Distinct clinical signatures and sex-specific determinants of functional versus structural coronary microvascular dysfunction: insights from theJ-CMD registry

Background Coronary microvascular dysfunction (CMD) is a pivotal driver of symptoms in patients with angina and non-obstructive coronary arteries (ANOCA). While CMD is categorized into functional and structural endotypes, their divergent clinical phenotypes and sex-specific determinants remain poorly elucidated. Purpose This study aimed to delineate the unique clinical profiles and sex-dimorphic associations of functional versus structural CMD endotypes. Methods We analyzed 1,083 patients from the J-CMD registry (N=1,083), a nationwide prospective multicenter study of ANOCA. CMD was defined as a coronary flow reserve (CFR) <2.5. Patients were stratified by the index of microcirculatory resistance (IMR) into two endotypes: functional (IMR <25) and structural (IMR ≥25). Multivariable logistic regression was employed to identify independent predictors. Results Functional and structural CMD were identified in 13.8% and 14.7% of the cohort, respectively. These endotypes exhibited strikingly divergent clinical signatures. Structural CMD was characterized by a "remodeling-dominant" phenotype, showing strong associations with hypertension (OR 1.75), left atrial enlargement (OR 1.06), and diastolic dysfunction (E/e' OR 1.07), culminating in a higher prevalence of effort angina (OR 2.16). Functional CMD, conversely, was independently associated with female sex (OR 1.48) and exhibited fewer correlations with traditional structural remodeling markers. Sex-stratified analyses further revealed notable dimorphism: In females, structural CMD was uniquely driven by diastolic impairment (E/e' OR 1.10) and advanced age, while functional CMD was uniquely correlated with a lower body mass index (OR 0.92), suggesting a non-traditional metabolic profile. In males, structural CMD presented with a more classic ischemic profile, predominantly manifesting as effort-induced angina (OR 3.02), whereas associations with chronic kidney disease were observed in the overall male CMD population (OR 1.70). Conclusion Functional and structural CMD represent distinct clinical entities within the ANOCA spectrum. Structural CMD is characterized by hypertensive heart disease and hemodynamic remodeling, particularly in women. Functional CMD is more prevalent in women and follows a unique pathophysiological trajectory independent of traditional remodeling. These findings underscore the imperative for endotype-specific and sex-tailored diagnostic and therapeutic strategies in ANOCA.