Sex Differences in Cardiac Function, Biomarkers and Exercise Performance in Heart Failure with Preserved Ejection Fraction: Findings from the RELAX Trial

While the lifetime risk of heart failure with preserved ejection fraction (HFpEF) is comparable across sexes,1 its prevalence is higher in women.2 Women with HFpEF have worse patient-reported outcomes but lower risk of adverse cardiovascular events.3, 4 The mechanisms underlying these sex differences in HFpEF are not well established. Accordingly, we evaluated the sex differences in the burden of myocardial injury, stress, fibrosis, and inflammation, and their contribution toward exercise capacity among patients with HFpEF. This study included all participants from the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial with available exercise capacity measurements at baseline. RELAX was a randomized, double-blind trial that examined the effect of sildenafil on exercise capacity among patients with HFpEF.5 The inclusion criteria for the RELAX trial are detailed in the online supplementary Table S1. Trial participants underwent 6 min walk test, cardiopulmonary exercise test, and resting echocardiogram. The blinded biomarker core laboratory assessed biomarkers of inflammation [high-sensitivity C-reactive protein (hs-CRP)], fibrosis [galectin-3, C-terminal telopeptide of collagen type I (CITP)], N-terminal pro-B-type natriuretic peptide (NT-proBNP), chronic myocardial injury [high-sensitivity cardiac troponin I (hs-cTnI)], and pulmonary vascular function [endothelin-1 (ET)].5 Cardiopulmonary exercise test was performed using either cycle or treadmill ergometry with simultaneous expired ventilatory gas analysis. Peak oxygen uptake (VO2Peak) was defined as the highest 30 s median VO2 value during the final minute of exercise. Ventilatory anaerobic threshold was determined by the modified V-slope method. Peak oxygen pulse was determined as the ratio of VO2Peak and peak heart rate. Sex differences in baseline characteristics were compared using chi-square and Kruskal–Wallis tests for categorical and continuous variables, respectively. To assess for differences in VO2Peak among adults with vs. without HFpEF across sexes, RELAX participants were matched 1:1 with age-, race-, and sex-matched adults without heart failure from the Activity Counseling Trial (ACT). ACT was a randomized trial of physical activity counselling among sedentary but otherwise healthy adults (online supplementary Table S2).6 Successful matching was achieved for 78% women and 80% men with HFpEF (online supplementary Table S3). Multivariable linear regression analysis was used to evaluate the associations of sex with biomarkers, echocardiographic, and exercise parameters among participants with HFpEF. Separate models were constructed for each biomarker, echocardiographic, and exercise parameter outcome with adjustment for relevant covariates that included demographics, cardiovascular risk factors, and co-morbidities (Figure 1). Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) with a two-sided P <0.05 considered statistically significant. The study included 216 participants (214 with VO2Peak data), of which 48% were women. Women (vs. men) had significantly lower body weight, prevalence of co-morbidities (diabetes mellitus, chronic obstructive pulmonary disease, ischaemic heart disease), and smaller left ventricular volume. There were no significant sex differences in resting measures of cardiac function and biomarkers of myocardial stress (NT-proBNP), pulmonary vascular function (ET), and inflammation (hs-CRP) in unadjusted as well as adjusted analysis. In contrast, women (vs. men) had a significantly lower burden of biomarkers of myocardial injury (hs-cTnI) and fibrosis (CITP) in unadjusted comparison as well as multivariable adjusted regression analysis (Table 1 and Figure 1). Heart failure-specific quality of life, as assessed by the Minnesota Living with Heart Failure score, was comparable in women and men with HFpEF. Among exercise parameters, women with HFpEF (vs. men) had lower VO2Peak, peak workload, anaerobic threshold, and peak oxygen pulse (Table 1). As compared with age-, sex-, and race-matched sedentary adults without HFpEF, VO2Peak was 44% and 46% lower among women and men with HFpEF, respectively (Figure 1). In adjusted analyses among participants with HFpEF, female sex was significantly associated with lower levels of most exercise capacity measures independent of clinical characteristics, cardiac function, and biomarkers (Figure 1). Taken together, these study findings suggest that women with HFpEF had comparable resting cardiac function, lower burden of myocardial injury and fibrosis, but worse exercise capacity as compared with men. Women and men with HFpEF had similar, proportionally lower VO2Peak compared with age- and race-matched sedentary adults. Prior studies have demonstrated that women with HFpEF have worse patient-reported outcomes and lower overall quality of life.3, 4 These sex differences in patient-reported outcomes may be related to lower exercise capacity, with up to 18% lower VO2Peak in women (vs. men). In contrast, measures of myocardial stress and injury, which are predictors of adverse clinical events, were similar or lower in women (vs. men) with HFpEF. This may explain the comparable to lower risk of adverse events such as hospitalization and mortality among women vs. men in prior studies.3, 7 Heart failure-specific quality of life was not different across sexes in the RELAX trial, which is consistent with some prior reports and may be related to the small sample size.4 The mechanisms underlying the observed lower exercise capacity in women is not well established. Prior studies have attributed these sex differences to greater abnormalities in ventricular structure and function in women with smaller left ventricular size, greater diastolic dysfunction, and higher burden of microvascular dysfunction.8 Our study findings demonstrate comparable resting cardiac function, NT-proBNP levels, and lower burden of myocardial injury and fibrosis in women vs. men. It is plausible that despite comparable cardiac function and favourable fibrosis and injury pattern at rest, women have lower exercise cardiac reserve that may contribute to lower exercise capacity. Along these lines, we observed significantly lower peak oxygen pulse in women (vs. men). A recent study also demonstrated comparable resting echocardiographic characteristics but marked differences in exercise haemodynamic parameters among women and men with HFpEF.9 Furthermore, exaggerated myocardial injury with exercise has been associated with lower exercise reserve in HFpEF.10 In contrast, resting hs-cTnI is not associated with VO2Peak in patients with HFpEF.11 Future studies are needed to evaluate sex differences in myocardial injury in response to exercise stress among patients with HFpEF. Our study has some noteworthy limitations. First, sex differences in exercise cardiac reserve could not be assessed due to lack of exercise haemodynamic assessment. Second, these findings may not be generalizable to patients with HFpEF that would not meet the inclusion criteria for the RELAX trial. Third, the study sample was relatively small and may be underpowered to detect smaller sex differences. Future studies in larger HFpEF cohorts are needed to validate these findings and better understand how these sex differences in HFpEF pathophysiology can guide diagnostic and management strategies. We would like to thank the National Heart Lung and Blood Institute BioLINCC data repository for providing the de-identified data from the RELAX and ACT trials for this analysis. Dr. Patel is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant (5T32HL125247-03). Drs. Pandey and Grodin are funded by the Texas Health Resources Clinical Scholarship. Conflict of interest: none declared. Table S1. Inclusion criteria in the RELAX trial. Table S2. Inclusion, exclusion criteria, and exercise testing protocol for the Activity Counseling Trial (ACT). Table S3. Baseline demographic and clinical characteristics according to sex and HFpEF status. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.