Causes of Coronary Microvascular Disease (CMD)
Coronary microvascular disease results from traditional cardiovascular risk factors, inflammatory conditions, and pathophysiological mechanisms that cause structural and functional alterations in the coronary microvasculature, with hypertension, diabetes, dyslipidemia, smoking, and age being the primary drivers. 1
Traditional Cardiovascular Risk Factors
The most common causes of CMD are the same traditional risk factors that drive atherosclerotic disease:
Hypertension causes both functional and structural alterations in the microvasculature, promoting endothelial dysfunction and capillary rarefaction, which are the most significant mechanisms in CMD development among hypertensive patients. 2
Diabetes mellitus is strongly associated with CMD through multiple pathophysiological mechanisms, creating microvascular injury that occurs early in the disease course. 1
Dyslipidemia contributes through elevated lipid levels that cause endothelial dysfunction and microvascular structural changes. 1
Cigarette smoking causes direct microvascular injury and promotes endothelial dysfunction in the coronary microvasculature. 1
Advancing age is independently associated with progressive microvascular dysfunction, reflecting cumulative damage over time. 1
Inflammatory and Autoimmune Conditions
Systemic inflammatory diseases represent an important and often overlooked cause of CMD:
Systemic lupus erythematosus and rheumatoid arthritis are associated with microvascular angina and frequently encountered in patients with angina and non-obstructive coronary disease. 1
Chronic inflammatory disease states (including HIV, viral hepatitis, and systemic autoimmune diseases) are associated with overall poor cardiovascular outcomes and contribute to CMD pathogenesis. 3
Inflammatory diseases occur more often in women after menopause than in men, contributing to sex differences in microvascular angina prevalence. 1
Pathophysiological Mechanisms
CMD develops through three primary mechanisms that often coexist:
Endothelial dysfunction is present in 80% of patients with angina and non-obstructive coronary artery disease when tested with acetylcholine, representing the most common pathophysiological mechanism. 1
Impaired coronary flow reserve is present in 50% of patients with angina and non-obstructive coronary artery disease, reflecting structural microvascular remodeling. 1
Abnormal vasoconstriction of coronary arterioles causes dynamic arteriolar obstruction, leading to ischemia without fixed stenosis. 1
Additional Risk Factors and Conditions
Several other conditions promote CMD development:
Obesity and insulin resistance contribute through multiple mechanisms affecting microvascular structure and function. 4
Chronic kidney disease causes CMD through uremic toxins, oxidative stress, and endothelial dysfunction. 5
Hypertrophic cardiomyopathy and aortic valve stenosis cause CMD through increased myocardial oxygen demand and compression of intramural vessels. 5
Critical Clinical Pitfall
A critical error is assuming that normal epicardial coronary arteries on angiography exclude significant coronary disease—CMD can cause myocardial ischemia and adverse cardiovascular outcomes even with completely normal-appearing epicardial vessels. 1 This misconception leads to underdiagnosis and undertreatment of a condition that significantly increases cardiovascular risk and is detectable early in the disease course before clinical symptoms become apparent. 5
Risk Factor Interaction
Multiple risk factors act synergistically rather than additively, with patients having multiple traditional risk factors at significantly higher risk than those with single risk factors. 6
Risk factors for epicardial atherosclerosis also promote endothelial dysfunction and abnormal vasomotion throughout the entire coronary tree, meaning CMD and obstructive disease frequently coexist. 7