Lecture 10 Coronary Artery Disease

From Iusmphysiology

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(MzHy25 Thanks so much for the article post.Really thank you! Much obliged.)
 
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*continued here from [[Lecture 9 Hypertension and Diabetes]] on 01/28/11 at 11:50pm.
*continued here from [[Lecture 9 Hypertension and Diabetes]] on 01/28/11 at 11:50pm.
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==Coronary Artery Disease, Myocardial Infarction, and Heart Failure==
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MzHy25 Thanks so much for the article post.Really thank you! Much obliged.
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*Expressing CAD is a balance of how much blood you need and how much you provide.
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*Supplying oxygen to heart:
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**Diastolic bp must be good because no blood delivered during systole
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**Coronary vascular resistance:
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***external compression = heart contracts and microvessels are compressed
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***High arterial pressure means microvessels will be extra squeezed during systole
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***If you can't relax during diastole, the caps can't perfuse as well
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**Intrinsic problems with the vessels
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**O2 carrying capacity could be too low
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***Too few RBCs
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***Poor Hb
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***Poor lungs
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*Oxygen use
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**Wall tenstions = pressure of the heart during systole * radius
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***Get higher when pressure has to be high.
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***Dilated heart inappropriately consumes O2
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**Heart rate
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***Oxygen use goes up much faster than the rate of heart rate increase.
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***Because contractility goes up, too.
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**Contractility
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***NE and epi make contractility go up but o2 need goes up even faster
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*When these two don't match, we have coronary deficits and the heart can't take care of itself.
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*stopped here on 01/28/11 at 12PM.
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===Objectives===
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*Why can a heart with partially occluded coronary arteries work well at rest to moderate loads but develop contractile impairment at high work loads? 
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*When the heart is deprived of oxygen for any reason,  how does the lack of ATP production effect contractility and passive filling of the heart?  Be able to use cardiac pressure-volume curves to demonstrate your reasoning.
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*When a sustained lack of tissue oxygenation occurs in cardiac muscle, why is the heart at risk for each of the following:
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**Ion distribution abnormalities inside the cell
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**Arrhythmias of the heart beat
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**Decreased ability to relax the muscle during diastole
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**Protein damage due to intracellular acidosis
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*What are 5 typical symptoms of a myocardial infarction and what is the physiological basis of each?
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*What are the four major cardiac proteins which leak into blood after a myocardial infarction?  Which are used to diagnose a very recent infarction versus an infarction which occurred several days earlier?
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*What is the definition of heart failure?  How do the following abnormalities contribute to heart failure?
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**Coronary artery occlusion
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**Heart valve dysfunction
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**Chronic hypertension
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**Cardiac tamponade or constrictive pericarditis
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*How does the body use the sympathetic nervous system to compensate for heart failure?  Consider the following
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**Increased contractility of viable cells
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**Hypertrophy of heart cells
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**Constriction of veins and arteries
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**Blood volume expansion
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*How does the bodies adaptation to heart failure eventually lead to even worse cardiac performance?  Consider each of  the following  a.  Increased contractility of viable cells
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**Hypertrophy of heart cells
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**Constriction of veins and arteries
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**Blood volume expansion 
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*What are the six major types of interventions to treat heart failure?  What physiological abnormality does each attempt to correct?
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*started here on 01/31/11 at 9AM.
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===I. Problems of reduced coronary blood flow which do not kill myocardial cells===
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====A.  Basic problems of oxygen demand====
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*Blood flow can not always provide enough oxygen for the work load of the heart: increased extraction of oxygen is not likely
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*There are three conditions under which it is likely that oxygen consumption will out-pace oxygen supply:
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**Increased contractility - heart capable of more work and less efficient in oxygen use
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***Higher EDV burns more oxygen
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**Increased heart rate - more beats per minute, more work per minute, more oxygen required
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**Wall tension - enlarged heart requires more tension to do work than a smaller heart - more tension means more oxygen required
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*During exercise:
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**Little vessels can double in size
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*During plaque:
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**Flow goes down
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**Then the little vessels dialate
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**Then you try to exercise and the little vessels can't dialate any more.
