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SDL 13- Ischemic Heart Disease Ischemic Heart Disease AKA Coronary artery disease, coronary heart disease 4 syndromes from myocardial ischemia: angina pectoris, myocardial infarction, chronic IHD with CHF, sudden cardiac death Etiology: 80% cases, coronary artery obstruction by atherosclerotic plaques Decades of silent, slowly progressive, coronary atherosclerosis Mean age ischemia 60 years Epidemiology: most common type of heart disease in US—80% of all cardiac deaths Less frequent in underdeveloped countries Anginal Syndromes Chronic Stable Angina Pectoris Exercise induced retrosternal chest pain (or slightly left of midline) Avg age: 67 women and 60 men Clinical manifestations: precip by exertion, eating, cold, stress Constricting, squeezing, choking Radiate bilaterally into the arms (left more than right), neck and lower jaw Relieved in 5-15 min by rest or vasodilator durgs (NTG) Morphology: coronary atherosclerosis affects at least one large epicardial coronary arteries Reduce the cross-sectional area more than 70% Plaque is small lipid-pool and thick fibrous cap (“hard” plaque) Pathophysiology: Myocardial ischemia caused by excessive increase in O2 demand in presence of severe (>70%) fixed coronary stenosis Exercise ECG (stress test) shows ST- segment depression—indicates subendocardial ischemia Etiology: coronary atherosclerosis Prinzmetal Angina (Variant Angina) Atypical form of angina that occurs at rest and caused by coronary artery spasm Epidemiology: rare; 90% male; younger than those with chronic stable angina (51-57); cigarette smokers Clinical Manifestations: occurs at rest, more often at night (early morning) without cause Last no longer than 15 min and respond to nitroglycerine Exercise EKG is negative in 70% Transient ST-segment elevation (transmural ischemia) that disappears rapidly Pathophysiology: caused by focal epicardial coronary artery spasm usually at atherosclerotic stenosis Some pts have normal coronary arteries 25% generalized vasospastic diathesis, includes migraine and Raynaud phenomenon Acute Coronary Syndromes A set of signs and syndromes that result of abruptly decreased blood flow Subtypes unstable angina, subendocardial infarction, transmural infarction, sudden cardiac death Morphology: immediate cause is disruption of atherosclerotic plaque in man, epicardial coronary artery Great majority of ACS’s follow the disruption of a previously non-severe atherosclerotic lesion Patients have mild-to-moderate disease before plaque disruption (vulnerable plaque) less than 70% stenosis Plaque biology defines risk for rupture Vulnerable plaques: large-lipid pool with inflammatory cells and a thin, fibrous cap Soft, more prone to rupture and exposure of thrombogenic core to blood intracoronary thrombosis Hard plaques: small lipid-pool and thick, collagen rich cap that may progress chronic stable angina pectoris SDL 13- Ischemic Heart Disease Unstable Angina Preinfarction angina, accelerated angina, “crescendo” angina, intermediate coronary syndrome, acute coronary isufficiency Less predictable relationship to exercise than does chronic stable 3 patterns: angina pain at rest or sleep, episodes of chest pain that become progressively more frequent and longer in duration over a 3-4 day period, angina pain with efforts that previously tolerated Classification: unstable angina and subendocardial infarction (non-ST-segment elevation infarction) previously considered as separate conditions Common pathophysiologic basis and clinical manifestations that are difficult to distinguish Difference btw them is NSTEMI is reduced flow enough to produce detectable necrosis Morphology: erosion or rupture of atherosclerosis with a non-occlusive thrombus causing a severe narrowing of coronary artery lumen No biochemical evidence of myocardial necrosis Pathophysiology: unpredictable clinical manifestations due to intermittent epicardial coronary artery obstruction from coexistent thrombosis and thrombolysis, coronary vasospasm, distal platelet thrombi Clinical manifestations: ECG canges are not characteristic of infarction Serum cardiac markers are normal Pts at risk of ST-segment elevation infarction or sudden death Principles of treatment: symptoms stabilize with conservative medical therapy Antiplatelet (aspirin), anticoagulants (LMWH) and coronary vasodilators (NTG) Thrombolytic therapy has no beneficial effect Sudden cardiac Death Unexpected death due to cardiac causes within a short time period from the onset of symptoms (1hr) Prodromal symptoms such as palpitations, chest pain, dyspnea Epidemiology: avg age 65yrs, 70-80% men Pathophysiology: immediate cause of sudden death is ventricular arrhythmia: vfib, vtach in 70%; brady/asystole in 30% Etiology: coronary atherosclerosis underlies more than 80% of cases Acute arterial lesion (plaque fissure, plaque ulceration, luminal thrombosis, plaque hemorrhage) 95% Only a fraction have total occlusion Half of patients resuscitated show evidence of MI by elevated cardiac enzymes 20% cases: cardiomyopathy, valvular heart disease, myocarditis, CHD, hypertension with LV hypertrophy Chronic Ischemic Heart Disease (Ischemic cardiomyopathy) CIHD: progressive congestive heart failure as a consequence of ischemic myocardial damage Clinical: CHF predominates, loss of 50% or more of LV myocardium Pathophysiology: mortality associated with acute MI is 5-7% Progressive coronary atherosclerosis eventually develop chronic CHF due to several factors Irreversible loss of myocardium (infarcts), replacement with scar tissue, hypoperfusion of remaining myocardium which leads to chronic ventricular contractile dysfunction (hibernating myocardium), severe mitral regurgitation due to papillary mm scarring Morphology: heart is globally enlarged similar to dilated cardiomyopathy Transmural or subendocardial scars are present—old myocardial infarcts Non-infarcted regions show hypertrophy combined with increased interstitial fibrosis Subendocardial “hibernating” myocardium reveals diffuse vacuolization (myocytolysis) SDL 13- Ischemic Heart Disease Myocardial Infarction Discrete focus of ischemi muscle necrosis in the heart Subendocardial Infarct NSTEMI, non-Q wave MI—inner 1/3 to ½ of LV May arise within 1 epicardial coronary arteries or may be circumferential involving subendocardial territories of all the coronary arteries Clinical presentation: similarly to unstable angina, but with evidence of necrosis ST segment depression on EkG, and cardiac markers of necrosis (CK-MB or troponin) are elevated Morphology: cause is non-occlusive thrombus that develops on a disrupted atherosclerotic plaque Subendocardial zone is normally least perfused region of myocardium and most vulnerable to any reduction in coronary blood flow Special subtype-Circumferential infarct: from massive hemorrhage, global hypotension or shock, superimposed on chronic otherwise non-critical, atherosclerotic coronary stenoses on 2-3 arteries Epidemiology: more frequent than transmural Complications: necrosis limited to inner layers of heart, pericarditis and ventricular rupture are not seen Prognosis: better than transmural infarction Transmural infarct (ST segment elevation, Q-wave MI) Full or nearly full thickness Etiology: most lethal acute coronary artery syndrome—occlusive coronary thrombosis results in total cessation of coronary blood flow EKG manifestations: ST segment elevation due to full thickness of ischemia, followed by new Q wave Morphology: vast majority with coronary atherosclerosis 90% associated with superimposed luminal thrombus—disruption of atherosclerosic lesions that are not hemodynamically significant (50-60% narrowing of cross-sectional area of coronary artery Topography of Myocardial Infarcts Segmental process limited to the distribution of affected artery 1. Left anterior descending artery (LAD): 50%; occlusion of proximal portion of LAD necrosis of anterior wall of lV, IV septum, apex circumferentially 2. Right coronary artery (RCA): 30%; occlusion of proximal RCA--> inferior/posterior wall fo LV, posterior IV septum, sometimes inferior/posterior wall of the RV 3. Left circumflex artery (LCX): 20%; occlusion of proximal protion of LCX lateral wall of LV except at apex (lateral infarct) Early Biochemical Consequences of Myocardial Ischemia Normal Myocardium: under aerobic conditions-- fatty acid 60-90% of energy for synthesis of ATP Rest comes from anaerobic glycolysis and oxidation of pyruvate and lactate in Krebs cycle 2/3 of ATP used for contraction; 1/3 by ion pumps Ischemic Myocardium: sudden occlusion causes shift from anaerobic metabolism to anaerobic glycolysis within seconds Anaerobic glycolysis is inefficient; ATP formation decreases Ion pumps are impaired resulting in loss of intracellular K+ and accumulation of intracellular Na+ and H2O Anaerobic glycolysis produces lactic acid; rise in H+; fall in pH Lactate and K+ accumulate in blood of cardiac vein Loss of myocardial contractility occurs within 2 min; ischemia lasting 20 min irreversible injury of subendocardial cardiomyocytes (structural defects in sarcolemmal membrane) Prolonged ischemia (60 min) injury to microvasculature SDL 13- Ischemic Heart Disease Wavefront Phenomenon Necrosis spreads from endocardium toward epicardium: the myocardium supplied by the affected artery is defined as the “area at risk” Irreversible injury to cardiomyocytes begins in the subendocardium for 20 min Spreads toward the epicardium and injury occurs maximally in almost the entire area at risk when 6 hours 6 hr coronary artery occlusion results in an almost transmural infarction Most of the damage occurs in 2-3 hrs; restoration of blood flow by thrombolysis within the first 4-6 hrs is associated with salvage of ischemic myocardium and improved mortality Greater if restoration occurs in 1-2 hrs Role of collateral flow within area of risk: 40% pts with acute MI have a well developed collateral circulation Never achieves 100% of the area at risk, limited to endocardial 2/3 of wall Lack of collateral circulation causes 100% involvement of area at risk (progresses to epicardium with acute fibrinous pericarditis Infarct Size Ultimate infarct size is major predictor of long-term outcome Depends on: severity of obstruction, size of area at risk; duration of obstruction; O2 needs of myocardium Gross Morphology of Acute MI First 12 hours of acute MI: not identifiable grossly; can be enhanced by tetrazolium salt solutions Nitroblue tetrazolium (NBT) and tetrazolium chloride (TTC) are dyes sensitive to tissue dehydrogenase enzyme Infarcted area revealed as an unstained pale zone Contrary, non-infarcted myocardium shows a deep-blue (NBT) or brick-red (TTC) Infarcted myocardium detected within 2-3 hrs after the onset of ischemia Myocardial pallor: earliest change occurs 12 hrs after onset of ischemia 2nd to 3rd day: central area of yellow discoloration (necrotic myocardium) with thin peripheral, dark-red rim of highly vascularized inflammatory tissue at the border 5th to 7th day: more distinct w/ central, soft and yellow area and thicker and depressed dark-red rim (young granulation) 2nd to 4th weeks: central, yellow area decreases in size and progressively larger dark-red border becomes gray (young scar tissue) When healing is complete the necrotic myocardium is removed and granulation tissue progressively matures into a young (gray) and later a mature (white) scar Healing may be complete as early as 4-6 weeks in small infarcts but takes 2-3 months when large Healed infarcts are white and hard from scarring, ventricular wall may be thinned in transmural infarcts Subendocardial infarcts do not result in thinning Light Microscopic Findings in Acute MI Wavy fiber change: discerned at 1 hr after the onset of chest pain Groups of cardiomyocytes have become thinner with elongated sarcomeres as a result of stretching of ischemic non-contractile fibers by the adjoining viable contractile cardiomyocytes Coagulative necrosis of myocardial cells and neutrophilic infiltration: hypereosinophilic myocardial cells can be discerned between 12-24 hours—indicates coaguative necrosis Various degrees of nuclear pyknosis, karyorhexis, and karyolysis Hypereosinophilic myocardial cells preserve their cross striations, which show elongated sarcomeres Necrotic myocardium elicits acute inflammation Present by 24 hrs at the border areas (where blood flow is maintained) 3-4d: neutrophils invade diffusely the entirely infracted area and fragment resulting in nuclear dust 5d: few if any neutrophils remain Macrophagal infiltration: at 4 days macrophages appear at the border area and phagocytize the necrotic fibers Fibers replaced by ingrowth of granulation tissue (grossly dark-red border) Fibroblasts proliferate along new capillary vessels, new collagen is deposited; scar tissue at 4d at periphery SDL 13- Ischemic Heart Disease Myocardial scar: granulation tissue becomes less vasculatized and more fibrous (grossly gelatinous and gray scar) Infarct completely healed, scar tissue matures and becomes dense and white General evolution of morphologic changes in MI Infarct Modified by Reperfusion Most effective way to salvage ischemic myocardium is to restore tissue perfusion as rapidly as possible By: thrombolysis, balloon angioplasty, and coronary arterial bypass grafting Salvage of Ischemic Myocardium: reperfusion in 4-6 hrs following onset of chest pain of ECG changes Infarct is likely to be subendocardial without transmural ectension Contraction band necrosis: alters the morphology of cells already irreversibly inured at the time of reflow Lethally inured cardiomocytes