Pathogenesis of Atherosclerosis

Step 1 - Endothelial Injury and Dysfunction

• Hemodynamic disturbances (turbulent flow at branch points, ostia, posterior abdominal aorta wall)
• Hyperlipidemia / hypercholesterolemia (the two most important causes)
• Hypertension
• Cigarette smoke toxins (oxidative stress, NO suppression)
• Inflammatory cytokines (e.g., TNF)
• Diabetes-associated advanced glycation end-products
• Infectious agents (e.g., Chlamydia pneumoniae, CMV)

• Increased permeability - allowing lipoprotein entry into the intima
• Upregulation of adhesion molecules (VCAM-1, ICAM-1, selectins) - promoting leukocyte adhesion
• Enhanced thrombogenicity
• Reduced NO bioavailability - impairing vasodilation and enabling SMC proliferation

Step 2 - Lipoprotein Accumulation and Oxidation

• Plaques are dominated by cholesterol and cholesterol esters
• Genetic LDL receptor defects (familial hypercholesterolemia) cause accelerated atherosclerosis
• Diets high in cholesterol produce atherosclerosis in experimental animals
• Reducing LDL dramatically decreases coronary events clinically

• Stimulates ECs and macrophages to release cytokines and growth factors
• Is chemotactic for monocytes
• Is taken up avidly by macrophage scavenger receptors (not the normal LDL receptor), driving foam cell formation
• Is directly cytotoxic to ECs and SMCs

Step 3 - Monocyte Recruitment and Foam Cell Formation

1. Dysfunctional ECs upregulate VCAM-1 and selectins, causing monocytes and T lymphocytes to roll, adhere, and transmigrate into the intima.
2. Chemokines (e.g., MCP-1/CCL2) produced by ECs and SMCs attract monocytes into the sub-endothelial space.
3. Monocytes differentiate into macrophages, activated by cytokines and oxLDL.
4. Activated macrophages engulf oxLDL via scavenger receptors (SR-A, CD36) - a process that is unregulated (unlike the downregulatable LDL receptor) - leading to massive lipid accumulation.
5. Lipid-engorged macrophages become foam cells, which cluster under the intima to form the earliest visible lesion: the fatty streak.

Step 4 - SMC Recruitment, Proliferation, and ECM Deposition

• Migration of SMCs from the tunica media (or from circulating precursors) into the intima
• Phenotypic change of SMCs from "contractile" to "synthetic" phenotype
• Proliferation of intimal SMCs
• ECM synthesis - collagen, elastic fibers, proteoglycans - forming the fibrous cap

Step 5 - Advanced Plaque Formation

• Neovascularization (plaque angiogenesis) from adventitial vasa vasorum - can bleed into the plaque (intraplaque hemorrhage)
• Calcification within older plaques
• Plaques are eccentric on cross-section (don't involve the full circumference)

Step 6 - Plaque Complications (Acute Plaque Change)

Vulnerable ("Unstable") vs. Stable Plaques

Mechanisms of Plaque Destabilization

• Macrophage-derived MMPs (matrix metalloproteinases) degrade collagen in the fibrous cap
• Interferon-γ from T cells inhibits SMC collagen synthesis - thinning the cap
• Intraplaque hemorrhage from ruptured neovessels increases lipid core volume
• Adrenergic surges (emotional stress, morning waking) increase blood pressure and shear stress on the plaque

Consequences of Plaque Rupture

1. Thrombosis - exposure of the necrotic core activates platelets and the coagulation cascade; partial or total occlusion → unstable angina or MI
2. Embolization - thrombus or plaque debris occludes distal vessels
3. Luminal stenosis - progressive plaque growth causing chronic ischemia
4. Aneurysm - media ischemia and SMC loss due to increased diffusion distance weakens the wall

Summary Diagram of Key Steps

Endothelial injury/dysfunction
         ↓
 LDL entry → Oxidation (oxLDL)
         ↓
Monocyte adhesion (VCAM-1) → Macrophage
         ↓
 Foam cell formation (SR-mediated lipid uptake)
         ↓
         Fatty streak
         ↓
 SMC migration & proliferation (PDGF, FGF)
 + ECM synthesis (fibrous cap)
         ↓
    Fibrofatty atheroma
         ↓
 Plaque progression: necrotic core enlarges,
 cap thins, inflammation persists
         ↓
 Vulnerable plaque → Rupture → Thrombosis
         ↓
   ACS / MI / Stroke / Peripheral ischemia

Key Molecular Players

• Robbins & Kumar Basic Pathology - Chapter 8, pp. 314-320 (Response to Injury Hypothesis, Plaque Morphology, Acute Plaque Change)
• Robbins, Cotran & Kumar Pathologic Basis of Disease - Chapter 11, pp. 473-475 (Atherosclerosis summary)
• Fuster and Hurst's The Heart, 15th Edition - Chapter 16 (Endothelial Dysfunction, Smoking and Atherogenesis)