Sex Differences in Risk Profiles, Coronary Calcium and Outcomes in Coronary Microvascular Dysfunction

Background Coronary microvascular dysfunction (CMD) is a common cause of ischemic symptoms without obstructive coronary disease and is disproportionately observed in women. However, sex-specific patterns linking CMD, coronary calcification and prognosis remain unclear. Purpose To define sex differences in clinical characteristics, coronary calcium phenotype and outcomes in PET-defined CMD. Methods In this prospective cohort study, patients referred for stress myocardial perfusion imaging with 82Rb-Positron Emission Tomography (PET) were enrolled. Perfusion findings were classified as normal perfusion, localized ischemia (summed difference score ≥2) or CMD (reduced global coronary flow reserve (CFR <2.0) without localized ischemia). Multivariable logistic regression models identified independent predictors of CMD. The primary prognostic endpoint was major adverse cardiovascular events (MACE; death, myocardial infarction, or coronary revascularization) within 2 years, analyzed using Cox proportional hazards models. Results Of 3,228 patients, 55.8% had normal perfusion, 36.4% localized ischemia, and 7.8% CMD. The prevalence of CMD was significantly higher in women than in men (11.3% vs 6.1%; OR 1.95 [1.51–2.53], p<0.001). In multivariable analysis, age (aOR 1.73 per 10 years [1.50–2.01], p<0.001) and diabetes (aOR 1.94 [1.42–2.64], p<0.001) were independent predictors of CMD. Within the CMD cohort (n=251), women and men were of similar age (median 72 vs 71 years). Compared with men, women with CMD had less established coronary artery disease (31% vs 45%, p=0.039) and less smoking as a risk factor (43% vs 67%, p<0.001). However, women more often presented with angina pectoris (22% vs 10%, p=0.02) and had a higher prevalence of hypertensive heart disease (17% vs 6.6%, p=0.02). Women with CMD had lower coronary calcium burden than men (median 28 vs 357, p<0.001) and more often had coronary artery calcium (CAC) score of zero (35% vs 5.2%, p<0.001). In multivariable adjusted models, higher CAC was associated with CMD in men (aOR 1.66 [1.24–2.21]) but not in women (aOR 0.98 [0.77–1.23]). A zero-calcium score was associated with lower odds of CMD in men (aOR 0.33 [0.11–0.93] vs 1.19 [0.71–1.99] in women). During 2-year follow-up, both localized ischemia and CMD were associated with increased risk of MACE compared with normal perfusion (localized ischemia: aHR 3.14 [2.17–4.55]; CMD: aHR 2.26 [1.21–4.20]; p<0.001). Within CMD, MACE risk did not differ between women and men (female vs male aHR 0.54 [0.14–2.08]). Conclusions CMD was associated with a two-fold increase in adverse events compared with normal perfusion, underscoring that microvascular ischemia is not benign. CMD was over-represented in women despite lower coronary calcium, whereas in men it was more often accompanied by greater calcified plaque burden and known coronary artery disease. Importantly, a zero-calcium score does not exclude CMD, particularly in women.