NU608 CAD and Cardiomyopathies PDF

1 Coronary artery disease is any vascular disorder that narrows or occludes the coronary arteries of which arteriosclerosis and atherosclerosis are a major cause. Arteriosclerosis (not to be confused with atherosclerosis) is a chronic disease of the arterial system that results in abnormal thicken...

1 Coronary artery disease is any vascular disorder that narrows or occludes the coronary arteries of which arteriosclerosis and atherosclerosis are a major cause. Arteriosclerosis (not to be confused with atherosclerosis) is a chronic disease of the arterial system that results in abnormal thickening and hardening of the vessel walls. Smooth muscle cells and collagen fibers migrate to the tunica intima (the inner lining of the artery)  causing it to stiffen and harden. Ultimately the changes cause a decrease in the artery’s ability to change lumen size This may worsen pathophysiologic conditions that already exist such as hypertension, or insufficient perfusion to tissues (peripheral vascular disease). Arteriosclerosis may be a part of normal aging. 2 Diagram of narrowed arteriole vs normal. 3 Atherosclerosis is a slowly progressive disease and is a form of arteriosclerosis, in that it is a narrowing and thickening of the blood vessel wall…but…it is caused by the accumulation of lipid-laden macrophages within the arterial wall. This then leads to the formation of a lesion known as a plaque. Atherosclerosis is not a single disease but rather a pathologic process that can affect vascular beds throughout the body  ischemic syndromes  leading contributor to coronary artery disease (CAD) and cerebrovascular disease (see path map on next slide. 4 5 Atherosclerosis is an inflammatory disease progressing from endothelial injury to plaque formation: 1. The development of atherosclerosis begins with damage or dysfunction of the endothelial cells that line the arteries. This may occur following injury of the cells or in response to some other stimuli  leading to inflammation of endothelium Injury allows the cells to become more permeable  this leads to substances such as triglycerides and fatty acids access to the inside of the artery 2. Cellular proliferation Due to inflammatory response neutrophils, monocytes, and platelets migrate to the area Numerous inflammatory mediators are released (TNF, interferons, oxygen radicals) 3. Macrophage migration Then start to adhere to injured endothelium Macrophages release enzymes and toxic oxygen radicals that create oxidative stress, oxidize the fatty acids that are present -the low-density-lipoprotiens (LDL) And, all these leads to further damage of the vessel wall 4. The process of LDL oxidation is an important step in the development of atherogenesis Oxidized LDL is toxic to endothelial cells Causes smooth muscle proliferation which causes smooth muscle cells to grow into the tunica intima And, activates further inflammatory & immune response Oxidized LDL penetrates into intima of arterial wall they are the engulfed by macrophages macrophages filled with oxidized LDL  called foam cells ***inflammation with oxidative stress & activation of macrophages are the primary mechanism in atherosclerosis development*** 5. Fatty streak forms Foam cells accumulate to form the lesion  fatty streaks Fatty streak is a flat, yellow, lipid-filled smooth muscle cell that causes no obstruction of the affected vessel These streaks produce more oxygen radicals  inflammation  progressive damage to the vessel wall (Decreasing levels of LDL can cause regression of atherosclerotic lesions & improve endothelial function – the best mechanism we have for this is pharmacologic management with statins – which we’ll learn more about in pharmacology – oh, fun) 6. Fibrous plaque develops over time Smooth muscle cells have proliferated producing collagen Migrate over the fatty streak forming fibrous plaque Plaque may calcify and protrude into vessel lumen  can obstruct blood flow  causing angina Many plaques are “unstable  meaning they are prone to rupture even before blood flow is affected significantly clinically silent until they rupture  known as complicated plaque Once ruptured  exposure of underlying tissue initiates clotting cascade thrombus formation sudden occlusion  ischemia & infarction (the hallmarks of coronary artery disease) 6 As we mentioned at the beginning of the module - Coronary artery disease is any vascular disorder that narrows or occludes the coronary arteries. Atherosclerosis is the major cause. There are several hypotheses as to what first initiates the dysfunction of the endothelial