Pre‐diagnostic free androgen and estradiol levels influence heart failure risk in both women and men: A prospective cohort study in the UK Biobank

Abstract

AimsSerum sex hormones have been linked to cardiovascular disease risk. However, their roles in the pathogenesis of heart failure (HF) in both men and women are unclear. We investigated the associations between free androgen, testosterone, and estradiol, and future risk of HF.Methods and resultsThis prospective cohort study evaluated UK Biobank participants free of prevalent cardiovascular disease and HF at baseline. Unitless free androgen, testosterone, and estradiol indices were generated using serum concentrations of total testosterone (nmol/L), estradiol (pmol/L), sex hormone binding globulin (SHBG, nmol/L), and albumin (g/L) in blood collected at enrolment. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HF in relation to quartiles (Q) of free androgen (FAI), testosterone (FTI), estradiol (FEI) indices, and potential confounders. There were 180 712 men (including 5585 HF cases with FAI and 571 HF cases with FEI), and 177 324 women (including 2858 HF cases with FAI and 314 HF cases with FEI) with complete data. Increased FAI was associated with decreased HF risk in both men (HRQ4 vs. Q1: 0.86, 95% CI 0.79–0.94, p‐trendcontinuous < 0.0001) and post‐menopausal women (HRQ4 vs. Q1: 0.83, 95% CI 0.73–0.95). Similar inverse associations were observed for FTI only in men (HRQ4 vs. Q1: 0.91, 95% CI 0.83–0.98). Higher FEI was significantly associated with decreased HF risk among men (HRQ4 vs. Q1: 0.76, 95% CI 0.59–0.98), but was positively associated among pre‐menopausal women (HRQ4 vs. Q1: 2.16, 95% CI 1.11–4.18).ConclusionsSex hormones potentially influence HF pathogenesis and may offer pathways for interventions.

Regional differences in heart failure risk in the United Kingdom are partially explained by biological aging

“…CRP is a pro-inflammatory cytokine that can trigger the release or is correlated with other inflammatory markers such as interleukin-6, interleukin-8 and tumor necrosis factor-α ( 27 ), which suggests possible involvement of specific cell-mediated immunity and apoptotic pathways as well. Interestingly, CRP has been found to reflect circulating sex hormone levels and hormone replacement therapy ( 24 , 28–30 ), which we have previously linked to HF risk in the UK Biobank ( 31 ) and suggests the involvement of metabolic alterations in the pathway.…”

Associations between mosaic loss of sex chromosomes and incident hospitalization for atrial fibrillation in the United Kingdom

“…The biological mechanisms underlying these relationships with heart diseases in humans remain unclear. However, studies have suggested links between mLOY and increased total and bioavailable testosterone 17 , metabolic biomarkers that we recently found to be associated with incident hospitalization for heart failure 18 .…”