin and neutralizes it. Notice that you can get an immune response to protamine (comes from salmon sperm).
 * Seriously, who thinks, "Hey, I'll jack off some salmon and inject it in my patient, maybe that'll help?"
 * Low-molecular weight heparin:
 * MOA: Also combines with circulating ATIII, but can only help it to inactivate Factor **Xa** (not IIa).
 * Onset: Minutes
 * Test to monitor: None (no effect on aPTT/PT). Look at dosing levels instead. Once you've got the dose set, patients generally don't need monitoring.
 * Pharmacokinetics: Given subcutaneously or IV. (large, highly-charged molecules; don't cross the BBB or **placental barrier** .)
 * Adverse drug reactions: As above-- bleeding, thrombocytopenia, DIC.
 * Overdose treatment: Protamine as above.
 * Warfarin:
 * MOA: Prevents vitamin-K mediated synthesis of **II**, **VII** , **IX** , and **X** in the liver. (also affects anticoagulants **Proteins C and S** as well). As such, it can be antagonized by increased dietary vitamin K intake.
 * Onset: Days
 * Test to monitor: PT/INR.
 * Pharmacokinetics: Narrow therapeutic drug. Excellent oral absorption, so it generally goes //po// . Metabolized by CYP450 enzymes. **Crosses the placental barrier.**
 * Note that genetics can influence both how fast your CYP450 enzymes break down warfarin and how fast your 'used' vitamin K is recycled to be able to carboxylate more clotting factors (ie. vitamin K reductase).
 * Adverse drug reactions: Bleeding; since proteins C and S are also affected, can initially see some pro-coagulant effects. **Contraindicated in pregnancy**.
 * Watch out for antibiotics that decrease vitamin K levels; also anything that affects CYP450 activity. Also aspirin.
 * Overdose treatment: Skip a dose; administration of vitamin K. In severe cases can also administer fresh frozen plasma.
 * [Nice thing about heparin: immediate action. Nice thing about unfractionated heparin: outpatient injection therapy. Nice thing about warfarin: long-term, oral admin.]
 * Antiplatelets:
 * Aspirin:
 * Used low-dose for cardioprotective effect by being COX-1 selective. Note that aspirin isn't, by itself, COX-1 selective, but that's the effect of giving it low-dose. This comes about for a couple reasons:
 * (1) The largest concentration of acetylsalicylic acid, when it's still good and active, is in the portal vein. Once it gets into the liver, it's inactivated by esterases. This means that it has a lot of effect on platelets (all of which flow through the portal vein at some point), but not much effect on endothelia (only a small amount of which is in the portal vein).
 * This is significant because COX-1 is preferentially expressed in platelets (TXA, pro-platelet aggregation) and COX-2 is preferentially expressed in endothelia (PGI2, anti-platelet aggregation). So you're mainly targeting COX-1, and thus platelet aggregation, with low-dose aspirin.
 * (2) Aspirin irreversibly inhibits COX enzymes. This means not much to the endothelia, which can always make more, but a lot to the platelets, which have no nucleus and thus can't. So a single low dose of aspirin can put the circulating platelets out of TXA action for their entire lifetimes (which, recall, is about 7 or 8 days).
 * Generally no adverse reactions to low-dose aspirin. Some very sensitive patients can get stomach upset and/or GI bleeds.
 * Large, anti-inflammatory doses of aspirin can result in bleeding and stomach upset/GI bleeds.
 * Clopidrogel/Ticlopidine:
 * __ADP receptor agonists__-- block activation of platelets, thus prevent those platelets from releasing more TXA and ADP as well as preventing them from expressing gp IIb/IIIa and binding to adjacent platelets.
 * Pharmacokinetics: //per orem// admin-- consumed as a prodrug that's activated upon cleavage by CYP450 enzymes. Note synergistic action with aspirin.
 * Adverse reactions: clopidrogel: well tolerated. Ticlopidine: mild GI effects, rash, neutropenia.
 * Dipyridamole:
 * __PDE inhibitor__-- stops breakdown of cAMP, thus increasing the effect of PGI2 on platelet aggregation. Doesn't seem to actually do much, though.
 * PK: orally dosed.
 * Adverse: minimal side effects (some GI/dizziness).
 * Abciximab, epifibatide, tirofiban:
 * __Glycoprotein IIb/IIIa blockers__. These don't prevent platelet activation (like ADP blockers) but prevent platelet aggregation by gpIIb/IIIa-fibrinogen-gpIIb/IIIa binding between adjacent platelets. Recall that abciximab is a chimeric human antibody (Fab part of human antibody).
 * PK: IV admin.
 * Adverse: Bleeding.
 * Thrombolytics:
 * **Tissue plasminogen activator** (tPA): Recombinant human tPA. Binds to fibrin and then activates plasminogen.
 * Note that since tPA preferentially activates plasminogen near activated fibrin, your chances of getting systemic thrombolysis (ie, thrombolysis where you don't want it) are lower. But watch out for cranial hemorrhage anyway.
 * Variations on tPA: **Reteplase** (can be given as IV bolus, less fibrin-specific), **Tenecteplase** (can also be given as IV bolus, more fibrin-specific).
 * **Streptokinase** : //Strep// compound isolate that complexes with and activates plasminogen. Generally results in systemic thrombolysis (systemic activation of plasmin, not specifically in areas of fibrin activation).
 * **Urokinase** : similar to streptokinase. Evidently this has been discontinued.
 * **Anistreplase** : Also discontinued, but apparently an attempt at making clot-selective streptokinase-- it's streptokinase stuck to plasminogen that can't be activated until it's within arm's reach of fibrin.
 * The deal with all this systemic vs clot-specific crap: if you activate plasminogen systemically, the plasmin will chew up not only fibrin, but factors V and VIII-- it's very thorough. That's not good.
 * Note that streptokinase is relatively cheap ($400) and tPA and its variants aren't ($2400). But also note that tPA/variants do a better job at clearing clots.
 * Adverse effects of all: hemorrhage, particularly internal hemorrhage, particularly particularly cranial hemorrhage.
 * Can get antibodies against streptokinase/anistreplase.

Myocardial/Pericardial Disease Tuesday, April 01, 2008 4:10 PM


 * Myocardial/Pericardial Disease, 4/2/08:**


 * List the anatomic classes and features of cardiomyopathies
 * Note that all these are essentially disorders of the myocardium, generally without an apparent cause. Note that here he seems to be mainly talking about primary cardiomyopathies-- as opposed to getting ventricular hypertrophy secondary to high blood pressure.
 * **Dilated** cardiomyopathies: the chambers of the heart, particularly the left ventricle, dilate and weaken. Leads to arrhythmias, loss of contractility and heart failure, thromboembolisms, etc.
 * **Hypertrophic** cardiomyopathies: the myocardium hypertrophies. Here he seems to mainly be talking about **HOCM**, __H__ypertrophic __O__bstructive __C__ardio__M__yopathy, which will be covered in the next LO.
 * **Restrictive** cardiomyopathies: the chambers, particularly the ventricles, are stiff and inelastic. Leads to diastolic dysfunction, lowering cardiac output and leading to heart failure.
 * Concerning hypertrophic obstructive cardiomyopathy, outline; a) causes; b) epidemiology; c) anatomy, hemodynamic and clinical features; and d) treatment
 * **HOCM** (charmingly pronounced "hokum," which is sort of an old-school way of saying "bullshit") is when you get an abnormal thickening of the interventricular septum in towards the left ventricle. This narrows the outflow (aortic) tract and has some interesting fluid-dynamic consequences. The outflow of blood is more pressurized (going through a tighter lumen) and is relatively closer to the mitral valve. As the high-speed blood rushes past the valve, it creates a small vacuum ("the Venturi effect," Jim Carry's new movie) which pulls on the nearest flap of the valve, pulling it across the aortic outflow tract and interposing between the aorta and the ventricle. Once the flap is open and the aortic tract is obstructed, the blood can also flow back into the left atrium instead.
 * Anything that __decreases__ LV preload and causes decreased left ventricular EDV will make this effect more severe. The argument seems to be that less volume in the ventricle allows the valve leaflet to get closer to the outflow tract and thus obstruct it more easily. I'm not sure I buy that explanation, but if you do a Valsalva maneuver (increase thoracic pressure), the preload goes down slightly (less right preload, thus less blood going out from the right ventricle, thus less left preload), the murmur gets louder. By the same logic, it should get softer when you inhale (more preload, less occlusion).
 * Notice that the Wiki article ([]) disputes the vacuum theory and argues that drag, not vacuum, is responsible for a valve leaflet occluding the outflow tract.
 * From the same article: the leaflet occlusion "may be considered anteriorly directed mitral prolapse," which is a nice pithy way of saying it.
 * (a) Causes: genetic abnormalities in contractile proteins.
 * (b) Epidemiology: generally runs in families; occasionally it's a new mutation.
 * (c):
 * Anatomy: Thickening of the intraventricular septum.
 * Hemodynamic features: Asymmetrical left ventricular (septal) hypertrophy, mid-systolic murmur at the apex, increased left ventricle-aortic pressure gradient.
 * Clinical features: Similar to aortic stenosis: shortness of breath, chest pain, syncope or near syncope. Note a "notched" pulse (upstroke, downstroke, upstroke, all in one pulse).
 * The notched pulse is due to a brief period of acute occlusion, followed by increased flow through the tract as the ventricular pressure increases to a point where it can get fluid through even an obstructed valve.
 * (d) Treatment: beta blockers or calcium channel blockers to decrease contractility; surgical resection of the hypertrophied septum; avoidance of extreme exertion; ventricular pacemaker implantation.
 * Describe the presenting symptoms, signs and diagnostic approaches to acute pericarditis:
 * Presents with sudden onset of severe chest pain that varies with position and breathing.
 * Can hear a "rub" on auscultation.
 * Can see fluid in the pericardium on echocardiogram.
 * Shows up as nonreciprocal ST segment elevation-- that is, ST elevation on most or all surfaces of the heart, not a local area.
 * Responds to anti-inflammatories (NSAIDs).
 * Outline the clinical manifestations, diagnosis and treatment of cardiac tamponade
 * Presents as hypotension with distended neck veins.
 * Can diagnose on x-ray (enlarged heart, but without congested lungs as in heart failure) or echocardiogram (fluid around the heart).
 * This is interesting. There's a "paradoxical pulse" in pericardial effusion, in which the systolic pressure goes down (by 10 mm Hg or more) during inspiration.
 * Here's what normally happens: recall that right-sided filling goes up during inspiration due to negative thoracic pressure. Normally the heart expands its total volume (swells) to accommodate the extra fluid.
 * However, in cardiac tamponade, the heart can't expand (it's restricted by all the fluid around it) and thus the enlarged right heart pushes into the left heart instead, decreasing the stroke volume from the left ventricle and lowering the systolic pressure generated.
 * This seems kind of whack to me - how does a relatively small increase in filling cause the right, puny ventricle to bulge through the muscular IV septum to impinge on the left? - but there you go. Anyone want to send me their brilliant explanation, I'm listening.
 * You get an increased venous pressure because the right side of the heart is compressed and its diastolic filling is impaired (thus fluid backs up into the veins).
 * Treat with IV fluids (support ventricular filling) and pericardiocentesis (drawing blood from around the heart with a needle).
 * [Note from Lilly: look for a slowly falling, wide //v// wave on a venous pressure curve-- the right ventricle can't rapidly expand to admit more blood from the atrium.]
 * Note that you do __not__ use diuretics, as in congestive heart failure-- that'll make it worse by further limiting ventricular filling.

