Atherosclerosis

Definition

Atherosclerosis is an intimal-based disease of large and medium-sized arteries characterized by the formation of atheromatous plaques - raised lesions with a soft, grumous lipid core (mainly cholesterol and cholesterol esters with necrotic debris) covered by a fibrous cap. It is the single leading cause of morbidity and mortality in Western nations, responsible for roughly half of all deaths, and underlies coronary artery disease, stroke, aortic aneurysm, and peripheral vascular disease.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 467

Epidemiology

While risk reduction and improved therapies have sharply decreased atherosclerosis-related mortality in high-resource nations over recent decades, adoption of Western diet and lifestyle in lower-resource countries has driven sharp increases there. Death rates for coronary artery disease in Africa, India, and Southeast Asia now exceed those in the United States; Eastern European countries have rates 3-5 times higher than the United States and 7-12 times higher than Japan.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 467

Risk Factors

Risk factors identified through prospective studies (e.g., the Framingham Heart Study) include:

Non-Modifiable (Constitutional)	Modifiable
Genetic variation / family history	Hyperlipidemia (elevated LDL, low HDL, elevated Lp(a))
Increasing age	Hypertension
Male sex	Cigarette smoking
	Diabetes mellitus
	Obesity / metabolic syndrome
	Physical inactivity
	High-sensitivity CRP (inflammation markers)
	Homocysteinemia

Multiple risk factors have greater-than-additive effects. Familial predisposition is usually polygenic; Mendelian disorders (e.g., familial hypercholesterolemia) account for only a small fraction.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 468

Pathogenesis: The Response-to-Injury Hypothesis

The central concept is that atherosclerosis is a vascular response to endothelial injury and chronic inflammation. Key sequential steps:

Endothelial injury / dysfunction - increased permeability, enhanced leukocyte adhesion, altered gene expression
Lipoprotein accumulation - LDL and oxidized LDL enter the vessel wall
Monocyte adhesion and migration - monocytes adhere to dysfunctional endothelium via adhesion molecules, cross into the intima, and differentiate into macrophages
Foam cell formation - macrophages ingest oxidized LDL via scavenger receptors → lipid-laden foam cells → fatty streak (earliest visible lesion)
Platelet adhesion and growth factor release
SMC recruitment and proliferation - smooth muscle cells migrate from the media into the intima, proliferate, and produce ECM
Extracellular lipid accumulation and necrosis → necrotic core
Calcification of ECM and necrotic debris in late stages → "hardening of the arteries"

Three Key Causes of Endothelial Dysfunction

Hemodynamic disturbances: Plaques preferentially occur at branch points, vessel ostia, and the posterior abdominal aorta where turbulent, non-laminar flow predominates. Laminar flow induces the transcription factor KLF2 (Krüppel-like factor-2) which upregulates atheroprotective genes; turbulent flow reverses this (notably, statins also work in part via KLF2 upregulation).
Hypercholesterolemia: Elevated LDL, reduced HDL, and elevated Lp(a). Oxidized LDL is particularly atherogenic - it stimulates monocyte adhesion, is toxic to endothelium, and is taken up by macrophage scavenger receptors (bypassing normal feedback regulation).
Inflammation: Systemic inflammation (elevated CRP, fibrinogen) and local cytokine production sustain the atherogenic process.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 469-471

Diagrams of Pathogenesis

Monocyte adhesion → foam cell formation:

Monocyte adhesion to damaged endothelium, migration into the intima, and transformation into macrophage foam cells engulfing lipoprotein particles

Fig. 69.8A from Guyton & Hall: Monocyte adhesion via adhesion molecules, migration into the intima, and conversion to macrophage foam cells releasing growth/inflammatory factors.

Full progression - healthy artery to fibrofatty atheroma:

Stepwise evolution from healthy endothelium to endothelial dysfunction with monocyte/platelet adhesion, to macrophage activation and fatty streak, to mature fibrofatty atheroma with foam cells, collagen, and lipid debris

Fig. 11.8 from Robbins Cotran: Five stages from healthy vessel to fibrofatty atheroma with SMC proliferation, ECM deposition, and extracellular lipid accumulation.

