Ischemic Heart Disease — Pathology

Atherosclerotic Plaque Development and Coronary Stenosis

• Endothelial injury from mechanical stress (hypertension, turbulent flow at branch points), smoking, hyperlipidemia, and diabetes initiates atherosclerosis
• Lipoprotein accumulation occurs via oxidative modification of LDL, promoting uptake by macrophages via scavenger receptors to form foam cells
• Progressive intimal thickening with smooth muscle cell proliferation and extracellular matrix deposition creates stable atherosclerotic plaques; stenosis >70% of luminal diameter typically produces significant flow limitation at rest
• Compensatory coronary vasodilation maintains resting flow until critical stenosis develops, but reserve is exhausted during increased metabolic demand

Myocardial Ischemia and Oxygen Deprivation

• Reduced coronary blood flow decreases oxygen delivery to mitochondria, impairing oxidative phosphorylation and ATP synthesis
• Anaerobic metabolism becomes predominant, producing lactate accumulation and intracellular acidosis
• Loss of Na+/K+-ATPase function leads to intracellular sodium and calcium accumulation, causing myocyte swelling (hyperacute phase, minutes)
• Calcium overload activates proteases and phospholipases, triggering myocyte necrosis and release of intracellular contents

Acute Plaque Rupture and Thrombosis

• Vulnerable plaques with thin fibrous caps (composed of sparse smooth muscle and collagen) and lipid-rich cores undergo rupture, often at the shoulder region where mechanical stress is greatest
• Tissue factor exposure from plaque rupture activates the extrinsic coagulation cascade
• Platelet adhesion and activation via von Willebrand factor and collagen leads to primary hemostasis and white thrombus formation
• Secondary hemostasis generates thrombin, which crosslinks fibrin to form a red thrombus that may completely occlude the coronary lumen

Temporal Progression of Myocardial Necrosis

• 0-4 hours (hyperacute phase): Wavy myofibers, mitochondrial swelling; light microscopy appears normal
• 4-12 hours (acute phase): Coagulation necrosis with contraction band necrosis, early neutrophilic infiltration
• 1-3 days: Maximal neutrophilic infiltration, loss of nuclei and striations, dense eosinophilic cytoplasm
• 3-7 days: Granulation tissue with fibroblasts, macrophages (removing debris), and new capillaries
• >7 days: Fibrosis with collagen deposition and scar formation; complete remodeling by 8 weeks

Major Causes of Coronary Obstruction

• Atherosclerotic plaque rupture with thrombosis (~80-90% of acute MI): Accounts for the vast majority of acute coronary syndromes; plaques with large lipid cores, thin fibrous caps, and heavy macrophage infiltration are most prone to rupture
• Coronary artery vasospasm (Prinzmetal angina): Episodic vasospasm of epicardial coronary arteries, often at sites of atherosclerotic plaques; more common in smokers and cocaine users
• Plaque erosion (~10-20% of acute MI): Denudation of endothelium overlying plaque without frank rupture; more common in STEMI with female preponderance and associated with smoking
• In situ thrombosis: Occurs on intact or minimally stenotic atherosclerotic plaques
• Secondary coronary obstruction: Coronary artery dissection (spontaneous or traumatic), embolism (from endocarditis, left atrial thrombus), vasculitis

Non-modifiable Risk Factors

• Age: Risk increases with advancing age; men >45 years, women >55 years
• Male sex: Males develop IHD 10-15 years earlier than postmenopausal women
• Positive family history: Premature CAD in first-degree relatives (<55 years in men, <65 years in women) doubles risk

Modifiable Risk Factors

• Hyperlipidemia: Elevated LDL cholesterol directly promotes atherosclerotic plaque formation; low HDL increases risk
• Hypertension: Increases endothelial shear stress and promotes atherosclerotic plaque formation and rupture
• Diabetes mellitus: Promotes atherosclerosis through multiple pathways (hyperglycemia, oxidative stress, inflammation); increases risk 2-4 fold; women with diabetes lose cardioprotective effects of estrogen
• Smoking: Causes endothelial injury, increases platelet aggregability, and reduces oxygen carrying capacity; single most modifiable risk factor
• Obesity: Associated with metabolic syndrome and increases overall cardiovascular risk
• Chronic kidney disease: Promotes atherosclerosis through uremia-induced inflammation and mineral metabolism disturbances
• Inflammatory markers: Elevated hsCRP, IL-6, and TNF-α predict increased risk independent of lipid levels

