Atherosclerosis

Definition

• Robbins & Kumar Basic Pathology, p. 314

Epidemiology & Risk Factors

Pathogenesis: "Response-to-Injury" Hypothesis

Step 1 - Endothelial Injury & Dysfunction

• Causes: hemodynamic turbulence (at branch points, ostia), hypercholesterolemia, smoking, hypertension, toxins, homocysteine
• Results in: increased permeability, upregulation of adhesion molecules (VCAM-1, ICAM-1), decreased nitric oxide production, altered gene expression
• Laminar flow normally induces the transcription factor KLF-2 which suppresses pro-inflammatory genes ("atheroprotective"); turbulent flow abolishes this effect

Step 2 - Lipoprotein Accumulation & Oxidation

• LDL enters the intima through the dysfunctional endothelium and is oxidized (ox-LDL)
• Oxidized LDL is pro-inflammatory: it stimulates endothelial cells to express more adhesion molecules and chemokines
• HDL has a protective role by reverse cholesterol transport

Step 3 - Monocyte Recruitment & Foam Cell Formation

• Monocytes adhere to the activated endothelium via adhesion molecules, then migrate into the intima
• In the intima, monocytes differentiate into macrophages, which ingest oxidized LDL via scavenger receptors (not downregulated like normal LDL receptors) → become foam cells (lipid-laden macrophages)
• Foam cells aggregate to form visible fatty streaks - the earliest grossly visible lesion (reversible, seen even in aortas of children)

Step 4 - Smooth Muscle Cell (SMC) Migration & Proliferation

• Activated macrophages, platelets, and endothelial cells release growth factors (PDGF, FGF, TGF-β) and cytokines
• SMCs migrate from the media into the intima, proliferate, and synthesize extracellular matrix (collagen, proteoglycans) → forming a neointima
• T lymphocytes also accumulate and sustain local inflammation

Step 5 - Advanced Plaque Formation

• Progressive accumulation of lipid, foam cells, SMCs, ECM, and T cells forms a full fibrous atheromatous plaque
• Central lipid core (necrotic debris from dead foam cells) is covered by a fibrous cap (collagen-rich, SMC-derived)
• Late stages: calcification of ECM and necrotic debris ("hardening of arteries")

Morphology of Atherosclerotic Plaques

• Yellow-white raised intimal lesions
• Sites: aorta (esp. posterior abdominal), coronary arteries, popliteal arteries, carotid bifurcation, circle of Willis

1. Fibrous cap - SMCs, collagen, proteoglycans, T cells
2. Lipid core - cholesterol crystals, necrotic debris, foam cells, extracellular lipid
3. Shoulder region - more cellular (macrophages, foam cells, T cells) - most vulnerable to rupture
4. Neovascularization and calcification in advanced lesions

Consequences of Atherosclerosis

1. Atherosclerotic Stenosis

• Gradual plaque growth occludes the lumen
• Initially compensated by Glagov phenomenon (outward remodeling of the media)
• Critical stenosis occurs when the lumen cross-section is reduced by 70-75% - causes tissue ischemia and angina
• Result: chronic ischemic heart disease, peripheral vascular disease

2. Acute Plaque Change (Plaque Rupture / Erosion)

• The most dangerous complication
• Rupture of the fibrous cap (especially at the thin "shoulder" region) exposes the thrombogenic lipid core
• Triggers acute thrombosis → sudden occlusion → acute MI, stroke, sudden cardiac death
• Erosion (endothelial loss without rupture) can also trigger thrombosis

3. Aneurysm Formation

• Plaque thickens the intima, impeding diffusion from lumen to media
• Ischemia of the media weakens the arterial wall → aortic aneurysm (especially abdominal aorta)

4. Embolism

• Thrombus or atheromatous debris can embolize distally → embolic stroke, renal infarction, limb ischemia

Summary Table