cells, thereby starting the process. It is likely that different initiating events are involved to different degrees in different people. Some are seen as traditional risk factors including the two major ones: High cholesterol Cholesterol and triglycerides are carried in the blood encased in fat-carrying proteins called lipoproteins. High-density lipoprotein (HDL) carries fat away from cells to be degraded by the liver and is known to be protective against atherosclerosis Low-density lipoprotein (LDL) and very-low-density lipoproteins (VLDL) carry fat to the cells of the body, including the endothelial cells of the arteries Those with elevated levels of LDL and low levels of HDL are at increased risk for development of atherosclerosis High blood pressure Chronically high blood pressure produces shear forces that scrape away at the endothelial layer of the arteries and arterioles, initiating their injury. Shear forces especially occur in the sites of arterial bifurcation or bending (a trait characteristic of the coronary arteries, the aorta, and cerebral arteries). Any thrombus that develops can be sheared off the artery 7 Non-traditional risk factors are looking at: Hyperhomocysteinemia Occurs d/t lack of an enzyme that breaks down homocystein (an amino acid formed by the metabolism of methionine) Or, d/t nutritional deficiency of folate, B12, or B6 are also associated with elevated levels Research suggests that elevated homocystein levels are associated with endothelial dysfunction & increased tendency for thrombosis formation High iron levels Iron is rapidly oxidized and capable of producing artery-damaging free radicals Some suggest that this may explain the higher incidence of CAD in men compared to premenopausal women, who typically have lower levels of iron Infection is having an emerging role in research. Chlamydia & helicobacter pylori are often present in atherosclerotic lesions ***Pediatric Consideration…now, this is something that is scary for our children. Autopsy studies of children who have died in accidents have shown that fatty streaks on the arteries may occur in children 10 years of age or younger, Even though this may be asymptomatic, they may be predictive of later coronary artery disease. Smoking in the teen years also increases the incidence of fatty streaks. 8 Coronary artery disease (the narrowing and/obstruction of blood flow) can lead to Myocardial Ischemia Myocardial ischemia occurs when the supply of coronary blood cannot meet the demands of the myocardium for oxygen and nutrients Most common cause is the formation of atherosclerotic plaques Other causes include: Coronary artery spasm Hypotension Arrhythmias The myocardial cells will become ischemic within 10 seconds of occlusion. However, if the ischemia is less than 20 minutes it is considered reversible in that the cells remain viable. Clinical manifestations is the resultant angina that develops. If ischemia progresses or extends beyond 20 minutes there is the development of myocardial infarct. 9 Flow map of ischemia: reversible and irreversible with the subsequent possible complications 10 Angina pectoris is severe pain originating from the heart that occurs in response to myocardial ischemia. There are three types of angina: stable, Prinzmetal (variant), and unstable. Stable angina (also called classic angina) Occurs when atherosclerotic coronary arteries cannot dilate to increase blood flow when oxygen demand is increased Chronic coronary obstruction results in predictable chest pain is precipitated by physical activity, mental stress, and/or anger Discomfort transient (3-5 minutes) and if blood flow restored no permanent damage Pain is due to the build up of lactic acid or abnormal stretching of the ischemic myocardium that irritates the myocardial nerve fibers Usually relieved by rest and nitro *****Lack of relief may indicate developing infarction***** Prinzmetal angina (also called variant) occurs due to abnormal vasospasm of coronary vessels resulting in unpredictable chest pain occurs almost exclusively at rest, at night during REM sleep this abnormal vasospasm of one or more major coronary arteries can be with or without atherosclerosis may be d/t hyperactivity of sympathetic nervous system, or increased calcium influx into arterial smooth muscle ****if spasm persists  infarction results**** Treated with nitroglycerin and Calcium antagonists 11 When there is sudden coronary obstruction over a ruptured or ulcerated atherosclerotic plaque, the acute coronary syndromes result. Unstable angina is included along with myocardial infarction under this heading. What