Sex Differences in Cardiometabolic Traits and Determinants of Exercise Capacity in Heart Failure With Preserved Ejection Fraction

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Abstract
Heart failure with preserved ejection fraction (HFpEF) is an important public health concern. It accounts for more than 1 million hospitalizations each year, and its prevalence is expected to exceed heart failure with reduced ejection fraction in the near term.1 Its clinical phenotype is highly heterogeneous, making its diagnosis and treatment challenging. To date, to our knowledge, there is no uniform definition and no existing targeted pharmacotherapies have been shown to improve outcomes in clinical trials.2 Sex differences in HFpEF have been well described and likely contribute to its clinical heterogeneity.3,4 The prevalence of HFpEF is markedly higher in women than men.5 Differences in cardiovascular structure, adaptations to physiologic stress, and comorbidity burden have all been proposed to explain this difference, but true mechanistic understanding is lacking, limited by the paucity of women enrolled in heart failure trials and the neutrality of these trials.6 Prior studies have shown that hypertension and aging preferentially predispose women to the development of left ventricular (LV) hypertrophy.7,8 Separately, a recent study demonstrated that cardiometabolic traits are more strongly associated with risk of future HFpEF compared with heart failure with reduced ejection fraction, particularly in women.9

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