Introduction:Heart failure (HF) is the commonest complication of myocardial infarction (MI).Hypothesis:Large-scale plasma proteomics cross-referenced to unbiased single-cell transcriptomics can prioritize circulating proteins and cell subpopulations for post-MI HF target validation.Methods:We employed aptamer-based affinity-capture proteomics to measure 1305 plasma proteins in 181 post-MI patients rehospitalized for HF, compared with 250 post-MI patients remaining event-free (median follow-up 1762 days). Differentially-expressed (DE) proteins were validated in another 200 patients of which 19 patients were rehospitalized for HF (median follow-up 392 days). Weighted coexpression network analysis, differential network analysis and Ingenuity Pathway Analysis were conducted to rank proteins according to network connectivity (D-connectivity). We then cross-referenced the DE proteins with single-cell transcriptomes of 2031 cells from 11 cell populations primarily cultured from murine AMI and HF model systems.Results:Sixty-two DE proteins were significantly associated (False Discovery Rate ?10%) with HF events in both cohorts. Single-cell RNA sequencing of murine model systems confirmed directionally-consistent differential gene expression of 36 targets, mostly matricellular proteins within cardiac fibroblasts (CF); qPCR validation showed strong concordance in murine and human cardiac cells. These proteins included transmembrane protein receptors such as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), junctional adhesion molecules such as desmocollin-2 (DSC2), and many matricellular proteins (e.g. lumican). Network analysis prioritised 12 hub proteins regulating post-MI HF events including ephrin-A4 (D-connectivity 0.27, P=1.44E-71), TNRSF1A (D-connectivity=0.27, P=1.20E-72) and DSC2 (D-connectivity=0.0.25, P=1.83E-71) over established cardiac markers B-type natriuretic peptide (D-connectivity=0.007 and P=0.069) and cardiac troponin (D-connectivity=0.006 and P=0.109).Conclusion:Large-scale plasma proteomics prioritized lesser-explored protein targets associated with post-MI HF. Unbiased single-cell transcriptomics confirmed that many targets were CF-enriched.