Prioritizing Candidates of Post–Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics

• Published in: Circulation (New York, N.Y.) Vol. 142; no. 15; pp. 1408 - 1421
• Main Authors: Chan, Mark Y., Efthymios, Motakis, Tan, Sock Hwee, Pickering, John W., Troughton, Richard, Pemberton, Christopher, Ho, Hee-Hwa, Prabath, Joseph-Francis, Drum, Chester L., Ling, Lieng Hsi, Soo, Wern-Miin, Chai, Siang-Chew, Fong, Alan, Oon, Yen-Yee, Loh, Joshua P., Lee, Chi-Hang, Foo, Roger S.Y., Ackers-Johnson, Matthew Andrew, Pilbrow, Anna, Richards, A. Mark
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 13.10.2020; Lippincott Williams & Wilkins
• Subjects: Original s
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.119.045158

BACKGROUND:Heart failure (HF) is the most common long-term complication of acute myocardial infarction (MI). Understanding plasma proteins associated with post-MI HF and their gene expression may identify new candidates for biomarker and drug target discovery. METHODS:We employed aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at one month post-MI in a New Zealand cohort (CDCS) including 181 post-MI patients who were subsequently hospitalized for HF compared with 250 post-MI patients who remained event-free over a median follow-up of 4.9 years. We then correlated plasma proteins with left ventricular ejection fraction measured at 4 months post-MI and identified proteins potentially co-regulated in post-MI HF using Weighted Gene Co-expression Network Analysis (WCGNA). A Singapore cohort (IMMACULATE) of 223 post-MI patients, of which 33 patients were hospitalized for HF (median follow-up 2.0 years), was used for further candidate enrichment of plasma proteins using Fisher meta-analysis, resampling-based statistical testing and machine learning. We then cross-referenced differentially-expressed proteins with their differentially-expressed genes from single-cell transcriptomes of non-myocyte cardiac cells isolated from a murine MI model, and single-cell and single-nuclei transcriptomes of cardiac myocytes from murine HF models and human HF patients. RESULTS:In the CDCS cohort, 212 differentially-expressed plasma proteins were significantly associated with subsequent HF events. Of these, 96 correlated with left ventricular ejection fraction measured at 4 months post-MI. WCGNA prioritised 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF compared with event-free controls (dataset 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (dataset 2) while single-cell transcriptomes identified 15 gene-protein candidates (dataset 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly-enriched proteins that were common to all 3 datasets included well-established biomarkers of post-MI HF – N-terminal B- type natriuretic peptide and troponin T - as well as newly-emergent biomarkers - angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4 and follistatin-related protein-3. CONCLUSIONS:Large-scale human plasma proteomics, cross-referenced to unbiased cardiac cell transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.