Plaque growth to rupture and thrombosis:

Normal artery cross-section evolving to small plaque, then large plaque, then thrombosis of a ruptured plaque with lipid core and thrombus occluding the lumen

Fig. 69.8B from Guyton & Hall: Progression from small plaque → large plaque → plaque rupture with thrombosis.

Morphology of the Atherosclerotic Plaque

A fully developed atheromatous plaque consists of:

Fibrous cap: Dense collagen, scattered SMCs, macrophages, and T lymphocytes
Necrotic core: Cholesterol crystals, lipid debris, dead foam cells, calcifications
Shoulder regions: More cellular - SMCs, macrophages, T cells (structurally weakest zones)
Neovascularization: Small vessels grow into the plaque, potentially contributing to intraplaque hemorrhage

Plaque Distribution

Large elastic arteries (aorta, carotid, iliac) and large-to-medium muscular arteries (coronary, popliteal) are the primary sites. In any given artery the abdominal aorta is more affected than the thoracic aorta.

Stable vs. Vulnerable (Unstable) Plaques

Feature	Stable Plaque	Vulnerable Plaque
Fibrous cap	Thick, dense	Thin
Lipid core	Small	Large
Inflammation	Minimal	Dense (macrophages, T cells)
Calcification	Often present	Variable
Risk	Chronic ischemia by stenosis	Rupture → acute thrombosis

The "Glagov phenomenon": early plaques cause outward remodeling of the media to preserve lumen size, so luminal narrowing is a late event. Critical stenosis occurs when the plaque produces a 70-75% reduction in luminal cross-sectional area, enough to cause ischemia at rest or with minimal exertion.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 473

Complications of Atherosclerotic Plaques

Plaque rupture / fissuring - the most dangerous complication; exposes the thrombogenic necrotic core to blood, triggering acute thrombosis (cause of most MIs and strokes)
Luminal thrombosis - may be occlusive (infarct) or non-occlusive (mural thrombus)
Atheroembolism - plaque debris or thrombus breaks off and occludes distal vessels (e.g., "cholesterol emboli" to kidneys, retina, toes)
Calcification - leads to arterial stiffness ("hardening of the arteries")
Aneurysm formation - medial ischemia (from impaired diffusion through thick intima + inflammation) weakens the wall, particularly in the abdominal aorta

Clinical Manifestations

Territory	Manifestation
Coronary arteries	Angina, unstable angina, myocardial infarction, sudden cardiac death
Cerebral/carotid arteries	TIA, ischemic stroke
Aorta	Abdominal aortic aneurysm
Renal arteries	Renovascular hypertension, ischemic nephropathy
Mesenteric arteries	Intestinal ischemia
Lower limb arteries	Claudication, rest pain, gangrene

Prevention and Treatment

Lifestyle modifications: Smoking cessation, Mediterranean diet, aerobic exercise, weight loss, blood pressure control, glycemic control.

Pharmacotherapy:

Statins (HMG-CoA reductase inhibitors): First-line for LDL reduction; also have pleiotropic anti-inflammatory effects (including via KLF2 upregulation). Recent meta-analysis (JAMA Cardiol, 2025) showed that alternative LDL-lowering strategies combining lower-intensity statins + ezetimibe achieved comparable cardiovascular outcomes to high-intensity statin monotherapy.
Ezetimibe: Reduces intestinal cholesterol absorption; used add-on to statins.
PCSK9 inhibitors (evolocumab, alirocumab): Markedly reduce LDL; used in statin-intolerant patients or very high-risk cases.
Antihypertensives: ACE inhibitors, ARBs have vascular-protective effects beyond BP lowering.
Antiplatelet agents: Aspirin, clopidogrel for secondary prevention.
GLP-1 receptor agonists: Emerging evidence for cardiovascular risk reduction.

Summary Points

Atherosclerosis = endothelial injury + inflammation + lipid accumulation in the intima
The fatty streak is the earliest lesion; mature plaques take decades to develop
Stable plaques cause gradual stenosis; vulnerable plaques rupture and cause acute events
Roughly half of deaths in Western nations are attributable to atherosclerotic disease
Risk factor modification (especially LDL lowering) significantly reduces events

Sources: Robbins & Kumar Basic Pathology, p. 314 | Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 467-474 | Guyton and Hall Textbook of Medical Physiology, p. 851

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