Abstract
Introduction: Heart failure (HF) is a highly fatal manifestation of many cardiovascular diseases (CVDs). Free testosterone and 17β-estradiol have been linked to future risk of CVD. However, their roles in the pathogenesis of HF in both men and women are unclear. Hypothesis: We investigated the associations between free testosterone and 17β-estradiol (unbound to sex hormone binding globulin), and future risk of HF in the UK Biobank. Methods: Multivariable Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of incident HF (first hospitalization) in relation to quartiles (Q) of free testosterone and 17β-estradiol, and potential confounders, while stratifying by sex and in women by menopausal status. Non-linear relationships were tested using cubic splines. Results: There were 180,712 men (5585 cases with free testosterone and 571 cases with 17β-estradiol), and 177,324 women (2858 cases with free testosterone and 314 with 17β-estradiol). Increased free testosterone was associated with decreased HF risk in both men (HR Q4 vs. Q1 =0.86, 95%CI: 0.79-0.94, p-trend continuous <0.0001) and post-menopausal women (HR Q4 vs. Q1 =0.83, 95%CI: 0.73-0.95), with non-linear relationships. Additionally, 17β-estradiol was significantly associated with decreased HF risk among men (HR Q4 vs. Q1 =0.76, 95%CI: 0.59-0.98), but positively associated among pre-menopausal women (HR Q4 vs. Q1 =2.16, 95%CI: 1.11-4.18). Conclusions: In this large cohort free of CVD at baseline, we detected a significant protective association between free testosterone and new HF diagnosis among men. In women however, the association differed by menopausal status as increased free testosterone was associated with elevated risk of HF before menopause but not after menopause. Further, 17β-estradiol was associated to elevated HF risk among pre-menopausal women but not post-menopausal women and men. Our findings suggest that sex hormones influence the pathogenesis HF and may offer potential pathways for interventions.
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