Etiology of Coronary Artery Disease
Coronary artery disease is fundamentally caused by atherosclerotic plaque accumulation in the epicardial coronary arteries, driven by the interaction of multiple genetic predispositions and modifiable cardiovascular risk factors, with contemporary understanding now recognizing additional contributions from coronary microvascular dysfunction and structural abnormalities. 1
Primary Pathophysiological Mechanism
Atherosclerosis represents the core pathological process, characterized by progressive plaque formation in the coronary arterial wall 1. The disease evolves through distinct stages:
- Initial endothelial dysfunction precedes visible atherosclerotic changes and represents the earliest manifestation of coronary disease 1
- Extracellular lipid accumulation in the subintima progresses to the fibrofatty stage 1
- Fibrous cap formation with underlying lipid core develops, which may subsequently weaken 1
- Plaque disruption triggers thrombogenesis, leading to acute coronary syndromes when the fibrous cap ruptures 1
Major Modifiable Risk Factors
The following risk factors directly promote atherosclerotic plaque development and progression 1, 2:
- Hypertension accelerates endothelial injury and plaque formation 1, 2
- Elevated LDL cholesterol is a major contributor to atherosclerotic plaque accumulation 2
- Diabetes mellitus significantly increases CAD risk and is considered a coronary heart disease risk equivalent 1, 2
- Cigarette smoking causes direct vascular injury and oxidative stress 1, 2
- Low HDL cholesterol independently predicts cardiovascular disease incidence 2
Underlying Contributing Factors
Beyond traditional risk factors, additional etiologic contributors include 1, 2:
- Obesity and overweight affect blood pressure, lipid metabolism, and glucose tolerance through multiple mechanisms 2
- Physical inactivity represents a significant modifiable risk factor 2
- Atherogenic diet high in saturated fats and low in fruits/vegetables 2
- Socioeconomic and psychosocial stress independently contribute to disease development 2
Genetic Component
CAD has substantial hereditary contribution, with family history representing the most significant independent risk factor 3:
- Multifactorial genetic architecture involves interactions between multiple predisposing genes and environmental factors 4, 3
- Monogenic disorders such as familial hypercholesterolemia explain a small percentage of cases, particularly early-onset CAD 3
- Genome-wide association studies have identified approximately 40 genetic loci explaining 6% of CAD heritability 5
- Chromosome 9p21.3 has been associated with premature onset of CAD 6
- Somatic DNA mutations from oxidative stress may contribute to pathogenesis, similar to carcinogenic processes 7
Expanded Pathophysiological Mechanisms
Contemporary understanding has evolved beyond simple fixed stenoses to recognize multiple mechanisms 1:
Macrovascular Level
- Fixed flow-limiting stenoses in large or medium coronary arteries 1
- Diffuse atherosclerotic lesions without identifiable luminal narrowing that cause ischemia under stress 1
- Myocardial bridging and congenital arterial anomalies 1
- Dynamic epicardial vasospasm causing transient ischemia 1
Microvascular Level
- Coronary microvascular dysfunction (CMD) is increasingly recognized as prevalent across the entire CCS spectrum 1
- Functional and structural microcirculatory abnormalities can cause angina and ischemia even without obstructive epicardial disease (ANOCA/INOCA) 1
- Capillary rarefaction results from adverse effects on myocardial capillaries 1
Systemic Contributions
- Anemia, tachycardia, and blood pressure changes contribute to myocardial oxygen supply-demand mismatch 1
- Myocardial hypertrophy and fibrosis affect the pathophysiology of non-acute myocardial ischemia 1
Critical Clinical Consideration
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. This results in: