Sex Differences in Heart Failure With Preserved Ejection Fraction

Abstract

Background The female preponderance in heart failure with preserved ejection fraction (HFpEF) is a distinguishing feature of this disorder, but the association of sex with degree of diastolic dysfunction and clinical outcomes among individuals with HFpEF remains unclear. Methods and Results We conducted a prospective, multicenter, observational study of patients with HFpEF (PURSUIT-HFpEF [Prospective Multicenter Observational Study of Patients with Heart Failure with Preserved Ejection Fraction]: UMIN000021831). Between 2016 and 2019, 871 patients were enrolled from 26 hospitals (follow-up: 399±349 days). We investigated sex-related differences in diastolic dysfunction and postdischarge clinical outcomes in patients with HFpEF. The echocardiographic end point was diastolic dysfunction according to American Society of Echocardiography/European Association of Cardiovascular Imaging criteria. The clinical end point was a composite of all-cause death and heart failure readmission. Women accounted for 55.2% (481 patients) of the overall cohort. Compared with men, women were older and had lower prevalence rates of hypertension, coronary artery disease, and chronic kidney disease. Women had diastolic dysfunction more frequently than men (52.8% versus 32.0%, P<0.001). The incidence of the clinical end point did not differ between women and men (women 36.1/100 person-years versus men 30.5/100 person-years, P=0.336). Female sex was independently associated with the echocardiographic end point (adjusted odds ratio, 2.839; 95% CI, 1.884-4.278; P<0.001) and the clinical end point (adjusted hazard ratio, 1.538; 95% CI, 1.143-2.070; P=0.004). Conclusions Female sex was independently associated with the presence of diastolic dysfunction and worse clinical outcomes in a cohort of elderly patients with HFpEF. Our results suggest that a sex-specific approach is key to investigating the pathophysiology of HFpEF. Registration URL: https://upload.umin.ac.jp; Unique identifier: UMIN000021831.

Keywords: diastolic dysfunction; heart failure; preserved left ventricular function; prognosis; sex.

Figure 1. Comorbidities related to diastolic dysfunction in the overall cohort.

Multivariable binary logistic regression analysis was performed in order to assess the impact of multiple comorbidities on the echocardiographic end point (diastolic dysfunction) in the overall cohort (N=595). Results are illustrated as a forest plot. Female sex, anemia, and obesity were significant factors associated with diastolic dysfunction. OR indicates odds ratio.

Figure 2. Clinical outcomes stratified by sex.

A, The clinical end point of all‐cause death or heart failure readmission was assessed in a time‐to‐first‐event fashion with Kaplan–Meier analysis. In the crude comparison, no difference was found between women and men (log‐rank P=0.191). B, Adjusted probability curves in women and men created with the multivariable Cox proportional hazards model included the following covariates: female sex, C‐reactive protein, age, anemia (hemoglobin level <12 g/dL in women and <13 g/dL in men according to the World Health Organization definition ¹⁵ ), hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, chronic kidney disease, atrial fibrillation, obesity (body mass index ≥25), and cholinesterase level. ⁶ , ¹³ The cumulative probability curves show the model‐predicted event rates for the “average” patient in women and men. HF indicates heart failure; and HR, hazard ratio.

Figure 3. Prognostic factors for the clinical end point in the overall cohort.

A multivariable Cox proportional hazards model was constructed in order to assess the impact of multiple comorbidities on the postdischarge clinical end point in the overall cohort (N=870). The results are shown as a forest plot. Female sex, age, coronary artery disease, chronic kidney disease, and cholinesterase were significantly associated with the clinical end point. HR indicates hazard ratio.