The review reflects a broader change in how coronary disease is being conceptualized. Coronary computed tomography angiography, invasive angiography, and intravascular imaging have traditionally emphasized focal plaques and narrowing in the large coronary arteries, while the coronary microcirculation has often been treated as a parallel or downstream problem. Yet the microcirculation supplies the myocardium and accounts for at least 60% of total coronary vascular resistance. Because it is the main determinant of coronary blood flow, abnormalities in this vascular compartment can alter the hemodynamic environment throughout the coronary tree. The review therefore evaluates whether microvascular disease belongs closer to the starting point of atherogenesis, while preserving the possibility that plaque and shared risk factors can also damage the microcirculation.

Shear stress provides the central physical link in this hypothesis. It is the tangential force generated by blood flow against the arterial lining and influences vascular growth, nitric oxide production, and endothelial biology. Regions exposed to low shear stress tend to have wider spaces between endothelial cells, allowing lipid-rich particles to enter the arterial wall more readily. Local flow patterns help explain why plaques preferentially arise at bends, branch points, tortuous segments, and sites affected by myocardial bridging. Reduced flow can also favor atheroma formation: clinical observations after coronary artery bypass grafting have linked accelerated plaque progression in native arterial segments proximal to an anastomosis to competition for flow from the bypass conduit. Experimental and computational work in coronary arteries likewise associates low shear stress with plaque initiation and progression.

Microvascular dysfunction can create this adverse upstream environment by restricting distal runoff. When resistance rises in the small vessels, resting coronary flow falls and the microcirculation’s ability to increase flow when oxygen demand rises is impaired. Autoregulation can buffer moderate changes by preserving myocardial perfusion over a range of pressures, but that reserve is more likely to be exhausted during increased oxygen demand or severe, diffuse microvascular disease, as can occur with diabetes, hypertension, and ischemia without obstructive coronary arteries. A clinical study of 65 patients with early non-obstructive coronary artery disease found lower calculated endothelial shear stress in coronary segments belonging to arteries with abnormal microvascular function than in arteries with normal microvascular function. Every patient with epicardial endothelial dysfunction also had microvascular endothelial dysfunction, indicating overlap but not establishing which process came first.

Animal experiments provide the clearest evidence for temporal order. In swine exposed to diabetes and a high-fat diet, impaired endothelium-dependent relaxation and increased passive microvascular resistance appeared after 10 to 20 weeks without detectable epicardial plaque. After about 15 months, structural changes and non-flow-limiting plaques had emerged, with plaque burden below 30%. In another hamster model, diabetes and hyperlipidemia together accelerated capillary narrowing, basement-membrane thickening, and expansion of perivascular matrix, with these microvascular changes preceding overt macrovascular atherosclerosis. Diabetes alone produced similar changes more slowly, whereas hyperlipidemia alone produced macrovascular atherosclerosis without detectable microvascular effects. These findings support a possible sequence from metabolic stress to microvascular injury and then plaque, but animal disease models only partly reproduce the slower, multifactorial course of human cardiovascular disease.

Human imaging studies show that impaired perfusion often fails to align neatly with visible narrowing of a major coronary artery. In the prospective CORE320 study of 381 symptomatic patients referred for angiography, 8% had ischemia with no obstructive coronary artery disease, and perfusion abnormalities were not always located in territories supplied by stenotic arteries. Research summarized in the review found that roughly 70% to 80% of patients with chest pain and no obstructive coronary artery disease had diffuse non-obstructive epicardial atherosclerosis, while more than half had longitudinal pressure gradients despite the absence of focal stenosis. In a study of 837 symptomatic patients assessed with coronary CT and oxygen-15 water PET, many vessels supplying ischemic territories had relatively little stenosis or plaque, pointing to microvascular dysfunction or occlusion as possible contributors. These discordances challenge the assumption that visible narrowing explains every region of ischemia.

The relationship also appears to run in the opposite direction, making a simple one-way model inadequate. Plaque erosion or rupture can release particles and soluble mediators that obstruct or constrict the microcirculation, producing patchy microinfarction and impaired microvascular reserve. Similar microembolic injury can occur during percutaneous intervention. Diffuse epicardial atherosclerosis may also reduce the pressure driving blood through the distal circulation, while perivascular fibrosis can be both a consequence and a contributor to microvascular dysfunction. At the same time, diabetes, hypertension, obesity, dyslipidemia, inflammation, and oxidative stress can injure both vascular compartments in parallel. The review consequently frames microvascular and epicardial disease as a bidirectional continuum, with shared drivers potentially explaining some of their observed association without proving that one causes the other.

