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Title: Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics
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 Sy
Ackers-Johnson, Matthew Andrew 
Pilbrow, Anna
Richards, A Mark 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
heart failure
myocardial infarction
Issue Date: 13-Oct-2020
Citation: 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 Sy, Ackers-Johnson, Matthew Andrew, Pilbrow, Anna, Richards, A Mark (2020-10-13). Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics. CIRCULATION 142 (15) : 1408-1421. ScholarBank@NUS Repository.
Abstract: 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 used aptamer-based affinity-capture plasma proteomics to measure 1305 plasma proteins at 1 month post-MI in a New Zealand cohort (CDCS [Coronary Disease Cohort Study]) including 181 patients post-MI who were subsequently hospitalized for HF in comparison with 250 patients post-MI 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 coregulated in post-MI HF using weighted gene co-expression network analysis. A Singapore cohort (IMMACULATE [Improving Outcomes in Myocardial Infarction through Reversal of Cardiac Remodelling]) of 223 patients post-MI, of which 33 patients were hospitalized for HF (median follow-up, 2.0 years), was used for further candidate enrichment of plasma proteins by 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 nonmyocyte cardiac cells isolated from a murine MI model, and single-cell and single-nucleus transcriptomes of cardiac myocytes from murine HF models and human patients with HF. 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. Weighted gene co-expression network analysis prioritized 63 of the 212 proteins that demonstrated significantly higher correlations among patients who developed post-MI HF in comparison with event-free controls (data set 1). Cross-cohort meta-analysis of the IMMACULATE cohort identified 36 plasma proteins associated with post-MI HF (data set 2), whereas single-cell transcriptomes identified 15 gene-protein candidates (data set 3). The majority of prioritized proteins were of matricellular origin. The 6 most highly enriched proteins that were common to all 3 data sets included well-established biomarkers of post-MI HF: N-terminal B-type natriuretic peptide and troponin T, and newly emergent biomarkers, angiopoietin-2, thrombospondin-2, latent transforming growth factor-β binding protein-4, and follistatin-related protein-3, as well. Conclusions: Large-scale human plasma proteomics, cross-referenced to unbiased cardiac transcriptomics at single-cell resolution, prioritized protein candidates associated with post-MI HF for further mechanistic and clinical validation.
ISSN: 00097322
DOI: 10.1161/CIRCULATIONAHA.119.045158
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