Arethrosclerosis

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"atherosclerosis"[MeSH Terms] AND "pathogenesis"[MeSH Terms]

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Here is a comprehensive overview of Atherosclerosis, drawn from Robbins & Kumar Basic Pathology and Robbins, Cotran & Kumar Pathologic Basis of Disease.

Atherosclerosis

Definition

Atherosclerosis is a chronic inflammatory disease of the arterial wall best understood as the vascular response to endothelial injury (the "response to injury" hypothesis). It is characterized by intimal lesions called atheromas (atherosclerotic plaques) - raised lesions composed of a soft, friable lipid core (mainly cholesterol and cholesterol esters with necrotic debris) covered by a fibrous cap. It underlies the pathogenesis of coronary, cerebral, and peripheral vascular disease, causing roughly half of all deaths in the Western world.

Robbins & Kumar Basic Pathology, p. 314

Epidemiology

Although atherosclerosis is nearly universal in high-resource nations, risk reduction and improved therapies have sharply decreased morbidity and mortality over recent decades. However, the adoption of Western diets and lifestyles in lower-resource nations has increased the burden of ischemic heart disease globally. 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 US and 7-12 times higher than Japan.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 465

Risk Factors

Category	Factors
Nonmodifiable	Genetic variation, family history, increasing age, male sex
Modifiable	Hyperlipidemia (high LDL, low HDL), hypertension, cigarette smoking, diabetes mellitus, obesity, physical inactivity
Novel/Emerging	Elevated CRP, hyperhomocysteinemia, lipoprotein(a), metabolic syndrome

Roughly 20% of cardiovascular events occur in the absence of identifiable risk factors.

Family history is the single most important independent risk factor. The predisposition is usually polygenic, related to cumulative effects of many shared alleles.

Pathogenesis

The central model involves a cascade of events triggered by endothelial injury:

Endothelial cell (EC) injury - increased permeability, leukocyte adhesion, altered gene expression
Lipoprotein accumulation in the vessel wall (especially oxidized LDL and cholesterol crystals)
Monocyte adhesion to the endothelium, migration into the intima, and transformation into macrophages and foam cells
Platelet adhesion
Smooth muscle cell (SMC) recruitment from the media, with proliferation and ECM production
T-cell recruitment
Lipid accumulation extracellularly and within macrophages and SMCs
Calcification of ECM and necrotic debris (late stage)

Evolution of arterial wall changes in atherosclerosis - showing progression from healthy endothelium to foam cells and fibrofatty plaque

Key Mechanisms

Hemodynamic disturbances: Plaques form preferentially at branch points, ostia of vessels, and the posterior abdominal aorta - sites of turbulent, non-laminar flow. Laminar flow upregulates the transcription factor KLF2 (Kruppel-like factor-2), which promotes atheroprotective gene expression. Turbulent flow reverses this effect. Notably, some protective effects of statins also work via KLF2 upregulation.

Hypercholesterolemia: Elevated LDL is the dominant lipid risk factor. LDL that enters the vessel wall undergoes oxidative modification to oxidized LDL (oxLDL), which is:

Taken up by macrophages via scavenger receptors, forming foam cells
Directly cytotoxic to endothelial cells and SMCs
A stimulus for local inflammatory cytokine production
Chemotactic for additional monocytes

HDL acts protectively by "reverse cholesterol transport" - removing cholesterol from vessel walls.

Inflammation: Chronic low-grade inflammation is fundamental. Inflammatory cytokines (especially TNF) stimulate proatherogenic patterns of EC gene expression.

Morphology of Plaques

Fatty Streak (Early Lesion)

Flat or slightly raised yellow intimal lesion
Composed of lipid-laden macrophages (foam cells) and some intimal SMCs
Appear in the aorta of children as young as 1 year; coronary arteries by age 10
Not all progress to full plaques

Fibrous Plaque (Advanced Lesion)

Fibrous cap: collagen, SMCs, and scattered inflammatory cells
Necrotic core: lipid debris, cholesterol crystals, foam cells, dead cells
Shoulder regions: more cellular, with macrophages, T cells, and SMCs (most vulnerable area)
Neovascularization from the vasa vasorum penetrates the base of the plaque

Histology of coronary artery atherosclerotic plaque - fibrous cap (F), central necrotic core (C), and compromised lumen (L); with calcification and neovascularization at higher magnification

Clinical Consequences

1. Atherosclerotic Stenosis

Gradual progressive luminal narrowing
Symptoms appear when stenosis reaches approximately 70% occlusion in coronary arteries
Causes stable angina (chest pain on exertion), bowel ischemia, intermittent claudication, and chronic ischemic encephalopathy

2. Acute Plaque Change (Most Dangerous)

Plaque changes fall into three categories:

Rupture/ulceration/erosion of the fibrous cap - exposes thrombogenic substances, triggers acute thrombus formation
Hemorrhage into the plaque - raptures overlying cap or intimal neovessels, expanding the plaque suddenly
Vasospasm - induced by platelet aggregation products (thromboxane A2, serotonin)

Plaque rupture is the proximate cause of most acute coronary syndromes (unstable angina, NSTEMI, STEMI) and many strokes.

3. Aneurysm Formation

Ischemia-induced atrophy of the media (pressure or diffusion barrier) with loss of elastic tissue
Wall weakening leads to aneurysmal dilation and potential rupture
Most common in the infrarenal abdominal aorta

4. Major Affected Sites and Clinical Manifestations

Affected Vessel	Clinical Result
Coronary arteries	Myocardial infarction, stable angina, sudden cardiac death
Cerebral/carotid arteries	Stroke, TIA
Aorta	Abdominal aortic aneurysm
Peripheral (iliac, femoral, popliteal)	Peripheral artery disease, gangrene
Renal arteries	Renovascular hypertension, renal ischemia
Mesenteric arteries	Bowel ischemia

Prevention and Management Principles

Lipid lowering: Statins are the cornerstone; they lower LDL and have anti-inflammatory effects (partly via KLF2)
Antihypertensives: Reduce endothelial shear stress and hemodynamic injury
Antiplatelet agents: Aspirin reduces thrombotic complications
Lifestyle: Smoking cessation, exercise, dietary modification
Glycemic control: In diabetics reduces microvascular and macrovascular risk
Emerging therapies: PCSK9 inhibitors for severe hypercholesterolemia, anti-inflammatory approaches (colchicine)

Sources: Robbins & Kumar Basic Pathology 10e, pp. 314-320; Robbins, Cotran & Kumar Pathologic Basis of Disease 10e, pp. 465-474

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