Phenotype-Specific Gradients of NT-proBNP Reflect Distinct Functional and Structural Remodeling Signatures in Heart Failure

Background/Objectives: Heart failure (HF) classification based on left ventricular ejection fraction (LVEF) provides an incomplete representation of disease complexity, as it does not fully integrate functional impairment, structural remodeling, and clinical severity within a unified framework. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) is widely used for diagnosis and risk stratification, prior studies have primarily evaluated its role in isolation or within individual HF phenotypes, leaving its phenotype-specific distribution and integrative capacity across the HF spectrum insufficiently defined. This study aimed to address this gap by systematically evaluating NT-proBNP across HF phenotypes and assessing its potential as an integrative biomarker linking ventricular dysfunction, structural remodeling, and clinical severity. Methods: A cross-sectional study was conducted including 125 participants, comprising 65 clinically stable HF patients and 60 age- and sex-matched controls. HF patients were stratified according to LVEF into HF with reduced EF (HFrEF) (n = 28), (HFmrEF) (n = 20), and HF with preserved EF (HFpEF) (n = 17). Serum NT-proBNP concentrations were measured using a standardized electrochemiluminescence immunoassay. Clinical and echocardiographic parameters, including LVEF, left ventricular end diastolic diameter (LVEDD), left atrial diameter (LAD), and New York Heart Association (NYHA) functional class, were recorded and analyzed. Results: NT-proBNP levels were significantly higher in HF patients compared with controls (1845 ± 620 vs. 95.7 ± 40.5 pg/mL; p < 0.001) and demonstrated a clear stepwise increase across phenotypes (HFrEF: 2850.6 ± 710.4; HFmrEF: 1620.8 ± 480.2; HFpEF: 920.9 ± 310.3 pg/mL; p < 0.001). NT-proBNP showed a strong inverse correlation with LVEF (r = −0.68, p < 0.001) and significant positive correlations with LVEDD (r = 0.61, p < 0.001) and LAD (r = 0.57, p < 0.001). Higher levels were associated with more advanced NYHA functional class (III–IV vs. II: 2510 ± 680 vs. 980 ± 340 pg/mL; p < 0.001). ROC analysis demonstrated robust discriminatory performance across HF phenotypes, with the highest accuracy observed in HFrEF. Conclusions: NT-proBNP exhibits a phenotype-dependent gradient and consistently reflects ventricular dysfunction, adverse structural remodeling, and clinical severity across the HF spectrum. These findings support its role as an integrative biomarker that captures the multidimensional nature of HF, with potential implications for phenotype-based risk stratification and more precise clinical decision making.