From the Guidelines
Atherosclerosis is primarily caused by an inflammatory response to injury in the arterial wall, triggered by risk factors such as hypertension, hyperlipidemia, diabetes, and smoking 1.
Pathogenesis of Atherosclerosis
The process can be broken down into several key steps:
- Initiation: Endothelial dysfunction and increased permeability, resulting from risk factors such as hypertension, hyperlipidemia, diabetes, and smoking, lead to endothelial injury and expression of adhesion molecules 1.
- Monocyte Adhesion and Migration: Monocytes adhere to the endothelium and migrate into the intima, mediated by adhesion molecules (e.g., VCAM-1, ICAM-1) and chemokines (e.g., MCP-1) 1.
- Macrophage Activation and Foam Cell Formation: Monocytes differentiate into macrophages, which ingest lipids and become foam cells, mediated by scavenger receptors (e.g., CD36, SR-A) and modified lipoproteins (e.g., oxidized LDL) 1.
- Smooth Muscle Cell Proliferation and Migration: Smooth muscle cells migrate from the media to the intima and proliferate, mediated by growth factors (e.g., PDGF, TGF-β) and inflammatory cytokines (e.g., IL-1, TNF-α) 1.
- Extracellular Matrix Accumulation: Smooth muscle cells produce extracellular matrix components (e.g., collagen, elastin), mediated by growth factors (e.g., TGF-β) and inflammatory cytokines (e.g., IL-1, TNF-α) 1.
- Plaque Formation and Progression: Accumulation of lipids, macrophages, smooth muscle cells, and extracellular matrix leads to plaque formation and progression, complicated by inflammation, calcification, and thrombosis 1.
- Clinical Manifestations: Atherosclerotic plaques can lead to various clinical manifestations, including myocardial infarction, stroke, peripheral artery disease, and aortic aneurysm 1. Some key points to note include:
- Inflammation plays a crucial role in the pathogenesis of atherosclerosis, with circulating levels of inflammatory markers such as C-reactive protein (CRP) and interleukin-6 correlating with the clinical course and outcome of acute coronary syndromes 1.
- Plaque disruption and thrombosis can be triggered by various factors, including physical or emotional stress, and can lead to acute coronary syndromes 1. Prevention and treatment strategies for atherosclerosis include:
- Lifestyle modifications: diet, exercise, smoking cessation
- Medications: statins (e.g., atorvastatin 20-80 mg/day), anti-hypertensives (e.g., ACE inhibitors, beta blockers), anti-platelet agents (e.g., aspirin 75-100 mg/day) 1.
From the Research
Pathogenesis of Atherosclerosis
The pathogenesis of atherosclerosis is a complex process involving multiple factors and cellular processes. Key factors that influence atherogenesis include:
- Oxidative stress
- Inflammation
- Hypertension
- Hyperlipidemia These factors ultimately drive the accumulation of low-density lipoprotein cholesterol within the arterial wall of medium and large arteries 2.
Cellular Processes
The accumulation of low-density lipoprotein cholesterol stimulates the infiltration of immune cells, such as:
- Monocytes/macrophages
- T-lymphocytes These cells take up the lipoprotein, leading to the formation of lipid-laden foam cells. Foam cell death results in increased accumulation of dead cells, cellular debris, and extracellular cholesterol, forming a lipid-rich necrotic core 2, 3.
Plaque Progression
Plaque progression is characterized by the formation of a fibrous cap composed of extracellular matrix proteins and smooth muscle cells. This cap acts to stabilize the atherosclerotic plaque. Degradation, thinning, and subsequent rupture of the fibrous cap leads to lumen-occlusive atherothrombosis, most commonly resulting in heart attack or stroke 2, 4.
Key Participants
Key initial participants in the pathogenesis of atherosclerosis include:
- Focal intimal influx and accumulation of low-density lipoprotein (LDL)
- Preferential recruitment of blood monocytes
- Smooth muscle cell migration and proliferation
- Formation of foam cells through the receptor-mediated uptake of oxidized LDL by macrophages 3, 5.
Inflammatory Insult
The inciting event of atherosclerosis is likely an inflammatory insult that occurs decades before the disease becomes clinically apparent. This insult initiates a series of changes in the constituent cellular make-up of the vessel wall, leading to the progression of atherosclerosis 6.