develop extensive contraction bands—eosinophilic (4-5 mm wide) Closely packed hypercontracted sarcomeres Produced by exaggerated contraction of myofibrils at instant perfusion Plasma reperfusion the infarction irreversibly injured cells, which have lost the control of their cell membranes Concentration of calcium ions inducing hypercontraction of dead myocardial cells Hemorrhagic infarct: reperfused infarct develops a confluent area of hemorrhage because the vasculature injured leaks Reperfusion injury: despite salvage of some myocardium some small amount of new cellular damage may occur Mediated by generation of O2 fee radicals from infiltrating leukocytes Prominent myocardial cell apoptosis—clinical significance uncertain No-reflow phenomenon: reperfusion of ischemic myocardium after an interval longer than 2-3 hrs-> no reflow in subendocardial zone Failure of blood flow to reperfuse an ischemic area after the physical obstruction has been removed or bypassed Associated with microvascular damage No reflow areas consist of swollen endocardial cells Plugging of the capillaries by red cells neutrophils, platelets, and fibrin microthrombi Myocardial stunning: salvaged myocardium demonstrates prolonged but reversible mechanical (contractile) dysfunction Recovery may take hours or days Efficacy of thrombolysis measured by evidence of restoration of contractile function of the salvaged myocardium Echo demonstrates ischemic reperfused area as diskinetic or akinetic—does not contract but bulges out during the LV systole—improves 2 weeks later Hibernating myocardium: similar and different from the concept of stunned myocardium Occlusion of single major coronary artery with depression of contractile function and dependent upon collateral circulation SDL 13- Ischemic Heart Disease Characterized by chronic, sublethal ischemia, associated with contractile dysfunction Once flow is restored- contractility of hibernating myocardium is restored Morphologically: show vacuolar degeneration or mycytolysis, los of myofibrils an formation of large vacuolar space in the preinuclear region and throughout the cytoplasm Clinical Manifestations of Myocardial Infarction Diagnosed by typical symptoms, biochemical evidence or necrosis and EKG Typical symptoms of acute myocardial infarction include: Sudden onset of severe retrosternal anginal pain Anginal pain lasts more than 30-45 minutes Anginal pain is described as pressure, aching, burning, crushing, squeezing in quality Anginal pain is not relieved by nitroglycerin Anginal pain radiates over the anterior chest, left arm or both arms (particularly the medial aspect), and into the neck or jaw Associated symptoms include dyspnea, nausea, vomiting, diaphoresis Marked apprehension is common 23% of MI’s go unrecognized due to absence of symptoms or atypical symptoms Plasma Diagnostic Markers Creatinine Kinase (CK): M monomer predominates in skeletal muscle and heart B monomer predom in brain and internal visceral organs 3 isoenzymes formed by 2 monomers: CK-MM (muscle, 85% heart), CK-MB (15% heart), CK-BB (brain and lungs) CK-MB: highly sensitive and specific in diagnosis of acute myocardial infarction Reflects necrosis and does not occur with reversible ischemia; sensitive and specific Myoglobin: low molecular weight through cardiac and skeletal muscle Muscle injury unspecific and does not differentiate btw skeletal and cardiac mm Cardiac troponins T and I: part of sarcomere complex I is not present in skeletal muscle- specific immune assays for measurement Normal levels near 0, not upregulated with heart hypertrophy Temporal profiles of cardiac markers released into plasma Plasma CK-MB activity: increased after 6 hrs; max at 12-24 hrs; baseline again at 48-72 hrs Baseline total CK: 55-170 IU/L Baseline CK-MB: 2-4 IU/L CK-BM: 3-5 ng/mL Diagnosis of CK-MB: increase above 9IU/L or protein >7ng/mL CK-MB subforms: converted to MB-2 into MB-1 due to proteolysis MB-2 to MB-1: 1:1 ratio Total CB-MB does not change, MB-2/MB-1 ratio changes Plasma myoglobin: increased within 2 hrs of onset of MI (ref <90, max btw 7-12hrs, normal after 24 hrs) SDL 13- Ischemic Heart Disease Plasma troponin I or T: increased after 6 hrs (ref ranges: T: <.2ng/ml; I: <.03 ng/ml) Max levels: 25-36 hrs and return to normal 10-12 days Diagnosis of acute MI <6 hrs from symptoms: CK-MB subforms and myoglobin Diagnosis of acute MI 6-10 hrs from symptoms: CK-MB (or total CK) and troponin T and I Myoglobin not sensitive after 7 hrs due to rapid renal excretion Diagnosis of acute MI >48 hrs