Circulating C-peptide as an independent predictor of HFpEF: influence of cardiometabolic risk beyond diabetes

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndromecharacterized by diastolic dysfunction, preserved left ventricular ejection fraction, and arange of myocardial structural and metabolic abnormalities1. Rather than representingan isolated cardiac disorder, HFpEF is increasingly recognized as a multisystemdisorder, driven by multiple comorbidities, and manifesting as diverse clinicalphenotypes defined by differences in comorbidity burden, disease severity, cardiacstructure, biomarkers, and prognosis. Metabolic comorbidities such as obesity,dyslipidemia, type 2 diabetes (T2D), and hypertension are highly prevalent in HFpEFand may define a distinct cardiometabolic HFpEF (cmHFpEF) phenotype, marked bymore severe symptoms and poorer quality of life2. The coexistence of metaboliccomorbidities drives multisystem pathophysiological changes, worsening prognosis,and limiting the effectiveness of current therapies3.This study aimed to investigate the pathophysiological mechanisms of HFpEF, with afocus on cardiometabolic risk burden as a major contributor to HFpEF phenotypicheterogeneity, to inform future phenotyping strategies and therapeutic approaches.