What are the etiopathogenesis mechanisms of the 3 etiologies of Coronary Artery Disease (CAD): atherosclerotic obstructive CAD, coronary microvascular dysfunction (CMD), and epicardial coronary vasospasm?

Etiopathogenesis of the Three Major Etiologies of Coronary Artery Disease

Coronary artery disease results from three distinct but often overlapping pathophysiological mechanisms: atherosclerotic plaque-related obstruction of epicardial arteries, coronary microvascular dysfunction, and focal or diffuse epicardial coronary vasospasm. 1

1. Atherosclerotic Obstructive CAD

Initial Endothelial Injury and Lipid Accumulation

• The process begins with endothelial dysfunction, which triggers lipid accumulation in the arterial wall, followed by inflammatory cell infiltration and smooth muscle cell proliferation. 2
• Imbalanced lipid metabolism creates the foundation for atherosclerotic plaque development, with lipoproteins penetrating the damaged endothelium and becoming oxidized in the subendothelial space. 3

Inflammatory Response and Plaque Formation

• A maladaptive immune response drives chronic inflammation of the arterial wall, with leukocyte trafficking and homeostasis governed by chemokines and their receptors shaping the disturbed equilibrium between lipid accumulation and clearance. 3
• The inflammatory cascade involves macrophage infiltration, foam cell formation, and release of pro-inflammatory cytokines that perpetuate the atherosclerotic process. 2

Plaque Characteristics and Vulnerability

• Plaques prone to rupture typically contain a large lipid core, low smooth muscle cell density, high macrophage density, and a thin fibrous cap. 2
• Stable plaques create fixed stenoses that cause effort-induced angina by limiting coronary blood flow during increased myocardial oxygen demand. 1

Systemic Risk Factor Contribution

• Traditional cardiovascular risk factors (hypertension, diabetes, dyslipidemia, smoking) promote both epicardial atherosclerosis and endothelial dysfunction throughout the entire coronary tree. 2

2. Coronary Microvascular Dysfunction (CMD)

Functional Alterations

• CMD is characterized by heightened sensitivity to vasoconstrictor stimuli and severely limited microvascular vasodilator capacity, resulting in an attenuated coronary blood flow response to vasodilatory agents. 4
• Endothelial dysfunction in the microvasculature leads to impaired flow-mediated vasodilation, even in the absence of obstructive epicardial disease. 2, 5
• Macro- and microcirculatory vasoconstriction occurs due to endothelial dysfunction affecting the entire coronary vascular tree. 2

Structural Changes

• The pathogenesis involves both functional and structural alterations in the coronary microcirculation, including capillary rarefaction, perivascular fibrosis, and smooth muscle cell hypertrophy in arterioles. 5, 6
• Structural microcirculatory abnormalities can cause angina and ischemia independent of epicardial disease status. 2

Risk Factor Overlap

• CMD shares many similar risk factors with macrovascular CAD, including diabetes, hypertension, dyslipidemia, and smoking. 4
• Cardiometabolic risk factors increase oxidative stress and inflammation, leading to microvascular injury through both endothelium-dependent and independent mechanisms. 7

Clinical Context

• CMD can occur as a primary condition (microvascular angina) or coexist with obstructive epicardial CAD, cardiomyopathies, Takotsubo syndrome, and heart failure with preserved ejection fraction. 5, 6
• The condition is more prevalent in women, particularly middle-aged women, contributing to the higher prevalence of angina in this demographic despite lower rates of obstructive CAD. 1

3. Epicardial Coronary Vasospasm

Mechanism of Vasospasm

• Focal or diffuse spasm of epicardial coronary arteries can occur in both normal and plaque-diseased vessels, causing transient ischemia even without significant fixed stenosis. 1, 2
• Vasospasm represents a dynamic stenosis that can cause rest angina, distinguishing it from the effort-induced symptoms typical of fixed obstructive lesions. 1

Endothelial Dysfunction Component

• Endothelial dysfunction plays a central role by impairing the normal vasodilatory response and promoting paradoxical vasoconstriction in response to stimuli that would normally cause vasodilation. 2
• The same risk factors that promote epicardial atherosclerosis also contribute to abnormal vasomotion throughout the coronary tree. 2

Vasospasm Subtypes

• Epicardial vasospasm can be focal (localized to a specific coronary segment) or diffuse (affecting longer segments or multiple vessels), and can occur at the epicardial level or involve the microvasculature. 1
• Vasospasm can occur in coronary arteries with no atherosclerotic plaque on intravascular imaging, representing pure functional abnormality. 7

Critical Clinical Considerations

Mechanism Overlap

• These three mechanisms frequently act concomitantly in the same patient and can change over time, creating a dynamic and progressive disease state. 1, 2
• Vasoconstriction at the site of dynamic stenosis can combine with underlying epicardial stenoses and microvascular dysfunction to produce complex ischemic syndromes. 1

Prognostic Implications

• All three mechanisms contribute to adverse cardiovascular outcomes, including myocardial infarction, heart failure, and increased mortality. 6, 7
• The presence of CMD, even in patients without obstructive CAD, carries significant prognostic implications and contributes to recurrent hospitalizations and reduced quality of life. 7

Common Pitfall

• Clinicians often focus exclusively on epicardial obstructive disease while overlooking CMD and vasospasm, leading to persistent symptoms despite revascularization and inadequate risk stratification in patients with non-obstructive coronary arteries. 4, 6, 7