Functional abnormalities in the microcirculation carry prognostic weight even when large-artery obstruction is absent. A meta-analysis covering 79 studies and nearly 60,000 participants found that reduced coronary flow reserve was associated with higher rates of major adverse cardiovascular events and all-cause mortality, with the strongest association occurring in people who had isolated microvascular dysfunction. Other meta-analyses of coronary and myocardial flow reserve reported similar associations with adverse outcomes. In the iPOWER prospective cohort of 1,681 women with angina and no obstructive coronary artery disease, each 0.1-unit decrease in coronary flow velocity reserve was associated with a higher risk of a composite endpoint comprising cardiovascular death, myocardial infarction, heart failure, stroke, and coronary revascularization. Among 329 patients with ischemia and non-obstructive coronary arteries followed for a median of eight years, both coronary flow reserve and hyperemic microvascular resistance predicted major adverse cardiovascular events independently of coronary artery disease severity.

Microvascular disease is also closely intertwined with heart failure with preserved ejection fraction, or HFpEF. In the multinational PROMIS-HFpEF study, 75% of 202 patients with HFpEF had microvascular involvement, defined by a coronary flow reserve below 2.5, and this involvement was independently associated with cardiovascular and heart-failure-related events during follow-up. Other evidence indicates that combined microvascular and diastolic dysfunction can be associated with more than a fivefold increase in HFpEF hospitalization risk. A substantial share of patients with ischemia and no obstructive coronary artery disease also meet HFpEF criteria. These findings indicate that impaired microvascular reserve may help connect ischemic symptoms, vascular remodeling, fibrosis, reduced ventricular compliance, and eventual heart failure, although they do not establish a single causal sequence for every patient.

Imaging could make this broader view of coronary disease more visible. Positron emission tomography, cardiac magnetic resonance, and CT perfusion can quantify myocardial blood flow and flow reserve, while invasive measurements can assess coronary flow reserve, hyperemic microvascular resistance, and vasomotor responses. The review reports that population-based estimates suggest nearly half of people with angina have non-obstructive coronary artery disease, with 60% to 70% of that group potentially attributable to microvascular dysfunction. Women are disproportionately affected by this presentation, although microvascular dysfunction also occurs in men. Combined structural and functional assessment may identify disease that anatomy alone misses, refine risk stratification, and distinguish clinical patterns such as microvascular angina and vasospastic angina. These are potential applications of the evidence, not proof that imaging-guided microvascular treatment can prevent plaque.

For patients with angina or objective ischemia but no obstructive coronary disease, the evidence supports a possible clinical role for physiological testing, not a new treatment recommendation. Existing studies indicate that stratified medical therapy selected using invasive coronary physiology can improve angina and quality of life, while SGLT2 inhibitors improve outcomes in HFpEF irrespective of diabetes status. Their value specifically as therapies for the microvascular-HFpEF axis has not yet been established in dedicated trials. The central takeaway is therefore substantial but bounded: experimental models, prospective cohorts, perfusion studies, and outcome analyses support microvascular dysfunction as an early and prognostically important component of coronary disease, potentially capable of encouraging upstream plaque formation. Direct human causality, the ideal timing of detection, and whether treating the microcirculation changes the course of epicardial atherosclerosis remain unanswered and require prospective validation and interventional study.

Subject of Research: Evidence linking coronary microvascular dysfunction to bidirectional relationships with epicardial atherosclerosis

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

Article References: Salameh, E., Hoballah, M., Ebrahimihoor, E., Zadeh, A., Schuijf, J. D., & Lima, J. A. C. (2026). Coronary microvascular disease as potential mechanism of coronary epicardial atherogenesis: an overview of current evidence. Frontiers in Cardiovascular Medicine, 13, 1946683. https://doi.org/10.3389/fcvm.2026.1946683

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1946683

Keywords: coronary microvascular dysfunction, epicardial atherosclerosis, coronary artery disease, wall shear stress, myocardial perfusion, coronary flow reserve, cardiac imaging, heart failure with preserved ejection fraction, atherogenesis, ischemia without obstruction, Coronary, microvascular