Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure

Abstract

Background: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear.

Objectives: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF.

Methods: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio.

Results: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001).

Conclusions: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

Keywords: biomarkers; heart failure; predictive value; risk factors; sex differences.

Graphical abstract

Central Illustration

Associations of Cardiovascular Biomarkers With Incident Heart Failure: Men Versus Women Associations of individual biomarkers with incident heart failure were evaluated using Fine-Gray models adjusting for the competing risk of death, and for the following variables: age, smoking, diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, and presence of left ventricular hypertrophy/left bundle branch block. Natriuretic peptides include N-terminal pro–B-type natriuretic peptide or B-type natriuretic peptide. Cardiac troponins include cardiac troponin-T or I. Interaction p value denotes sex•covariate interaction on a multiplicative scale in the total population. None of the biomarkers displayed a significant interaction with sex for heart failure outcome. CI = confidence interval; PAI = plasminogen activator inhibitor; sHR = subdistribution hazard ratio; sST2 = soluble interleukin-1 receptor-like 1; UACR = urinary albumin-to-creatinine ratio.