Pathology of Arterial and Venous Diseases Tuesday, April 01, 2008 4:11 PM


 * Pathology of Arterial and Venous Diseases, 4/2/08:**


 * [Whether or not she gets to this and the next lecture next week, it's gonna be on the boards, so might as well learn it now.]
 * Define "aneurysm" and list the type of aneurysms, their most common sites of involvement, etiologies and clinical associations
 * Aneurysm: localized abnormal vessel dilation due to weakening of the wall.
 * Berry aneurysms: due to congenital defects. Usually occur at the bifurcation of cerebral vessels; most common cause of spontaneous subarachnoid hemorrhage. Sometimes associated with polycystic kidney disease. Can present as a sudden headache.
 * Atherosclerotic aneurysms: most common type of aneurysm, associated with severe atherosclerosis of the aorta, usually in older men. Commonly located in the lower abdominal aorta below the renal arteries. Often asymptomatic, but can present as a pulsatile mass, and can lead to thromboemboli, dissection, and rupture.
 * Syphilitic aneurysms: Rare, since tertiary syphilis is also now rare. Involves inflammation of the proximal thoracic aorta, leading to a loss of elastic tissue and muscle, leading to dilation and aneurysm, with an option on aortic valve problems.
 * Handout: present as "asymptomatic mass" with "abdominal/chest pain," which I would have thought was a symptom. Learn something new every day.
 * Understand vessel dissection and know the predisposing causes of aortic dissection
 * Dissection: defect in the tunica intima allows blood into the wall of the vessel (usually the aorta). From there, blood can go back into the lumen, stay in the wall but run back into the pericardial sac (causing tamponade, see below), or rupture out into the mediastinum or retroperitoneum.
 * Recall that the wall of the aorta is contiguous with the pericardial sac. Thus if the blood gets out into the wall, it can run back into the sac, causing tamponade.
 * Aortic dissection occurs mainly in patients who are hypertensive (90+%) or have cystic medial necrosis (a weakening of collagen/elastin in large vessels) and/or Marfan's syndrome.
 * Know which vascular lesions are benign and malignant
 * Benign:
 * Granuloma Pyogenicum
 * Capillary Hemangioma
 * Cavernous hemangioma
 * Glomangioma
 * Malignant:
 * Angiosarcoma
 * Kaposi's Sarcoma
 * Describe the pathogenesis, pathology and main organs/vessels involved in temporal arteritis, leukocytoclastic vasculitis, polyarteritis nodosa, Wegener's granulomatosis, Churg Strauss syndrome and thromboangiitis obliterans
 * **Temporal** (giant cell) arteritis: granulomatous inflammation of carotid artery branches, particularly the temporal artery. __Most common arteritis__, usually shows up in elderly females as headache, tenderness, maybe visual symptoms.
 * **Polyarteritis nodosa** : necrotizing vasculitis of small and medium arteries. Affects kidney, GI, heart, but usually not the lungs. Usually hits middle-aged men, often with Hep B, often with positive p-ANCA antibodies.
 * **Wegener's** granulomatosis: necrotizing granulomatous inflammation of small and medium vessels. Hits the respiratory tract particularly hard, as well as the kidneys. Patients are mostly c-ANCA positive men.
 * **Churg Strauss** syndrome: necrotizing granulomatous inflammation of small arteries and veins. Causes asthma and eosinophilia, mainly in young adults-- manifests in lungs, spleen, heart, GI, and CNS (it's rare to see renal involvement).
 * **Leukocytoclastic** vasculitis: inflammation of arterioles, venules, and capillaries in the skin mucosa, thus shows up as palpable purpura. May be a hypersensitivity reaction to medications or infectious organisms.
 * **Thromboangiitis obliterans** : inflammation of the radial and tibial arteries. Often affects young male smokers, often causes thrombosis. Hard to tell from peripheral vascular disease or diabetes complication.
 * Note her classification of vasculitis based on size of vessels involved:
 * Giant cell/Takayasu (real big)
 * PAN/Kawasaki (big-medium)
 * Wegeners/Churg Strauss (medium-small)
 * Leukocytoclastic vasculitis (small-itty)
 * Note breakdown of necrotizing granulomatous dxs:
 * PAN: no lung involvement, renal involvement, p-ANCA+
 * Wegener's: lung/RT involvement, renal involvement, c-ANCA+
 * Churg-Strauss: lung involvement, no renal involvement, no ANCA
 * Note First Aid has a different opinion about ANCA involvement.
 * Describe the main causes of lymphedema
 * Lymphatic obstruction:
 * Primary: Familial Milroy's disease (primary cause, congenital fibrosis of the lymph vessels)
 * Secondary: Inflammation, malignancy, surgery, filariasis (parasitic infestation)

Pathology of Ischemic Heart Disease and Arterial/Venous Dx Tuesday, April 01, 2008 4:11 PM


 * Pathology of Ischemic Heart Disease and Arterial/Venous Disease, 4/2/08:**


 * Review the causes of ischemic heart disease and exacerbating factors in coronary atherosclerosis
 * 90+%: Coronary atherosclerosis.
 * Can lead to plaque rupture or coronary artery thrombosis
 * Worsened by CA vasoconstriction (vasospasm), platelet aggregation, or anything that decreases or slows blood flow (ie hypotension in shock).
 * Thyrotoxicosis (overly increased O2 demand due to elevated metabolic rate)
 * Anemia (decreased O2 carrying capacity)
 * Arteritis
 * Emboli
 * Cocaine
 * Know the pathogenesis of myocardial infarction and transmural vs subendocardial infarcts. Describe the factors that can influence the ultimate size of an infarct
 * Recall that an MI is irreversible myocardial necrosis due to ischemia, most commonly due to a coronary artery thrombus at the same site as a plaque.
 * MIs start in the subendocardium (most poorly perfused area of heart wall) and progress towards the epicardium over several hours-- a good window for intervention. Note that low blood flow is an exacerbating factor.
 * __Transmural__ infarct: infarcted across the entire thickness of the myocardium. Usually caused by thrombus plus plaque.
 * __Subendocardial__ infarct: infarcted only 1/3 to 1/2 the thickness of the wall. Usually caused by hypotensive episode plus plaque.
 * Ultimate extent of the infarct is determined by where the blockage is, how long the ischemia goes on, how much collateral circulatory supply there is, what the metabolic rate of the myocardium is, and how much reperfusion injury (free-radicals) takes place after oxygen supply is restored.
 * Note reperfused infarcts can cause hemorrhage out of damaged vasculature, acute inflammation, myocardial contraction due to calcium leakage in O2 radical-damaged cells.
 * Note most MIs (97+%) involve the left ventricle and septum, either alone or with right ventricular involvement.
 * Know that in acute MI irreversible changes take place by electron microscopy after 1-2 hours and after 4 hours by light microscopy
 * Ok.
 * [Good to know: coronary arterial supply to left ventricle in most people:]
 * Left Anterior Descending artery: supplies anterior wall and apex of the left ventricle, also 2/3 of the septum.
 * Right coronary artery: supplies posterior wall of the left ventricle, also the other 1/3 of the septum.
 * Left circumflex artery: supplies lateral wall of the left ventricle.
 * Know the chronologic sequence of morphologic light microscopic changes a) contraction bands & myocyte necrosis; b) neutrophilic infiltrates; c) macrophages; d) granulation tissue and e) fibrosis (weeks later)
 * Ok. Note this follows normal patterns (necrosis, neutrophil, macrophages, granulation tissue (type III collagen), scarring (type I collagen).
 * Note also that about 4-7 days after the MI occurs is the point of maximal softening-- so if you're going to get a ventricular aneurysm or rupture and bleed out, it'll probably happen half a week to a week after an acute MI.
 * List the complications of acute myocardial infarction and their clinico-pathological correlations
 * Arrhythmias
 * Left ventricular failure (pulmonary edema)
 * Cardiogenic shock (systemic reaction to hypotension) if enough of the ventricle is involved-- 40% seems to be the cutoff.
 * Can rupture or infarct papillary muscle, leading to mitral regurgitation.
 * Can rupture through the wall itself, usually in the week after the MI.
 * Thrombogenesis
 * Ventricular aneurysm
 * Pericarditis
 * Describe the pathologic findings in chronic ischemic heart disease and its clinical significance
 * Myocyte atrophy, interstitial fibrosis (caused by chronic hypoperfusion). Leads to contractile dysfunction. [Note can also lead to ventricular aneurysms, which are about as bad as you think they are.]
 * List the common causes of sudden death
 * Mainly, ischemic heart disease; some hypertrophic cardiomyopathy (athletes), mitral valve prolapse (this seems to be very rare if it happens at all), or aortic valve stenosis.
 * Also: drug-related, mostly cocaine; myocarditis; conductive abnormalities.
 * Describe the cardiac pathologic features of hypertensive (systemic) heart disease and cor pulmonale. Know the most common causes of cor pulmonale
 * Hypertension: leads to left ventricular hypertrophy (concentric). Also predisposes to atherosclerosis.
 * Cor pulmonale: right ventricular hypertrophy due to pulmonary hypertension. Acutely, often __caused by a large thrombus__ in the pulmonary arteries. Chronically, can be caused by COPD, interstitial fibrosis, or cystic fibrosis. Essentially, anything that blocks up the passage of blood through the lungs can give you cor pulmonale.