Stable Angina Pectoris

• Cardinal symptom: Substernal chest pressure, heaviness, or tightness, often radiating to left arm, jaw, or epigastrium; characteristically provoked by exertion (walking, stair climbing) or emotional stress and relieved by rest or nitroglycerin within 5-15 minutes
• Morphological basis: Occurs with coronary stenosis >70% luminal diameter; myocardial ischemia develops during increased metabolic demand when coronary vasodilatory reserve is exceeded
• Anginal equivalent: Dyspnea, fatigue, nausea, diaphoresis, or syncope may occur instead of chest pain, particularly in elderly, diabetic, or female patients
• Typical Canadian Cardiovascular Society (CCS) grading: Grade I (angina with strenuous exertion), Grade II (angina with moderate exertion), Grade III (angina with minimal exertion), Grade IV (angina at rest)

Acute Coronary Syndrome (ACS) — Unstable Angina and Acute Myocardial Infarction

• Acute coronary syndrome presentation: Sudden onset of severe, persistent chest pain (typically >20 minutes), often with diaphoresis, dyspnea, nausea, and sense of impending doom
• Anterior wall MI: Left anterior descending (LAD) occlusion; presents with anterolateral chest pain, anterior ST elevation, Q waves in V1-V4
• Inferior wall MI: Right coronary artery (RCA) occlusion; presents with epigastric/inferior chest pain, inferior ST elevation, ST changes in II, III, aVF; may include right ventricular involvement
• Posterior wall MI: Circumflex occlusion; presents with posterior ST depression (reciprocal change in V1-V2), tall R waves
• Physical exam findings: Anxiety, diaphoresis, cool extremities (↓ cardiac output), S3 gallop (ventricular dysfunction), new systolic murmur (papillary muscle rupture or ventricular septal defect), pulmonary crackles (pulmonary edema), hypotension (cardiogenic shock)
• Laboratory findings: Elevated cardiac troponins (I or T) peak 24-48 hours post-MI; elevated CK-MB, myoglobin; elevated LDH with LDH >AST (ischemic pattern); leukocytosis

Sudden Cardiac Death

• Presentation: Abrupt loss of consciousness and pulse; occurs within 1 hour of symptom onset in majority of cases
• Morphological basis: Ventricular fibrillation (VF) triggered by acute transmural ischemia, particularly in the first 24-48 hours of MI when myocardium is electrically unstable
• Risk period: Highest risk in hyperacute phase (0-4 hours) when severe ischemia causes maximal myocardial irritability

Chronic Ischemic Heart Disease

• Presentation: Progressive dyspnea, fatigue, exercise intolerance resulting from repeated ischemic episodes and progressive myocardial fibrosis
• Morphological basis: Recurrent ischemia leads to chronic myocardial remodeling with hypertrophy, fibrosis, and progressive systolic dysfunction
• Dilated left ventricle with reduced ejection fraction (HFrEF)

Electrocardiography (ECG)

• Stable angina: May show ST depression or T wave inversion during ischemia; baseline ECG may be normal between episodes
• STEMI: ST segment elevation ≥1 mm in contiguous leads (≥2 mm in precordial leads) reflects transmural ischemia; may progress to pathological Q waves (≥40 ms duration, ≥1/3 QRS amplitude) within hours to days, indicating established infarction
• NSTEMI: ST depression or T wave changes without ST elevation; reflects subendocardial ischemia
• Unstable angina: ECG changes may be dynamic or absent
• T wave inversion in specific leads localizes ischemia (e.g., V1-V4 = anterior/LAD, II/III/aVF = inferior/RCA)

Cardiac Biomarkers

• Cardiac troponin I or T: Most specific and sensitive markers for myocardial necrosis; rise within 2-4 hours of MI onset, peak at 24-48 hours, remain elevated 7-14 days; serial measurements (0, 3, 6 hours) improve diagnostic sensitivity; high-sensitivity troponin assays detect infarction earlier
• CK-MB (myocardial fraction): Traditional marker; rises 3-12 hours, peaks at 24-48 hours; less specific than troponin but useful for detecting reinfarction (recurrent elevation after initial decline)
• Myoglobin: Earliest rise (1-4 hours) but least specific; rapidly cleared by kidneys
• LDH (lactate dehydrogenase): LD1 > LD2 pattern ("flipped pattern") appears 24-48 hours post-MI; historically important before troponin era

