Longitudinal proteomic organ-specific aging in heart failure

Abstract 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.