Invasive assessment of coronary microvascular dysfunction and its prognostic significance in stable coronary artery disease: a meta-analysis

Background Coronary microvascular dysfunction (CMD) refers to a broad spectrum of structural and functional abnormalities of the coronary microcirculation and, in clinical practice, is commonly defined by impaired flow augmentation in response to a pharmacological vasodilator in the presence of nonobstructive coronary artery disease. In chronic coronary syndrome (CCS), CMD is frequent, yet its prognostic significance has not been consistently quantified. Objectives To evaluate the association between invasively assessed CMD and adverse clinical outcomes in CCS. Methods Databases (PubMed, Embase, Web of Science) were searched from inception to March 2025. We included studies enrolling CCS patients undergoing invasive assessment of coronary microvascular function (using study-specific CMD definitions/cut-offs) with subsequent reporting of clinical events. The primary outcome was major adverse cardiac events (MACE). Secondary outcomes were all-cause mortality, cardiovascular mortality, hospitalization for heart failure (HHF), myocardial infarction (MI), and repeat revascularization. Random-effects models were used to pool risk ratios (RRs). Heterogeneity was quantified with I². Results Eighteen studies including 9,290 CCS patients (CMD: 3,229; no CMD: 6,061) were included. CMD was associated with a higher risk of MACE (RR 2.65, 95% CI 2.19–3.20; P<0.001; I²=51.0%). All-cause mortality was increased in CMD across 12 studies (n=8,443; RR 3.22, 95% CI 2.44–4.26; P<0.001; I²=55.4%), as was cardiovascular mortality across 8 studies (n=5,067; RR 2.60, 95% CI 1.82–3.71; P<0.001; I²=0%). CMD was also associated with HHF (2 studies; n=407; RR 2.23, 95% CI 1.52–3.29; P<0.001; I²=0%) and MI (6 studies; n=3,941; RR 1.88, 95% CI 1.07–3.31; P=0.028; I²=0%). Repeat revascularization did not reach statistical significance (3 studies; n=1,841; RR 1.78, 95% CI 0.99–3.22; P=0.055; I²=0%). Conclusions In CCS, invasively assessed CMD identifies a markedly higher-risk phenotype, with an approximately 3-fold higher risk of MACE and ~3-fold higher risk of both all-cause and cardiovascular mortality. CMD was also associated with an elevated risk of HHF and MI, whereas repeat revascularization was not significantly increased. These findings indicate that CMD is not a benign condition. In line with the 2024 ESC Guidelines for the management of chronic coronary syndromes1, invasive CMD assessment should be an integral component of the diagnostic work-up in patients with angina and non-obstructive coronary arteries, to improve risk stratification and management of this high-risk, underdiagnosed population.CMD in CCS: MACE and MortalityCMD in CCS: MI, Revasc, HF Hosp, Stroke