In 8,056 UK Biobank participants followed for a median of 12.8 years, circulating androgen markers — free androgen index (FAI) and sex hormone-binding globulin (SHBG) — imprinted detectable signatures on lead-I ECG parameters that independently predicted incident cardiovascular disease. In premenopausal women, elevated FAI increased QRS amplitude (β=19.17μV), and the FAI-predicted QRS component carried a 41% higher CVD hazard (HR=1.41). In men, FAI inversely shortened QTc (β=−0.95ms), yet its ECG-predicted component still elevated CVD risk (HR=1.32), while higher SHBG prolonged QTc and conferred additional risk (HR=1.15). Notably, FAI-associated ST deviation appeared protective in men (HR=0.76).
The finding matters because it bridges endocrinology and electrocardiology through a mechanistic intermediate: hormones reshaping myocardial depolarization and repolarization in ways detectable non-invasively. Prior work has established sex-hormone receptors on cardiomyocytes and androgen-driven ion-channel remodeling, but direct prospective evidence linking hormone-ECG-CVD pathways in a population this large is scarce. The two-stage mediation design is methodologically elegant, though observational and subject to residual confounding. The premenopausal subgroup (N=980) is relatively modest, limiting statistical power and generalizability. Hormones were measured at a single baseline, ignoring fluctuation across menstrual cycles or aging trajectories. Crucially, this is a preprint posted on medRxiv and has not yet undergone peer review — findings and effect sizes may shift substantially. If replicated, routine ECG combined with FAI/SHBG screening could stratify CV risk with greater hormonal precision, particularly in younger women and androgen-deficient men.