Peripheral Vascular Disease Thursday, April 03, 2008 9:28 AM


 * Peripheral Vascular Disease, 4/3/08:**


 * Understand the basic mechanisms of the major manifestations of vascular disease.
 * Atherosclerosis leads to arterial occlusive disease.
 * Alterations in the arterial wall lead to aneurysms and dissection.
 * Thrombosis leads to local occlusion of veins and to pulmonary emboli.
 * Describe the role of arterial stenosis or occlusion on limb hemodynamics that lead to symptoms of claudication and critical leg ischemia.
 * Well, arterial stenosis can lead to ischemia, particularly during exercise. Makes sense to me. For all the gory details, go back to this LO in Wallace's "Coronary and Skeletal Muscle Circulation" or do a find on "craptastic."
 * I think what he's getting at here is that in intermittent claudication, there's pain and hypoperfusion of the leg tissues with walking or exercise but not at rest..
 * ..Whereas in critical leg ischemia, the limited blood flow and pain occurs both at rest and during exercise. Really it just seems like a way of differentiating levels of severity.
 * Note that the symptoms (pallor, pain) get worse in CLI with elevation of the foot.
 * [Note ankle-brachial index-- a ratio of pressure in the ankle to that of the upper arm.]
 * Less than .90 is an accurate predictor of arterial occlusion in the lower limb.
 * Understand the major risk factors for aortic aneurysms and the role of aneurysm size on risk of rupture.
 * ["True" aneurysm: all three layers of the vessel are enlarging together.]
 * Risk factors: he mainly talks about abdominal aortic aneurysms (AAAs).
 * Age (older is worse)
 * Gender (male is worse)
 * Smoking (more is worse)
 * Family history of AAA (any is worse)
 * Pathogenesis:
 * The aortic wall can be weakened by decreased levels of elastin and collagen.
 * Inflammation can damage and weaken the aortic wall, as can the matrix metalloproteinases released by foam cells in atherosclerosis.
 * Biomechanical stress (hypertension, turbulent blood flow, wall thrombi) can also damage and weaken the aortic wall.
 * The bigger the AAA is, the more likely it'll rupture. At 5 m maximum diameter, you're looking at a 25% 5-year rupture rate (compared to 2% under 4 cm).
 * I find this morbidly amusing: "70% of patients are asymptomatic, then present with sudden death."
 * Describe the pathophysiology and consequences of aortic dissection.
 * Generally comes about either because of a tear in the tunica intima or a rupture of the vasa vasorum (arteries that supply the tunica layers). Blood pushes between the tunica layers and causes expansion (both out and into the lumen) there. Note that this is kind of like necrotizing fasciitis-- the blood can follow the line of least resistance down the aorta, making a long, spiraling dissection down the length of the aorta, blocking large arteries, causing strokes and ischemia, etc.
 * Note that this makes a 'false lumen' down the side of the aorta filled with blood. It can evidently be hard sometimes to distinguish it from the real McCoy.
 * Most aortic dissections present with __severe, tearing pain__. Note the difference from aneurysms, most of which are symptomatic before they kill you-- I mean, before you present with sudden death.
 * This disruption of circulation leads to:
 * Stroke
 * Syncope
 * MI
 * Intestinal ischemia
 * Renal failure
 * To treat, need to control pulse pressure (which affects the formation and enlargement of the 'false lumen') as well as overall blood pressure. Do this with beta-blockers, venodilators, ACE inhibitors, calcium channel blockers.
 * Surgically fix when it impinges on the aortic root, valve, or vital end organs.
 * Understand the primary factors that relate to venous thrombosis and the mechanisms of how thrombosis causes chronic venous insufficiency.
 * Main venous problem: thrombosis (low-pressure, high-volume system).
 * Note DVTs get worse when you stand on them.
 * The clot __destroys valves__ in the backed-up veins by stretching out the distal vasculature-- thus after a DVT you often get chronic edema and venous insufficiency in the distal parts of the affected limb, because the blood can't travel well back up into the heart without its valves.
 * __Virchow's triad__ of venous thrombogenesis: injury, static blood flow, hypercoagulable states.
 * Risk factors:
 * Surgery, trauma, MI, stroke, cancer (alter coagulation), paralysis, clotting disorders, previous history, immobilization, age over 40, pregnancy or birth control pills.
 * Note a lot of these take place in the hospital.
 * Goal here is to prevent the clot from forming, or failing that, to prevent it from going to the lungs or major vessels.
 * Clinically, mainly use heparin (acutely) and warfarin (chronically) to treat.

Ischemic Heart Disease I Thursday, April 03, 2008 9:31 AM


 * Ischemic Heart Disease I, 4/3/08:**


 * ["Ischemic heart disease" more or less = "coronary artery disease" more or less = "coronary heart disease."]
 * [Remember-- atherosclerosis is a continuum, not an absolute state. All of us have the first stage, 'fatty streaks,' in our arteries by this point in our lives. Or, shit, this is Colorado, so maybe all of you were born with nordic tracks in your hands and your arteries are clean as a whistle. I've earned a few fatty streaks, myself. Got at least five from one night at Port of Call on Esplanade sucking down those fantastic burgers. I think the air in New Orleans may be so full of lipids that just breathing it gives you fatty streaks. Best place on earth. Aside from the racism, crime, corruption, flood damage, incompetence, and economic stagnation.]
 * Understand risk factors for development of coronary atherosclerosis.
 * Treatable with proven effect of treatment:
 * Smoking (+50% risk of CAD):
 * Induces a hypercoagulable state
 * Contains directly endothelially injurious compounds
 * Induces vasospasm
 * Alters lipoprotein metabolism
 * Decreases oxygen content of blood
 * Hypertension (more is worse):
 * Chronic increases in shear stress cause direct endothelial injury and indirect injury through oxidant stress and cellular proliferation.
 * Note that normally, increased shear stress would cause NO production, causing vasodilation. With endothelial damage, on the other hand, NO can't be produced.
 * Chronic angiotensin, aldosterone, and NE release damage endothelium.
 * Left ventricular hypertrophy causes increased, chronic compression of coronary arteries.
 * Dyslipidemia:
 * Oxidized LDL in the vessel wall is nasty due to cytokine-mediated macrophage activation into MMP-producing foam cells. More LDL is bad.
 * HDL inhibits oxidation of LDL, stimulates NO in endothelium, transports LDLs out of the vessel wall, etc. It's the responsible cousin dragging its loser relative out of the scrapes he gets into. More HDL is good.
 * //Animal Farm// : "HDL goo-ood. LDL baa-aad." Everybody together now.
 * Treatable, but without proven effect of treatment:
 * Diabetes
 * Premature menopause
 * Obesity
 * Infection/inflammation
 * Psychological stress
 * Untreatable:
 * Being male
 * Being old
 * Genetics
 * [Recall that atherosclerosis is an inflammatory process- thus look for elevated C-reactive protein levels (though this is hardly specific to CAD).]
 * [Dr. Schwartz: "Angina pectoris is the cardinal symptom of coronary heart disease."]
 * Understand distinguishing features of the coronary circulation and the principle determinants of myocardial oxygen supply and demand.
 * Coronary circulation: can't rely on anaerobic metabolism, can't step up its oxygen extraction efficiency (always near maximum).
 * As mentioned by Dr. Wallace, the only way to increase O2 supply to coronary muscle is to increase its blood flow.
 * This occurs largely by autoregulation (myogenic and adenosine-mediated).
 * Recall that the left ventricle is perfused during diastole only (during systole the arteries are compressed in the ventricular walls). Recall also that the length of diastole is largely determined by heart rate.
 * Thus determinants of O2 supply:
 * Coronary blood flow rate (perfusion pressure, duration of diastole, vascular resistance in the coronaries)
 * O2 content of blood
 * And determinants of O2 demand (all make it go up):
 * Heart rate (ie duration of diastole)
 * Wall tension in left ventricle (a main source of ATP use in the heart wall is withstanding wall tension from inrushing blood in diastole)
 * Recall LaPlace: wall tension dependent on radius, inversely dependent on wall thickness.
 * Inotropic state
 * Understand key elements of pathophysiology and treatment of stable coronary heart disease.
 * Pathophys: Problem is that your O2 supply/demand ratio in the coronaries is out of whack. Chronically, this is the result of long-term problems with one, the other, or both.
 * Chronic stable angina, in particular, involves some chest pain associated with a particular, generally steady level of exertion.
 * Treatment: either you increase the supply of coronary O2 or you decrease the demand for coronary O2, or both.
 * Increase supply:
 * Prevent hypotension
 * Slow heart rate (beta-blockers)
 * Decrease coronary resistance (vasodilators)
 * Decrease demand:
 * Slow heart rate (beta-blockers)
 * Lower pressure load (vasodilators)
 * Lower inotropic function (Class II or IV antiarrhythmics)
 * Understand key elements of pathophysiology and treatment of unstable coronary heart disease (unstable angina or myocardial infarction).
 * Pathophys: same as chronic, but due to some acute situation:
 * __Unstable angina__: increase in chest pain, sometimes at rest, sometimes with mild exertion. The level of exercise required to prompt chest pain varies significantly. Caused by near-complete occlusion of coronary artery by a thrombus.
 * __MI__: Abrupt onset of chest pain, usually severe, usually constant. Look for symptoms related to decreased systolic function (shortness of breath) or sympathetic activation (sweating, pallor, anxiety).
 * __Markers__: inflammation of arterial wall (look for C-reactive protein levels), weakening of plaque wall, rupture of thrombogenic plaque contents, complete occlusion with thrombus, myocardial necrosis, etc.
 * [Get very rapid impairment of diastolic function first (no ATP, can't pump calcium back into the SR to relax the ventricle); a few minutes later, you get systolic dysfunction (depletion of phosphocreatines, acidosis).]
 * Treatment: early reperfusion (angioplasty, venodilators, etc, see next lecture)-- however, notice that reperfusion injury can still take place (accumulation of free-radical-generating compounds).
 * Note that after four hours myocardial ischemia is complete and irreversible (ie. total infarct of the affected area). Have about half an hour to reverse all damage.
 * Understand approaches to diagnosis and treatment using medications, catheter procedures, and/or surgery.
 * As mentioned, look for C-reactive protein levels (goes up in inflammation). Also look for troponins and cardiac creatine kinase (breakdown products of cardiomyocytes) when detecting MIs or myocardial injury.
 * The rest of this LO is covered in the next lecture.

Ischemic Heart Disease II Thursday, April 03, 2008 9:32 AM


 * Ischemia Heart Disease II, 4/3/08:**


 * Describe approaches to diagnosis of coronary artery disease.
 * History: Angina, dyspnea, risk factors. Note similarity to heart failure.
 * Examination: listen for bruits in large proximal arteries, particularly in the carotids. Listen for a fourth heart sound that indicates diastolic dysfunction.
 * EKG: Look for T wave inversion or Q waves at rest. Look for focal areas of ST segment depression during exercise vs. at rest.
 * Radiolabeled flow imaging improves sensitivity and specificity. Comparison allows differentiation between transient ischemia during exercise and permanent ventricular defects (infarcts).
 * Describe approaches to treatment with medications.
 * Treat dyslipidemia and endothelial dysfunction: statins.
 * Treat thrombogenesis: aspirin.
 * Treat chest pain: nitrates, beta-blockers, Ca++ channel blockers.
 * Prevent __recurrence__ of MIs: beta-blockers, ACE inhibitors, statins, aspirin.
 * Describe approaches to coronary angioplasty and stents.
 * Advance a catheter into the blocked vessel, pop it open with an inflatable balloon, place a wire stent to keep the vessel open (stent is coated with anti-proliferation drugs such as paclitaxel), get the catheter out. Tell patients to take low-dose aspirin and stop eating bacon.
 * Describe approaches to coronary bypass surgery (CABG).
 * Essentially you find a spare vessel in the body, preferably arterial, preferably nearby (usually the internal thoracic artery, failing that the small saphenous vein). If it's the internal thoracic artery, stitch it onto the left anterior descending artery and leave the other end attached to the subclavian artery. If it's the saphenous vein, stitch one end onto the aortic root and the other onto a coronary artery of your choice.
 * Note that all prosthetics tried thus far clot off and are therefore not useful for this.
 * Generally CABG is indicated in:
 * Left main coronary artery stenosis (occlusion during stenosis could be fatal)
 * Three-vessel coronary artery disease (LAD, right coronary artery, left circumflex are all occluded)
 * "Lesions with difficult anatomy"
 * Describe approaches to case studies.
 * Go read 'em.

