Androgen metabolism and heart failure risk: sex-specific associations with NT-proBNP in a population-based cohort
C Evers, N Friedrich, S Gross, T Ittermann, K Lehnert, M Bahls, C Templin, A LebedevaAbstract
Background
Sex differences in heart failure (HF) are well established, with a higher prevalence in men, particularly HF with reduced ejection fraction. However, the role of sex hormone imbalance in early myocardial stress remains incompletely understood.
Purpose
To investigate sex-specific associations of androgen metabolites and regulatory proteins, including sex hormone–binding globulin (SHBG), androstenedione, and total testosterone, with N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a biomarker of myocardial stress.
Methods
Data were derived from the population-based Study of Health in Pomerania (SHIP). SHIP-START-0 (n = 2,590) was used for cross-sectional analyses, and SHIP-START-1 (n = 1,835) and SHIP-START-2 (n = 1,387) for longitudinal NT-proBNP follow-up. Baseline SHBG, androstenedione, and total testosterone were related to NT-proBNP levels using sex-stratified multivariable linear regression models adjusted for demographics, smoking, metabolic syndrome, diabetes and HbA1c, hypertension, kidney function, lipid profile, physical activity, and cardiovascular disease.
Results
Baseline NT-proBNP as a marker of myocardial stress was independently and positively associated with both SHBG and androstenedione, and these associations remained significant after adjustment for traditional cardiovascular risk factors (adjusted β = 0.32, p < 0.001 for SHBG; β = 10.32, p < 0.001 for androstenedione). Moreover, initial SHBG and androstenedione levels were also positively associated with NT-proBNP concentrations during follow-up at SHIP-START-1 and SHIP-START-2 (β for SHIP-START-1 = 0.46, p < 0.001 for SHBG; β = 29.22, p < 0.001 for androstenedione). The association of NT-proBNP at baseline with SHBG was significant in both men (β = 0.80, p = 0.023) and women (β = 0.22, p < 0.001), while for androstenedione only in women (β = 13.31, p < 0.001, Figure 1). Longitudinally, SHBG and androstenedione were positively associated with NT-proBNP only in women (β = 0.43, p = 0.001 for SHBG; β = 42.21, p < 0.001 for androstenedione, Figure 2). Finally, total testosterone was also positively associated with NT-proBNP only in women at baseline (adjusted β = 19.0, p = 0.008), with a trend but no significant association in the longitudinal analysis.
Conclusion
In this population-based cohort, circulating SHBG and androstenedione were independently and positively associated with NT-proBNP concentrations, predominantly in women but not in men, both cross-sectionally and longitudinally. These findings suggest that androgen metabolism and SHBG-mediated regulation are linked to myocardial stress in individuals without overt heart failure, with clear sex interaction, whereas absolute testosterone levels appear less informative. Our results highlight the relevance of androgen bioavailability in myocardial stress, especially in women, and support further studies combining hormonal profiling with cardiac imaging phenotyping.Figure 1Figure 2