17.2: Coronary Artery Disease II: Pathophysiology

Coronary Artery Disease (CAD) originates from a series of events that impair the function of coronary arteries, the blood vessels responsible for delivering oxygen-rich blood to the heart muscle. The pathophysiology of CAD is closely linked to atherosclerosis, a chronic inflammatory and lipid-driven condition affecting the vascular endothelium.

1. Endothelial Damage

The process begins with damage to the vascular endothelium, which serves as a protective barrier between the blood and the vessel wall. This damage may result from multiple etiological factors, such as:

• Hypertension (mechanical stress on the vessel walls).
• Smoking (introduction of free radicals and toxins).
• Diabetes mellitus (hyperglycemia-induced oxidative stress).
• Dyslipidemia (elevated levels of LDL cholesterol).

2. Endothelial Dysfunction

Damaged endothelial cells lose their ability to:

• Produce nitric oxide (NO), a potent vasodilator and anti-inflammatory mediator.
• Inhibit adhesion of inflammatory cells. This dysfunction fosters a pro-inflammatory and pro-thrombotic environment, setting the stage for further pathological changes.

3. LDL Oxidation and Inflammatory Response

• LDL Penetration: Low-density lipoproteins (LDL) infiltrate the damaged endothelial layer and accumulate in the subendothelial space.
• Oxidation: The trapped LDL undergoes oxidation, which transforms it into a highly immunogenic molecule.
• Inflammation: Oxidized LDL attracts immune cells and stimulates the release of pro-inflammatory cytokines, amplifying vascular inflammation.

4. Monocyte Recruitment and Foam Cell Formation

• Monocyte Migration: The inflamed endothelium expresses adhesion molecules (e.g., VCAM-1), facilitating the recruitment of monocytes from the bloodstream.
• Macrophage Transformation: Once in the arterial intima, monocytes differentiate into macrophages, immune cells that engulf oxidized LDL.
• Foam Cells: Macrophages overloaded with oxidized LDL transform into foam cells, a hallmark of early atherosclerotic plaques.

5. Fatty Streak Formation

Foam cells aggregate, forming fatty streaks—the earliest visible lesions in atherosclerosis. These streaks are the precursors to more advanced plaques.

6. Plaque Development

• Smooth Muscle Cell Migration: Smooth muscle cells (SMCs) from the medial layer migrate to the intima under the influence of growth factors such as platelet-derived growth factor (PDGF).
• Collagen and Elastin Production: SMCs secrete extracellular matrix proteins like collagen and elastin, creating a fibrous cap over the lipid core.
• Plaque Types:
  • Stable Plaques: Characterized by thick fibrous caps and small lipid cores, these plaques are less likely to rupture.
  • Unstable Plaques: These have thin caps and large lipid cores, making them more prone to rupture.

7. Plaque Rupture and Thrombosis

• Rupture: Mechanical stress or inflammatory activity can weaken the fibrous cap, leading to plaque rupture.
• Exposure: The lipid core is exposed to circulating blood, triggering platelet activation and aggregation.
• Thrombus Formation: A blood clot (thrombus) forms over the rupture site, potentially occluding the coronary artery.

8. Clinical Consequences

If a thrombus significantly narrows or completely blocks a coronary artery:

• Myocardial Ischemia: Reduced blood flow to the heart muscle causes oxygen deprivation.
• Myocardial Infarction: Prolonged ischemia leads to myocardial necrosis (death of heart tissue), commonly known as a heart attack.