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**That means that the heart has to work harder to get the blood flow to appropriate levels.
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**Then bp is up.
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====B. Problems of oxygen supply====
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*Intrinsic regulation:
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*Diastolic perfusion pressure too low to push blood past partially occluded vessel: Systolic pressure of little value to coronary blood flow
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*External compression - contraction of the heart muscle limits its own blood flow in the endocardium by compression of small  vessels
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*Vascular regulation - arteries and arterioles not responding appropriately to tissue signals for increased blood flow
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**Sick blood vessels don't respond apprp to signals to dilate
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**They've already dilated because they need their own blood flow and then they don't respond to their own environment.
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**They may even start reacting in the exact opposite way as is needed.
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*Oxygen content of blood
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**anemia - too few red blood cells
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**hypoxia - inadequate ventilation or damaged lung tissue
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**Having something wrong with the blood like anemia or respiratory problems, the heart is in a world of trouble.
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====C.  Acute problems caused for the myocardial muscle cells before compensation====
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*Upon hypoxia of the heart muscle, alsmot immediately there is not enough ATP.
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*The cardiac muscle cells produce less ATP which has a several effects:
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**Contractility is decreased because less calcium is stored in the SR because the Ca pumps are ATP-driven.
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**The myocytes are less-able to relax because ATP is required for Ca pumps so less Ca is removed from cytoplasm so more myosin-actin cross bridges remain intact.
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**The heart does not fully relax during systole and therefore requires a higher filling pressure if the heart wants to keep it's EDV normal.
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*Bottom line is that stroke volume drops.
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====D.  Survivable types of inadequate coronary blood flow====
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*For coronary blood flow, you can have lots of compromise to the lumen and still survive.
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**At 70-80% compromise, even at rest the flow is starting to be less than sufficient.
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*For maximum coronary blood flow, the ability to raise blood flow is compromised at 50-60%.
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**Noticed via pain at 70%.
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*There are two types of survivable cardiac hypoxia: variant angina and stable angina
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=====Variant angina=====
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*Spasm of coronary artery or constriction of other vessels
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*This is called "Variant or Prinzmetal’s angina"
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*two minutes ago they are fine, then the artery constricts inappropriate.
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*This means blood flow is too little
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*You then have ST elevation and beat droppoing (2nd degree heart block)
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*Tx: give nitroglycerin, or on a longer term give Ca channel blockers
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*This will hurt, sometimes.
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*This can happen in the brain, too.
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**Foggy vision, weakness on that side of the brain.
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**Give Ca blockers
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*Pretty rare: 2-3%
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*The risk is that you can form an arrhymia and die in ventricular fibrilation.
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**Then the autopsy will show well dilated coronary arteries because they will ahve relaxed by then.
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=====Stable angina=====
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*This is a chronic problem.
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*Here there is just not enough blood flow, not enough oxygen
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*Chronic inadequate oxygen delivery but cells survive: stable angina
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*Collaterals can allow some blood flow to the occluded artery.
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*Clots are the usual suspect in stable angina.
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=====Consequences of  actively forming clots in coronary arteries=====
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*When clotting factors are exposed to the blood, we get a clot.
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*Platelets are just coronary disasters waiting to happen.
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**They release:
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**thromboxane (a potent vasoconstrictor),
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**serotonin (alot is a vasoconstrictor, a little is an NO agonist),
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**adenosine-diphosphate (activates platelets),
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**thrombin (platelet activator),
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**platelet-activating factor (from tissue and platelets, activates platelets).
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*So all these factor cause:
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**A clot
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**Micro clots in down-stream arterioles
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**Vasoconstriction
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*This is a bad thing!
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*Normally we have some tissue plasminogen activator as well as beneficial prostaglandins and NO in the coronary arteries to keep clots from forming.
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**This is good!
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*The afore-mentioned brew damages endothelial cells such that they don't produce this nice, clot-killing brew in the coronary arteries, so once clotting gets going it is double bad.
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*Aspirin works by stabilizing platelets by limiting cycloxygenase so that Thromboxane A2 isn't generated and platelets aren't activated.
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**MI pts should chew and swallow an aspirin.
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**Will work in a few minutes.
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**Will stop clot formulation.
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===II. Coronary artery problems which kill myocardial muscle without intervention===
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====A. Rupture of a coronary artery plaque with thrombosis of the injury site====
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*When the plaque ruptures and there is thrombosis--clot formation--at the site of the rupture, two effects cause cardiac hypoxia that requires treatment:
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**The effective lumen diameter of the coronary artery is too small to get enough blood flow through to maintain cardiac function.
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**The tissue dies for lack of oxygen thus decreasing cardiac function.
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====B.  Key problems for the cells====
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*Several cellular responses to hypoxia end up damaging the cardiac cells:
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*A shift to aerobic energy production produces lactic acid.
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**This drops pH.
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**DNA clumps into chromatin.
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**Proteins get damaged.
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*A decrease in ATP (for lack of oxygen to generate it) causes increase of intracellular Na and extracellular increases leading to inappropriate depolarizations (arrythmias)
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*Intracellular Ca increases and ATP decreases cause inappropriate activity of lipases and proteases and cell death.
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===III. Diagnosis of myocardial infarction based on physiological findings===
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*How do you tell if someone is having an infarct?
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====A.  In 70-80% of patients, severe pain in left chest radiating to left arm, neck and jaw====
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*People grab their chest, their arm or their face.
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*They say there is an elephant standing on them.
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*In diabetic neuropathy:
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**Bedcause of the neuropathy (not just periphaeral) there is less info about pain and less regulation of the heart.
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**They will feel bad and weak but may not feel pain.
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*In women:
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**Have a higher pain threshold than mena nd put of medical attention longer because they don't hurt as much.
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**Show up 2-3 hours later than men at ER during coronyar event.
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**Have smaller coronary arteries than men
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**Have same size clots
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**50% higher morotality on first MI (25% of men die, 35% of women).
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**MI leading cause of death in women.
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***1 in 9 women have breast cancer
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***40% of women have vascular disease
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====B. Elevated or depressed ST segment of EKG
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*A change in the ST segment reflects an area of the heart which leaks electrical current at rest
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*The tissue is actually depolarized relative to areas of the heart muscle which is electrically    healthy
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*A good hint:
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**Look for which precordial lead has a problem because that will tell you where in the heart the problem is occurring.
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====C.  Decreased systolic motion of damaged muscle  - low contractility area====
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*Ultrasound iming of the heart
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**Started in MS building!
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**Can get image of how heart changes shape wiht contraction
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**Areas that aren't working do one of two things:
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***Contract slowlsy (decreased systolic mostion of the damaged muscle)
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***Bulge outward (in really bad situations)
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====D.  Heart diastolic size often decreased and ejection fraction is subnormal====
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*A decreased diastolic size and low ejection fraction is an early sign of MI.
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*A small diastolic size can happen whether diastolic volume is high or low.
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====E. Third and fourth heart sounds====
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*In an MI, the third and fourth heart sounds are more prominent.
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What are the third and fourth heart sounds?
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*This is because the ventricle resists being filled and sound is heard
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*The heart doesn't relax like it should, so the ventricls must be forced to fill.
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====F.  Leakage of enzymes from damaged muscle====
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*Enzymes leak from dying tissue.
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*What comes out first and why?
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*Myoglobin:
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**Comes out really fast.
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**Then the kidney and liver clear it quickly.
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**Comes out quickly because it is dissolved int he cytoplasm of the cardio myocytes
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*CK
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**Comes out in the first hour or so
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**Also available in the cytoplasm
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*Troponin I
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**Comes out pretty quickly
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**Indicates that actin firbers are being chewed up by enzymes
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**First few hours
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*Cummulatively these enzymes peak at 30-46 hours.
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*Lactate dehydrogenase
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**Coems form mt
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**Takes a bit of time for mt to leak out
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**Long term indication of muscle damage
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**The higher it goes the worse prognosis for pt.
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===IV. Heart failure===
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*For most people with an heart attack, something will be done for them.
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*TP can be used to open up clot area
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**Good measure until flown to hospital where they can be stinted.
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*If TP doesn't work, the heart gets super huge (more than 1/2 the width of the chest cavity).
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*So what's the problem with these pts' hearts?
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====A.  Fundamental problem is inadequate stroke volume====
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*MI patients all have inadequate stroke volume.
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*This could be due to several factors.
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*The most common factor, by far, is coronary artery disease.
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=====1.  Lower than normal contractility causing low stroke volume=====
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*Stroke volume could decrease because the contractility has decreased.
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*Contractility may decrease when:
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**Coronary artery dieases is limiting the oxygen obtained by the cardiac tissue
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**There is an infection of the heart (cardiomyopathy) by a virus or bacteria
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**There is trauma of the heart muscle (car accident)
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**Genetic defects
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=====2.  Problem with heart valves causing low stroke volume=====
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*A fautly valve can cause a decrease in stroke volume because of regurgitation or decreased EDV.
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=====3.  Arterial pressure too high for the heart to generate proper stroke volume=====
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*The arterial pressure can become so high that the heart cannot generate enough pressure to push out a sufficient volume of blood to sustain the heart.
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*This would be rampant hypertension and is not uncommon.
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=====4.  Cardiac tamponade or constrictive pericarditis can cause low stroke volume=====
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*Tamponade: "is the compression of the heart caused by blood or fluid accumulation in the space between the myocardium" per [http://www.google.com/url?ei=pyxITZr_K4GtgQfIldDYBQ&sig2=_kAcuxkiA0z25itAGK10nQ&q=http://www.erheadquarters.com/doctors_chart/medical_terms.htm&sa=X&ved=0CAwQpAMoAg&usg=AFQjCNGrXFb9WPQgRV_oUA6ToffWH7XpJw ER headquarters]
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**This would cause the ventricles to be unable to fill even though the cardiac tissue is healthy.
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**This is something between the heart and the pericardia.
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*Pericarditis is an inflammation of the sac surrounding the heart.
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**"Constructive pericarditis" can cause a similar restriction to movement of the heart and thus decrease stroke volume.
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**When you lay people down, the pt will hurt worse.
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**MI victims feel short of breath when they lay down but don't usually hurt.
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=====5. Chronic alcoholism=====
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*This is simple damage of the heart muscle and its innervation.
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====B. Adaptations of the cardiovascular system and its control to heart failure====
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*So what do you do for these patients?
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=====1.  Increased sympathetic nervous system activity=====
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*Increasing the sympathetic innervation will cuase increased contractility, increased rate, and increased electrical conductivity.
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*There will also be an increase in angiotensin II / aldosterone secretion because of increased production by the endothelial cells.
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*These changes will have positive effects on the stroke kvolume:
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**a. Increase heart rate to improve cardiac output
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**b. Increase atrial contractile force to improve ventricular filling
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**c. Constriction of veins to raise venous pressure to improve filling
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**d. Increased constriction of peripheral vasculature by norepinephrine, angiotensin II, and endothelin
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***Damaged arteries release endothelin.
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***Note that this will restore the arterial pressure but will end up lowering the blood flow through most tissues.
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***So organs are slowly but surely going downhill: brain decreases in blood flow, gi tract works poorly, muscle wastes
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**e. Increase sodium retention by kidney to increase blood volume which elevates venous pressure to fill ventricles.
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***Blood volume goes way up to increase ventricular pressure to make ventricle fill as much as possible.
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***Causes ventricular edema.
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=====2.  Chronic adaptations of the heart and coronary vasculature=====
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*What does the heart do in response to low stroke volume? / What do we do to help the heart counter?
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*The parts of the heart that are getting enough oxygen will hypertrophy.
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**One reason is because they will be getting lots of sympathetic stimulation telling it to work harder (see sympathetic increase).
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**Sometimes 70% of the heart is fine after an MI, so that part will try to compensate.
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*The heart may develop more vessels that connect well perfused arteries to clogged arteries and thus generate more collateral blood flow.
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**This is something we ''hope'' for.
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**Awesome!
