Etiologies and Pathogenic Mechanisms of Coronary Artery Disease
Primary Etiologies of CAD
The three main etiologies of CAD are atherosclerotic plaque formation in epicardial arteries, coronary microvascular dysfunction, and epicardial coronary vasospasm. 1
Atherosclerotic Obstructive CAD
- Atherosclerosis is the predominant cause of CAD worldwide, accounting for the vast majority of cases and representing a systemic inflammatory disease process affecting epicardial coronary arteries. 2, 1
- This etiology is strongly associated with classic risk factors including smoking, diabetes mellitus, hypertension, hyperlipidemia, family history of premature CAD, and postmenopausal state. 2, 3
- Atherosclerotic CAD is the leading cause of sudden cardiac death and acute myocardial infarction in adults over age 30-40 years. 1
Coronary Microvascular Dysfunction (CMD)
- Microvascular dysfunction affects the coronary microvasculature and causes ischemia even without obstructive epicardial disease, with prevalence ranging from 26% to 54% in patients with non-obstructive CAD depending on assessment technique. 1
- This mechanism is increasingly recognized as prevalent across the entire CAD spectrum and can cause angina with structurally normal epicardial arteries. 1, 4
- Risk factors for CMD include smoking, age, diabetes, hypertension, dyslipidemia, and inflammatory conditions. 1
Epicardial Coronary Vasospasm
- Vasospastic angina results from abnormal vasoconstriction of epicardial coronary arteries leading to dynamic coronary obstruction, which can occur with or without underlying atherosclerosis. 1
- Epicardial vasospasm can cause transient ischemia even without significant fixed stenosis. 1, 4
- Microvascular angina and epicardial vasospasm frequently coexist, which is associated with worse prognosis. 1
Three Main Pathogenic Mechanisms
1. Atherosclerotic Plaque Formation and Thrombosis
The atherosclerotic process begins with endothelial dysfunction, followed by lipid accumulation, inflammatory cell infiltration, and smooth muscle cell proliferation in the arterial wall. 1, 4
- Plaques prone to rupture contain a large lipid core, low smooth muscle cell density, high macrophage density, and thin fibrous cap. 1, 4
- Three distinct thrombotic mechanisms cause acute coronary syndromes: plaque rupture (more common in men), plaque erosion (more common in women), and calcified nodules. 1
- The inflammatory nature of atherosclerosis involves oxidative stress, altered matrix metabolism, platelet activation, and thrombosis. 5, 6
2. Microvascular Dysfunction and Impaired Vasodilation
Functional and structural microcirculatory abnormalities cause angina and ischemia through impaired coronary flow reserve and reduced microcirculatory conductance, even with non-obstructive epicardial disease. 1, 4
- Endothelial dysfunction leads to impaired flow-mediated vasodilation in both epicardial arteries and microcirculation. 4
- Risk factors for epicardial atherosclerosis also promote endothelial dysfunction and abnormal vasomotion throughout the entire coronary tree. 1, 4
- Macro- and microcirculatory vasoconstriction can occur due to endothelial dysfunction, creating a dynamic component to ischemia. 4
3. Myocardial Supply-Demand Mismatch
Myocardial ischemia results from an imbalance between myocardial oxygen demand and coronary blood flow, influenced by both coronary factors and systemic conditions. 2, 4
- Anemia, tachycardia, and blood pressure changes contribute to myocardial ischemia by altering the supply-demand balance. 4
- Myocardial hypertrophy and fibrosis increase oxygen demand and contribute to ischemia, particularly in patients with hypertension or valvular disease. 2, 4
- Hypertension increases left ventricular output impedance and intramyocardial wall tension, raising myocardial oxygen demand; systolic hypertension and wide pulse pressure increase aortic impedance and central systolic pressure augmentation. 4
Additional Non-Atherosclerotic Etiologies
- Spontaneous coronary artery dissection (SCAD) accounts for 87-95% of cases in women with mean presentation age 44-53 years, responsible for up to 43% of acute coronary syndrome cases in pregnancy. 1
- Congenital coronary anomalies, myocardial bridging, Kawasaki disease, vasculitis (including giant cell arteritis, Takayasu's disease, polyarteritis nodosa), and cardiac transplant vasculopathy represent additional etiologies. 2, 1
- Thromboangiitis obliterans (Buerger's disease) is an arterial obliterative and thrombotic process most frequently observed in young smokers. 2
Critical Clinical Considerations
Different ischemic mechanisms frequently act concomitantly in the same patient, requiring comprehensive evaluation beyond simple angiographic assessment. 1, 4
- CAD should be viewed as a dynamic, progressive condition that may destabilize at any moment throughout a patient's lifetime, with patients potentially transitioning between different types of chronic coronary syndromes and acute coronary syndromes. 1, 4
- Women with CAD more often have non-obstructive disease, coronary vasospasm, and abnormal vasodilator reserve compared to men, with up to 37% showing non-obstructive CAD on angiography despite positive biomarkers. 2
- In patients with congenital heart disease, abnormal glucose metabolism and diabetes mellitus prevalence is significant, with at least 1 in 5 adults with congenital heart disease affected, representing a special population at increased risk for premature CAD. 2