What is the pathophysiology of atherosclerosis?

Pathophysiology of Atherosclerosis

Atherosclerosis is a chronic inflammatory disease initiated by lipid accumulation in the arterial intima, progressing through distinct pathological stages from fatty streaks to vulnerable plaques that can rupture and cause thrombotic occlusion. 1

Initiation: The Fatty Streak

• The earliest pathological abnormality is the fatty streak, which represents an accumulation of lipid-filled macrophages (foam cells) within the intima of medium and large arteries 1
• This process begins in childhood and adolescence, with fatty streaks present in 50% of children and 85% of young adults 1
• The fundamental trigger is the accumulation and retention of low-density lipoprotein cholesterol within the arterial wall, which undergoes oxidation and modification 2
• Oxidized lipids provoke endothelial dysfunction and chronic inflammation at susceptible arterial sites 2, 3

Progression: Fibrous Plaque Formation

• As lipid continues to accumulate with age, macrophages and smooth muscle cells proliferate and migrate from the media into the intima in response to this lipid burden 1
• Vascular smooth muscle cells take up lipids to become foam cells and produce extracellular matrix proteins including collagen and elastin 2
• This cellular response forms a fibrous plaque lesion characterized by a lipid-rich necrotic core covered by a fibrous cap composed of smooth muscle cells and extracellular matrix 2
• The prevalence of fibrous plaques increases from 8% in childhood to 69% in young adulthood 1

The Role of Risk Factors

• Cardiovascular risk factors accelerate plaque development through cumulative, long-term exposure that overwhelms arterial defense mechanisms 4
• Elevated LDL cholesterol, hypertension, smoking, diabetes, and obesity are directly associated with both the presence and extent of atherosclerotic lesions in young persons aged 15-34 years 1, 5
• The extent of atherosclerotic lesions rises exponentially with increasing number of risk factors present 1
• Each 10-15 mg/dL increase in non-HDL cholesterol is associated with an additional year of vascular aging 1

Plaque Vulnerability and Complications

• Advanced fibrous plaques become vulnerable to rupture through several mechanisms: development of a large lipid-rich necrotic core, thinning and destabilization of the fibrous cap by chronic inflammation, and hemodynamic stress 1, 4
• Activated macrophages and T lymphocytes at the plaque shoulder increase expression of metalloproteinases that cause thinning and disruption of the fibrous cap 1
• Foam cell death results in accumulation of dead cells, cellular debris, and extracellular cholesterol, expanding the necrotic core 2
• Plaque rupture initiates a cascade of thrombotic events leading to arterial occlusion and subsequent myocardial infarction or stroke 1

Alternative Mechanisms of Acute Events

• Plaque complications can also occur through vascularization of the plaque, leading to intraplaque hemorrhage, swelling, and luminal occlusion 1
• Surface erosion of plaques and rupture of calcific nodules into the arterial lumen can trigger thrombosis without frank plaque rupture 6
• Dynamic obstruction from intense focal coronary artery spasm (Prinzmetal's angina) or diffuse microvascular dysfunction represents a less common mechanism 1

Compensatory Mechanisms and Stenosis Development

• Early plaque extension is compensated by focal vessel widening (vascular remodeling), preventing lumen obstruction 4
• For stenosis to emerge, conventional plaques must convert to complicated plaques characterized by rupture and atherothrombosis 4
• This conversion typically starts with small- to medium-sized plaques rather than the largest lesions 4

Clinical Implications

• Atherosclerosis has a long asymptomatic phase with progression accelerated by cardiovascular risk factors 3
• Endothelial dysfunction is one of the first recognizable signs of atherosclerosis development, present long before clinical cardiovascular disease 3
• The pathological process is identical regardless of race, ethnicity, sex, or geographic location, though the rate of development varies with risk factor burden 6
• Treatment with statins favorably alters plaque size, cellular composition, inflammation, and cholesterol metabolism, with clinical benefit beginning within 4 months 6