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**This may be an enlargement of pre-existing collaterals.
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***Most people think this is what is happening.
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**We're not sure if new vessels are actually produced.
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*The heart will extend its capillary bed to feed the hypertorphying cells and areas of damage.
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**In normal people, there is one capillary per muscl cell.
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**In well conditioned poeple, there are more caps / muscl cell.
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====C.  Consequences of adaptation to chronic heart failure====
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*All these adaptations (sympathetics, hormones, and cardiac changes) have consequenes on the body, though.
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*If you survive the first month, you'll likely make it for many years.
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*There will be lots of adaptation over these years.
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=====1.  Myocardial cells become less responsive to norepinephrine=====
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*If the cardiac is really sick, we have to keep throwing NE at the pt to keep their stroke volume up.
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*However, over time, there is a down regulation of alpha and beta receptor sin the herat.
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**This is caused by the excessive exposure to NE.
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**More and more NE from sympahtetics is needed and eventually this fatigues.
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*A decrease in alpha and beta receptors means that cells are not signaled to pump Ca into the SR and therefore the cardiomyocytes don't relax.
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**This, with hypertrophy (stiffness) causes decrease in stroke volume.
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=====2.  As myocardial cells enlarge, oxygenation may not be adequate=====
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*As hypertrophy occurs, caps can't grow fast enough to keep up.
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*ST elevation and depression occurs.
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*Heart isn't pumping properly.
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=====3.  Chronically high ventricular diastolic pressures=====
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*As ventricular diastolic pressures go up and up (because ventricles aren't relaxing and yet the atria and venous system are trying to increase their filling pressure), one get a significant enlargement of the ventricular chambers.
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*This makes sense because the body is taking advantage of the Frank-STarling mechanism (more in, more out) to try to increase the stroke volume.
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*However, this principle can be taken to excess at the cardiomyocytes move outside their proper force-length curve and start trading volume (increased length) for decreased force.
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*Also, at a higher volume, more tenstion has to be produced in the ventricle wall to generate the same systolic pressure.
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**This requires more oxygen which is a problem because this heart is barely getting enough oxygen as it is.
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**This makes sense because Pressure = Muscle Tension / Radius of Chamber; so as the radius goes up the muscle tension has to go up, too.
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=====4.  Evidence of endothelin production leading to vascular constriction of the blood vessels and hyperstimulation of ventricular muscle=====
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*Prof said we had talked about this already
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=====5.  End point: beating an overly large, fatigued heart with excessive norepinephrine and blood volume expansion=====
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*Not much we can do at this point.
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*We could give them a new heart.
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*In South American they cut out a chunk of the heart to decrease the oxygen need.
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**Did it in the US but had a high mortality rate.
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===V. Treating Heart Failure===
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*How do we treat heart failure?
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**We need to reduce the work load.
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*We can reduce the work in several ways: reduce work load (rest), surgury on coronary arteries, diuretics, diet changes, renin-angiotensin blockade, ionotropic, Na/K ATPase inhibitors, beta blockers, vasodilators
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*Minimize stress and work by increase rest
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**This will decrease oxygen consumption by the heart and thus reduce the work needed to keep the heart tissue alive.
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**However, patients should still be encouraged to exercise
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*Surgically fix the coronary arteries
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**This will reduce the resistance against which the heart must push and thus reduce the work of the heart.
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**Gives pt 10 years.
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*Use diuretics and sodium restriction to decrease blood volume
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**This will decrease the pressure against which the heart must push and thus reduce the work of the heart.
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*Block the renin-angiotensin system
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**This will reduce fibrosis, reducing the pressure against which the heart must push.
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**This will reduce aberent cell depolarization, increasing the ability of the heart to do coordinated work.
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**This will increase conduction through gap junctions between cardiomyocytes, increasing the ability of the heart to do coordinated work.
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**Chronic angiotensin II causes stiffening of heart, too; so decreasing angiotensin will decrease stiffening over time.
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*Ionotropic drugs
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**These drugs improve the contractility, increasing the ability of the heart to do work.
