What is the etiology of coronary artery disease?

Etiology of Coronary Artery Disease

Coronary artery disease results from atherosclerotic plaque accumulation in the epicardial coronary arteries, driven by a complex interplay of genetic predisposition, traditional cardiovascular risk factors, and pathophysiological mechanisms affecting both the macrovascular and microvascular coronary circulation. 1, 2

Primary Pathological Process

Atherosclerosis represents the fundamental disease mechanism, characterized by progressive plaque formation in the coronary arterial wall that evolves through distinct stages 2:

• Endothelial dysfunction precedes visible atherosclerotic changes and represents the earliest manifestation of coronary disease 2
• Extracellular lipid accumulation in the subintima progresses to the fibrofatty stage 2
• Fibrous cap formation with underlying lipid core develops, which may subsequently weaken and rupture 2
• Plaque disruption triggers thrombogenesis, leading to acute coronary syndromes 2

Major Modifiable Risk Factors

The following factors directly accelerate atherosclerotic plaque formation and disease progression:

• Hypertension accelerates endothelial injury and plaque formation 2, 3
• Elevated LDL cholesterol is a major contributor to atherosclerotic plaque accumulation 2, 3
• Diabetes mellitus significantly increases CAD risk and is considered a coronary heart disease risk equivalent 2, 3
• Cigarette smoking causes direct vascular injury and oxidative stress 2, 3
• Low HDL cholesterol independently predicts cardiovascular disease incidence 2, 3

Contributing Lifestyle and Environmental Factors

• Obesity and overweight affect blood pressure, lipid metabolism, and glucose tolerance through multiple mechanisms 2, 3
• Physical inactivity represents a significant modifiable risk factor 2, 3
• Atherogenic diet high in saturated fats and low in fruits/vegetables contributes to disease development 2, 3
• Socioeconomic and psychosocial stress independently contribute to disease development 2, 3

Genetic Architecture

At least 60 independent genetic loci contribute to CAD susceptibility, with each individual locus contributing a small effect 1. This polygenic nature distinguishes CAD from monogenic diseases:

• Approximately 80% of identified genetic loci reside in noncoding regions with uncharacterized biological function 1
• Genetic risk substantially increases CAD susceptibility, with high genetic risk (top quintile) conferring a 91% higher relative risk compared to low genetic risk (bottom quintile) 4
• However, genetic risk can be substantially modified by lifestyle: among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events compared to an unfavorable lifestyle 4

Expanded Pathophysiological Mechanisms

Current understanding has evolved beyond simple fixed stenoses to embrace a complex, dynamic model involving both macrovascular and microvascular abnormalities 1:

Macrovascular Level

• Fixed flow-limiting stenoses in large or medium coronary arteries 1, 2
• Diffuse atherosclerotic lesions without identifiable luminal narrowing that cause ischemia under stress 1, 2
• Structural abnormalities including myocardial bridging and congenital arterial anomalies 1, 2
• Dynamic epicardial vasospasm causing transient ischemia 1, 2

Microvascular Level

Coronary microvascular dysfunction (CMD) is increasingly recognized as prevalent across the entire spectrum of chronic coronary syndromes 1, 2:

• Functional and structural microcirculatory abnormalities can cause angina and ischemia even without obstructive epicardial disease (ANOCA/INOCA) 1, 2
• Traditional cardiovascular risk factors cause structural and functional alterations in the coronary microvasculature 5
• Endothelial dysfunction is present in 80% of patients with angina and non-obstructive coronary artery disease 5

Systemic Contributions

• Anemia, tachycardia, and blood pressure changes contribute to myocardial oxygen supply-demand mismatch 2
• Myocardial hypertrophy and fibrosis affect the pathophysiology of non-acute myocardial ischemia 1, 2

Critical Unifying Concept

Risk factors that promote epicardial atherosclerosis simultaneously cause endothelial dysfunction and abnormal vasomotion throughout the entire coronary tree, including the arterioles regulating coronary flow and resistance 1, 2. This explains why:

• Impaired flow-mediated vasodilation occurs in epicardial arteries 2
• Macro- and microcirculatory vasoconstriction contribute concomitantly 2
• Multiple mechanisms of ischemia often act simultaneously in individual patients 2

Common Clinical Pitfall

A critical error is assuming that normal epicardial coronary arteries on angiography exclude significant coronary disease—coronary microvascular disease can cause myocardial ischemia and adverse cardiovascular outcomes even with completely normal-appearing epicardial vessels 5. This underscores the importance of recognizing the full spectrum of coronary pathophysiology beyond visible stenoses.