Applying Similarity Network Fusion to 92 circulating inflammatory proteins and 49 clinical variables in 698 HFpEF patients, researchers identified two prognostically distinct clusters within each sex. High-risk women faced a 2.45-fold greater risk of worsening heart failure (HR 2.45, 95% CI 1.32–4.54), while high-risk men showed even steeper separation (HR 2.77, 95% CI 1.27–6.04). Shared biomarkers across sexes included VEGF-A, TNFRSF9, and TGF-β, but women's high-risk profile was dominated by inflammatory and glycemic markers (CD40, HGF, TNF), while men's featured immune-regulatory and renal indicators (IL-10RB, PD-L1, eGFR). Findings were validated in an independent 342-patient cohort.
HFpEF remains one of cardiology's most frustrating therapeutic frontiers — over a dozen large trials have failed to show mortality benefit — partly because the syndrome aggregates vastly different underlying pathobiologies. This work advances a precision medicine framework by demonstrating that sex is not merely a demographic variable but a fundamental axis of molecular heterogeneity. The inflammatory-glycemic signature in women aligns with prior observations linking adipose inflammation and insulin resistance to female HFpEF, while the renal-immune axis in men mirrors comorbidity patterns seen in hypertensive cardiomyopathy. The C-index of 0.62–0.63 is modest, suggesting these clusters capture real but limited prognostic signal. Crucially, this is a preprint posted on medRxiv and has not yet undergone peer review — biological interpretations and cluster stability should be treated as preliminary until independent scrutiny confirms them.
