Impact of Sex on Ventricular‐Vascular Stiffness and Long‐Term Outcomes in Heart Failure With Preserved Ejection Fraction: TOPCAT Trial Substudy

BACKGROUND: Women have higher vascular stiffness with aging. The aim of this study was to characterize sex differences in vascular and ventricular structure and function, and to investigate the impact on the primary outcome in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). METHODS AND RESULTS: Data from the Americas cohort of the TOPCAT trial were analyzed. Patients with echocardiography (n=654) were compared according to sex, and achievement of the primary end point (a composite of death from cardiovascular causes and heart failure hospitalization) assessed. Echocardiography revealed higher arterial, systolic, and diastolic ventricular elastance and worse ventricular‐vascular coupling in women. Women had better overall survival and heart failure hospitalization outcomes (hazard ratio 0.74, 95% CI 0.57–0.98, P=0.034), however, determinants of achievement of the primary outcome differed between the sexes. Pulse pressure was a key determinant of outcome in women (hazard ratio 1.04, 95% CI 1–1.09, P=0.034) whereas in men heart rate (hazard ratio 1.61, 95% CI 1.02–2.52 per 10 mm Hg increase, P=0.04) and B‐type natriuretic peptide (hazard ratio 1.01, 95% CI 1–1.02 per 10 ng/mL increase P=0.02) were associated with poorer outcome. CONCLUSIONS: Outcomes in patients with heart failure with preserved ejection fraction appear to be differentially influenced by key physiological factors that vary according to sex. In women, ventricular‐vascular stiffening was the most significant determinant of outcome, whereas in men overall survival was influenced by heart rate and B‐type natriuretic peptide; this highlights key sex differences in the pathophysiology and outcomes of heart failure with preserved ejection fraction and warrants further exploration. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT00094302.