Pathophysiology of Myocardial Ischemia

Introduction

Cardiovascular diseases remain the leading cause of death worldwide, and at the center of this epidemic lies myocardial ischemia—a condition where the supply of oxygenated blood to the heart muscle falls short of its demand. At its mildest, ischemia can cause angina pectoris, a temporary chest discomfort. At its most severe, it can culminate in myocardial infarction (MI), commonly known as a heart attack, leading to irreversible myocardial cell death.

Understanding the pathophysiology of myocardial ischemia—how it begins with atherosclerotic plaque formation and progresses to acute infarction—is crucial for preventing, diagnosing, and treating this deadly condition. This article provides a comprehensive review of the step-by-step mechanisms underlying myocardial ischemia, exploring the journey from plaque to infarction.

Basic Concepts of Myocardial Ischemia

What is Ischemia?

Ischemia refers to the restriction of blood flow (and therefore oxygen delivery) to tissues. In the myocardium, ischemia occurs when coronary blood flow cannot meet the metabolic demands of the cardiac muscle.

Oxygen supply factors: coronary artery blood flow, oxygen-carrying capacity of blood, and coronary vascular resistance.
Oxygen demand factors: heart rate, contractility, wall stress, and afterload.

When supply falls short of demand, myocardial cells switch to anaerobic metabolism, leading to acidosis, impaired contractility, and if prolonged, necrosis.

Chronic vs. Acute Ischemia

Chronic ischemia occurs in stable angina due to fixed atherosclerotic narrowing.
Acute ischemia develops rapidly, often due to plaque rupture and thrombus formation, leading to unstable angina or myocardial infarction.

Step 1: Atherosclerosis – The Root of Ischemia

Endothelial Dysfunction

The earliest event in ischemic heart disease is endothelial dysfunction, often triggered by risk factors such as:

Hypertension
Hyperlipidemia (especially elevated LDL cholesterol)
Diabetes mellitus
Smoking
Chronic inflammation

A dysfunctional endothelium produces less nitric oxide (NO), impairing vasodilation, while increasing permeability to lipoproteins and leukocyte adhesion.

Lipoprotein Retention and Oxidation

Low-density lipoproteins (LDL) penetrate the intimal layer of arteries and undergo oxidation. Oxidized LDL (oxLDL) is highly atherogenic, triggering local inflammation.

Inflammatory Cell Infiltration

Monocytes migrate into the intima, differentiate into macrophages, and engulf oxLDL, forming foam cells.
These clusters of foam cells create fatty streaks, the earliest visible atherosclerotic lesions.

Smooth Muscle Cell Migration and Plaque Growth

Smooth muscle cells (SMCs) migrate from the media into the intima and proliferate.
They secrete extracellular matrix proteins (collagen, proteoglycans), forming a fibrous cap over the lipid-rich core.

This structure becomes the atherosclerotic plaque, the hallmark of coronary artery disease (CAD).

Step 2: Plaque Evolution – Stable vs. Vulnerable Lesions

Not all plaques are equal.

Stable plaques:
- Thick fibrous cap
- Smaller lipid core
- Less prone to rupture
- Typically cause stable angina when they narrow the lumen by >70%.
Vulnerable (unstable) plaques:
- Thin fibrous cap
- Large lipid core
- High macrophage content and inflammation
- Prone to rupture, leading to thrombosis and acute ischemia.

The majority of myocardial infarctions arise from rupture of vulnerable plaques, even when they cause less than 50% stenosis prior to rupture.

Step 3: Plaque Rupture and Thrombus Formation

Plaque Destabilization

Inflammatory processes weaken the fibrous cap by degrading collagen and activating proteases. Mechanical stress, hypertension, or sudden surges in shear forces may cause rupture.

Exposure of Thrombogenic Core

When the fibrous cap ruptures, the underlying lipid-rich necrotic core—rich in tissue factor—is exposed to circulating blood.

Platelet Activation

Platelets adhere to exposed collagen and von Willebrand factor.
Activated platelets release ADP, thromboxane A₂, and serotonin, amplifying aggregation.

Coagulation Cascade

Tissue factor triggers the extrinsic coagulation pathway.
Thrombin generation leads to fibrin clot formation, stabilizing the platelet plug.