from symptoms: LDH isoenzymes peak 48-72 hrs, remain elevated 10-14 days Preferred is now troponin I or T Complications of Acute MI Decreasing mortality are advent of coronary care units and early reperfusion therapy 9pharmacological thrombolysis and percutaneous coronary intervention (stent and angioplasty) Arrhythmias: 90% develop; some form within 24 hrs (25%) Sudden death in large proportion, V-tach in 70% of cases within first 12 hrs AV block: 5-15% with anterior or inferior infarctions; Vascularization of heart’s conduction system: RCA: AV node, bundle of His RBB: LCA LBB: both Massive septal infarction with damage to both the bundle branches has been found in patients with anterior infarctions (such as obstruction of LAD). Patients with inferior/posterior infarctions (such as obstruction of RCA) usually have histologically normal conducting systems. The main cause of the AV block in patients with posterior infarction is necrosis of the atrial prenodal myocardium. Massive AV node necrosis has been described associated with AV node artery thrombosis, but is uncommon. Clinical presentation: complete heart block with anterior or inferior/posterior infarctions Escape rhythm is usually stable with narrow QRS and rates exceeding 40/min Inferior/posterior MI: responds to atropine Anterior MI precedes a complete AV block—occurs suddenlt and high mortality rate Cardiogenic shock: decreased pumping ability of the heart that causes shock-like state 10% of AMI cases, 9% of pts with ST-segment elevation; 2% pts with NSTEMI When more than 40% myocardium is irreversibly damages Decreased urine output, altered mental state, sustained hypotension, tissue hyperfusion, JVD, cardiac gallop Leading cause of death in AMI: overall hospital mortality rate 57% Infarct extension: Early in-hospital reinfacrtcion consists of recent areas within infarct zone may present as new necrosis in lateral margins Occurs between 2-10 days following infarction and clinically manifests as recurrent chest pain or sudden deterioration of cardiac function Reappearance or re-elevation of plasma cardiac markers Necrotic and healing myocardium of several different recent ages within the same vascular territory Infarct expansion: thinning of the transmurally infracted area, not an increase in necrosis Begins in hours- peak 7-14 days 40% of anterior transmural AMIs Usually develops in large transmural infarcts by stretching of cardiomyocyte bundles and dilatation of LV More congestive heart failure symptoms, greater mortality, infarct rupture and late aneurysm Myocardial rupture: laceration or tearing of the walls Up to 10% of AMIs; 2nd most common cause of in-hospital mortality (#1: cardiogenic shock) 3-5d when infracted wall is weakest bc coagulative necrosis, intense neutrophil infiltration, collagen matrix degradation Leads to hemopericardium and cardiac tamponade—fatal At border between the infracted area and the viable myocardium—only transmural infarcts rupture Ventricular free wall (10%), ventricular septum (2%), LV papillary mm (rarely atrial walls) Papillary muscle rupture: posteromedial papillary muscle of the LV is 2x as likely to rupture as anterolat Free wall rupture manifests with severe chest ain, abrupt electromechanical dissociation, asystole, hemodynamic collapse and death (VSD: CHF, cardiogenic shock; papillary m: pulmonary edema) SDL 13- Ischemic Heart Disease Right ventricular infarction: posterior/inferior infarction—IV septum and posterior RV wall Acute postinfarction pericarditis: associated with transmural infarcts, pain, friction rub, effusion Serofibrinous pericardial effusion—benign, 30% pts Dressler syndrome: delayed post-infarction pericarditis 1-4% pts with AMI; higher in open heart surgery Persistent low grade fever, pleuritic chest pain, pericardial friction rub, pericardial effusion 2-3 wks following AMI: can be delayed for a few months, subsides in a few days Immunologic mechanism: hypersensitivity with antigen released from injured tissue Autoantibodies againse pericardium Accumulation of a serofibrinous effusion Cardiac aneurysm: thinned LV protrudes in systole and diastole Complication of a large acute MI that underwent expansion 5-10% pts with AMI Anterior transmural infarctions are at greater risk Heart failure, ventricular arrhythmias, systemic embolism may be asymptomatic Expand during systole, ventricle gets put at mechanical disadvantage Mural thrombus and embolization: 20%; brin, kidneys, eye, spleen, bowel, legs Anterior infarcts more frequently associated with mural thrombosis