N‑Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) as a Biomarker in Heart Failure With Preserved Ejection Fraction (HFpEF) Versus Heart Failure With Reduced Ejection Fraction (HFrEF): The Way Forward in the Age of Proteomics

Abstract

Heart failure (HF) encompasses a spectrum of clinical syndromes with substantial global morbidity and mortality, primarily linked to coronary artery disease. Affecting over 37 million individuals worldwide, its prevalence increases with age. HF is classified into three major categories: heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and the intermediate phenotype, heart failure with mid-range ejection fraction (HFmrEF). Despite similar symptomatology, differentiating HFpEF from HFrEF remains challenging, particularly through biomarker evaluation. The diagnostic and prognostic roles of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are well established; however, an unmet need persists in accurately distinguishing HFpEF from HFrEF, as NT-proBNP levels are often influenced by age, renal function, and obesity, which confound its interpretation in HFpEF. This review uniquely integrates current evidence delineating the biomarker's pathophysiological underpinnings, clinical thresholds, and predictive capacities across HF phenotypes, while contrasting its limitations and interpretive nuances in real-world practice. For instance, while elevated NT-proBNP levels in HFrEF strongly correlate with ventricular dysfunction severity and guide therapy initiation, their diagnostic specificity in HFpEF is reduced, often necessitating adjunctive imaging or additional biomarkers for confirmation. Advances in proteomics are reshaping biomarker discovery, enabling the identification of novel cardiac stress markers such as soluble ST2 and growth differentiation factor-15 (GDF-15), which complement NT-proBNP by reflecting distinct molecular pathways of myocardial remodeling and inflammation. Although NT-proBNP remains the gold standard for prognostic assessment and risk stratification in HF, its diagnostic performance, particularly in HFpEF, must be interpreted within the broader biomarker landscape. Future directions should emphasize proteomic integration and multimarker strategies to achieve precision-based HF phenotyping and improved therapeutic outcomes.

Keywords: biomarkers; ejection fraction; heart failure; hfpef; hfref; nt-probnp; prognosis.

Figure 1. The newer biomarkers discovered over time for establishing the diagnosis and prognosis of heart failure

This illustration categorizes different types of biomarkers - diagnostic, prognostic, predictive, pharmacodynamic, and monitoring - highlighting their distinct roles in disease detection, treatment selection, therapy response assessment, and patient management. It visually represents how biomarkers contribute to personalized medicine and improved clinical outcomes (Image created by the authors using Canva.com)

Figure 2. Biomarkers in HFrEF vs. HFpEF

This illustration compares biomarkers associated with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). HFrEF is linked to angiogenesis-specific markers such as VEGFR, NT-proBNP, and GDF-15, while HFpEF is associated with inflammatory markers like Interleukin-6, hs-CRP, and Osteopontin. The central heart image emphasizes the distinct yet interconnected pathophysiological mechanisms of both conditions. (Image created by the authors using Canva.com) VEGFR: vascular endothelial growth factor; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; GDF-15: growth differentiation factor 15; proANP: pro atrial natriuretic peptide; MPO: myeloperoxidase; IL-1 receptor: interleukin-1 receptor; NGAL: renal marker neutrophil gelatinase-associated lipocalin; BUN: blood urea nitrogen; RAGE: inflammation marker receptor of advanced glycation end-products

Figure 3. BNP and NTproBNP: role in the etiopathogenesis of heart failure

This illustration depicts the dynamic interplay between natriuretic peptides and neurohormonal activation in heart failure. BNP and NT-proBNP are released in response to myocardial stretch and wall stress, promoting vasodilation, natriuresis, and inhibition of ventricular remodeling. In contrast, activation of the RAAS and sympathetic nervous system contributes to vasoconstriction, increased afterload, and fluid retention. Sacubitril, a neprilysin inhibitor, enhances BNP bioavailability by preventing its degradation, reflecting the therapeutic modulation of these pathways in HFrEF. The figure also highlights that the relative contribution of these mechanisms may differ across HF (Image created by the authors using Canva.com) RAAS: renin-angiotensin aldosterone system; BP: blood pressure; ANP: atrial natriuretic peptide; BNP: brain natriuretic peptide; NT-proBNP: N-terminal prohormone of brain natriuretic peptide