Plasma Proteomics in Acute Heart Failure: Survival-Associated Protein Signatures and 90-Day Trajectories

BackgroundAcute heart failure (AHF) patients face poor outcomes, particularly within the high-risk 90-day post-discharge phase. Additional biomarkers reflecting the multifaced pathophysiology of AHF are necessary to improve outcome prediction. ObjectiveThis study aimed to identify novel plasma protein biomarkers and biological pathways related to survival and recovery following an AHF event. MethodsPlasma samples were obtained from patients enrolled in the BeLOVE (Berlin Long-Term Observation of Vascular Events) cohort during an AHF event, at 90-day follow-up, and from a reference group (patients with cardiovascular risk but no recent AHF). Proteomics analysis was performed using both Mass Spectrometry (MS) and Olink Explore (Uppsala, Sweden). Cox proportional-hazards regression identified plasma proteins linked to 90-day all-cause mortality post-AHF. ResultsOut of 2,324 proteins analyzed from Olink and 533 from MS, 67 were significantly associated with 90-day mortality (|lnHR|>0.4, FDR<0.05). Inflammation, apoptosis, and extracellular matrix remodeling were key mortality predictors, while metabolic proteins, coagulation control, and complement system associated with survival. TNF receptor family members showed promise for risk stratification beyond natriuretic peptides. Comparison of plasma from survivors at acute setting and 90-day follow-up identified 591 significantly altered proteins via Olink and 131 via MS (logFC>75th percentile, FDR<0.05). CA125 (logFC = -1.8 [-2.2,-1.4], FDR {approx} 2x10-) emerged as a biomarker for clinical recovery, declining more sharply than NT-proBNP. ConclusionsCombining targeted and untargeted proteomic approaches identifies novel pathways and biomarkers to refine risk stratification in AHF. Profiling of proteomic changes post-AHF provides critical insights into the molecular processes underlying disease progression and recovery.