Longitudinal proteomic organ-specific aging in heart failure.

BACKGROUND: Heart failure (HF) is a systemic syndrome affecting multiple organs. Organ age gaps (OAGs), quantifying organ-level aging from plasma proteomics, are linked to organ-specific disease including HF but have been studied exclusively cross-sectionally. We examined how organ-specific aging evolves within individuals over the course of HF and whether it carries prognostic information beyond established HF markers. METHODS: We studied two complementary cohorts with repeated plasma proteomic profiling: 557 individuals including those at risk for HF, pre-HF, and newly diagnosed HF (HELPFul, mainly HFpEF)and 382 patients with established HF (Bio-SHiFT, all LVEF < 50%). OAGs for five organs plus a conventional clock were z-scored. Within each cohort, we modelled longitudinal OAG trajectories using linear mixed-effects models, and, in Bio-SHiFT, related OAGs to the primary endpoint using Cox models with progressive adjustment up to NT-proBNP and troponin T. RESULTS: Baseline OAGs differed across HF severity in both cohorts. Longitudinally, 50 HELPFul individuals with LVDD showed increasing artery and immune OAGs over 4.6 years. In Bio-SHiFT, event-free patients had stable trajectories, whereas those with adverse events showed sharply accelerating multi-organ aging over 2.1 years (immune β = 0.36 z-score per year, 95% CI 0.26 to 0.47; heart β = 0.29, 95% CI 0.17 to 0.40). Higher OAGs predicted the primary endpoint, and the kidney, lung, and immune OAGs remained prognostic after full adjustment including NT-proBNP and troponin T. CONCLUSION: In this exploratory study, multi-organ aging accelerated before adverse events, and the kidney, lung, and immune OAGs predicted outcome independently of conventional severity markers, supporting a dynamic, organ-level view of HF risk that warrants confirmation in larger cohorts.