Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.
In: Circulation, Jg. 142 (2020-10-13), Heft 15, S. 1408-1421
Online
academicJournal
Zugriff:
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. [ABSTRACT FROM AUTHOR]
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Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.
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Autor/in / Beteiligte Person: | 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 |
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Zeitschrift: | Circulation, Jg. 142 (2020-10-13), Heft 15, S. 1408-1421 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0009-7322 (print) |
DOI: | 10.1161/CIRCULATIONAHA.119.045158 |
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