Pathology 6020 - Year 2005 Paul Urie, M.D., Ph.D. Dec. 12, Monday 9:00-10:00 AM ISCHEMIC HEART DISEASE AND CARDIAC ENZYMES Reading: Robins Pathologic Basis of Disease 7th edition: pages 571-587; or in the 6th edition pages 550-564. I. Incidence Accounts for 80% of deaths caused by heart disease or 30% of the total mortality in the United States. Mortality from IHD in the U.S. has decreased by 50% since 1963. II. Pathogenesis IHD is caused by an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. A. Reduced coronary blood flow Reduction in coronary blood flow is due to progressive stenosis by atherosclerosis in 90% of patients with IHD. Other etiologic factors are: vasospasm, thrombosis, or circulatory changes leading to hypoperfusion. Basic principle - coronary artery perfusion depends on the pressure differential between the ostia (aortic diastolic pressure) and coronary sinus (right atrial pressure). Blood flow is reduced during systole because of Venturi effects at the coronary orifices and compression of intramuscular arteries during ventricular contraction. Factors reducing coronary blood flow 1. Decreased aortic diastolic pressure 2. Increased intraventricular pressure and myocardial contraction 3. Coronary artery stenosis - transient or fixed a. Fixed coronary stenosis b. Acute plaque change -Not dependent on percent of fixed stenosis -Role of Inflammation and C-reactive protein c. Coronary artery thrombosis d. Vasoconstriction 4. Aortic valve stenosis and regurgitation 5. Increased right atrial pressure Coronary artery distribution patterns and frequency of stenosis Left anterior: (40-50%) Right: (30-40%) Left circumflex: (15-20%) anterior wall left ventricle, apex descending, anterior IV septum posterior wall left ventricle, posterior IV septum lateral wall left ventricle Intramyocardial collateral vessels are present in all hearts with pressure gradients permitting flow despite occlusion of major vessels. The cross-sectional area of the coronary artery lumen must be reduced by more than 75 percent to significantly affect perfusion. Coronary atherosclerosis is segmental, and usually involves the proximal 2 cm of arteries (epicardial). III. B. Increased myocardial oxygen demand Tachycardia Hypertrophy Hypermetabolism - exercise Infection Pregnancy Hyperthyroidism Drugs C. Availability of oxygen in the blood Anemia Carboxyhemoglobin Pulmonary disease Right to left shunting of blood Patterns of ischemic heart disease A. Angina pectoris - a symptom complex of IHD characterized by paroxysmal attacks of chest pain, usually substernal or precordial, caused by myocardial ischemia that falls short of inducing infarction. B. 1. Stable angina (typical) - paroxysms of pain related to exertion and relieved by rest or vasodilator, subendocardial ischemia. Chronic, fixed atheromatous plaques that are >75%. 2. Variant or Prinzmetal's angina - angina that classically occurs at rest and is caused by reversible spasm of the coronary arteries. 3. Unstable angina - prolonged pain, pain at rest in a person with stable angina, or worsening of pain in stable angina. Abrupt disruption, fissure, or thrombosis that is nonocclusive. This may be the prodrome to MI. Sudden cardiac death - Unexpected death from cardiac causes usually within one hour after cardiac symptoms or without the onset of symptoms. Most common is plaque disruption and acute thrombus, platelet aggregates or thromboemboli. It strikes 300,000-400,000 persons annually. (Also includes other cardiac disorders (10-20%): congenital abnormalities, aortic stenosis, MVP, myocarditis, cardiomyopathies, pulmonary hypertension, conduction defects) Death is due to ventricular electrical instability (arrhythmia). C. Myocardial infarction 1.5 million people in US affected annually. 