Arteriosclerosis and Atherosclerosis Study Notes

Vascular Healing and Types of Arteriosclerosis

• Intimal Thickening: The standard healing response to vascular injury; it involves the migration of smooth muscle cells ($\text{SMC}$) from the media or circulation to the intima, followed by $\text{SMC}$ proliferation and extracellular matrix ($\text{ECM}$) deposition.

• Arteriosclerosis: A general term for arterial wall thickening and loss of elasticity. There are $4$ distinct types:

  • Arteriolosclerosis: Affects small arteries and arterioles; includes hyaline and hyperplastic variants typically associated with hypertension.

  • Mönckeberg medial sclerosis: Presence of calcific deposits in individuals older than $50$ years of age, usually centered on the internal elastic lamina; it does not encroach on the vessel lumen.

  • Fibromuscular intimal hyperplasia: A non-atherosclerotic, $\text{SMC}$-rich lesion driven by inflammation (e.g., arteritis or transplant arteriopathy) or mechanical injury (e.g., stents); it is a major cause of in-stent restenosis.

  • Atherosclerosis: The most frequent and clinically significant pattern, marked by intimal atheromas.

Atherosclerosis: Overview and Epidemiology

• Definition: Characterized by intimal lesions called atheromas (plaques) that consist of a lipid core (cholesterol and cholesterol esters) and a fibrous cap.

• Impact: Underlies coronary, cerebral, and peripheral vascular disease; it is responsible for roughly $1/2$ of all deaths in the Western world.

• Epidemiology: Ubiquitous in developed nations; however, incidence is rising in developing countries. Japanese emigrants who adopt American lifestyles acquire the same risk as $U.S.$-born individuals, highlighting environmental factors.

Risk Factors: Constitutional and Modifiable

• Constitutional (Nonmodifiable):

  • Genetics: Family history is the most important independent risk factor.

  • Age: $\text{MI}$ incidence increases $5$-fold between $40$ and $60$ years of age.

  • Gender: Premenopausal women are relatively protected compared to men; however, estrogen replacement after $65$ years of age may actually increase cardiovascular risk.

• Major Modifiable Factors:

  • Hyperlipidemia: High $\text{LDL}$ increases risk, while high $\text{HDL}$ reduces it. Statins lower cholesterol by inhibiting $\text{HMG-CoA}$ reductase.

  • Hypertension: Can increase the risk for ischemic heart disease ($\text{IHD}$) by approximately $60\%$.

  • Cigarette Smoking: Prolonged smoking of $1$ or more packs per day doubles $\text{IHD}$-related mortality.

  • Diabetes Mellitus: Associated with hypercholesterolemia; doubles $\text{MI}$ risk and causes a $100$-fold increase in atherosclerosis-induced gangrene.

• Additional Factors: Inflammation (measured by C-reactive protein or $\text{CRP}$), $\text{Hyperhomocysteinemia}$ (> 100\,\mu\text{mol/L}), metabolic syndrome, and elevated $\text{Lipoprotein(a)}$.

Pathogenesis: The Response-to-Injury Hypothesis

• Atherosclerosis is viewed as a chronic inflammatory response of the arterial wall to endothelial injury.

• Critical Steps:

1. Endothelial Cell ($\text{EC}$) Injury: Results in dysfunction, increased permeability, and leukocyte adhesion. Chief causes are hemodynamic disturbances (turbulent flow at branch points) and hypercholesterolemia.

2. Lipoprotein Accumulation: Oxidized $\text{LDL}$ and cholesterol crystals accumulate in the vessel wall.

3. Monocyte Adhesion and Migration: Monocytes differentiate into macrophages and transform into foam cells after engulfing lipids.

4. Inflammation: T lymphocytes and macrophages release cytokines (e.g., \text{IFN-\gamma}) and growth factors.

5. $\text{SMC}$ Recruitment and Proliferation: $SMC$s migrate to the intima and produce $ECM$ (collagen) to stabilize the plaque.

Morphology and Clinical Consequences

• Fatty Streaks: Earliest lesions; flat, yellow macules composed of lipid-filled foamy macrophages. Present in children older than $10$ years.

• Atherosclerotic Plaques: White-to-yellow raised lesions ($0.3$ to $1.5\,\text{cm}$ in diameter) consisting of cells ($\text{SMCs}$, macrophages, T cells), $\text{ECM}$, and lipids.

• Plaque Changes:

  • Stenosis: Gradual occlusion; critical stenosis occurs at $70\%\,$ vessel occlusion, leading to stable angina or claudication.

  • Acute Plaque Change: Rupture, erosion, or hemorrhage of "vulnerable" plaques (thin fibrous caps, large lipid cores, and high inflammation) triggers thrombosis.

• Clinical Outcomes: Myocardial infarction ($\text{MI}$), cerebral infarction (stroke), aortic aneurysm, and peripheral vascular disease.