Coronary Angiography

• Gold standard for diagnosis and localization of coronary artery stenosis
• TIMI flow grading: TIMI 0 (no flow) to TIMI 3 (normal flow); indicates severity of obstruction and perfusion status
• Identifies culprit lesion in acute MI; reveals collateral circulation (better prognosis if present)
• Allows assessment of lesion morphology: Eccentric vs. concentric, presence of ulceration, thrombus, or dissection

Stress Testing

• Exercise ECG: Induces ST depression ≥1 mm in ischemic myocardium; may show ischemic ST/T changes or angina; sensitivity 68%, specificity 77%
• Stress echocardiography: Reveals regional wall motion abnormality (hypokinesis or akinesis) in ischemic territory during stress; normal with dobutamine or exercise argues against significant stenosis
• Nuclear stress testing (myocardial perfusion imaging): Reversible perfusion defect (appears with stress, resolves at rest) indicates inducible ischemia; fixed perfusion defect indicates prior infarction with scar

Coronary Computed Tomography Angiography (CCTA)

• Noninvasive imaging of coronary arteries with high sensitivity/specificity for stenosis >50%
• Useful in low-to-intermediate pretest probability patients to rule out CAD

Histopathology

• Hyperacute phase: Light microscopy appears normal initially ("infarct too early to see"); ultrastructurally, mitochondrial swelling and loss of glycogen occur; myofibrils show wavy appearance
• Confirmed by electron microscopy showing mitochondrial matrix swelling and glycogen depletion

• Coagulation necrosis with loss of nuclear basophilia and myofiber striations
• Contraction band necrosis: Hallmark finding of acute myocardial necrosis; characterized by thick, dark-staining bands perpendicular to myofiber axis, representing hypercontracted sarcomeres with Z-disk material; appears at edges of infarct where viable and necrotic tissue meet
• Early neutrophilic infiltrate beginning at edges
• Hyperemia (vascular congestion)

• Maximal acute inflammation with dense neutrophilic infiltrate obscuring necrotic myofibrils
• Coagulation necrosis with loss of nuclei, striations, and organelles; myofibers appear as eosinophilic, homogeneous ghosts
• Myofiber borders still preserved early, then dissolved

• Granulation tissue formation with prominent macrophages (replacing neutrophils), fibroblasts, and new capillary formation
• Phagocytosis of necrotic myofibrils by macrophages; "brown" macrophages contain hemosiderin from myoglobin degradation
• Fibrovascular response represents transition to healing

• Progressive fibrosis with dense collagen deposition
• Decreased vascularity and chronic inflammation
• Complete replacement of necrotic tissue by scar tissue (acellular, collagen-predominant)
• Borders sharpen as inflammation subsides; no residual necrotic debris by 8 weeks
• Ventricular remodeling with hypertrophy of surviving myocytes and chamber dilation

• Myocardial fibrosis with patchy scarring and myocyte hypertrophy
• Atherosclerotic coronary arteries with variable degrees of stenosis
• Left ventricular remodeling with dilation and wall thinning

Gross Pathology

• Pale appearance initially, may be imperceptible; tissue appears normal or slightly swollen
• By 24 hours, tan-yellow discoloration appears due to lipid accumulation and tissue edema

• Hyperemic (red) border surrounding pale yellow infarct zone (central area of necrosis)
• Demarcation is indistinct initially, becoming sharper by day 3

• White, grayish scar tissue with sharp demarcation from surrounding viable myocardium
• Thinning of infarcted wall (wall thickness decreased)
• Chamber dilation with apical aneurysm formation possible
• Pale or yellowish hue to scar tissue; may contain iron deposits (appears brown with Prussian blue stain)

Acute Myocardial Infarction — Immediate Management

• First-line treatment

First 24–48 hours — electrical and pump failure

• Ventricular fibrillation / pulseless VT: reentry around ischemic, partially depolarized myocardium; the most common cause of pre-hospital death. Emergency — immediate defibrillation and CPR per AHA ACLS; no antiarrhythmic substitutes for the shock.
• Sinus bradycardia and AV block: the AV nodal artery arises from the RCA in most people, so inferior MI produces vagally mediated bradycardia or Mobitz I; anterior MI with new Mobitz II/complete block signals extensive septal necrosis and predicts a worse outcome.
• Right ventricular infarction: proximal RCA occlusion; hypotension with clear lungs and elevated JVP. Confirm with right-sided leads (V4R). Preload-dependent — avoid nitrates and diuretics, give IV fluids.
• Cardiogenic shock: loss of a critical mass of contractile myocardium; the ACC/AHA acute coronary syndrome guidelines support emergency revascularization regardless of time from onset. Emergency.