30% die - half in the first hour. 250,000 people/year die before reaching hospital. Women are relatively protected during reproductive years, but estrogen replacement does not slow atherosclerosis after menopause. Coronary artery with thrombus Transmural infarct - usually involves the LV or in 15-30% it may involve septum with extension into the RV. Isolated infarcts of RV and right atrium are extremely rare. Infarct is within area fed by one coronary vessel. Pathogenesis of transmural infarcts (most common type of MI) a. Occlusive coronary thrombus overlying an ulcerated or fissured stenotic plaque causes 90% of transmural AMI. b. Vasospasm with or without coronary atherosclerosis and possible association with platelet aggregation. c. Emboli from left sided mural thrombi, vegetative endocarditis, or paradoxic emboli from the right side of heart through a patent foramen ovale. Recent transmural infarct Subendocardial infarct - multifocal areas of necrosis or circumferential necrosis confined to the inner 1/3-1/2 of the LV wall. May be caused by hypotension, global ischemia, etc. and does not follow distribution of a single vessel. 1. Key Events in MI Time Seconds <2 minutes 20-40 minutes > 1 hour Feature Onset of ATP depletion Loss of contractility Irreversible cell injury Microvascular injury Mitochondrion with ischemia in an early infarct 2. Morphology of MI Time Reversible 0-1/2 hour Gross Features None Irreversible ½ - 4 hours 4-12 hours None Dark mottling 12-24 Dark mottling 1-3 days Mottling with yellow infarct center 3-7 days Hyperemic border, central yellow softening Maximally yellow and soft, depressed red margins Red-gray depressed infarct borders Gray-white scar, progressive from border to center of infarct Scarring complete 7-10 days 10-14 days 2-8 weeks >2 months Microscopic Features EM only relaxation of myofibrils; glycogen loss; mitochondrial swelling Waviness of fibers Edema, hemorrhage, early coagulative necrosis Coagulative necrosis, neutrophils infiltrate, pyknosis, contraction bands in reperfusion injury Complete coagulative necrosis with loss of nuclei and striations; interstitial neutrophils Dying neutrophils, macrophages begin phagocytosis of dead myocytes at border Phagocytosis of dead cells; early granulation tissue Granulation tissue with new vessels and collagen deposition Increased collagen and decreased cellularity and vascularity Dense collagenous scar Contraction bands in an early infarct. They are dark pink, and consist of greatly contracted, ineffective actin and myosin fibrils. Wavy fibers are another sign of an early infarct. Loss of nuclear basophilia in early infarct. Some contraction bands also present. Coagulative necrosis (~24h after infarct) Coagulative necrosis and a few inflammatory cells Coagulative necrosis, interstitial bleeding, and a few inflammatory cells. Coagulative necrosis plus many neutrophils (2-3 day old infarct). Coagulative necrosis with neutrophils and nuclear debris (2-3 day old infarct). Infarct with numerous macrophages (slightly older, ~7 days). Macrophages and granulation tissue (~ 10-day-old infarct) Mostly macrophages and granulation tissue. Note the hemosiderin (brown). 10-14-day-old infarct. Pale area in recent infarct Pale area in recent infarct Two areas of pale, recent infarction Large, pale areas of infarction, including papillary muscle that ruptured Old infarct. It is a firm scar Old infarct with scar and organizing thrombus. LV aneurysm with thrombus. 3. Complications of MI a. none (10-20%), death (7-13% of those receiving aggressive reperfusion therapy) b. arrhythmias and conduction defects (75-95%) c. congestive heart failure, pulmonary edema (60%) d. cardiogenic shock (10-15%) e. pericarditis (50%) f. mural thrombosis (40%) and thromboembolism (15%) g. rupture of ventricle, papillary muscle or ventricular aneurysm formation (4-8%) rupture usually occurs at 3-7 days Ruptured papillary muscle in recent MI. Recent infarct with mural thrombus. Recent infarct with perforation Another Rupture in an acute MI. This typically happens 3-5 days after the infarct. Recent infarct with rupture (arrow). Recent infarct with mural thrombus (arrow to thrombus). Infarct with mural thrombus Recent infarct with huge mural thrombus 4. Therapeutic modalities a. Infarct modification by thrombolysis b. PTCA - balloon dilatation c. Directional atherectomy d. Coronary bypass surgery e. Coronary artery stents Coronary artery bypass graft (saphenous). Coronary artery bypass graft (Dacron). 