Sex-specific phenotypes, biomarkers, and outcomes in chronic heart failure: insights from a contemporary cohort of women
D Abidova, J K UzokovAbstract
Background
Sex-related differences in chronic heart failure (CHF) remain insufficiently characterized, particularly regarding phenotypic heterogeneity, biomarker profiles, and prognostic determinants. Women with CHF often present with distinct cardiometabolic comorbidities, preserved or mildly reduced ejection fraction, and unique inflammatory and hormonal influences that may impact outcomes. This study aimed to investigate sex-specific clinical phenotypes, circulating biomarkers, and predictors of adverse outcomes in a contemporary CHF cohort with a focus on women.
Methods
A prospective observational study included 350 patients with stable CHF (mean age 62.8±11.4 years; 54% women). Patients underwent comprehensive clinical evaluation, echocardiography, functional capacity assessment (6-minute walk test [6MWT]), and biomarker profiling including NT-proBNP, high-sensitivity C-reactive protein (hs-CRP), galectin-3, and soluble ST2 (sST2). The primary endpoint was a composite of cardiovascular death or heart failure hospitalization during 18-month follow-up. Multivariable Cox regression, receiver operating characteristic (ROC) analysis, and interaction testing were performed to evaluate sex-specific predictors.
Results
Women were older than men (64.1±10.9 vs 61.3±11.7 years, p=0.02) and more frequently had HF with preserved ejection fraction (HFpEF) (48% vs 27%, p<0.001), hypertension (78% vs 62%, p=0.001), and obesity (41% vs 29%, p=0.01). Despite lower NT-proBNP levels (1,420 [IQR 820-2,650] vs 1,780 [1,050-3,100] pg/mL, p=0.03), women demonstrated higher inflammatory biomarkers (hs-CRP 4.8±2.1 vs 3.9±1.9 mg/L, p=0.004; galectin-3 21.6±6.3 vs 18.9±5.7 ng/mL, p=0.001). Functional capacity was lower in women (6MWT 312±78 vs 348±85 m, p<0.001) despite similar left ventricular ejection fraction.During follow-up, the primary endpoint occurred in 96 patients (27.4%), with comparable crude event rates between sexes (29% women vs 25% men, p=0.38). However, predictors differed significantly. In women, independent predictors included galectin-3 (HR 1.38 per SD increase, 95% CI 1.16-1.63, p< 0.001), sST2 (HR 1.29, 95% CI 1.08-1.54, p=0.004), and 6MWT distance (HR 0.78 per 50 m increase, 95% CI 0.66-0.92, p=0.002), whereas NT-proBNP showed weaker prognostic value (HR 1.12, p = 0.08). In men, NT-proBNP was the strongest predictor (HR 1.41, p<0.001). ROC analysis demonstrated superior risk discrimination in women when combining inflammatory and fibrosis biomarkers (AUC 0.82) compared with NT-proBNP alone (AUC 0.69, p=0.01).
Conclusions
Women with chronic heart failure exhibit distinct phenotypic and biomarker profiles characterized by greater inflammatory and fibrotic activation despite lower natriuretic peptide levels. Prognostic determinants differ by sex, with multimarker strategies providing improved risk stratification in women. T