Download SDL 13- Ischemic Heart Disease Ischemic Heart Disease AKA

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