5. Reperfusion modification of infarction <20 minutes get salvage of myocardium, may have stunning 2-4 hours get partial salvage with central necrosis > 6 hours of no benefit in reducing infarct size Gross findings show hemorrhage in infarcted and reperfused regions. Microscopic shows contraction bands and interstitial RBCs. D. Chronic IHD with heart failure, hypertrophy and interstitial fibrosis (ischemic cardiomyopathy). These patients make up 50% of heart transplant recipients. 1. Morphology Gross - LV usually dilated, moderate-severe atherosclerosis, focal small scars confined to the LV wall, pericardial fibrous adhesions Microscopic - myocyte hypertrophy and focal atrophy with myocytolysis of single and clusters of cells; focal small interstitial scars; coronary atherosclerosis 2. Clinical significance Slow, progressive heart failure with or without previous MI or angina, sometimes referred to as ischemic cardiomyopathy Responsible for 40% of the mortality in IHD Congestive failure in chronic ischemic heart disease Diffuse fibrosis in chronic ischemic heart disease. There is also myocyte hypertrophy and a decrease in small vessels. IV. Diagnostic laboratory testing in acute MI A. Serum enzymes - leak from necrotic cells, there is a more rapid rise with reperfusion treatment 1. Creatine kinase (CK, CPK) - composed of two subunits "M" and "B" which combine to yield three isoenzymes MM, MB, BB Tissue Skeletal muscle Myocardium Brain Bladder Bowel BB 0% 0% 90% 95% 100% MB 2% 15-40% 0% 0% 0% MM 98% 60-85% 10% 5% 0% CK-MB begins to rise in 2-4 hours, peaks at 24 hours and returns to normal by 72 hours. 2. Troponin - cardiac muscle specific enzymes, Troponin I and Troponin T appear within 2-4 hours, peak at 48 hours and remain elevated 7-10 days. Normally there is no troponin in the serum. 3. Aspartate aminotransferase (AST, SGOT) - found in the cytoplasm and mitochondria of a variety of tissues including liver, heart, and skeletal muscle 4. Lactate dehydrogenase (LD, LDH) - composed of four subunits of two different types "H" and "M," and yields five isoenzymes. LD-l (HHHH) LD-2 (HHHM) LD-3 (HHMM) LD-4 (HMMM) LD-5 (MMMM) 19-39% 25-50% 16-31% 2 - 9% 2 -17% Myocardium, erythrocytes, kidney Erythrocytes, kidney Lung Skeletal muscle Liver, skeletal muscle LD-2 (most abundant), LD-l, LD-3, LD-4, LD-5 (least abundant) LD-l/LD-2 < 1 (normally) V. C-reactive protein (CRP) may predict the risk of MI in patients with angina. A highly sensitive CRP of >3 mg/L is associated with high risk of cardiovascular disease. VI. Hyperhomocysteinemia - independent risk factor for vascular disease including coronary artery disease. Patients with an inborn error of metabolism causing homocystinuria have premature atherosclerosis. Other patients may have increased homocysteine due to decreased folate and B6 intake. A. Homocysteine plasma levels are increased by 15-40% in patients with CAD (levels >100 micromols/L). Normal <16 micromol/L. B. VII. Treated with folic acid, pyridoxine or vitamin B12 BNP – Brain natriuretic peptide (B-type natriuretic peptide) marker for CHF A. Neurohormone predominately produced in the left ventricle in response to pressure and volume expansion. Synthesis and secretion is a protective response that is up regulated in patients with heart failure, resulting in vasodilation and diuresis/natriuresis. Elevated BNP are seen in hypertension, tachycardia, cardiomyopathy, MI, mitral and aortic stenosis. B. Clinical utility Detect asymptomatic CHF Objectively assess heart failure severity – correlating with NYHA classification Monitor therapy and disease progression Predict 30-day and 10-month mortality after AMI C. BNP < 100 pg/ml – no heart failure BNP 100-300 pg/ml – heart failure is present BNP 300-600 pg/ml – mild heart failure BNP 600-1000 pg/ml – moderate heart failure BNP >1000 pg/ml – severe heart failure