The end result is a coronary thrombus that can partially or completely occlude the vessel, precipitating myocardial ischemia or infarction.

Step 4: Myocardial Ischemia

When a thrombus narrows or obstructs a coronary artery, blood supply drops dramatically.

Metabolic Consequences

Reduced oxygen delivery halts oxidative phosphorylation.
Cells shift to anaerobic glycolysis, producing lactic acid → intracellular acidosis.
ATP depletion impairs ion pumps (Na⁺/K⁺-ATPase, Ca²⁺-ATPase), leading to ionic imbalances.

Electrophysiological Disturbances

Ischemic myocardium exhibits depolarization abnormalities.
Conduction delays, re-entry circuits, and arrhythmias (e.g., ventricular fibrillation) can occur.

Contractile Dysfunction

Within seconds, contractility decreases (myocardial stunning).
Persistent ischemia causes irreversible cell injury.

Step 5: Myocardial Infarction – From Ischemia to Necrosis

If ischemia persists beyond 20–40 minutes, irreversible cell death occurs.

Cellular Pathology

Early phase (0–30 minutes): Reversible injury (edema, myofibril relaxation).
30–60 minutes: Onset of necrosis in subendocardial regions (most vulnerable due to high wall stress and least blood supply).
2–4 hours: Necrosis expands toward epicardium (wavefront phenomenon).
24 hours: Widespread coagulative necrosis with neutrophil infiltration.
1–2 weeks: Macrophages clear necrotic debris; granulation tissue forms.
>2 weeks: Collagen deposition and scar formation.

Types of Myocardial Infarction

Transmural MI: Full-thickness necrosis, usually due to complete vessel occlusion.
Subendocardial MI: Partial-thickness necrosis, often from incomplete or transient occlusion.

Clinical Correlates of Ischemia and Infarction

Symptoms

Angina pectoris (pressure, heaviness, radiating to left arm/jaw).
Shortness of breath, sweating, nausea.

Biomarkers

Troponins (cTnI, cTnT): Most sensitive and specific.
CK-MB: Useful for reinfarction detection.

ECG Changes

Ischemia: ST depression, T-wave inversion.
Acute infarction: ST elevation (STEMI), new Q waves.

Determinants of Infarction Size

Duration of occlusion (longer ischemia → larger infarct).
Collateral circulation (well-developed collaterals limit damage).
Location of occlusion (proximal LAD → large anterior infarction).
Reperfusion therapy timing (earlier restoration saves myocardium).

Ischemia-Reperfusion Injury

Ironically, restoring blood flow (via PCI or thrombolysis) can also cause damage:

Oxidative stress from reactive oxygen species.
Calcium overload leading to hypercontracture.
Mitochondrial permeability transition pore (mPTP) opening → cell death.

These contribute to arrhythmias, myocardial stunning, and no-reflow phenomenon.

Chronic Ischemia and Remodeling

Not all ischemia leads to sudden infarction. Chronic or repetitive ischemia causes:

Hibernating myocardium: Persistent but reversible dysfunction due to reduced blood flow.
Stunned myocardium: Temporary dysfunction despite restored flow.
Ventricular remodeling: Hypertrophy, dilation, fibrosis, leading to chronic heart failure.

Therapeutic Implications

Primary Prevention

Lifestyle modifications: diet, exercise, smoking cessation.
Statins: Reduce LDL and stabilize plaques.
Antihypertensives and diabetes management.

Acute Management

Antiplatelets (aspirin, P2Y12 inhibitors).
Anticoagulants (heparin).
Thrombolytics or percutaneous coronary intervention (PCI).
Oxygen, nitrates, beta-blockers, morphine (in selected cases).

Post-Infarction Management

ACE inhibitors/ARBs, beta-blockers, mineralocorticoid antagonists.
Statins for long-term lipid control.
Cardiac rehabilitation.

Future Directions

1. Plaque Stabilization Therapies

PCSK9 inhibitors for aggressive LDL reduction.
Anti-inflammatory drugs (e.g., canakinumab) to reduce vascular inflammation.

2. Regenerative Medicine

Stem cell and exosome therapy for myocardial repair.
Gene therapies targeting angiogenesis and cell survival.

3. Precision Medicine

Identifying genetic and molecular markers to predict plaque rupture risk.