Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.
Prioritizing Candidates of Post-Myocardial Infarction Heart Failure Using Plasma Proteomics and Single-Cell Transcriptomics.
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利用血浆蛋白质组学和单细胞转录组学确定心肌梗死后心力衰竭候选患者的优先级。
DOI：
10.1161/circulationaha.119.045158
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发表时间：
2020-10-13
期刊：
影响因子：
37.8
通讯作者：
Richards AM
中科院分区：
文献类型：
--
作者：
Chan MY;Efthymios M;Tan SH;Pickering JW;Troughton R;Pemberton C;Ho HH;Prabath JF;Drum CL;Ling LH;Soo WM;Chai SC;Fong A;Oon YY;Loh JP;Lee CH;Foo RSY;Ackers-Johnson MA;Pilbrow A;Richards AM
补充数字内容可在文本中找到。心力衰竭（HF）是急性心肌梗死（MI）最常见的长期并发症。了解与MI后HF相关的血浆蛋白及其基因表达可能会发现新的候选生物标志物和药物靶点。我们使用基于适体的亲和捕获血浆蛋白质组学在新西兰队列（CDCS [冠心病队列研究]）中测量了MI后1个月的1305种血浆蛋白，其中包括181名MI后随后因HF住院的患者，与之相比，250名MI后患者在中位随访4.9年内保持无事件。然后，我们将血浆蛋白与MI后4个月测量的左心室射血分数相关联，并使用加权基因共表达网络分析鉴定了MI后HF中可能共调节的蛋白质。新加坡队列（IMMACULATE [通过恢复心脏重构改善心肌梗死结局]）中223例MI后患者，其中33例患者因HF住院（中位随访时间为2.0年），通过使用Fisher荟萃分析、基于重采样的统计检验和机器学习，进一步富集血浆蛋白候选者。然后，我们交叉引用差异表达的蛋白质与它们的差异表达的基因从单细胞转录组的非心肌细胞心肌细胞分离的小鼠MI模型，和单细胞和单核转录组的心肌细胞从小鼠HF模型和人类HF患者。在CDCS队列中，212种差异表达的血浆蛋白与随后的HF事件显著相关。其中，96例与MI后4个月测量的左心室射血分数相关。加权基因共表达网络分析对212种蛋白质中的63种进行了优先排序，这些蛋白质在发生MI后HF的患者中与无事件对照组相比具有显着更高的相关性（数据集1）。IMMACULATE队列的跨队列荟萃分析确定了36种与MI后HF相关的血浆蛋白（数据集2），而单细胞转录组确定了15种基因-蛋白候选物（数据集3）。大多数优先的蛋白质是基质细胞来源的。所有3个数据集共有的6种最高度富集的蛋白质包括MI后HF的明确生物标志物：N-末端B型利钠肽和肌钙蛋白T，以及新出现的生物标志物：血管生成素-2、血小板反应蛋白-2、潜伏性转化生长因子-β结合蛋白-4和卵泡抑素相关蛋白-3。大规模的人血浆蛋白质组学，交叉参考无偏的心脏转录组学在单细胞分辨率，优先考虑与MI后HF相关的蛋白质候选物，以进行进一步的机制和临床验证。
Supplemental Digital Content is available in the text. 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. 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. 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. 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.