Cardiac Embryology- Fetal/Newborn Circulations Saturday, April 05, 2008 8:09 AM


 * Cardiac Embryology- Fetal/Newborn Circulations, 4/4/08:**


 * Name the 4 main regions of the heart present during the 4th week of development, and describe how the orientation of these regions shift during heart looping
 * Bulbus cordis (primitive outflow tract, sort of), ventricle (next to the bulbus cordis), atrium (next to the sinus venosus), and sinus venosus (primitive inflow tract).
 * Heart looping:
 * Basically the whole arrangement grows a bit and the atrium/sinus venosus moves dorsally (behind) and to the left, while the ventricle/bulbus cordis moves ventrally (in front) and to the right. **V** entricle moves **v** entrally.
 * Imagine a slug trying to kneel down and you've probably got it.
 * Note that the heart can 'loop' the wrong way (atrium goes right, ventricle goes left)-- called 'dextrocardia' and is, by itself, innocuous.
 * Describe how and when the left and right atria are separated.
 * Begins in week 4, finished by week 5.
 * Septum primum- first barrier, grows down between atria with a window in it.
 * (Technically there are two windows- the ostia primum and secundum. The ostium primum seals off. The ostium secundum sticks around to form part of the oval foramen.)
 * Seals with the endocardial cushions (see below) that form the atrioventricular septum/canal.
 * Septum secundum- second barrier, grows down between atria with another window in it.
 * Together, they work as a valve to allow blood to go from the right side to the left, but not left to right.
 * Oval foramen is the canal that runs through the two.
 * The whole point of this brouhaha is to minimize unnecessary fetal circulation to the lungs (they're not being used anyway).
 * Describe when and how the endocardial cushions grow to bisect the atrioventricular canal
 * Week 5:
 * Cushions: mesenchymal 'bulges' (derived from neural crest) covered by epithelium.
 * They grow out of all four sides, but only the superior and inferior fuse, leaving spaces to the left and right (the left and right cushions form the AV valves).
 * Describe how and when the truncus arteriosus is subdivided into the pulmonary and aortic outflow tracts
 * (bulbus cordis: divided into truncus arteriosus and conus cordis. Conus cordis forms large part of right ventricle; truncus arteriosus forms both outflow tracts.)
 * Truncus arteriosus:
 * At 4 weeks: a single outflow tract.
 * More endocardial cushions form here, push towards each other, and fuse in the middle, leaving separate tracts by 6 weeks for the pulmonary and aortic outflows.
 * This is important: the conotruncal cushions we've been talking about __spiral__ as they grow together and as they move down the truncus. What this seems to mean is that when they're done, the pulmonary tract is connected to the primitive right ventricle, and the aortic tract is connected to the primitive left ventricle. This makes sense if you think about it; the pulmonary artery is located to the left of the ascending aorta but is connected to the right ventricle, so something had to twist around to get that to happen. If this twisting doesn't happen, the fetus pumps aortic blood out of its right ventricle, generally causing it to die in the first month postpartum.
 * Describe the components of the embryonic heart that contribute to septation of the ventricles, and identify when this separation occurs
 * Week 5:
 * The components that contribute: mainly the __muscular__ wall of the ventricle itself, at the bottom (er.. caudal?). That portion of the ventricular wall sends a growth up towards the atrioventricular septum.
 * Note that there's also a smaller, later, __membranous__ part that forms after the muscular part's almost sealed off the two ventricle. It is of unclear origin, which means that about all we need to know about it is that it forms after the muscular part and that it's membranous.
 * Ventricles are fully separated by 7 weeks.
 * [By 8 weeks both the outflow tracts and ventricles are completely segregated right vs. left.]
 * Identify which aortic arch vessels are lost, and which are maintained by 8 weeks gestation, and what are the anatomical names of the remaining vessels
 * Aortic arch vessels: 1-4, 6. Note that each named arch comes out of its same-named pharyngeal pouch.
 * 1 and 2: mainly lost (wind up as parts of the maxillary and stapedial-hyoid arteries).
 * **3** :
 * ventral component forms part of the common carotid
 * dorsal component forms part of the internal carotid.
 * **4** :
 * right portion gives rise to part of the right subclavian
 * left portion gives rise to part of the aortic arch
 * **6** :
 * right portion gives rise to part of the right pulmonary
 * left portion gives rise to part of the left pulmonary and the ductus arteriosus
 * Identify 2 components of fetal cardiac circulation which are no longer patent after birth:
 * Oval foramen (between right and left atria)
 * Ductus arteriosus (between aorta and pulmonary arteries)
 * (Ductus venosus in the liver)

Lipids, Lipoproteins and Atherosclerosis I Sunday, April 06, 2008 8:21 AM


 * Lipids, Lipoproteins and Atherosclerosis I, 4/7/08:**


 * Describe the steps in the pathogenesis of the atherosclerotic plaque and the role of lipids and lipoproteins in this process.
 * (1) Disruption of endothelial function: the endothelium gets damaged by excess shear stress (chronic turbulent flow or hypertension) or some toxic agent (excess oxidants, elements in cigarette smoke, chronic high blood glucose in diabetes). This screws with the ability (recall "Endothelial Function") of the endothelium to produce NO and preserve a tight barrier.
 * (2) Lipid migration into the sub-endothelial space: Because the barrier's not as tight as it used to be, circulating lipoproteins (carrying lipids) can work their way between the endothelial cells and migrate into the sub-endothelial space. There they become modified by oxidation (if there's a high level of free oxygen radicals about) or glycation (if there's a lot of excess blood sugar about, as in diabetes).
 * (3) Inflammatory response: Lipid isn't really supposed to be in the sub-endothelial space, particularly not oxidized or glycated lipid. The sub-endothelium activates cytokines that call monocytes from the bloodstream to come take care of ('scavenge') the offending particles.
 * Lilly makes a point that the type of monocyte response prompted by this kind of cytokine signaling ('scavenging') is subtly different from normal monocyte lipid pickup. Lipid 'scavenging' takes place through a receptor that lacks a negative feedback mechanism, allowing the monocyte (once in the tissue, called a macrophage) to really engorge itself with lipid molecules. This has unfortunate consequences, specifically the activation of inflammatory cytokines and the release of matrix metalloproteinases (MMPs).
 * (4) Smooth muscle cell proliferation: no longer kept in check by NO, and stimulated by inflammation, the nearby smooth muscle infiltrates the plaque, making it grow in size and further obstructing the lumen. These smooth muscle cells can die inside the plaque, stimulating fibrosis and scarring of both themselves and surrounding endothelial tissue-- and fibrosis, recall, is essentially the formation a big plug of linked collagen. This becomes a problem when you realize that foam cells are generating matrix metalloproteinases that break down collagen.
 * (5) Rupture: if there's enough of a pro-inflammatory reaction within the plaque, there are sufficient proteinases to start to chew through the 'cap' of endothelium. Once this is completed, the lipids and foam cells can spill out into the bloodstream, being both emboli themselves and also intensely thrombogenic.
 * Note that plaques don't always have to progress to rupture-- you can have big plaques that obstruct the lumen without rupturing. These are mainly a problem when you throw a relatively small clot into an already largely occluded vessel like a coronary artery. You can also have small plaques that rupture anyway.
 * Once again: LDL baa-aad, HDL goo-ood. LDL builds up inside the plaque. HDL removes it. See next LO.
 * List the main classes of lipids and describe their relative polarities.
 * 5 main classes of lipids:
 * From most polar to least polar:
 * Fatty acids
 * Phospholipids
 * Cholesterol
 * Cholesterol esters*
 * *Note that he goes back and forth a bit between cholesterol and cholesterol esters. I gather that the important detail is that it's harder for cholesterol ester to go anywhere once it's esterified (very very hydrophobic), while cholesterol can be more easily transported (important for LDL-HDL lipid shift). Note that HDL can pick up cholesterol and then esterify it to make sure it's good and bound to HDL for transport back to the liver.
 * Triglycerides
 * The ones we're particularly interested in here are the **cholesterols** and **triglycerides**, since these are the very non-polar particles that the body uses specialized transport mechanisms to get through the bloodstream.
 * Lipoproteins: ways that the body moves non-polar lipids through the bloodstream. Phospholipid on the surface, but can contain much more non-polar lipids (cholesterol and cholesterol esters, and triglycerides) inside.
 * Note also 5 main classes of lipoproteins:
 * **Chylomicrons** : made in GI tract from dietary fat after meals; have mainly triglyceride with some cholesterol ester (10:1 ratio)
 * Very-Low-Density Lipoproteins (**VLDL** ): made by the liver to deliver triglycerides to tissues, mainly between meals; have a slightly lower ratio of triglyceride to cholesterol ester (5:1).
 * Remnant particles and Intermediate-Density Lipoproteins (**IDL** ): byproducts of chylomicron and VLDL metabolism. Contain roughly equal amounts of triglyceride and cholesterol ester (1:1).
 * Low-Density Lipoproteins (**LDL** ): byproducts of VLDL metabolism. They have more cholesterol ester than they do triglyceride; the higher this ratio is, the smaller and denser they become. They are atherogenic, particularly as they get smaller and denser (more cholesterol content = more atherogenic). They're cleared from circulation by the liver.
 * High-Density Lipoproteins (**HDL** ): proteins that transport cholesterol ester back from the tissues to the liver. They can also pick up cholesterol and other lipids from other lipoproteins. They thus aid in transporting cholesterol out of LDLs in plaques and are inversely correlated with atherogenic risk.
 * Note that high triglycerides correlate with low HDL cholesterol levels, probably because the HDL particles get preferentially loaded up with triglycerides and get recycled back to the liver instead of sticking around to circulate and pick up cholesterol from LDL.
 * List the functions of apo-lipoproteins and give examples of each.
 * (1) __Structural backbone__ of lipoproteins-- stretches of hydrophobic regions (to bind lipids) and stretches of hydrophilic regions (to interact with water-based bloodstream environment).
 * Examples: apoB48 for chylomicrons, apoB100 for VLDL/LDL, apoA1 for HDL.
 * (2) __Enzymatic co-factors__-- help lipoproteins acquire or dispense the lipids they carry.
 * Example: apoC2 allows chylomicrons to offload their triglycerides into tissues (more on this below); without it, you get very high triglyceride blood levels.
 * (3) __Ligands__-- allow lipoproteins to be recognized by receptors.
 * Examples: apoB100 allows LDL to be taken up into hepatocytes, apoE allows remnant particles to be picked up and cleared.
 * (4) __Something to do with atherosclerosis__-- about as exact as it sounds. Research is ongoing.
 * Example: "apo(a) (little a)" (wtf?)
 * Describe the Chylomicron, VLDL, and HDL pathways.
 * (These are all pathways of lipid metabolism:)
 * __Chylomicron pathway__:
 * Dietary triglyceride is hydrolyzed in the intestine to monoacylglycerol and free fatty acids, diffuse/transport across the membrane, and are reassembled into triglycerides again and packaged into chylomicron particles. These chylomicrons pick up apolipoproteins (apoC2 and apoE) from HDL that allow them to offload their cargo.
 * The chylomicrons travel through blood vessels in certain tissues (adipocytes, muscle cells), the endothelial surface of which contains an enzyme called **LPL** (lipoprotein lipase). LPL uses apoC2 (as mentioned above) as a co-factor to offload the bound triglycerides and uptake them for storage.
 * What's left after this: smaller (triglyceride-depleted) remnant particles, taken up by the liver.
 * Note that chylomicrons and remnant particles aren't generally found in the bloodstream during a fasting state.
 * __VLDL pathway__:
 * VLDL is synthesized by the liver to transport stored lipids to tissues, as mentioned, and it has a lower triglyceride to cholesterol ratio than chylomicrons.
 * That said, its catabolism at the tissue endothelium is pretty much the same-- it acquires apoC2 and apoE from circulating HDL and offloads its triglycerides through the apoC2-LPL pathway.
 * The result of this offloading is LDL, which are relatively cholesterol-rich lipoproteins from which most of the triglycerides has been extracted.
 * LDL is generally cleared by the liver and the cholesterol is re-uptaken there.
 * Or, germane to the discussion at hand, they can get stuck going under a damaged endothelium.
 * __HDL pathway__:
 * HDL is backwards from the others; instead of bringing lipids out to tissues, HDL functions to bring lipids back to the liver. Synthesized by the liver and intestine, HDL circulates, picking up cholesterol from cells or other lipoproteins. It also, as mentioned, donates apolipoproteins to VLDL and chylomicrons. Note that, under conditions of high triglyceride levels, HDL will actually offload its cholesterol into VLDL in exchange for those triglycerides, then return to the liver to be recycled (which is presumably why you see both decreased HDL and increased atherosclerotic risk in patients with high triglyceride levels).
 * List the relationship between each lipid class and cardiovascular risk.
 * LDL: high levels increase risk for cardiovascular disease and are involved with atherosclerosis, plus we've got a reasonably good biological explanation for it. Lots of good evidence for risk reduction by lowering LDL levels.
 * Triglycerides: high levels __sometimes__ increase CV disease risk, for unknown reasons. Not much evidence for risk reduction by lowering triglyceride levels.
 * HDL: low levels __sometimes__ increase CV disease risk, probably due to decreased cholesterol efflux out of nascent and established plaques. Not much evidence for risk reduction by raising HDL levels.

apoB48: chylomicron backbone apoB100: VLDL backbone, receptor ligand for uptake into liver apoE: receptor ligand for remnant particles for uptake into liver apoC2: enzymatic co-factor for LPL breakdown of chylomicrons/VLDL at tissue endothelium

Lipids, Lipoproteins and Atherosclerosis II, 4/7/08

Sunday, April 06, 2008 8:25 AM


 * Lipids, Lipoproteins and Atherosclerosis II, 4/7/08:**


 * Describe and be able to use the Friedwald equation for estimating LDL cholesterol levels.
 * Tough to directly measure LDL, so use indirect methods using parameters it's easier to measure.
 * Can easily measure total cholesterol and HDL levels; can also easily measure triglyceride levels, which gives a good indication of VLDL levels __as long as no chylomicrons are present__ (thus need to take these levels during a fasting state) __and the total triglycerides are under 400 mg/dL__.
 * Since total fasting cholesterol = HDL + LDL + VLDL, and triglycerides are related to VLDL levels:
 * **Friedwald** :
 * total LDL = total cholesterol - HDL - (triglyceride levels / 5)
 * List the cardiovascular risk factors used in the NCEP ATPIII risk stratification scheme and describe the process of risk stratification.
 * Age (for males, 45+ years; for females, 55+ years)
 * History (coronary heart disease in male first-degree relative < 55 years, or in a female first-degree relative < 65 years)
 * Current cigarette smoking
 * Hypertension (140/90 or higher, or on anti-hypertension meds)
 * Low HDL concentration (< 40 mg/dL)
 * Note that high HDL (> 60 mg/dL) is an 'anti-'risk factor.
 * Essentially you score a person based on these criteria, then if they have 2 or more of these risk factors, you also throw in a 10-year risk based on Framingham Study data.
 * List the LDL cholesterol targets for each risk category.
 * 0-1 risk factor: goal of 160 mg/dL LDL.
 * 2+ risk factors:
 * With a 10-year risk of less than 10%: goal of 130 mg/dL
 * With a 10-year risk of 10-20%: goal of 100 mg/dL
 * With a 10-year risk of more than 20%, or for patients that have atherosclerotic disease or diabetes ("CHD equivalents"): a sort-of goal of 100 mg/dL, but really a goal of 70 mg/dL (indecisive cardiologists).
 * Describe the use of "non-HDL" cholesterol targets for treating patients with high triglyceride levels.
 * Basically you set a goal that the total cholesterol, minus the HDL levels, will be 30 mg/dL above the LDL goal for that individual.
 * So in a guy with high triglycerides, with total cholesterol of 250 and a HDL level of 50, with a LDL goal of 130 mg/dL, you want him to get the non-HDL cholesterol to (130 + 30 = ) 160 mg/dL. Right now it's at (250 - 50 = ) 200 mg/dL.
 * The point is that you don't want to treat hyperlipidemic patients by lowering their HDL. This should be fairly self-evident by this point.
 * (side point: high triglycerides can lead to pancreatitis, possibly by overworking the thing.)
 * Describe the role of the following drugs in treating hyperlipidemia including side effects: statins, bile acid binding resins, ezetimibe, fibrates, fish oils and niacin.
 * Statins, bile acid binding resins, ezetimide: LDL medications.
 * Fibrates and fish oil: triglyceride medications.
 * Niacin: combination LDL/triglyceride/HDL medication.
 * **Statins** : inhibit HMG CoA reductase (full name: hydroxy-methylglutaryl CoA reductase), which is the rate-limiting enzyme in cholesterol synthesis. When cholesterol synthesis is inhibited, the liver upregulates LDL receptors in order to reuptake more LDL and thus more cholesterol for its processing/packaging functions. Essentially statins decrease LDL levels (recall they also, by another mechanisms, increase NO production in endothelia). Good evidence that statins reduce CVD risk.
 * Side effects of statins: liver toxicity, myositis (muscle inflammation-- particularly when co-administered with fibrates).
 * Contraindicated in pregnant/nursing women.
 * **Bile acid binding resins** : another mechanism for lowering cholesterol levels in the liver; this one decreases the bile salts that are how cholesterol is circulated in the liver. The liver then increases LDL receptor level expression, as before, and results in decreased LDL levels in the blood. Not as effective as statins; a second-line treatment.
 * Side effects: these taste like sand and can cause headache and GI upset. Can also inhibit uptake of other meds.
 * **Ezetimibe** : blocks cholesterol absorption by the GI tract. Functions synergistically with statins (together, cut LDL in half, raise HDL 7-9%, lower triglycerides by a quarter), so generally used in combination with statins if statins alone don't do the trick. But note contraindications (pregnancy, nursing, liver disease).
 * **Fibrates** : good for lowering triglycerides (20-40%). Side effects include GI upset and some increase in liver activity (as measured by liver function tests). Taken with statins, increase the risk of muscle inflammation (myositis).
 * **Fish oils** : also good for lowering triglycerides, due to high omega-3 fatty acid content (at 3-12 g/day). Side effect: you start to smell like a wharf.
 * **Niacin** : lowers LDL, lowers triglycerides, raises HDL (at 1-3 g/day). Mainly used to raise HDL. Side effects include flushing (attenuated by aspirin) and increased blood glucose, as well as potential GI upset and vomiting. Also minimal evidence one way or the other about its effects on morbidity/mortality of CVD.

Don't use statins in pregnant/nursing women or liver disease. Ezetimibe: blocks LDL absorption. Fibrates/fish oil: triglyceride lowering.

Pathology of Myocarditis and Specific Muscle Heart Diseases Monday, April 07, 2008 10:32 AM


 * Pathology of Myocarditis and Specific Muscle Heart Diseases, 4/7/08:**


 * List the three (3) major functional patterns of cardiomyopathies and describe for each the major pathologic changes present in the heart and the basic underlying mechanism for eventual heart failure.
 * As mentioned before: dilated, hypertrophic, restrictive.
 * Dilated CM: impaired contractility (systolic). The ventricle is.. what's the word.. poofed out and bigger but not thicker.. oh, it'll come to me.
 * Hypertrophic CM: impaired compliance (diastolic). The ventricle is thicker but not wider.
 * Restrictive CM: impaired compliance (diastolic). The ventricle doesn't change thickness or width, but gets very inflexible (often due to scarring/fibrosis).
 * List at least six (6) known factors associated with dilated cardiomyopathy.
 * Alcohol
 * Peripartum status (around the time of delivery)
 * Chronic anemia
 * Myocarditis
 * Hemochromatosis
 * Sarcoidosis
 * Describe the basic pathologic changes present in myocarditis.
 * More or less what you'd expect from inflammation of the myocardium-- inflammatory infiltrate, myocyte necrosis, fibrosis.
 * List the multiple sub-types of myocarditis presented and briefly describe the assumed pathogenesis for each.
 * Drug-induced: hypersensitivity vs. toxic.
 * Hypersensitivity: not dose-related; see eosinophils, no myocyte damage.
 * Toxic: dose-related, myocyte damage under electron microscope.
 * Giant cell myocarditis: lots of granulomas and necrosis. Idiopathic.
 * (Obviously can also be infectious, usually viral.)
 * Describe the basic pathogenesis and pathologic changes in the heart associated with hemochromatosis and sarcoidosis.
 * Hemochromatosis: excessive iron deposition in tissues. Causes thickened, brown ventricles. Caused by either genetic defects or multiple transfusions. Can lead to hypertrophic and dilated ventricular patterns.
 * Sarcoidosis: systemic granulomatous disease. Infrequently symptomatic, can get right heart overload due to granulomas in lungs. Granulomas can show up in heart but are difficult to detect by biopsy.
 * Briefly discuss the major underlying cause associated with hypertrophic cardiomyopathy and the major pathologic findings seen in the hearts of patients with this disease.
 * As mentioned ("Myocardial/Pericardial Disease"), this is hypertrophic obstructive CM (HOCM), an asymmetrical septal enlargement that causes outflow tract obstruction with one of the mitral valve leaflets.
 * Look for hypertrophic ventricle, particularly in the septum. No kidding, huh?
 * List several diseases known to be associated with restrictive cardiomyopathy and describe the basic pathogenesis and major pathologic changes found in one of these: amyloidosis.
 * Radiation-induced fibrosis, amyloidosis, malignancies.
 * Amyloidosis: extracellular protein deposition, showing up as amorphous and eosinophilic. Results in decreased compliance, predisposition to arrhythmias, sudden death, and a low-amplitude EKG.
 * Describe the major underlying causes of pericarditis and the basic pathologic changes associated with it.
 * Causes;
 * Viral infections
 * MIs/cardiac surgery
 * Radiation
 * Uremia (kidney failure)
 * SLE
 * Malignancy
 * Looks like what you'd expect-- an inflammation of the pericardium.
 * Describe major differences between a pleural effusion transudate and exudate.
 * Transudate: non-inflammatory, low protein content, not many cells in it. See it in hypoalbuminemia or cardiac failure.
 * Exudate: inflammatory, high protein content, lots of cells in it. See it in infection or malignancy.

Dilated CM: alcohol volume overload (peripartum, anemia) too much iron (hemochromatosis) inflammation of the myocardium sarcoidosis (why not?)

Hypersensitivity: not dose-related, eosinophils Toxic: dose-related, no eosinophils

Amyloidosis: extracellular protein deposition in the heart wall. Restrictive CM.