Days 3–14 — mechanical rupture (macrophage collagenolysis leaves the wall weakest before scar matures; all are surgical emergencies)

• Papillary muscle rupture: the posteromedial papillary muscle has a single blood supply (PDA), so inferior MI causes acute severe mitral regurgitation — new holosystolic murmur, flash pulmonary edema; urgent echo.
• Interventricular septal rupture: new murmur plus an oxygen saturation step-up from right atrium to right ventricle.
• Free wall rupture: hemopericardium → tamponade with sudden PEA arrest, JVD, muffled heart sounds.
• Pseudoaneurysm: rupture contained by pericardium; narrow neck, high rupture risk — unlike a true aneurysm.

Late complications

• True ventricular aneurysm: fibrotic thinned wall, persistent ST elevation weeks after MI, mural thrombus → systemic embolism/stroke.
• Pericarditis: early fibrinous peri-infarction pericarditis (days 1–3) versus Dressler syndrome (weeks; autoimmune, pleuritic pain, effusion). Aspirin and colchicine are preferred; high-dose NSAIDs and steroids may impair scar formation.
• Ischemic cardiomyopathy/HFrEF: remodeling and fibrosis; treat with all four GDMT classes per the 2022 AHA/ACC/HFSA heart failure guideline — ARNI (or ACEI/ARB), beta blocker, MRA, and SGLT2 inhibitor.

Treatment-related

• Reperfusion injury: restored flow delivers oxygen and calcium to injured myocytes → ROS burst, hypercontracture (contraction band necrosis), stunning, and reperfusion arrhythmias.
• Stent thrombosis: abrupt DAPT discontinuation → acute STEMI. Emergency. Contrast this with in-stent restenosis (neointimal hyperplasia, gradual angina months later).
• Bleeding: intracranial hemorrhage is the feared complication of fibrinolysis; contrast-associated AKI follows angiography.

• Timeline is the answer key: a stem that gives days since infarct is testing histology. Wavy fibers (<4 h) → coagulative necrosis with neutrophils (1–3 days) → macrophages and granulation tissue (3–7 days, the rupture window) → collagenous scar (weeks). Match the complication to the phase, not to the symptom.
• Contraction band necrosis = reperfusion: hypercontracted sarcomeres appear when calcium-loaded myocytes are re-oxygenated. If the stem mentions successful PCI or thrombolysis and then asks about the biopsy finding, this is it.
• Posteromedial papillary muscle rupture is the classic single-blood-supply association (PDA only), so acute mitral regurgitation follows an inferior MI. The anterolateral muscle has dual supply and rarely ruptures.
• Persistent ST elevation weeks after MI points to a true ventricular aneurysm — look for mural thrombus and embolic stroke, not re-infarction. Do not confuse it with a pseudoaneurysm (contained rupture, narrow neck, imminent rupture risk).
• Best next step in inferior MI with hypotension: obtain right-sided leads and give IV fluids. Nitroglycerin in RV infarction drops preload and can precipitate profound hypotension — this is the most commonly tested management error.
• Shockable rhythms are ventricular fibrillation and pulseless ventricular tachycardia — immediate defibrillation per AHA ACLS. PEA and asystole are not shocked.
• New LBBB is not a stand-alone STEMI criterion; apply Sgarbossa criteria (concordant ST elevation, concordant ST depression in V1–V3, excessively discordant ST elevation) before calling a code STEMI.
• Biomarker distractor: troponin stays elevated 7–14 days, so re-infarction within that window is diagnosed by a second rise in CK-MB (or a new rise in troponin above the prior plateau), because CK-MB normalizes in 2–3 days.
• Etiology distractor: not all MI is plaque rupture — plaque erosion, spontaneous coronary artery dissection (young peripartum women), vasospasm, and cocaine use produce infarction with minimal or no fixed stenosis. Beta blockers are avoided as initial monotherapy in acute cocaine-associated chest pain per ACC/AHA guidance.