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***These ionotropic drugs can work in two ways:
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****by potentiating the affects of endogenous beta agonists
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****by suppressing cAMP degradation (this is what is turning up contractility from beta receptors)
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*Na/K ATPase inhibitors (digitalis, ouabain)
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**Has been used for 3k or 4k years.
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**Comes from knight-seed family.
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**These suppress the Na/K ATPase
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***When suppressed, Ca / Na exchangeers will take in Ca and throw the Na away.
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**Ca accumulates in the cells increasing contractility and abiltiy of the heart to do work.
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***Contractility will go up but relaxation will go down; so there's a tradeoff.
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**Baroreceptor activity is also increased which lowers sympathetic activity (recall that it is an inhibitory signal that baroreceptors send)
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**Digitalis also causes Na and water to be lost at the kidneys (a kind of diuretic)
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***Because the same Na / K ATPase usually brings Na back in from the urine.
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**Digitalis slows conduction in the heart and thus avoids arrhythmias
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***Can cause heart block
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*Beta blockers
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**Used when everything above (which tries to make the heart stronger) doesn't work.
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**These force the heart to decrease its work-load.
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**These will allow the heart to live on a lower amount of oxygen.
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**These will cause the patient to be weaker and less able.
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**This buys some time and hopes that the heart will repair itself a bit.
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*Vasodilators
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**Usually given with beta blockers.
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**Vasodilators cause the blood volume of the venous system to decrease, thus increasing cardiac filling pressure.
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**Vasodilators can also cause the arterial system to dilate such that there is better blood flow at a lower mean arterial pressure (good for the heart's ability to do work!)
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**This also means that the heart actually has to work less (becuase of less pressure to push against) to get the same amount of pressure.
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===Overview: The Calcium AND ATP Problems in damaged or hypoxic cardiac cells===
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*This is a summary of pretty much everything.
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*We didn't talk about it.
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The cells in damaged/hypoxic areas do not make enough ATP for contractility and general housekeeping
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The Ryanodine Receptor Calcium Channels leak all the time due excessive activation by PKA system .  Raise diastolic calcium which may impair relaxation.  Later in heart failure, there may be too little PKA because of depleted norepinephrine in neurons - lowers contractility because of less calcium release, impairs relaxation because calcium pumps not activated.
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In most cases, less calcium available during systolic activation to activate the actin-myosin 
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Down regulation of numbers of beta receptors and impairments of PKA activation decrease the stimulation of opening of Ryanodine Receptor Calcium Channels - impairs contractility
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Lack of Protein Kinase A activation once beta receptor problems develop will lower the calcium pump activity which allows less relaxation - heart is harder to fill.
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The best treatment is more oxygen to make ATP but that is not always possible. 
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===Clinical case===
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*67 yo m
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*Moderate MI 16 months past
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*Exercises, active, walks
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*No chest, arm, neck pain
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*HR 62 bpm
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*No meds
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*Impotence with wife, though early morning erections
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*A. prescribe an erectile dysfunction medication such as Viagra.
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** could do this, would give him some confidence
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*B. investigate his cardiac performance during an exercise stress test.
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** could but he seems to be doing some good exercise; expensive
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*C. counseling on cardiac risks associated with intimacy.
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** not a bad idea; usually started when person leaves hospital after MI
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** don't want pt to get too excited
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** few people die during routine sex with spouse
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*D. advise increased exercise to improve cardiovascular performance.
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** well, he's already working pretty hard
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*E. advise to refrain from intimacy until the above tests/prescriptions  have effect.
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** but he's not doing all that bad.
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*A is the correct answer
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**The risk is that when paramedics show up to a second MI, they give nitrates / nitroglycerine.
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**If you have viagra on board, these work really at their function: to maintain NO effects on smooth muscle cells from disipated
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**The pt is likely to collapse (for lack of oxygen flow to the brain).
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**Tell the pt to tell his partner that the paramedics should not give nitrates!
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*continued on to [[Lecture 11 Fetal Physiology]] on 01/31/11 at 9:45AM.
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Current revision as of 08:55, 9 March 2012

MzHy25 Thanks so much for the article post.Really thank you! Much obliged.

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