Treatment of Angina Sunday, April 06, 2008 10:26 AM


 * Treatment of Angina, 4/7/08:**


 * Understand what the different types of angina are (stable, variant, etc.), as this is central to the type of antianginal therapy utilized.
 * **Stable angina** : generally caused by a fixed coronary blockage leading to insufficient O2 supply under conditions of increased demand (usually exercise).
 * Recall that stable angina tends to come on at a given, relatively steady level of exertion.
 * **Variant angina** : caused by vasospastic constriction of the coronary artery/arteries, also leading to insufficient O2 supply.
 * Note can be caused by drugs such as cocaine (damages endothelial walls).
 * Note can sometimes get ST segment __elevation__ (not depression).
 * Can sometimes induce with chemical agents to verify diagnosis.
 * **Mixed angina** : a mixture of stable and variant angina.
 * **Unstable angina** : a near (but not quite) complete occlusion of a coronary artery, often due to a thrombus getting stuck at a plaque location or a plaque rupture.
 * Clinically, presents as worsening (crescendo) angina in addition to pre-existing stable angina, or new angina brought on by minimal exertion, or angina at rest.
 * **Silent angina** : asymptomatic O2 insufficiency in the heart; can be detected by EKG or (as we all learned in PBL-- hopefully you didn't kill her like we did) a stress test.
 * [Note that ACh, when applied to a coronary vessel in which the endothelium has been damaged, actually causes vaso__constriction__ vs the normal dilation. So if your endothelium is pretty beat up, even in the absence of atherosclerotic plaques, you can get variant angina anyway. Not sure why this happens, but it's important.]
 * Understand the concepts of cardiac supply and demand. Know the factors that contribute to each of these.
 * This should be fairly old news by now.
 * O2 **supply** to myocardium: related to blood flow and O2 content of that blood, since O2 extraction in the heart always runs more or less at maximum (50-65%). Blood flow is regulated mainly by __vascular tone__ and __length of diastole__; O2 content is largely about effective __hemoglobin levels__.
 * Recall that the main determinant of coronary vascular tone is the adenosine content in the myocardium supplied by those arteries.
 * Note that a whole host of other factors influences coronary vascular tone as well, including NO, bradykinin, prostacyclin, endothelins, TXA2, NE, etc. Recall that NO synthesis is dependent on an intact endothelium-- thus in the presence of atherosclerosis, a coronary artery can go into vasospasm and/or increase thrombus generation.
 * Also note that blood supply to coronaries mostly occurs during diastole, and the length of diastole is regulated by heart rate.
 * O2 **demand** in myocardium: determined by wall tension, heart rate, and inotropic state.
 * Recall that wall tension in turn is primarily regulated by preload (more preload, more O2 consumed in maintaining the integrity of the ventricular wall).
 * Understand the rationale for using each of the three major pharmacological classes of antianginal agents and their mechanism(s) of action. **This is the "primary" learning objective.**
 * **Nitrates** :
 * Work by acting as nitric oxide donors to blood vessels, dependent on the presence of sulfhudryl (-SH) groups. Note two things:
 * (1) This mechanism is not dependent on the endothelium being intact
 * (2) The -SH groups in a vessel can become depleted, thus rendering the cell 'tolerant' to nitrate agents. This becomes important in dosing.
 * Despite the fact that coronary vascular resistance goes down, systemic (thus diastolic) blood pressure also goes down (thus reducing coronary filling); you would expect them to sort of balance out without a lot of coronary improvement, but in fact you do see a clinical benefit.
 * The reason for this seems to be a combination of the increased blood flow through the dilated vessels and a relative decompression of those vessels due to a decreased ventricular wall tension/pressure (due, in turn to the decrease in preload that results from decreased venous resistance).
 * Main nitrates: nitroglycerin, isosorbide dinitrate, isosorbide-5-mononitrate.
 * __Nitroglycerin__ is taken sublingually and has both a very rapid effect (less than 5 minutes) and a very short half-life (less than 30 minutes).
 * You want to worry about tolerance. If the -SH groups are depleted and the nitrate is withdrawn, the patient can go into withdrawal and vasoconstrict (not what you want in angina), raising MI risk.
 * Isosorbide dinitrate (__ISDN__): can be dosed sublingually or orally-- orally, it's extensively metabolized by first-pass effects. However, that route produces an active metabolite, ISMO (see next point).
 * Isosorbide-5-mononitrate (__ISMO__): metabolite of ISDN with a longer half-life (4-6 hours). Also can be dosed, either by itself or in ISDN form, as a sustained-release once-a-day formation.
 * Apart from its compliance benefits, sustained release is nice because the release rate changes to prevent development of nitrate tolerance.
 * Take-homes for nitrates (see if all of these seem intuitive):
 * Decreases preload (venodilation) and afterload (vasodilation)
 * Decrease in preload is the main effect.
 * Dilates epicardial vessels and decreases compression of subendocardial vessels due to ventricular wall tension
 * Increases perfusion of subendocardium
 * __Can cause hypotension and tachycardia__ (baroreceptor reflex responding to lowered blood pressure-- can counter with beta-blockers)
 * Develop tolerance very quickly-- thus need intermittant dosing.
 * **β-blockers** :
 * You probably know how they work by now. Blocking beta-1 receptors in the heart reduces heart rate and contractility, thus decreasing the oxygen consumption of the myocardial cells (decrease O2 demand). The decrease in heart rate also increases the duration of diastole, which allows greater coronary perfusion. The decrease in blood pressure reduces transmural ventricular stress, which also lowers O2 demand.
 * Watch out for blockers that block beta-2 as well as beta-1 (non-specific) -- can get systemic vasoconstriction due to accentuation of alpha-1 tone in peripheral vasculature. Can also get bronchoconstriction (beta-2s cause bronchodilation).
 * Recall also that some beta-blockers have a particularly negative inotropic effect, while other don't as much due to their maintenance of a certain level of sympathetic activation (that is, they activate the receptors they block; this is called __intrinsic sympathomimetic activity__ or ISA).
 * Main beta-blockers to consider here: propranolol and metoprolol.
 * Propranolol: non-selective beta-blocker (betas 1 and 2) with no ISA and profoundly negative inotropic effects. Thus results in a big drop in heart rate and contractility.
 * It's absorbed well with about a 30% bioavailability, and has a half-life between 3 and 6 hours.
 * Watch for the beta-2-blocking side effects mentioned above.
 * Note that you __don't want to use__ very negatively inotropic beta-blockers (like propranolol) in patients with heart failure.
 * Metoprolol: selective beta-blocker (beta-1 only). This is handy in patients with heart failure, presumably since you avoid the vasoconstriction and decreased lung function. Still not much ISA to speak of, but much less frankly negative inotropic effects than propranolol.
 * Take-homes for beta-blockers:
 * Consider whether or not an agent has ISA/is negatively inotropic
 * Consider whether or not an agent is beta-1 selective
 * Decrease heart rate, increase duration of diastole, reduce VO2 of heart
 * Stabilize membranes, anti-arrhythmic
 * Can be very negatively inotropic, frequently at least somewhat negatively inotropic (careful in patients with CHF-- recall, usually improve mortality but can worsen symptoms)
 * Generally show __AV block__ (careful in combination with digitalis or calcium-channel blockers)
 * Watch out for coronary vasospasm and asthma (beta-2 blockade) as well as intensity of insulin-induced hyperglycemia (no ideas why on that one)
 * Note propranolol can cause an increase in serum triglycerides and a lowering in HDL.
 * (to sum: propranolol can screw your triglycerides, raise your blood glucose, slow down your AV pacing, send your CHF patient into cardiac failure, and induce vasospasm, angina, and asthma. You see why we don't use it as much anymore.)
 * **Ca++ channel blockers** :
 * Remember these-- can slow down cardiac pacing APs, thus slow heart rate; can also decrease contractility. All of them reduce peripheral vascular resistance (act on vascular smooth muscle calcium channels), including in the coronary arteries.
 * Incidentally, turns out that L-type calcium channels in myocardium and L-type calcium channels in vascular smooth muscle are actually a little bit different. Second-generation CCBs can be tuned specifically to vascular effects and away from cardiac effects, which can be extremely handy.
 * In general, __CCBs (with nitrates) are the drugs of choice to treat variant angina__ (recall that's the kind due to vasospasm, not plaque blockage).
 * Main CCBs: dihydropyridines (DHPs), phenylalkylamines, benzothiazepines.
 * Tend to sort these out by their relative effects on the heart (heart rate and contractility effects).
 * Can take all of them orally or IV.
 * __DHPs__: prototypical is **nifedipine**.
 * Notice that the second-generation drug mentioned above is a DHP called **amplodipine** -- has an extremely long half-life (36 hours) and has minimal cardiac effects (thus safe to use in systolic-dysfunction patients).
 * __Phenaklyamines__: prototypical is **diltiazem**.
 * __Benzothiazepines__: prototypical is **verapamil**.
 * Heart rate decreases:
 * Verapamil is stronger than diltiazem is stronger than nifedipine.
 * Contractility decreases:
 * Verapamil is stronger than diltiazem is stronger than nifedipine.*
 * *Note French corrected Port on this one on Friday.
 * [Note verapamil is kind of scary strong. Seems to be due to its peculiar binding mechanism.]
 * Therefore if you're cool with your agent slowing down heart rate and contractility (an effect partially offset by the activation of baroreceptors), diltiazem and verapamil are fine. If not, might think about using nifedipine or some other -dipine instead.
 * Understand the reasons to use each type of agent (see above) depending on the type of angina.
 * Nitrates are generally useful for most types of angina (stably, nitroglycerin; unstably, probably once-a-day ISMO or ISDN), but it's also beneficial to add a second agent if nitrates alone aren't sufficient. What you want to consider is which one to use:
 * In unstable angina, you generally want to hit the patient with nitrates **plus aspirin and heparin**, then follow with beta-blockers; if there's some particular reason not to use beta-blockers, you can use CCBs instead. Note follow-up with other anti-platelet agents (ADP/gp blockers) and LMW heparin. Note also, of course, that you want to either cath them or use fibrinolytic agents pronto.
 * In chronic angina where the key issue is elevated O2 demand in the face of a fixed O2 supply (classic stable angina), probably want to use beta-blockers to bring down myocardial VO2.
 * In chronic angina where the issue is coronary tone (classic variant angina), probably want to use CCBs to dilate arteries.
 * Understand the fundamental basis for combination therapy, e.g., appropriate reciprocal effects.
 * I think what he's mainly getting at are these four attributes: effects on __heart rate__, __contractility__, __wall tension__, and __coronary resistance__.
 * Nitrates: HR up (baro reflex), CN up (baro reflex), WT down, CR down.
 * Beta-blockers: HR down, CN down, WT no effect, CR slightly up.
 * CCBs: HR slight effect*, CN slightly down, WT down, CR down.
 * *some decrease, but offset by baro reflex; thus usually a small effect.
 * So if you really want to address coronary vascular resistance, use nitrates and CCBs. If you want to administer nitrates but are concerned about heart rate and contractility, use beta-blockers as well.
 * Note French covered this more simply in his review ("French's Review for Unit II").
 * Understand the fundamental basis for contraindications or negative cumulative effects of combination therapy, e.g., additive effects on AV node conduction or negative inotropy.
 * Beta-blockers, digitalis, and CCBs all can cause AV block. Watch out if co-administering them.
 * Some beta-blockers and most first-generation CCBs decrease inotropy. Careful in heart failure.
 * If you use nitrates + CCBs in tandem, they both decrease blood pressure (both cause peripheral vaso/venodilation) and thus also both kick off reflex tachycardia-- so might want to use a gentle hand with that.

