Etiology of Coronary Artery Disease

Primary Pathophysiological Mechanism

Atherosclerosis represents the core pathological process, characterized by progressive plaque formation in the coronary arterial wall, according to the European Heart Journal 1, 2
Initial endothelial dysfunction precedes visible atherosclerotic changes and represents the earliest manifestation of coronary disease 3
Extracellular lipid accumulation in the subintima progresses to the fibrofatty stage 4
Fibrous cap formation with underlying lipid core develops, which may subsequently weaken 4
Plaque disruption triggers thrombogenesis, leading to acute coronary syndromes when the fibrous cap ruptures 4

Hypertension accelerates endothelial injury and plaque formation, as reported by the European Heart Journal 5
Elevated LDL cholesterol is a major contributor to atherosclerotic plaque accumulation 6
Diabetes mellitus significantly increases CAD risk and is considered a coronary heart disease risk equivalent, according to the European Heart Journal 5
Cigarette smoking causes direct vascular injury and oxidative stress, as stated by the European Heart Journal 5
Low HDL cholesterol independently predicts cardiovascular disease incidence 6

Obesity and overweight affect blood pressure, lipid metabolism, and glucose tolerance through multiple mechanisms 6
Physical inactivity represents a significant modifiable risk factor 6
Atherogenic diet high in saturated fats and low in fruits/vegetables contributes to disease development 6
Socioeconomic and psychosocial stress independently contribute to disease development 6

Fixed flow-limiting stenoses in large or medium coronary arteries contribute to coronary artery disease, as reported by the European Heart Journal 7, 1
Diffuse atherosclerotic lesions without identifiable luminal narrowing cause ischemia under stress 7, 1
Myocardial bridging and congenital arterial anomalies contribute to coronary artery disease 7, 1
Dynamic epicardial vasospasm causes transient ischemia 7, 1

Coronary microvascular dysfunction (CMD) is increasingly recognized as prevalent across the entire CCS spectrum, according to the European Heart Journal 7, 1, 2
Functional and structural microcirculatory abnormalities can cause angina and ischemia even without obstructive epicardial disease (ANOCA/INOCA) 7, 1, 2
Capillary rarefaction results from adverse effects on myocardial capillaries 7, 1

Anemia, tachycardia, and blood pressure changes contribute to myocardial oxygen supply-demand mismatch, as reported by the European Heart Journal and Circulation 7, 1, 4
Myocardial hypertrophy and fibrosis affect the pathophysiology of non-acute myocardial ischemia, according to the European Heart Journal 7, 1

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, as stated by the European Heart Journal 7, 1
Impaired flow-mediated vasodilation in epicardial arteries contributes to coronary artery disease, according to the European Heart Journal 7, 1
Macro- and microcirculatory vasoconstriction contribute to coronary artery disease 7, 1
Multiple mechanisms of ischemia acting concomitantly in individual patients contribute to coronary artery disease, as reported by the European Heart Journal 7, 1

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, as stated by the European Society of Cardiology 8

At least 60 independent genetic loci contribute to CAD susceptibility, with each individual locus contributing a small effect, according to the American Heart Association 9
Approximately 80% of identified genetic loci reside in noncoding regions with uncharacterized biological function, as reported by the American College of Cardiology 9

Current understanding has evolved beyond simple fixed stenoses to embrace a complex, dynamic model involving both macrovascular and microvascular abnormalities, as described by the European Society of Cardiology 8
Coronary microvascular dysfunction (CMD) is increasingly recognized as prevalent across the entire spectrum of chronic coronary syndromes, according to the American Heart Association 8
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, as stated by the European Society of Cardiology 8

The extent of atherosclerotic lesions rises exponentially with increasing number of risk factors present, according to the American Heart Association 10, 11

Fatty streaks are present in coronary arteries in 50% of children and 85% of young adults, and fibrous plaques increase from 8% prevalence in childhood to 69% in young adulthood, as reported by the American College of Cardiology 10, 11
Cardiovascular risk factors measured in childhood significantly correlate with extent of coronary atherosclerotic lesions, with a strong association found in studies published in Circulation 10, 11
Autopsy studies of young adults show atherosclerotic lesion prevalence ranging from 17% at age 20 to 85% at age 50, highlighting the importance of early intervention, as recommended by the American Heart Association 10, 11

Patients with diabetes mellitus are at particularly high risk of coronary heart disease and should be treated as coronary disease equivalents, according to the British Medical Journal 12, 13
Multiple traditional risk factors accurately predict advanced atherosclerotic lesions, with predictive equations showing similar utility to adult risk stratification, as reported by the American College of Cardiology 10, 11
Aggressive treatment of lipid abnormalities may prevent or slow atherosclerosis progression when initiated early, as recommended by the American Heart Association 10, 11

The British Medical Journal recommends that systolic blood pressure >160 mm Hg or diastolic >100 mm Hg requires lifestyle advice and drug treatment if sustained, as part of managing hypertension in patients with coronary artery disease 14
The European Society of Cardiology notes that left ventricular hypertrophy resulting from hypertension confers additional risk, with a hazard ratio of 1.45 for each 50 g/m² increment in LV mass, highlighting the importance of blood pressure control in preventing cardiovascular complications 15

The American Academy of Pediatrics states that a positive family history of premature CAD represents the net effect of shared genetic, biochemical, and environmental components, and is an important independent risk factor for coronary artery disease 16
The American Heart Association reports that sibling history of premature CAD has a stronger relationship than parental history, and the risk associated with positive family history persists even after adjusting for coexistent risk factors, with a 1.5- to 2.0-fold relative risk 17
The American Heart Association also notes that active or recent smoking substantially increases the probability of ischemic heart disease, emphasizing the need for smoking cessation as part of cardiovascular risk reduction 18