2. Atherosclerosis

Question 1

Definition of atherosclerosis

Answer 1

Degenerative disease of the tunica intima affecting large & medium- sized arteries, characterized by atheromas

Question 2

Risk factors for atherosclerosis

Answer 2

1. Higher incidence in developed countries
2. Constitutional risk factors:
   - Age (although atherosclerosis is progressive, usually does not present clinically until middle age or later)
   - Gender (male > female)
   - Family history & genetics
3. Modifiable risk factors:
   - Hyperlipidaemia (especially hypercholesterolemia)
   - Hypertension
   - Diabetes mellitus (induces hypercholesterolemia)
   - Cigarette smoking
4. Additional risk factors:
   - Inflammation (C-reactive protein)
   - Hyperhomocystinemia (Inborn errors of metabolism [IEM] or acquired vitamin B12/folate deficiency)
   - Metabolic syndrome (glucose intolerance, hypertension, central obesity)
   - Lipoprotein (a) (altered form of LDL)
   - Lack of exercise
   - Type A personality
   - Factors affecting hemostasis

Question 3

Pathogenesis of atherosclerosis

Answer 3

Sequence of events in atheroma formation

1. Endothelial injury
   - Caused by: hypertension, smoking, hyperlipidemia, hemodynamic disturbances, toxins & cytokines, homocysteine, viral infections, immune reaction
   - Results in: increased endothelial permeability &
   enhanced leukocyte adhesion
2. Lipoprotein accumulation in vessel wall
   - Occurs in a background of hyperlipidemia
   - Accumulation of LDL within intima (promoted by increased endothelial permeability)
   - LDL oxidation by oxygen free radicals locally generated by endothelial cells or macrophages
   - Oxidized LDL ingested by macrophages, intracellularly accumulated to form foam cells
   - Oxidized LDL also stimulates release of growth factors, cytokines & chemokines by endothelial cells
   & macrophages
3. Monocyte migration
   - Monocyte adhesion to vessel wall
   - Migration into intima
   - Transformation into macrophages & foam cells
4. Platelet adhesion
5. Factor release
   - By activated platelets, macrophages & endothelium
   - Induces smooth muscle cell recruitment (either from
   media or circulating precursors)
6. Smooth muscle cell proliferation & ECM production
   - Promoted by PDGF, FGF, TGF-alpha
   - Smooth muscle cells synthesize ECM (notably collagen) which stabilizes plaque
7. Lipid accumulation (both extracellularly & within cells)

Question 4

Progression of atheroma

Answer 4

Fatty streak → Fibrofatty plaque → Advanced plaque

1. Fatty streak
   - Earliest lesion, prior to smooth muscle cell proliferation & ECM synthesis
   - Contains foamy macrophages
   - Not significantly raised
2. Atheroma (both fibrofatty & advanced plaques)
   - Established lesion, after smooth muscle cell proliferation & ECM synthesis
   - 3 components: cells (macrophages, smooth muscle cells, T cells), ECM, lipid (both extra- & intracellular)
   - Structurally, made up of a superficial fibrous cap (smooth muscle cells, collagen) and a softer necrotic core deep to it (cholesterol crystals & cholesterol esters, cellular debris, foam cells)
   - Raised lesion, protrudes into vessel lumen
   - Note that atheroma composition is dynamic
3. Advanced plaque (vulnerable plaque, unstable plaque)
   - Relatively smaller in size with a large lipid core & thin fibrous cap
   - More likely to undergo an acute plaque change (fissure, rupture, ulcerate, plaque hemorrhage)
   - Paradoxically, larger & often more occlusive plaques tend to be more stable (smaller lipid core, more fibrous tissue)
   - Intrinsic factors (increased MMP, decreased tissue inhibitor of metalloproteinases-TIMP)
   - Extrinsic factors (blood pressure, platelet reactivity, vasoconstriction)

Question 5

Clinical consequences of atherosclerosis

Answer 5

1. Chronic atherosclerotic stenosis
   - Gradual process of vessel luminal occlusion by
   growing plaque which compromises blood flow with
   resultant ischemic injury
   - Critical stenosis is point at which chronic occlusion
   significantly limits flow, and demand starts
   exceeding supply
   - Ischemic manifestations: stable angina, chronic
   ischemic heart disease, bowel ischemia, ischemic
   encephalopathy, intermittent claudication
2. Acute plaque change
   - Rupture/fissuring (exposes thrombogenic plaque constituents, discharges atherosclerotic debris into bloodstream to produce atheroembolism)
   - Erosion/ulceration (exposes thrombogenic subendothelial basement membrane)
   - Hemorrhage into plaque (expands plaque volume and may secondarily promote plaque rupture)
3. Aneurysm Formation
   - Atherosclerosis-induced pressure or ischemic atrophy of the underlying media with loss of elastic tissue weakens vessel wall
   - Predisposes to aneurysmal dilation