Sex-based differences in invasive assessment of coronary microvascular dysfunction: a systematic review and meta-analysis

Abstract Background Coronary microvascular dysfunction (CMD) is increasingly recognised as a major contributor toangina in the absence of obstructive coronary disease. Despite evidence of higher prevalence in women, the magnitude and clinical significance of sex-based physiological differences remain poorly defined. Purpose To compare invasive indices of coronary microvascular function between women and men and assess their relationship with adverse cardiovascular outcomes. Methods Five databases (MEDLINE, Embase, Cochrane, Web of Science, Scopus) were systematically searched from January 2000 to June 2025 for studies reporting invasive coronary physiology using the index of microvascular resistance (IMR), coronary flow reserve (CFR), or hyperaemic microvascular resistance (HMR) stratified by sex. Random-effects meta-analyses (Hartung–Knapp) generated pooled mean differences (MD) and risk ratios (RR) with 95 % confidence intervals (CI). Heterogeneity (I²) and small-study bias (Egger) were assessed. Prespecified subgroup analyses included symptom status, comorbidity profile, and invasive vs thermodilution techniques. Results Eighteen studies (n = 4 312; women = 2 218, men = 2 094) were included. Women had significantly higher IMR values (MD +4.6 units; 95 % CI +2.3 to +6.8; p 0.001; I² = 41 %) and lower CFR (MD –0.34; 95 % CI –0.49 to –0.18; p 0.001). The prevalence of CMD (IMR ≥25 or CFR ≤2.0) was 1.6-fold higher in women (RR 1.58; 95 % CI 1.28–1.93). During median follow-up of 36 months, CMD predicted major adverse cardiac events (RR 2.21; 95 % CI 1.64–2.97) similarly in both sexes (p-interaction = 0.27). No publication bias was evident. Conclusion Women exhibit significantly higher microvascular resistance and lower flow reserve compared with men, supporting a true sex-related microvascular phenotype rather than referral bias. While CMD confers similar prognostic impact in both sexes, the higher burden in women highlights the need for sex-specific diagnostic thresholds and therapeutic strategies.Graphical AbstractFor image description, please refer to the figure legend and surrounding text.