Ischemic heart disease

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I now have all the essential material for a comprehensive answer. Here is the full structured overview of Ischemic Heart Disease.

Ischemic Heart Disease (IHD)

Definition

IHD is a broad term encompassing several overlapping syndromes caused by an imbalance between myocardial oxygen demand and coronary blood supply (perfusion). In more than 90% of cases, it results from coronary artery atherosclerosis, and IHD is used virtually synonymously with coronary artery disease (CAD). It remains the leading cause of mortality worldwide, accounting for approximately 7.5 million deaths per year.

Robbins & Kumar Basic Pathology, p. 351

Clinical Syndromes of IHD

IHD presents across a spectrum of four overlapping syndromes:

Syndrome	Mechanism	Key Feature
Angina Pectoris	Ischemia without myocyte death	Reversible chest pain
Myocardial Infarction (MI)	Ischemia severe/prolonged enough to cause myocyte necrosis	Cardiomyocyte death
Chronic IHD with CHF	Accumulated ischemic insults - pump failure	Progressive cardiac decompensation
Sudden Cardiac Death (SCD)	Ischemia-induced lethal ventricular fibrillation	Death within 1 hour of symptom onset

The term Acute Coronary Syndrome (ACS) applies to three of these: unstable angina, MI, and SCD.

Robbins & Kumar Basic Pathology, p. 351-352

Pathogenesis

The Two Core Mechanisms

1. Fixed (Chronic) Atherosclerotic Occlusion

< 70% luminal obstruction: Asymptomatic even with exertion
> 70% occlusion ("critical stenosis"): Symptoms on exertion - produces stable angina
≥ 90% occlusion: Inadequate flow even at rest - contributes to unstable angina

Clinically significant plaques tend to occur within the first several centimeters of the LAD and LCX takeoff from the aorta, and along the entire length of the RCA. Slowly progressive occlusion can allow collateral vessel formation, protecting against MI even with complete occlusion; acute blockage leaves no time for collaterals, so infarction results.

2. Acute Plaque Change with Superimposed Thrombosis/Vasospasm

This is the mechanism underlying ACS. The initiating event is sudden plaque disruption (rupture or erosion), exposing thrombogenic subendothelial contents, leading to rapid thrombus formation.

Vulnerable plaques are those with:

Large atheromatous (lipid) cores
Thin overlying fibrous caps
High macrophage infiltration (secrete metalloproteinases degrading collagen)
Few smooth muscle cells (less collagen synthesis)

A critical and sobering insight: two-thirds of ruptured plaques had ≤ 50% stenosis before rupture, and 85% had ≤ 70% stenosis. This means most MIs occur in plaques that were NOT previously causing symptoms.

Diagram of sequential progression of coronary artery lesions leading to acute coronary syndromes - from normal vessel to fixed obstruction to plaque disruption and its outcomes

Robbins & Kumar Basic Pathology, pp. 352-353

Angina Pectoris - Three Types

Angina is intermittent chest discomfort from transient, reversible ischemia - insufficient to cause myocyte necrosis. Mediators released include adenosine, bradykinin, and other molecules stimulating autonomic nerves.

Type	Mechanism	Relief
Stable (Typical) Angina	Fixed > 70% stenosis; triggered by exertion or increased demand	Rest or nitroglycerin
Prinzmetal (Variant) Angina	Coronary artery spasm, even in non-atherosclerotic vessels	Calcium channel blockers; can occur at rest
Unstable Angina	Plaque erosion/rupture + nonocclusive thrombus	Not relieved by rest or nitroglycerin; ACS requiring urgent treatment

Robbins & Kumar Basic Pathology, pp. 353-354

Myocardial Infarction

Sequence of Events in a Typical MI

Plaque erosion or disruption exposes subendothelial collagen and necrotic plaque contents
Platelets adhere, aggregate, and release thromboxane A2, ADP, and serotonin - causing further aggregation and vasospasm
Coagulation activation via tissue factor adds to the growing thrombus
Within minutes, the thrombus may completely occlude the lumen

Angiography within 4 hours of MI shows thrombosis in ~90% of cases. By 12-24 hours (without intervention), this falls to ~60%, as some thrombi lyse spontaneously.

Myocardial Response Timeline

Time After Occlusion	Effect
1-2 minutes	Loss of myocyte contractile function
20-40 minutes	Irreversible myocyte death begins
Hours to days	Gross and histologic changes of infarction develop

Morphologic Changes in MI - Timeline

Time	Gross Changes	Histologic Changes
0-12 hours	None visible	Early coagulative necrosis; wavy fibers
12-24 hours	Dark mottling	Coagulative necrosis; neutrophil infiltration begins
1-3 days	Mottling with yellow-tan center	Dense neutrophil infiltration
3-7 days	Hyperemic border; yellow-tan softening	Macrophages begin phagocytosing debris
1-2 weeks	Depressed, yellow-tan, soft	Granulation tissue with neovascularization
Weeks-months	Gray-white, contracted scar	Dense collagenous scar (fibrosis)

