Ongoing Enigma of NT-proBNP in HFpEF: Insights From Proteomics

B-type natriuretic peptides (BNPs) are widely utilized as circulating biomarkers for diagnosing, risk stratifying and monitoring heart failure (HF) regardless of left ventricular ejection fraction (LVEF).Importantly, BNPs are also central in the pathophysiology of HF, produced by cardiomyocytes as a counter-regulatory hormone in response to myocardial stress from stretch, injury and maladaptive neurohormonal responses.Expression of BNPs is intricately and tightly regulated from initial translation of messenger RNA in the cardiomyocyte nucleus to the mediation of biological effects on target cells.Higher circulating levels of BNPs are indicative of more advanced disease and a poorer prognosis in HF, while increasing BNP levels often serve as an early indicator of worsening HF.However, the precise biological processes and pathophysiological pathways that stimulate BNP expression are not fully understood.In response to myocardial stress, proBNP is cleaved to an inactive N-terminal fragment (NT-proBNP) and the biologically active the C-terminal peptide, which exerts its effect on target cells.Circulating concentrations of NT-proBNP demonstrate significant variability and are influenced by several factors beyond cardiomyocyte stretch including adiposity, renal function, sex, and genetic ancestry.1 NT-proBNP concentrations are below the diagnostic thresholds in a subset of patients with welltreated and compensated HF, particularly those a preserved LVEF (HFpEF).The biological mechanisms underlying this variability is also incompletely understood.Large-scale proteomics has emerged as a powerful tool to interrogate the complex mechanisms underlying HF.Assays quantifying up to one-third of an individual's circulating proteome have been leveraged to identify novel circulating proteins associated with risk of developing HF and with risk of adverse outcomes among individuals with prevalent HF.Despite recognized limitations with target assay specificity, these high through-put assays therefore hold promise for discovery of novel HF mechanisms and biomarkers.Importantly, despite the quantification of thousands of proteins, NT-proBNP has remained the strongest and most consistent predictor of risk of incident HF 2 and outcomes in prevalent HF 3 -