Prognostic Value of Parathyroid Hormone in Heart Failure with Reduced Ejection Fraction

Background/Objectives: Parathyroid hormone (PTH) has emerged as a novel biomarker in heart failure (HF), reflecting neurohormonal, renal, and metabolic dysregulation within the cardiorenal–mineral axis. However, its independent prognostic value and incremental contribution remain unclear when evaluated through formal nested structures Therefore, this study aimed to evaluate the association between PTH and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) and to determine whether PTH provides additional prognostic information beyond NT-proBNP. Methods: In this retrospective cohort study, 1594 patients with HFrEF (LVEF ≤ 40%) were analyzed. Serum PTH and NT-proBNP levels were log-transformed and evaluated as predictors of all-cause mortality. Patients were stratified according to PTH levels, and survival analysis was performed. Incremental model fit was evaluated using nested likelihood ratio tests. Stratified multivariable Cox models and formal interaction tests were executed across predefined clinical strata (age, renal function, and heart failure etiology). Results: During a median follow-up of 36 months, 525 deaths occurred. Elevated PTH levels were associated with worse survival outcomes. In multivariable Cox regression analysis, both LnPTH (HR: 1.233, p = 0.0147) and LnNT-proBNP (HR: 1.374, p < 0.0001) were independent predictors of mortality. Combined elevation of PTH and NT-proBNP identified patients at the highest risk. The addition of LnPTH to the baseline model significantly improved global model fit (χ2 = 4.242, p = 0.0394). Importantly, the prognostic value of LnPTH was significantly modified by age (Pinteraction = 0.026) and renal function (Pinteraction = 0.038), demonstrating independent predictive power specifically in patients aged < 65 years (HR: 1.402) and those with eGFR ≥ 60 mL/min/1.73 m2 (HR: 1.454), but not in older or advanced renal impairment strata. Conclusions: PTH is independently associated with mortality in patients with HFrEF and provides incremental prognostic value beyond NT-proBNP by optimizing global model fit. These findings support its role as a complementary biomarker within a multimarker strategy for improved risk stratification of the cumulative metabolic and cardiovascular burden.