Shweta Kanyal, Abhirami Das, Amreen Bashir, Ahmed H Syed, Savvy Aujla, Jainam Chaudhary, Dharmik Patel, Ashish Goel
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.