ISMO (ISDN) once-a-day

Metabolic Syndrome Monday, April 07, 2008 12:37 PM


 * Metabolic Syndrome, 4/8/08:**


 * List the features (components) of the metabolic syndrome
 * Metabolic syndrome: "A vascular disease with hyperglycemia as a late manifestation."
 * Components: Obesity, insulin resistance, type 2 diabetes.
 * Note that blood glucose is conspicuously absent from this list. Blood glucose doesn't seem to have a lot of effect on the progression of insulin resistance.
 * Here's how it seems to work:
 * I eat twenty cheeseburgers a day for a year.
 * I get kinda chubby (central obesity).
 * I keep eating cheeseburgers.
 * Now, when I eat a cheeseburger, I get this influx of triglycerides, which are normally stored in fat cells and muscle cells (see part I of "Lipids, Lipoproteins, and Atherosclerosis").
 * But since I'm kinda chubby, my fat cells are already stretched to the breaking point and really can't stuff any more triglycerides in there, so the triglycerides roam free through my circulation like fatty buffalo across the plains of yore.
 * Note that really 'full' fat cells, particularly in the abdomen, are prone to releasing their triglycerides under sympathetic stimulation, which doesn't help.
 * Lipases in the blood slowly degrade these triglycerides (which are just fatty acids on a glycerol backbone) to free fatty acids, which turn out to have deleterious effects in the blood at high concentrations (like fatty, toxic buffalo).
 * Increased levels of free fatty acids have a variety of ill effects:
 * FFAs are usually bound by proteins like albumin in the circulation. But if there's enough of them, they can't all be bound up and some react with various things they oughtn't.
 * They **induce insulin resistance** (leading to type 2 diabetes), possibly due to some kind of pro-inflammatory action.
 * They **induce endothelial dysfunction**, making it pro-thrombotic and unable to vasodilate. This results in more strokes and MIs.
 * They **increase oxidant activity** (thus increasing the rate of NO depletion). This may actually be the same point as the last one.
 * Note that this effect can be averted by co-administration of antioxidants.
 * Note that this implies that fat cells are actually protective, a hypothesis that's been borne out by research-- mice without the ability to make fat cells develop diabetes on a normal diet; if given fat transplants, the phenotype can be reversed.
 * Describe the relationship of the syndrome to type 2 diabetes
 * As I said, insulin resistance is linked to fat cell dysfunction and high free fatty acid levels in the circulation.
 * Recall that uncontrolled diabetes - meaning high blood glucose levels - is bad for cardiovascular health, possibly because it gunks up microcirculation.
 * Explain the linkage of obesity to cardiovascular risk
 * See above.
 * Note that abdominal fat in particular seems to be the main culprit. The main measurement for cardiovascular risk in this context isn't __weight__ per se but __girth__.
 * Note also that triglycerides, per se, aren't the causative agents in endothelial dysfunction, etc-- it's only when they're broken down into fatty acids by lipases that you start seeing increased insulin resistance.
 * Side note: __heparin__ seems to potentiate this high-FFA, lipase activity.
 * List therapeutic approaches to reduction of cardiovascular risk linked to the metabolic syndrome
 * **Statins** -- have anti-inflammatory (pro-NO) effects, in addition to lipid effects.
 * **ACE inhibitors** -- lower blood pressure, increase bradykinin (pro-NO) levels. Reduces both cardiovascular events and incidence of new onset diabetes (fairly dramatic effect, actually).
 * **TZDs** (thiazolidinediones)-- act on fat cells' PPAR-gamma receptors to increase triglyceride uptake, thus decrease free fatty acid levels and increase sensitivity to insulin. Mainly increase fat accumulation in subcutaneous regions, not abdomen.
 * Note that antioxidants, while they may prevent endothelial dysfunction in type 2 diabetes, have no studies supporting their effect on actual cardiovascular events (for much, much more in this vein, see "Cardiac Disease Prevention").


 * FFA** : induce insulin resistance, induce endothelial dysfunction, increase oxidant activity.

Congenital Heart Disease I and II

Tuesday, April 08, 2008 8:05 AM


 * Congenital Heart Disease I and II, 4/9/08:**


 * Discuss the incidence and epidemiology of congenital heart disease.
 * 5-8 per 1,000 live births in US-- obviously an underestimation given that many defects go unnoticed and also that many defects cause in utero fetal death.
 * Males more than females, but no difference in race or parents' age.
 * More common with family history or with a mother who has diabetes.
 * Review the anatomy and physiology of a normal heart
 * Go nuts there.
 * Present the most common congenital heart lesions, paying attention to anatomy, physiology, clinical presentation, and management/natural history.
 * **Atrial septal defects** (ASDs): Effectively a hole in the atrial septum. Oxygenated blood flows from chamber of greater pressure to chamber of lesser pressure (usually left atrium to right due to the slightly higher pressure of the left atrium, but can be right-to-left in cor pulmonale).
 * __Anatomy__: Just what it sounds like, a hole in the atrial septum. Note subtypes:
 * Secundum ASDs: due to a defect in septum primum (too large an ostium secundum) or an inadequate development of the septum secundum. Generally found more or less in the center of the septum, near the foramen ovale.
 * Sinus Venosus ASDs: due to a failure of the primitive pulmonary vein structure (the sinus venosus) to fuse well with the atrial septum, resulting in either an interatrial defect near the top of the septum (where the SVC comes in) or at its base (where the IVC comes in). Often co-presents with pulmonary vein malformation.
 * __Physiology__: Blood flows between the atria, //following its pressure gradient// . Note that this usually means from __left to right__, since the left atrium is usually a few mm Hg more pressurized than the right.
 * Why atrial pressures are different: the left ventricle is thicker, and thus more resistant to filling, than the right ventricle; thus, the pressures in the respective atria are also slightly different in order to facilitate filling. This is why you need to watch out for right-sided ventricular hypertrophy-- it can easily reverse the normal left-dominant pattern and give you a right-to-left shunt, which is significantly worse than a left-to-right (see below under "Eisenmenger's Syndrome").
 * Notice that if the defect is large (usually defined as "as big as the mitral valve"), the pressures between the atria can equilibrate.
 * Notice in turn that S1-S2 splitting will be exacerbated in patients with large ASDs-- the flow from left to right will increase the right heart volume and further delay pulmonary valve closure.
 * __Clinical presentation__: due to largely equal atrial pressures in infancy, it rarely presents that early. Once the baby's been breathing air for a while and the right ventricle shrinks (less pulmonary pressure) while the left ventricle thickens (more systemic pressure), watch out.
 * **ASD Murmur** : systolic murmur at pulmonic location and diastolic murmur at tricuspid location.
 * **The murmur in ASD is __NOT__ due to blood flow through the defect** . It's due to increased flow out of the pulmonary valve and increased flow through the tricuspid valve.
 * As mentioned, you can also get a wide S1-S2 splitting that does not come and go with respiration.
 * Shows up as right ventricular hypertrophy on a EKG. Note that most babies have (relative) right ventricular hypertrophy anyway.
 * On X-ray: look for enlarged right heart and pulmonary arteries.
 * Increased incidence of ASDs in patient with __Down's syndrome__.
 * __Natural History__: I think of ASDs, at least as they usually seem to occur, as //right heart overload// . Thus you get the complications that usually occur with right heart overload:
 * Pulmonary vascular disease-- the constant high pressures in the pulmonary arteries cause concentric hypertrophy and effective stenosis of the right heart outflow.
 * This can in turn lead to right heart failure as the heart loses its ability to contract under constant and increasing volume overload. Look for venous backup as well.
 * Can get arrhythmias, usually a-fib or a-flutter, due to enlarged chambers.
 * Also look for lung congestion-- too much blood being pumped through the pulmonary vessels.
 * __Management__: Diuretics can relieve the congestion, but generally in anyone other than an infant who responds well to medications, you should always **close the defect** . ASDs have a poor track record of closing by themselves.
 * You can do this surgically (open-heart) or you can do it percutaneously by popping a patch on each side of the defect (the larger patch goes on the more pressurized side).
 * **Ventricular septal defects** (VSDs): most common congenital heart lesion.
 * __Anatomy__: Just what it sounds like, a hole in the ventricular septum. Note subtypes:
 * **Perimembranous** VSD: Most common type. The membranous portion of the developing ventricular septum fails to form properly.
 * **Muscular** VSDs: Defects open in the muscular wall between the ventricles.
 * **Atrioventricular** VSD: The defect is in the AV canal itself. Usually this means both a VSD and an ASD (below).
 * **Subarterial** VSD: The defect occurs just below the aortic valve. This can have serious consequences for the valve itself (see below).
 * __Physiology__: Usually a faster flow of blood than ASD due to the wide discrepancies in left-right ventricular pressures during systole. Generally this will be a left-to-right shunt, but note that in some severe pulmonary obstructive conditions (pulmonary stenosis, Tetrology of Fallot) it can become a left-to-right shunt instead-- again, see "Eisenmerger's Syndrome," below.
 * To be classified as "large," VS defects must be at least as large as the aortic valve.
 * Note that in subarterial VSD in particular, the location of the defect right next to the aortic valve means that the nearest valve leaflet often gets sucked into the defect during systole; over time, the leaflet can effectively plug up the defect (fixing the systolic murmur), but now you have lasting __aortic regurgitation__ (creating a diastolic murmur), and will have to fix two problems surgically instead of one.
 * [**Eisenmenger's Syndrome** :]
 * This is what happens when you have a large left-to-right defect that goes uncorrected for a long period of time.
 * Usually this progression happens in VSDs, but you can see it in ASDs as well.
 * The increased pulmonary blood flow leads to concentric hypertrophy of the pulmonary arteries, leading to pulmonary hypertension and increased right ventricular pressure to compensate.
 * However, recall that the direction of the shunts is largely dependent on the relative pressures in the ventricles (or atria, which pressures are still linked to the ventricles).
 * Right ventricular hypertrophy can lead to a change in the direction of the shunt from left-to-right to right-to-left.
 * This is bad because all a sudden your body ain't getting enough of its red love juice. Leads to cyanosis and clubbing, heart failure, and death or transplant. That progression is called Eisenmenger's Syndrome.
 * __Clinical Presentation__: Again, generally left-to-right blood flow. However, unlike ASD, the left ventricle is participating in the fluid overload situation, and thus the //left// ventricle gets dilated with VSD as well as the right, reflecting chronically increased EDV from the increased refill from the pulmonary vessels.
 * Generally this is asymptomatic until after birth, when the left ventricle develops a lot more pressure than the right.
 * Note development is slower at high altitudes due to lower O2 content (right ventricle has to work harder, thus stays thicker longer).
 * **VSD Murmur** : systolic murmur at tricuspid area (lower left sternal border); can also get a diastolic murmur at the mitral valve area if the VSD is large. Note that, unlike ASDs, the tricuspid valve isn't involved.
 * **The systolic murmur in VSD __is__ due to blood flow through the defect, and tends to get larger when the defect is smaller (more turbulent flow).**
 * This is why the systolic murmur in Tetrology of Fallot (which has both pulmonary stenosis and a large VSD) isn't caused by the VSD-- it's too large to cause one.
 * Note that VSDs often spontaneously close.
 * This means that a murmur that gets louder is not always a bad thing (the VSD could be closing, or the pulmonary resistance may have gone down, causing more inflow to the right), while a murmur that gets softer is frequently not a good thing (VSD is large enough for pressures to equilibrate, or pulmonary arterial tension has gone way up and they're on the way to right-sided heart failure).
 * Echocardiography is the best way to detect VSDs. Can also use it to find the aortic regurgitation problems in subarterial VSDs.
 * X-ray: Enlarged pulmonary arteries, enlarged heart silhouette, increased vascularity of the lungs.
 * __Natural History__: Most small VSDs close; most large VSDs shrink over time. However, a large VSD left untreated can easily progress to Eisenmenger's Syndrome.
 * __Treatment__: Can treat excessive pulmonary flow with diuretics to ease congestion. Also digoxin and ACE inhibitors. If complications (ie. pulmonary hypertension) are beginning, surgically close the thing. Mostly open-heart, but some limited percutaneous techniques are available.
 * **Tetralogy of Fallot** (TOF):
 * __Anatomy__: Four defects. All of them arise from an anteriosuperior deviation of the upper ("infundibular") portion of the ventricular septum.
 * (1) **VSD**
 * (2) **Dextraposition of the aorta** (aorta runs atop the VSD)
 * (3) **Right ventricular outflow (pulmonary) obstruction**
 * (4) **Right pulmonary hypertension**
 * __Physiology__: TOF is the most common cyanotic disease.
 * Generally speaking TOF is a disease of //insufficient flow to the lungs through the pulmonary arteries//.
 * When the right ventricle has hypertrophied, the pressure it generates to try and force blood to the lungs is higher than the pressure in the left ventricle-- thus the VSD becomes a right-to-left shunt.
 * Put another way, the blood finds it easier to go through the VSD than out through the obstructed pulmonary artery-- so it does so.
 * Often the only thing that keeps these kids alive is their patent ductus arteriosus, which allows blood to return from the aorta to the lungs to be oxygenated.
 * __Clinical presentation__: TOF patients often show "Tet spells," cyanotic episodes brought on by crying, anemia, dehydration, or nothing in particular.
 * Effectively anything that causes decreased pulmonary blood flow can be life threatening-- decreased venous return, decreased systemic resistance, etc.
 * Baby turns blue, it's hard to miss.
 * Note that TOF patients, if their right ventricular hypertrophy isn't pronounced, can have a left-to-right VSD shunt instead-- the so-called "pink babies." Look for typical systolic-flow problems.
 * Older children can show the "squatting sign," in which they squat to increase venous return to the heart under conditions of physical stress.
 * EKG: right ventricular hypertrophy.
 * __Natural history__: Can progress to cyanosis and death.
 * Also watch out for **cerebral abscesses** !
 * These evidently form because the lungs are a reasonably competent immune organ and the blood that goes to your brain - which isn't a particular competent immune organ - now no longer goes through the lungs first.
 * __Treatment__: Need to keep that ductus arteriosus patent. Use **prostaglandins**.
 * Treat Tet spells by increasing pulmonary blood flow-- IV fluid expansion, etc.
 * Surgical repair at 2-4 months. Watch out for the ductus arteriosus closing.
 * Note that you normally have to pretty much obliterate the pulmonary valve in the process-- usually get pulmonary insufficiency.
 * Can also use the **BT** shunt, in which you connect the right subclavian artery to the pulmonary artery instead of trying to directly fix the septal defect/pulmonary outflow.
 * **Coarctation of the aorta:**
 * __Anatomy__: A dramatic narrowing of the aortic lumen, generally in the vicinity of the ductus arteriosus (can be pre-, post-, or juxta-ductal); occasionally can be in the thoracic/abdominal aorta.
 * Note that the aorta tends to dilate before and after the coarctation.
 * The coarctation generally happens after the left subclavian/left carotid.
 * __Physiology__: More or less what you'd expect from large decreases in blood flow to the lower body: decreased flow to the bowel, claudication, increased RAA activation due to impaired renal flow (can cause lifelong hypertension).
 * Note that most of the upper vasculature is still getting perfused fine.
 * Watch out for clinical worsening as the ductus arteriosus closes-- the patent d.a. often allows a greater blood flow to the lower body than would occur in its absence.
 * __Clinical Presentation__:
 * Watch for a blood pressure in the upper limbs that's much higher than the pressure in the lower limbs.
 * Emphasized: __look for femoral pulses__!
 * If the d.a. closes and the blood flow to the lower body drops, can present with tachypnea, tachycardia, diaphoresis, and poor feeding, or can present in shock due to cardiac failure (secondary to chronic volume overload).
 * Also can see pulmonary rales (blood backs up into lungs), S2/S3, a soft systolic murmur, and a systolic click if there's a bicuspid aortic valve, as there often is with coarctation.
 * EKG: initially (infancy) see right ventricular hypertrophy, then get a developing left ventricular hypertrophy in childhood; in adulthood, see a 'strain pattern' of ST depression and T wave flattening/inversion.
 * X-ray: Cardiomegaly, prominent pulmonary arteries, congestion/edema.
 * In older children and adults: look for the __3-sign__:
 * Dilation above coarctation, coarctation, dilation below coarctation.
 * Also look for 'rib notching': dilated intercostal arteries.
 * __Turner's syndrome__ is associated with coarctation of the aorta.
 * __Natural History__: Can develop aortic collaterals to compensate for inadequate flow; lots of death from heart failure or aortic rupture/dissection.
 * __Treatment__: Keep infants on prostaglandins (to maintain patent d.a.) until surgery.
 * Surgery: remove all ductal tissue and both ends of the coarctation, then sew an anastomosis between the two exposed ends. Risk of recoarctation/aneurysm in the long term.
 * Can put a stent in adults, with middling results.

