Atherosclerosis and Peripheral Vascular Disease
MRCS Part A & B — Comprehensive Study Notes
Atherosclerosis: Pathophysiology and Pathology
Response-to-Injury Hypothesis
Atherosclerosis develops through a well-characterised sequence of events. The process begins with endothelial injury caused by chronic hypertension, smoking, hyperglycaemia, or dyslipidaemia. This injury compromises the endothelial barrier function, allowing low-density lipoprotein (LDL) particles to accumulate in the subendothelial space. Within the vessel wall, LDL undergoes oxidation, generating oxidised LDL (oxLDL), which triggers an inflammatory cascade. Circulating monocytes adhere to activated endothelium via adhesion molecules (ICAM-1, VCAM-1) and migrate into the intima. Here, monocytes differentiate into macrophages and internalize oxLDL through scavenger receptors, forming foam cells (lipid-laden macrophages). Accumulation of foam cells creates the fatty streak, the earliest morphological evidence of atherosclerosis.
Over time, smooth muscle cells (SMCs) in the media migrate into the intima and proliferate, synthesising extracellular matrix components (collagen, elastin, proteoglycans). This creates a fibrous cap overlying the lipid-rich core of the plaque. The fibrous cap provides mechanical stability, but the plaque continues to enlarge, gradually narrowing the arterial lumen. The lesion is now classified as a complicated plaque when it contains a lipid core, a fibrous cap, smooth muscle cells, and evidence of neovascularisation and calcification.
Macrophage-Mediated Inflammation
The macrophage is central to plaque progression. Macrophages within the plaque (derived from circulating monocytes) orchestrate the inflammatory response by secreting numerous cytokines and growth factors: tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), and macrophage colony-stimulating factor (M-CSF). These cytokines perpetuate the inflammatory cascade, recruiting additional monocytes and macrophages. Macrophages also produce matrix metalloproteinases (MMPs), which degrade the extracellular matrix of the fibrous cap, weakening it and predisposing to rupture. The balance between VSMC proliferation and MMP-mediated cap degradation determines plaque stability: a thick fibrous cap with few macrophages is stable; a thin cap infiltrated with macrophages is unstable.
Plaque Structure: Stable vs. Unstable
| Feature | Stable Plaque | Unstable Plaque |
|---|---|---|
| Fibrous Cap | Thick (>200 μm), smooth muscle-rich, few macrophages | Thin (<65 μm), few SMCs, abundant foam cells |
| Lipid Core | Small, peripheral | Large, central, cholesterol crystals |
| Surface | Intact endothelium | Ulcerated, eroded, thrombosis adherent |
| Inflammation | Minimal macrophages | Dense infiltrate, CD4+ T-cells, mast cells |
| Neovessels | Few | Prominent, immature, leaky |
| Clinical Effect | Gradual stenosis → claudication | Cap rupture → thrombosis → acute ischaemia |
Risk Factors for Atherosclerosis
Modifiable risk factors include smoking (single greatest modifiable risk), hypertension, diabetes mellitus, dyslipidaemia (elevated LDL, low HDL, elevated triglycerides), obesity, sedentary lifestyle, and poor diet. Smoking accelerates atherosclerosis through direct endothelial damage, promotion of LDL oxidation, impaired endothelial NO production, increased platelet reactivity, and reduced HDL. Hypertension causes shear stress at arterial bifurcations where atherosclerosis preferentially develops. Diabetes accelerates atherosclerosis via glycation of LDL (making it more atherogenic), impaired endothelial function, increased inflammation, and increased VSMC proliferation. Dyslipidaemia—particularly elevated apoB-containing lipoproteins—is the fundamental driver; LDL accumulation in the arterial wall is necessary and sufficient for atherosclerosis initiation.
Non-modifiable risk factors include age (>50 in men, >60 in women), male sex (6:1 male predominance), family history of premature atherosclerotic disease (parent or sibling with MI or stroke before age 55 in men or 65 in women), and ethnicity (South Asian, African-Caribbean populations at higher risk). Chronic kidney disease, HIV infection, and autoimmune diseases (rheumatoid arthritis, SLE) accelerate atherosclerosis.
Clinical Correlation: The INTERHEART Study
This landmark case-control study of 15,000 people with MI across 52 countries demonstrated that nine modifiable risk factors account for 90% of myocardial infarction risk: smoking, dyslipidaemia, hypertension, diabetes, abdominal obesity, psychosocial stress, physical inactivity, excessive alcohol use, and low fruit/vegetable consumption. Smoking alone carries a relative risk of 3.5 for MI, emphasising its dominance as a modifiable risk factor in vascular disease.