Sex differences in 82Rubidium PET-derived myocardial flow reserve and implications for long-term cardiac outcomes

Abstract Introduction Coronary small vessel disease (CMD), defined by reduced myocardial flow reserve (MFR) in the absence of obstructive coronary artery disease, holds prognostic information on major cardiac events (MACE). We aimed to investigate if the prognostic value of MFR is independent of sex. Method A multicenter registry-based study of 7169 consecutive patients referred to clinically 82Rubidium PET myocardial perfusion imaging. We excluded patients with abnormal perfusion (defects >5% at rest or stress), previous revascularization, cardiomyopathy, or a diagnosis of heart failure. Global MFR≤2 was considered reduced. Patients were followed in registries for major adverse cardiac events (MACE) comprising all-cause mortality and admission for myocardial infarction, stroke, heart failure or unstable angina pectoris. Results A total of 2591 patients were included, 51% women, median age 69 [IQR 60-75] years. Women were older and men had a higher burden of cardiovascular risk factors. Overall, 31% had MFR≤2 (34% women vs 28% men, p<0.001). Mean MFR was lower in women compared with men (2.30 (SD 0.66) vs 2.44 (0.70), respectively) with higher myocardial blood flow both at rest and during stress among women (both p<0.001, Figure 1). In a linear regression model, sex remained associated with MFR after adjustments for age (p<0.001). At 3-year follow-up, MACE was less frequent in women than men (7.0% vs 9.4%, p=0.03). MFR≤2 was associated with MACE with an age-adjusted hazard ratio (HR) of 1.83 (95% CI: 1.20-2.77, p<0.01) in women and 1.75 (1.21-2.54, p<0.01) in men (p for interaction 0.82). The association remained significant after adjustments for left ventricular ejection fraction and charlson comorbidity index with a HR of 1.58 (1.07-2.31, p<0.05) in men and a HR of 1.68 (1.09-2.58, p<0.05) in women (p for interaction 0.69). On a continuous scale, MFR per every 0.1 unit decrease remained significantly associated to MACE (Figure 2). Conclusions Among patients suspected of obstructive CAD, CMD is more prevalent among women than men. The increased hazard of adverse outcomes with CMD did not differ by sex. This study provides new insight into the phenotype and prognosis of patients with CMD.Figure 1:Baseline distribution of MFRFigure 2:HR for MACE