Lab Findings in Heart Disease, Detection, Management Thursday, April 10, 2008 8:05 AM


 * Lab Findings in Heart Disease, Detection, and Management, 4/10/08** :

[No LOs provided-- these are a smattering of notes. Probably good to go through his slides.]

B-type natriuretic peptides (**BNPs** ): Found only in ventricles, released in response to stretch and increased volume Correlates with: Left ventricular EDP CHF diagnosis (> 100 = indicator of heart failure) Renal insufficiency Normal levels tend to be higher in women than men

Cardiac enzymes: Creatine kinase- CK-MB is an isoform found predominantly in the heart. Troponin I or troponin T-- specific isoforms found in cardiac muscle. Both of these are released in myocardial necrosis. Level of more than 0.50 is abnormal. Dr. Weinburger says these are much more specific to the heart; Wiki says they're also found in skeletal muscle. Take with 65 mg salt. These only start to rise __3-12 hours__ after myocardial necrosis, peaking about a day after the event. Troponin stays elevated longer (10 days vs 36-48 hours). Recall that until 6 hours after the event, EKG is your gold standard for detecting MIs.

Recall that you can use specialized CT scans (CT angiography) to look for calcium content of the arteries, to test for CAD noninvasively.

French's Review for Unit II Friday, April 11, 2008 7:51 AM


 * French's Review for Unit II, 4/11/08** :

You increase HDL levels with niacin and fibrates, particularly. Look for CRP as a marker of inflammation, (here) particularly in atherosclerosis. Atherosclerosis: To prevent plaque //formation// : try to prevent __platelet aggregation__ (lo-dose aspirin) To prevent //further damage// from ruptured plaques: try to prevent __coagulation__ (heparin/warfarin) Magical words: "Fixed obstruction" generally = "stable angina" = __use drugs to decrease O2 demand__. (mainly nitrates and beta-blockers) "Prinzmetal variant" = __use drugs to increase O2 supply__ (vasodilators: CCBs, nitrates-- NOT beta-blockers) "Unstable" or "Acute coronary syndrome" = clot emergency (effects on ST seg) -- use __anti-clotting agents__ as well as anti-platelets, nitrates, beta-blockers, statins, ACE inhibitors, and pain management. "Kitchen sink" therapy?

Note distinction between anti-platelet and anti-coagulant drugs-- anti-coagulants tend to be more important on the venous side (warfarin for venous thrombotic disorders), anti-platelets on the arterial side (aspirin to prevent MIs). Note you use them both in unstable angina, since that's a situation in which both platelets and clotting factors are involved.

Note clopidogrel is an __irreversible__ inhibitor of ADP. Note aspirin, clopidogrel, and abciximab all eventually target glycoproteins IIb/IIIa and thus target platelet-platelet cross-linking by fibrinogen. Note further that aspirin blocks one gpIIb/IIIa pathway (TXA2), clopidogrel blocks the other (ADP), but the direct gpIIb/IIIa inhibitors (abciximab etc) block the end results of both of them (thus more effective). Can also, of course, use both plavix and aspirin to cover both your ADP and TXA2 bases.

__Effects on VO2__: HR: target with beta-blockers Contractility: target with beta-blockers Wall stress (preload): target with CCBs and nitrates. (note some CCBs target HR and contractility somewhat as well, see below) AV nodal blockers: CCBs, beta-blockers, digoxin.

__Distinguish between CCBs as follows__:**note correction from Port's notes** Verapamil: big effect on SA/AV nodal conduction, large effect on contractility Diltiazem: big effect on SA/AV nodal conduction, medium effect on contractility Nifedipine: minimal effect on SA/AV conduction, __minimal__ effect on contractility

[Note that nitrates have similar effects to nifedipine: no effect on SA/AV conduction or contractility, large effect on peripheral resistance (due mainly to veno, not vaso, dilation).]

All the CCBs are vasodilators and all cause reflex tachycardia due to decreased CO. But notice that the reflex tachycardia will be modulated in verapamil and diltiazem by the SA/AV nodal blockage, usually working out to a net mild bradycardia.

Note that Nifedipine here is being treated as roughly equal to all other -dipines (such as amlodipine), as opposed to in Port's notes.

Add beta-blockers to nitrates to blunt the reflex tachycardia (for example, to treat persistent stable angina). Might add beta-blockers to nifedipines, but adding them to verapamil or diltiazem is going to exacerbate the SA/AV nodal conduction blockage. Use nitrates + CCBs to relieve coronary vasospasm (variant angina).

Don't use propranolol in CHF-- decrease inotropy, also can get vasoconstriction. Instead, use metoprolol or atenolol.

Cardiac Disease Prevention Friday, April 11, 2008 8:23 AM


 * Cardiac Disease Prevention, 4/11/08:**


 * Describe the meaning of primary and secondary prevention and observational and interventional studies.
 * Primary- prevent the event itself from presenting.
 * Secondary- prevent the recurrence/worsening of an event that's already presented.
 * Observational- give people without the disease primary prevention therapy, see who develops it anyway.
 * Interventional- give people with the disease secondary prevention therapy, see if there's a reduction in worsening/recurrence.
 * HYPERTENSION - List measures that reduce the development of complications due to hypertension
 * He said nothing about hypertension. I get the feeling these are old LOs. For that reason, you probably want to go read through his slides.
 * ENDOTHELIAL DYSFUNCTION - Describe its role in the development of coronary artery disease, list its causes and features, and list therapeutic approaches that improve endothelial function.
 * We've covered endothelial dysfunction and CAD fairly thoroughly by now.
 * Therapy:
 * Treat risk conditions
 * Aspirin for anti-platelet aggregation
 * Statins for LDL and also for NO generation
 * ACE inhibitors (ACE breaks down bradykinin, which promotes NO generation; also lower chronic hypertension/shear stress)
 * Note that ARBs by themselves won't help with NO generation (not blocking ACE-mediated degradation of bradykinin), although they will negate the hypertensive effects of angiotensin II.
 * Beta-blockers (unknown mechanism, but used to prevent CAD/MI recurrence)
 * Niacin/fibrates for raising HDL cholesterol.
 * HEART FAILURE/VENTRICULAR DYSFUNCTION - list the causes of ventricular dysfunction, describe techniques useful in its detection, and list treatments that blunt its progression to heart failure.
 * Again, I think we've covered ventricular dysfunction pretty well.
 * Therapy:
 * Treat underlying cause (HTN, CAD, valvular disease)
 * ACE inhibitors or angio receptor blockers (Losartan) for anti-remodeling effects
 * Beta-blockers for anti-remodeling effects
 * Spironolactone (aldosterone receptor inhibitor)-- generally __reserved for heart failure__ (not used in left ventricular dysfunction that hasn't progressed to heart failure) due to risk of hyperkalemia.


 * [Stuff on supplements:]
 * No interventional benefit of vitamin E for CV events; very small absolute risk reduction as observational prophylatic. Same for C. Mixed evidence on folate, B6, B12.
 * Niacin: increases HDL, decreases carotid medial wall thickness, but a minimal effect on event-free survival.
 * Fish and fish oils seem to actually be shown to improve CV mortality interventionally.
 * Observational studies: non-placebo controlled, statistical value can be dubious.
 * [bunch of biostats stuff about non-randomized groups and relative vs. absolute risk]