Robbins & Kumar Basic Pathology, pp. 354-357

Infarct Location and Affected Vessels

Occluded Vessel	Territory at Risk
LAD (most common)	Anterior LV wall, anterior 2/3 of interventricular septum, apex
RCA	Posterior LV wall, posterior 1/3 of septum, RV free wall
LCX	Lateral LV wall

Types of MI

Transmural (STEMI): Full-thickness necrosis, typically due to complete occlusive thrombus
Subendocardial (NSTEMI): Inner 1/3-1/2 of myocardium, typically due to partially occlusive thrombus or severe fixed stenosis with increased demand

Complications of MI

Complication	Timing	Notes
Arrhythmias	Immediate-hours	Most common cause of early death; V-fib
LV pump failure / cardiogenic shock	Hours-days	10-15% of hospitalized MI patients
Free wall rupture	3-7 days	Peak timing; hemopericardium and tamponade
Interventricular septal rupture	3-7 days	Acute VSD; harsh systolic murmur
Papillary muscle rupture	2-7 days	Acute mitral regurgitation
Ventricular aneurysm	Weeks-months	Paradoxical wall motion; risk of mural thrombus
Pericarditis (Dressler syndrome)	Days to weeks	Fibrinous or autoimmune
Mural thrombus	Days-weeks	Risk of systemic embolism

Robbins & Kumar Basic Pathology, pp. 357-360

Risk Factors

Non-modifiable:

Age (risk rises progressively)
Male sex (though gap narrows post-menopause in women)
Family history / genetic predisposition

Modifiable (major):

Hyperlipidemia (elevated LDL)
Hypertension
Smoking
Diabetes mellitus
Obesity
Physical inactivity

Mortality from IHD in the US has declined by ~50% since its peak in 1963, largely due to smoking cessation programs, treatment of hypertension and diabetes, and cholesterol-lowering agents (statins), with a smaller contribution from therapeutic advances.

Robbins & Kumar Basic Pathology, p. 352; Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 2778

Diagnosis

Troponin (I and T) are the gold-standard biomarkers - cardiac-specific, begin rising within 3-4 hours of MI, peak at 12-24 hours, remain elevated for up to 10-14 days (troponin T). MI is diagnosed by symptoms + ECG changes + abnormal cardiac troponins.

STEMI: ST elevation in ≥ 2 contiguous leads; requires emergent reperfusion
NSTEMI: No ST elevation; troponin elevated; may show ST depression or T-wave changes

Management

Angina (Stable)

All patients with IHD should receive guideline-directed medical therapy including lifestyle modification and modifiable risk factor management.

Anti-ischemic drugs:

Beta-blockers (first-line): Reduce heart rate and contractility, lowering myocardial O2 demand. Cardioselective beta-1 blockers preferred. Avoid in vasospastic angina.
Calcium channel blockers: Arterial vasodilators. First-line for vasospastic (Prinzmetal) angina. Avoid non-dihydropyridines in HFrEF.
Organic nitrates (nitroglycerin): Reduce preload and dilate coronary arteries. All angina patients should have sublingual nitroglycerin. Nitrate-free interval required to prevent tolerance.
Ranolazine: Sodium channel blocker; reduces late inward Na current, decreasing intracellular Ca overload. Used when other therapies fail; can prolong QT interval.
Lippincott Illustrated Reviews: Pharmacology, p. 424

ACS (Unstable Angina / NSTEMI / STEMI)

Antiplatelet therapy: Aspirin + P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) - dual antiplatelet therapy (DAPT)
Anticoagulation: Heparin (unfractionated or LMWH), bivalirudin
Beta-blockers (early)
Statins (high-intensity)
ACE inhibitors / ARBs (especially with reduced EF or anterior MI)

Reperfusion Therapy (STEMI)

Primary PCI (percutaneous coronary intervention): Preferred when available within 90 minutes (door-to-balloon time); most effective at limiting infarct size
Thrombolysis (fibrinolytics): When PCI is not available within 120 minutes; most effective when given early (< 3 hours)
CABG (coronary artery bypass grafting): For multivessel or left main disease not amenable to PCI; also used in cardiogenic shock

Early thrombolysis and/or angioplasty can be highly successful in limiting myocardial necrosis, since myocyte death begins at 20-40 minutes and is not complete for several hours.

Robbins & Kumar Basic Pathology, p. 355; Tintinalli's Emergency Medicine, p. 221

Key Concepts Summary

IHD = supply-demand mismatch, most often from atherosclerotic CAD
Most MIs arise from non-critically stenotic plaques that rupture acutely
The four syndromes: stable angina, unstable angina/NSTEMI, STEMI, SCD
"Time is muscle" - reperfusion within the first 1-2 hours salvages the most myocardium
Statins are beneficial beyond lipid-lowering: they stabilize plaques by reducing inflammation and reversing endothelial dysfunction

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