Invasive assessment of coronary microvascular dysfunction with MACEs: a meta-analysis

Abstract Aims Although obstructive coronary artery disease (CAD) is considered a prerequisite for myocardial ischemia, it is established that abnormalities of coronary microcirculation may restrict myocardial perfusion in the absense of CAD. Coronary microvascular dysfunction (CMD) is likely associated with elevated risk for MACEs. We performed a meta-analysis of randomized controlled trials to determine the prognostic value of CMD, assessed by invasive techniques, in predicting cardiovascular endpoints in patients without epicardial CAD. Methods and results We identified all studies between 1 January 2000 and 1 December 2023, where coronary flow was invasively measured and clinical outcomes were reported. We included RCTs and all prospective and retrospective studies with a control group, which measured coronary flow reserve (CFR) and/or index of microcirculatory resistance (IMR), as assessed invasively. The endpoints were all-cause mortality and MACEs, including cardiovascular death, myocardial infarction, hospitalization for heart failure (HF) and coronary revascularization. Twenty-five articles enrolling a total of 9.800 subjects (mean age: 55.5±10.6 years) were included with a mean follow-up period of 37 months were eventually deemed eligible for our final analysis. Of these, 3.421 (34,9%) patients had CFR<2.5 and/or IMR>25, indicating CMD, while 6.379 (65,1%) subjects were found without CMD. The analysis of the pooled results demonstrated that the presence of CMD depicted by abnormal CFR and/or IMR was associated with a substantially higher risk for all-cause mortality during a median follow-up period of 3.2 years. The odds ratio for all-cause mortality in patients with CMD compared with those without CMD was 2.31 (95% CI: 1.62 - 2.54, p<0.01). A similar effect of abnormal CFR and IMR was also observed for cardiovascular morality (HR 2.47, 95% CI: 1.81 - 3.38, p<0.01). In addition, the composite of revascularization was also assessed in the total of the selected studies. In particular, the pooled analysis demonstrated a positive association of CMD with a higher future risk for revascularization (HR 1.87, 95% CI: 1.33 – 2.62, p<0.01). The composite of hospitalization for heart failure was also assessed. In addition, the pooled analysis demonstrated a positive association between CMD and hospitalization for HF (HR 2.50, 95% CI: 1.63 - 3.85, p<0.01).A similar effect of abnormal CMD was also observed for myocardial infraction (HR 1.73, 95% CI: 1.33 - 2.24). Elevated IMR (>40) seems to be to be prognostically more relevant than abnormal CFR in the setting of acute myocardial infarction. Conclusions CMD is associated with a nearly 3-fold increase in mortality and a 2-fold increase in major adverse cardiac events. Impaired coronary flow is strongly associated with increased risk of all-cause mortality and MACEs. Future studies and randomized controlled trials are needed to identify strategies to diagnose and treat CMD.