Pathogenesis

Coronary artery atherosclerotic disease (CAD) results from the progressive accumulation of atherosclerotic plaques within the walls of coronary arteries. These plaques can restrict blood flow to the myocardium, leading to ischemic heart disease. The pathogenesis involves multiple interrelated processes:

1. Endothelial Injury and Dysfunction

• Triggers: Risk factors such as hypertension, diabetes, hypercholesterolemia, smoking, and systemic inflammation lead to endothelial damage.
• Effects: Damaged endothelial cells lose their ability to maintain vascular homeostasis, resulting in:
  • Reduced production of nitric oxide (a vasodilator and anti-inflammatory mediator).
  • Increased permeability to lipoproteins.
  • Enhanced expression of adhesion molecules, which recruit inflammatory cells.

2. Lipid Deposition

• Low-density lipoprotein (LDL) particles infiltrate the subendothelial space through the damaged endothelium.
• LDL undergoes oxidation, becoming pro-inflammatory and attracting immune cells.

3. Inflammatory Response

• Oxidized LDL activates endothelial cells and attracts monocytes.
• Monocytes enter the intima, differentiate into macrophages, and engulf oxidized LDL, forming foam cells.
• Foam cells and activated macrophages release pro-inflammatory cytokines, perpetuating local inflammation.

4. Formation of Fatty Streaks

• Foam cells accumulate in the intima, creating fatty streaks, the earliest visible lesions of atherosclerosis.
• This process often starts early in life and progresses silently over decades.

5. Fibrous Plaque Development

• Smooth muscle cells migrate from the media to the intima in response to inflammatory signals.
• These cells proliferate and secrete extracellular matrix proteins (e.g., collagen), forming a fibrous cap over the fatty core.
• The fibrous cap stabilizes the plaque but also contributes to luminal narrowing.

6. Plaque Instability and Rupture

• Chronic inflammation weakens the fibrous cap through the action of matrix metalloproteinases (MMPs) and other enzymes.
• Plaques with thin caps and large lipid cores are prone to rupture.
• Plaque rupture exposes thrombogenic contents (e.g., tissue factor), triggering thrombus formation.

7. Clinical Manifestations

• Stable plaques lead to stable angina due to fixed narrowing of coronary arteries.
• Unstable plaques (rupture or erosion) cause acute coronary syndromes (unstable angina, myocardial infarction).

Key Risk Factors

• Non-modifiable: Age, male sex, family history.
• Modifiable: Dyslipidemia, hypertension, smoking, diabetes, obesity, sedentary lifestyle.

Pathophysiological Mechanisms

• Oxidative stress: Drives LDL oxidation and endothelial damage.
• Inflammation: Central to all stages of plaque development and instability.
• Hemodynamic forces: Areas of low shear stress (e.g., vessel bifurcations) are more susceptible to plaque formation.

Understanding these mechanisms is critical for developing preventive and therapeutic strategies targeting lipid levels, inflammation, and endothelial function.

 

ST-segment elevation myocardial infarction (STEMI) occurs due to acute and complete occlusion of a coronary artery, leading to myocardial ischemia and necrosis in the affected region of the heart. The key steps in the pathogenesis of STEMI are outlined below:

1. Atherosclerosis Development

• Initiation: Chronic endothelial injury (e.g., due to hypertension, hyperlipidemia, diabetes, smoking) leads to endothelial dysfunction.
• Plaque Formation: Lipid accumulation and infiltration of inflammatory cells result in the formation of an atherosclerotic plaque within the arterial wall.
• Plaque Vulnerability: Over time, plaques can become unstable due to thinning of the fibrous cap, increased lipid content, and infiltration of inflammatory cells.

2. Plaque Rupture or Erosion

• Rupture of a vulnerable plaque exposes highly thrombogenic contents (e.g., collagen, tissue factor) to circulating blood.
• Alternatively, erosion of the endothelium overlying a plaque can also trigger thrombus formation.

3. Thrombus Formation

• Platelet adhesion, activation, and aggregation occur rapidly at the site of plaque rupture or erosion.
• The coagulation cascade is activated, leading to fibrin deposition and the formation of a thrombus.
• The thrombus partially or completely occludes the coronary artery.

4. Acute Coronary Occlusion

• Complete occlusion of the coronary artery leads to cessation of blood flow (ischemia) in the myocardium supplied by that artery.
• The ischemia causes cellular hypoxia, reduced ATP production, and impaired myocardial function.

5. Myocardial Injury and Necrosis

• Without timely reperfusion, ischemia progresses to irreversible myocardial injury (necrosis).
• The necrotic myocardium releases biomarkers (e.g., troponin, creatine kinase-MB) into the bloodstream, which are diagnostic of myocardial infarction.
• Myocardial cell death occurs in a wavefront pattern, starting in the subendocardium and progressing to the epicardium.

6. Electrocardiographic Changes

• ST-segment elevation on the ECG reflects transmural ischemia (ischemia affecting the full thickness of the myocardium).
• These changes are localized to the leads corresponding to the affected coronary artery and myocardial territory.

7. Reperfusion and Remodeling (If Treated)

• Timely reperfusion (e.g., via percutaneous coronary intervention or thrombolysis) can restore blood flow, salvage ischemic myocardium, and limit the infarct size.
• Delayed treatment or persistent occlusion can lead to larger infarcts, impaired left ventricular function, and complications such as heart failure or arrhythmias.

Commonly Involved Coronary Arteries

• Left Anterior Descending (LAD): Leads to anterior wall STEMI.
• Right Coronary Artery (RCA): Causes inferior wall STEMI.
• Left Circumflex (LCx): Results in lateral wall STEMI.

Would you like further details on specific treatments or pathophysiological mechanisms?

 

 

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Occlusion of one coronary artery usually leads to ischemia or necrosis of the corresponding cardiac muscle.

Cardiac muscle is perfused by coronary arteries with very little redundant or shared circulation;.

When there is insufficient oxygen available for the cardiac muscle, the glycolytic pathway is used, which leads to a very small amount of ATP per glucose molecule. The malate-aspartate shuttle can offer 2 or 3 more times the ATP by oxidizing NADH to regenerate cytosolic NAD+ by reducing oxaloacetate to malate by cytosolic malate dehydrogenase.

 

 

Inadequate perfusion of cardiac muscle results in insufficient oxygen delivery from coronary obstruction such as stenosis, complete occlusion or spasm.

This causes the affected muscle to rely on anaerobic metabolism for its energy supply with concomitant production of lactic acid. Even transient ischemia can lead to changes in muscle tissue, but prolonged ischemia leads to breakdown of muscle cells and release of cellular proteins such as creatine kinase, lactic acid dehydrogenase, and troponin I. 

Myocardial infarction causes changes in the pathways of energy generation triggered by oxygen insufficiency in the affected heart muscle.

Myocardial infarctions occur in patients with more than one severely narrowed (>75% narrowing of the cross-sectional area) coronary artery.

Anterior, apical, and septal infarcts of the left ventricle are usually due to thrombosis in the left anterior descending circulation;

Lateral and posterior left ventricular infarcts result from occlusions in the left circumflex system,

Right ventricular and posterior-inferior left ventricular infarcts result from thrombosis in the right coronary artery.

Subendocardial (nontransmural, or “non-Q wave”) infarctions more often occurs in the setting of reduced myocardial perfusion due to hypotension or intimal hemorrhage, and less commonly follows coronary plaque rupture and thrombosis.

 

Myocardial Infarction, ST Elevation

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