Sex-specific physiological landscapes in ANOCA: the interplay between epicardial resistance and coronary vasomotor dysfunction—insights from the J-CMD Registry

Background In patients with angina and non-obstructive coronary arteries (ANOCA), fractional flow reserve (FFR) reflects the functional burden of epicardial atherosclerosis, even within the non-ischemic range. However, the extent to which age and sex modulate the interplay between epicardial conductance (FFR) and vasomotor dysfunctional endotypes—ranging from epicardial spasm to microvascular vasomotor dysfunction—remains poorly understood. Methods We analyzed ANOCA patients from the nationwide, multicenter, prospective J-CMD registry (UMIN000047609) (stenosis <50% and FFR >0.80). Endotypes were classified into coronary microvascular dysfunction (CMD; CFR <2.5), epicardial vasospasm (EVS), and microvascular spasm (MVS). CMD was further stratified into functional (IMR <25) and structural (IMR ≥25) phenotypes. Sex- and age-specific associations between FFR and these endotypes were investigated using multivariable regression models. Results Among 889 patients (45.1% men; mean age 62.9 ± 13.9 years), 27.8% had CMD (13.7% functional; 14.1% structural). Men were younger and exhibited significantly lower FFR values than women (0.90 vs. 0.92, P<0.001), reflecting a higher epicardial atherosclerotic burden. Although FFR showed a modest inverse correlation with age (R=−0.104, P=0.002), its association with vasomotor dysfunction was markedly sex-dependent. In women, preserved FFR (mid-to-highest tertiles) was paradoxically yet strongly associated with MVS (OR: 2.62, 95% CI: 1.66–4.13, P<0.001) and functional CMD (OR: 2.13, 95% CI: 1.08-4.21, P=0.029), independent of BMI (OR: 0.89, 95% CI: 0.84-0.96, P<0.001). Conversely, FFR showed no significant correlation with specific endotypes in men, suggesting a decoupling of epicardial resistance and microvascular vasomotor dysfunction. Conclusions FFR in ANOCA is fundamentally governed by sex rather than age. In women, higher FFR values identify a distinct microvascular vasomotor phenotype (MVS and functional CMD) that manifests inversely (paradoxically) related to epicardial disease. Conversely, the absence of such an association in men underscores a divergent physiological coupling between the epicardial and microvascular compartments, necessitating a sex-specific paradigm shift in ANOCA profiling and management.