are the possible causes of rupture  can be spontaneous, but also anything associated with surge of sympathetic activity with increased BP, increased HR, physical or emotional stress. Unstable angina  is a combination of classic and variant angina it is seen in individuals with worsening CAD typically the atherosclerotic plaque has become complicated episodes of unstable angina increase in frequency signals infarct is near Myocardial infarction  results if there is prolonged ischemia (>20 minutes) causing irreversible damage it is the death of myocardial cells following prolonged deprivation it is the culminating lethal response to unrelieved myocardial ischemia 12 When there is sudden coronary obstruction over a ruptured or ulcerated atherosclerotic plaque, the acute coronary syndromes result. Unstable angina is included along with myocardial infarction under this heading. What are the possible causes of rupture  can be spontaneous, but also anything associated with surge of sympathetic activity with increased BP, increased HR, physical or emotional stress. Unstable angina  is a combination of classic and variant angina it is seen in individuals with worsening CAD typically the atherosclerotic plaque has become complicated episodes of unstable angina increase in frequency signals infarct is near Myocardial infarction  results if there is prolonged ischemia (>20 minutes) causing irreversible damage it is the death of myocardial cells following prolonged deprivation it is the culminating lethal response to unrelieved myocardial ischemia 13 Cardiac cells can withstand ischemic conditions for ~ 20 minutes before cellular death occurs. EKG changes can be noted after 30-60 seconds of hypoxia. However, the cells can remain viable if blood flow returns within that 20 minutes. After this period, the ability of the cells to produce ATP aerobically is exhausted and the cells fail to meet their energy needs. (Remember, way back in the beginning of the course  without ATP, the sodium-potassium pump fails, and the cells fill with sodium ions..and along follows water… eventually causing the cells to burst (hydroptic injury). Cellular death  leads to tissue necrosis (coagulative). Structural & functional changes Despite almost immediate onset of EKG changes, gross tissue changes in the area of infarction may not be apparent for several hours The infarcted myocardium is surrounded by a zone of hypoxic injury which may progress to: Necrosis Undergo remodeling or, return to normal Tissue surrounding the area of infarction also undergoes changes known as: Myocardial stunning temporary loss of contractile function Can last for hours to days after perfusion has been restored Hibernating tissue undergoes metabolic adaptation to preserve the cell until perfusion is restored Remodeling (under influence of angiotension II) causes hypertrophy and loss of contractile function in areas distant from the site of infarction Repair (usually starts within 10-14 days after episode) consists of degradation of damaged cells, proliferation of fibroblasts  formation of scar tissue Scar tissue is strong but unable to contract & relax like healthy myocardial tissue By six weeks the necrotic area is completely replaced by scar tissue 14 Flow map of progression of Myocardial ischemia/ infarction 15 Myocardial diseases are diseases originating in the myocardium but not from cardiovascular disease (such as atherosclerosis, coronary heart disease). Both myocarditis & cardiomyopathies  are causes of sudden death & heart failure  ~ 25% of cases of heart failure are result from idiopathic dilated cardiomyopathy (remember “idiopathic” means we really don’t know the reason “why” or it’s undetermined. 16 Let’s look at Myocarditis first. It’s an inflammation of heart muscle & conduction system without evidence of coronary artery disease or MI. Most often it is a result of viral infections of the myocardium (but bacterial and fungal infections can also be culprits). Of the viruses the ones that are the most important cause of myocarditis in north America and Europe are the coxsackie viruses and other enterovirus - these usually manisfest as flu-like symptoms  hint, hint  Systemic disease such as lupus may also be an etiology of myocarditis Radiation therapy Hypersensitivity rxns  in which the body develops antibodies against the myocardial cells 17 Myocarditis results in weakening of the heart muscle and a decrease in cardiac contractility. The heart becomes dilated and flabby, with many foci of pinpoint hemorrhage developing in the endocardium, myocardium and epicardial layers. Myocarditis which