Small Peptide, Large Implications: Endotrophin in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF), the most prevalent type of heart failure (HF), is associated with significant morbidity and mortality and a high rate of hospitalizations. HFpEF incidence is projected to continue to rise over the coming decades, primarily due to the increasing prevalence of multiple risk factors that contribute to the development of this syndrome. Obesity, low cardiorespiratory fitness, hypertension, and chronic kidney disease (CKD) have emerged as crucial elements in the pathogenesis of the syndrome. Obesity, in particular, can trigger and potentiate the systemic inflammatory state that is now recognized as central to the pathogenesis of HFpEF. In HFpEF, a range of cardiovascular changes are observed at the cellular and molecular level, including endothelial dysfunction, cardiomyocyte hypertrophy, abnormal calcium handling, microvascular rarefaction, interstitial fibrosis, and excessive collagen deposition (1). A biomarker to assist in diagnosis and risk stratification of HFpEF would improve patient evaluation and management and enable clinical and preclinical research to impact the course of this syndrome. The ideal biomarker would reliably aid in the diagnosis of HFpEF at early stages, guide medical management, and predict disease complications. However, the quest to identify a biomarker with these characteristics has proven elusive as most previous biomarker candidates have fallen short of reaching the clinical stage. Of the biomarkers currently used in the clinic, B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) support the diagnosis of HFpEF in symptomatic individuals and predict adverse outcomes but cannot distinguish HFpEF from heart failure with reduced ejection fraction (HFrEF). Moreover, levels can be normal in up to 30% of patients with HFpEF; are commonly suppressed in patients with high body mass; and are increased substantially in the setting of CKD, pulmonary hypertension, and atrial fibrillation (1). In asymptomatic individuals, small elevations in NT-proBNP and high sensitivity troponin T and I identify individuals at risk for HF but cannot accurately differentiate future risk of HFpEF from HFrEF.