Coronary microvascular dysfunction endotypes and clinical outcomes in patients with ischemia and no obstructive coronary arteries: A meta-analysis

Background Coronary microvascular dysfunction (CMD) contributes significantly to angina syndromes, characterized by impaired coronary flow reserve (CFR) and/or elevated index of microvascular resistance (IMR) with non-obstructive coronary artery disease. Recent advances identify 2 CMD endotypes—structural and functional—based on combined CFR and IMR measurements Purpose This study assesses the prognostic significance of CMD endotypes, measured invasively via thermodilution. It aims to refine understanding of their clinical implications,guiding personalized diagnostic and therapeutic strategies. Methods We conducted a systematic literature search for studies evaluating invasively both CFR and IMR in patients without significant epicardial coronary artery disease. Patients were categorized into 4 groups based on their CFR and IMR invasive measurements: Group 1 (G1) Normal CFR & IMR, Group 2 (G2) Normal CFR & abnormal IMR, Group 3 (G3) Abnormal CFR & normal IMR (functional endotype) & Group 4 (G4) Abnormal CFR & IMR (structural endotype). These groups were analyzed for outcomes including all-cause mortality (ACM), cardiovascular mortality (CVM), hospitalization for HF (HHF), as well as combined endpoints (MACE) at maximal follow-up. We extracted the event rates (or the odds ratios ODs, where available) for those endpoints for the groups. Pooling of the odds ratios was conducted according to a random effects model. I2 was chosen as the measure of between-study heterogeneity, with values exceeding 50% being considered significant. Results We identified a total of 123 studies, of which 5 were ultimately selected for data extraction & inclusion in the meta-analysis after screening of title/abstract/full-text. The follow-up duration ranged from 1 to 10 years. The mean age did not exceed 65 years in either group, with the majority of participants being females. According to the meta-analysis results, compared to G1, the presence of CMD (G3 & G4) was associated with higher rates of the combined endpoints of major adverse cardiovascular events (MACE) (Figure 1), as well as their individual components (Figure 2). G4 had the highest MACE (OR: 2.97; 95% CI 2.16 to 4.06) and mortality rate (OR: 3.61; 95% CI .17 to 6.01) compared with G1. Interestingly, G2 (discordance between CFR and IMR) MACE, CVM, ACM and HHF rates did not differ significantly from G1. There was no evidence of between-study heterogeneity or publication bias, as confirmed by funnel plot inspection and Egger’s test. Additionally, the results remained consistent following a sensitivity analysis using the leave-one-out method. Conclusions Abnormal CFR and abnormal MR are associated with an increased risk of MACEs and all-cause mortality. The structural endotype demonstrates a higher MACE risk compared to the functional endotype. In contrast, discordant normal CFR with abnormal IMR is not linked to a higher risk of MACEs or mortality when compared to the non-CMD control group.Fig. 1- MACE Fig. 2 - ACM, CVM, HHF