Coronary microvascular disease as potential mechanism of coronary epicardial atherogenesis: an overview of current evidence

Coronary artery disease (CAD) remains a leading global health burden despite major advances in prevention and treatment, highlighting limitations of the traditional epicardial plaque-centric framework. Increasing evidence suggests that myocardial coronary microvascular disease (CMD) may represent an upstream determinant of atherogenesis. This review synthesizes experimental, clinical, and imaging data supporting the hypothesis that microvascular dysfunction may contribute to the initiation and progression of epicardial atherosclerosis. The latter may, in turn, contribute to CMD, and the relationship between the two compartments is best understood as bidirectional rather than strictly unidirectional. Mechanistically, microvascular dysfunction increases coronary resistance and impairs distal runoff, leading to alterations in wall shear stress that may promote endothelial dysfunction, lipid infiltration, and plaque development in upstream epicardial vessels. Experimental models demonstrate that microvascular abnormalities often precede overt macrovascular disease, while multimodality imaging studies consistently show impaired myocardial perfusion and reduced coronary flow reserve in the absence of obstructive CAD. These functional abnormalities are strongly associated with adverse cardiovascular outcomes, including major adverse cardiovascular events (MACE) and heart failure with preserved ejection fraction (HFpEF). The frequent discordance between perfusion deficits and epicardial stenosis further supports a central role for microvascular dysfunction in ischemic heart disease. Collectively, these findings challenge a purely anatomical framework and highlight the value of quantitative imaging of coronary flow and perfusion for disease characterization and risk stratification. A shift toward a microvascular-centered paradigm may enable earlier detection, improve phenotyping, and inform targeted preventive and therapeutic strategies.