Q1 LONG ANSWER 10M ★ High-yield

Define atherosclerosis. Describe its risk factors, pathogenesis, morphology and complications.

Pathology · 2nd Professional — Para-Clinical

Definition

Atherosclerosis is a disease of large and medium-sized arteries characterised by intimal lesions called atheromas (fibrofatty plaques) that protrude into the lumen, weaken the underlying media, and may rupture to cause catastrophic thrombosis.

Term	Meaning
Arteriosclerosis	The general term — "hardening of the arteries"
ATHEROsclerosis	Intimal plaques in large and medium arteries; by far the most important
Monckeberg medial sclerosis	Calcification of the media of muscular arteries in the elderly; does not narrow the lumen and is usually of no clinical consequence
Arteriolosclerosis	Small arteries and arterioles; hyaline type in diabetes and benign hypertension, hyperplastic ("onion-skin") type in malignant hypertension

Risk Factors

Category	Factors
Non-modifiable	Age (the strongest single factor); male sex (women are protected until the menopause); family history and genetic factors, including familial hypercholesterolaemia
Modifiable — major	Hyperlipidaemia — raised LDL and low HDL; hypertension; smoking; diabetes mellitus
Minor and emerging	Obesity, physical inactivity, stress and "type A" personality, raised C-reactive protein, hyperhomocysteinaemia, lipoprotein(a), metabolic syndrome

The four major modifiable factors are multiplicative, not additive — a smoker with hypertension and diabetes has a risk far greater than the sum of the three
South Asians develop coronary disease about a decade earlier and at lower body mass indices than Europeans, with a characteristic pattern of low HDL, high triglycerides and central obesity

Pathogenesis — the Response-to-injury Hypothesis

1. Endothelial injury or dysfunction — from haemodynamic stress, hyperlipidaemia, smoking, hypertension, toxins → 2.
Increased permeability
LDL enters the intima and is oxidised → 3.
Monocytes adhere (through VCAM-1) and migrate into the intima → They become macrophages, take up oxidised LDL through scavenger receptors — which are not downregulated by cholesterol — and become foam cells → 4.
Fatty streak forms — the earliest lesion, present even in children → 5.
Smooth muscle cells migrate from the media to the intima, driven by PDGF, FGF and TGF-alpha → They proliferate and secrete collagen and matrix → 6.
Fibrofatty plaque (atheroma) — a fibrous cap over a necrotic lipid core → 7.
Complications — rupture, thrombosis, calcification, aneurysm
Chronic inflammation drives the whole process; atherosclerosis is now understood as an inflammatory disease of the vessel wall, not simply lipid deposition
The scavenger receptor is the key to foam cell formation — unlike the normal LDL receptor it is not suppressed by intracellular cholesterol, so the macrophage goes on ingesting lipid until it is engorged

Morphology

Sites, in descending order of severity — lower abdominal aorta > coronary arteries > popliteal > internal carotid > circle of Willis
Plaques form at points of turbulence — ostia, branch points and the posterior abdominal aorta, where laminar flow is disturbed
Fatty streak — flat yellow intimal discolouration of lipid-laden macrophages; present in the aorta of nearly all children over 10; not all progress to plaques

Component of the plaque	Contents
Fibrous cap	Smooth muscle cells, dense collagen, elastin, proteoglycans; determines stability
"Shoulder" region	Macrophages, T cells, smooth muscle cells; the site where rupture usually begins
Necrotic core	Lipid (chiefly cholesterol, seen as cholesterol clefts), foam cells, cell debris, fibrin, calcium, neovascular channels

CLINICAL PEARL

The plaques that kill are not the ones that narrow the lumen most. Most infarcts arise from a plaque causing less than 50% stenosis that ruptures. A vulnerable plaque has a thin cap, a large lipid core and many inflammatory cells; a stable one has a thick fibrous cap and little lipid. This is why statins save lives largely by stabilising plaques, not by shrinking them, and why an angiogram cannot predict where the next infarct will occur.

Complications

Complication	Consequence
Rupture, ulceration or erosion	Exposes thrombogenic material → acute thrombosis → myocardial infarction, stroke, gangrene — the major mechanism of death
Haemorrhage into the plaque	From fragile neovessels; expands the plaque abruptly
Atheroembolism	Cholesterol crystal emboli → blue toe syndrome, renal impairment
Progressive stenosis	"Critical stenosis" at about 70% — ischaemia on exertion: angina, intermittent claudication, mesenteric angina
Aneurysm formation	Pressure atrophy and weakening of the underlying media — abdominal aortic aneurysm
Calcification	Rigidity; visible on radiographs

Clinical Consequences BY Territory

Artery involved	Syndrome	Presentation
Coronary	Ischaemic heart disease	Stable angina (fixed stenosis), unstable angina and myocardial infarction (plaque rupture), sudden cardiac death, chronic ischaemic cardiomyopathy
Cerebral and carotid	Cerebrovascular disease	Transient ischaemic attack, ischaemic stroke, vascular dementia
Lower limb	Peripheral arterial disease	Intermittent claudication, rest pain, ulceration, gangrene
Mesenteric	Chronic mesenteric ischaemia	Post-prandial abdominal pain ("mesenteric angina"), weight loss, food fear; acute occlusion gives bowel infarction
Renal	Renovascular disease	Secondary hypertension, ischaemic nephropathy
Abdominal aorta	Aneurysm	Asymptomatic pulsatile mass; rupture

The consequence depends on whether the plaque narrows slowly or ruptures suddenly — slow narrowing gives exertional symptoms and allows collaterals to form; rupture gives an acute event with no warning

Applied Aspects

Prevention is far more effective than treatment — stopping smoking, controlling blood pressure and diabetes, exercise, and diet
Statins lower LDL and stabilise plaques, and reduce events more than the cholesterol reduction alone would predict, because of their anti-inflammatory effect
Familial hypercholesterolaemia — an LDL receptor defect causing tendon xanthomas, corneal arcus and myocardial infarction in early adult life; requires family screening
Coronary artery disease is rising steeply in India, presenting a decade earlier than in the West and increasingly in rural populations
Atherosclerosis is a systemic disease — a patient with peripheral vascular disease almost certainly has coronary disease too, and should be assessed for it
The process begins in childhood and progresses silently for decades, which is the argument for lifelong risk factor control rather than treatment at presentation
Regression is possible — intensive lipid lowering reduces plaque volume modestly, but the greater benefit is in stabilising the cap
Diabetes confers a risk equivalent to existing coronary disease, and diabetic patients are treated as secondary prevention from the outset
C-reactive protein predicts events independently of cholesterol, consistent with the inflammatory model, though its use in routine practice is debated
Coronary calcium scoring quantifies plaque burden non-invasively and refines risk in intermediate-risk patients
A normal angiogram does not mean normal arteries — plaque expands outward before it narrows the lumen (Glagov remodelling), so early disease is angiographically invisible

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