progresses to a dilated cardiomyopathy is a major cause of heart transplantation in the U.S. (Have you seen the movie “Beaches” with Bette Middler? Well the girl in it develops a viral myocarditis which progresses to dilated cardiomyopathy and subsequently dies from progresses heart failure ….very, very, sad. Okay, I probably just dated myself…if you haven’t hear of Beaches then what about Izzy and Denny in Grey’s Anatomy – Denny had a dilated cardiomyopathy) Clinical manifestations: Vary widely from totally asymptomatic to sudden death Some may experience chest pain, fatigue and dyspnea May pick up murmur in some cases Echocardiogram and coronary artery catheterization show normal arteries and cardiac valves. The diagnosis of myocarditis is done by biopsy of the muscle which shows inflammation. In ½ of the cases of myocarditis, it is transient & symptoms resolve in 1-2 months. However, the other half progress to heart failure, arrhythmias leading to sudden death while awaiting heart transplantation. Treatment is symptomatic and trying to prevent myocardial damage. 18 Cardiomyopathy refers to any disease or injury of the heart not related to coronary artery disease, hypertension, or congenital malformations. Cardiomyopathies and congestive heart failure are not synonymous – while they often occur together they are not the same thing. Cardiomyopathies may develop as “primary” or “secondary” disorders The primary cardiomyopathies are heart muscle diseases of unknown origin (idiopathic) Three main types of primary cardiomyopathies  dilated, hypertrophic, restrictive Secondary cardiomyopathies  conditions that arise from a “known” etiology such as another cardiovascular disease such as myocarditisis, autoimmune disease such as lupus, or following exposure to certain toxins, including alcohol and cocaine, and many anticancer drugs. Clinically, myopathies are divided into those resulting in ventricular dilation and those characterized by hypertrophy of the myocardium. With dilated cardiomyopathy, the ventricle stretches becoming enlarged and flabby, leading to heart failure With hypertrophic cardiomyopathy, the cardiac muscle thickens, especially along the interventricular septum  the ventricles become very still resulting in decreased compliance and diastolic filling (the ventricles have difficulty relaxing and filling with blood during diastole). With restrictive disease it is a result of decreased ventricular compliance and endocardial fibrosis. Onset of primary cardiomyopathies is often silent & symptoms don’t appear until the disease is advanced. Often the patients present in heart failure and when a work-up is done to see why there is heart failure – then the cardiomyopathy is discovered ***Cardiomyopathies should be suspected whenever a young, previously healthy, normotensive person experiences cardiomegaly & heart failure***** So, let’s look at the different types – you will need to know this – you’ll see quiz questions in which I will describe a scenario and then based on that information have to chose what type of cardiomyopathy it is  19 In dilated cardiomyopathy there is progressive cardiac enlargement (increase in heart size – cardiomegaly) & dilation and grossly impaired systolic function (which means that this big, flabby heart has difficulty contracting. Whenever you see systolic dysfunction it means there is a problem with the heart’s ability to contract. And if it can’t contract well – what happens to stroke volume? …you’re right it does down….and if stroke volume decreases what happens to cardiac output? You got it! It does down). The dilated heart muscle can cause impaired pumping of one or both ventricles As the heart enlarges the walls of the ventricle thin Can see micro-thrombi develop within the heart (as the heart can’t eject the blood out well- it “pools” leading clots to develop The valves (tricuspid and mitral) are often normal but can develop incompetence over time as the ventricle dilates and stretches. Causes  often unknown (hence – idiopathic) Often 20-30% of cases have a familial origin (autosomal dominant most common) Genes have no yet been identified Is seen in a disportionate number of alcoholics – though this is reversible if drinking stops Can be a result of post- viral myocarditis Manifestations Heart failure  usually initial finding Profound dyspnea on exertion (d/t decreased cardiac output and development of pulmonary edema) Sinus tachycardia, atrial fib, & ventricular dysrhythmias lead to sudden death Left heart failure is cause of death in 75% of individuals with dilated cardiomyopathies Ejection fraction is