Key result
Plasma proteomics and single-cell transcriptomics identified 6 highly enriched proteins, including angiopoietin-2 and thrombospondin-2, associated with post-myocardial infarction heart failure.
Why the study?
Heart failure is the most common long-term complication of acute MI, and understanding associated plasma proteins and their gene expression may identify new candidates for biomarker and drug target discovery.
Which plasma proteins and gene expressions are associated with the development of heart failure following myocardial infarction?
Cohort (n=654)
Yes
Which plasma proteins and gene expressions are associated with the development of heart failure following myocardial infarction?
Large-scale plasma proteomics cross-referenced with single-cell transcriptomics identified both established and novel protein biomarkers associated with the development of heart failure after myocardial infarction.
Prioritizes 4 novel matricellular proteins for post-MI HF risk stratification; leaves open clinical adoption pending prospective validation.
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.
No takes yet. Share an insight, caveat, or question.
Chan et al. (2020) conducted a cohort in Post-myocardial infarction heart failure (n=654). Plasma protein levels vs. Event-free post-MI patients was evaluated on Hospitalization for heart failure. Plasma proteomics and single-cell transcriptomics identified 6 highly enriched proteins, including angiopoietin-2 and thrombospondin-2, associated with post-myocardial infarction heart failure.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: