I-14. Atherosclerosis

動脈硬化（アテローム性動脈硬化症）

Definition & Significance

Atherosclerosis = accumulation of lipids and fibrous material in the intimal layer of arteries → vessel stiffening.
Cardiovascular disease (heart disease, stroke) is a leading cause of death.
Complications: tissue ischemia, thrombus → vessel occlusion → acute ischemia, MI/angina, stroke/TIA, aneurysm (esp. abdominal aorta), claudicatio intermittens, ulcers, gangrene.

Risk Factors

Constitutional: age (organ damage in middle age+), gender (premenopausal women protected by estrogen, with equal risk after menopause), genetics (multifactorial).
Modifiable: smoking, metabolic syndrome, hypertension, hypercholesterolemia — all activate the inflammatory cascade (NF-κB).

Pathomechanism

Initiation

High LDL cholesterol.
Dysfunctional endothelium lets LDL enter the intima → oxidized by ROS.
Monocytes adhere (adhesion molecules) → become intimal macrophages.
Macrophages take up ox-LDL via scavenger receptors → foam cells.

Progression

Smooth muscle cells migrate from media to intima (chemoattractants from T-cells/monocytes).
SMCs produce collagen/elastin (ECM) → fibrous cap + intimal thickening.
ECM promotes further LDL accumulation.
Foam cell apoptosis → necrotic core.
Calcification.

Complication

T-cells produce IFN-γ → inhibits ECM synthesis → thinner cap → easier rupture.

Factors Influencing AS

Injured endothelium: ↓vasodilators, ↑adhesion molecules, turbulent flow damages anti-inflammatory/antithrombotic properties.
LDL (“bad”): delivers cholesterol to periphery (animal fats, butter, egg — omega-3 ↓LDL). HDL (“good”): mobilizes cholesterol to liver for biliary excretion (obesity + smoking ↓HDL, alcohol ↑LDL). Lipoprotein(a): modified LDL → ↑coronary risk.
Hypertension: high systolic & diastolic BP injures vessels.

Plaque Stages

Fatty streaks: intimal foam cells, no flow disturbance, appearing even in infants (aorta).
Atherosclerotic plaque: white-yellow raised lesion (intimal thickening + lipid). 3 components — cells (SMC, macrophages/foam, T-cells), ECM (collagen, elastin, proteoglycans), lipid (intra-/extracellular, cholesterol crystals), plus peripheral neovascularization.
Complicated plaque: aneurysm (wall weakening → dilation), ulcer (membrane break → coagulation/thrombosis), thrombus (→ MI/stroke/embolism), bleeding (→ hematoma → rapid expansion/rupture), calcification (late).

A thin fibrous cap ruptures easily → activates clotting factors → thrombus → emboli → death. Superficial erosion of the cap → white thrombus.

一問一答

▶What is the definition of atherosclerosis?

Accumulation of lipids and fibrous material in the intimal layer of arteries, leading to vessel stiffening.

▶What are the steps of atherosclerosis initiation?

High LDL → dysfunctional endothelium lets LDL enter the intima → LDL oxidized by ROS → monocytes adhere and become intimal macrophages → macrophages take up ox-LDL via scavenger receptors → foam cells.

▶What are the major complications of atherosclerosis?

Tissue ischemia, thrombus → vessel occlusion (acute ischemia, MI/angina, stroke/TIA), aneurysm (especially abdominal aorta), claudicatio intermittens, ulcers, and gangrene.

▶What are the constitutional (non-modifiable) risk factors for atherosclerosis?

Age, gender (premenopausal women are protected by estrogen, with equal risk after menopause), and genetics (multifactorial).

▶What modifiable risk factors drive atherosclerosis, and through what common pathway?

Smoking, metabolic syndrome, hypertension, and hypercholesterolemia — all activate the inflammatory cascade (NF-κB).

▶What is the role of smooth muscle cells in plaque progression?

SMCs migrate from the media to the intima and produce collagen/elastin (ECM), forming the fibrous cap and causing intimal thickening.

▶How are foam cells formed in atherosclerosis?

Intimal macrophages take up oxidized LDL via scavenger receptors, becoming lipid-laden foam cells.

▶How does the necrotic core of a plaque form?

Through apoptosis of foam cells, followed by calcification.

▶How does IFN-γ contribute to plaque complication?

T-cells produce IFN-γ, which inhibits ECM synthesis → a thinner fibrous cap → easier rupture.

▶What are the opposing roles of LDL and HDL in atherosclerosis?

LDL ("bad") delivers cholesterol to the periphery; HDL ("good") mobilizes cholesterol back to the liver for biliary excretion.

▶What characterizes fatty streaks?

Intimal foam cells with no flow disturbance; they can appear even in infants (in the aorta).

▶What is lipoprotein(a) and why is it relevant to atherosclerosis?

It is a modified LDL associated with increased coronary risk.

▶What are the three components of an atherosclerotic plaque?

Cells (SMCs, macrophages/foam cells, T-cells), ECM (collagen, elastin, proteoglycans), and lipid (intra-/extracellular, cholesterol crystals), plus peripheral neovascularization.

▶What features define a complicated plaque?

Aneurysm (wall weakening → dilation), ulcer (membrane break → thrombosis), thrombus (→ MI/stroke/embolism), bleeding (→ hematoma → rapid expansion/rupture), and late calcification.

▶Why is a thin fibrous cap dangerous?

It ruptures easily, exposing thrombogenic material that activates clotting factors → thrombus → emboli; superficial erosion of the cap produces a white thrombus.

▶What changes occur in injured endothelium that promote atherosclerosis?

Decreased vasodilators, increased adhesion molecules, and turbulent flow that damages the anti-inflammatory/antithrombotic properties of the endothelium.

▶How does gender/estrogen influence atherosclerosis risk?

Premenopausal women are protected by estrogen; after menopause their risk becomes equal to men's.

▶Which dietary factors raise versus lower LDL?

Animal fats, butter, and eggs raise LDL; omega-3 fatty acids lower LDL.

▶What lowers HDL?

Obesity and smoking lower HDL (while alcohol raises LDL).

▶How does hypertension contribute to atherosclerosis?

High systolic and diastolic blood pressure mechanically injures the vessel wall, promoting intimal thickening.