Massachusetts General Hospital, Boston (S.A.M., A.C., N.E.I., H.G., D.D., E.C., G.D.L., J.L.J.).
Harvard Medical School, Boston, MA (N.E.I., H.G., E.G., G.D.L., J.L.J.).
Circ Heart Fail. 2020 Aug;13(8):e006794. doi: 10.1161/CIRCHEARTFAILURE.119.006794. Epub 2020 Jul 29.
Proteomics have already provided novel insights into the pathophysiology of heart failure (HF) with reduced ejection fraction. Previous studies have evaluated cross-sectional protein signatures of HF, but few have characterized proteomic changes following HF with reduced ejection fraction treatment with ARNI (angiotensin receptor/neprilysin inhibitor) therapy or left ventricular assist devices.
In this retrospective omics study, we performed targeted proteomics (N=625) of whole blood sera from patients with American College of Cardiology/American Heart Association stage D (N=29) and stage C (N=12) HF using proximity extension assays. Samples were obtained before and after (median=82 days) left ventricular assist device implantation (stage D; primary analysis) and ARNI therapy initiation (stage C; matched reference). Oblique principal component analysis and point biserial correlations were used for feature extraction and selection; standardized mean differences were used to assess within and between-group differences; and enrichment analysis was used to generate and cluster Gene Ontology terms.
Core sets of proteins were identified for stage C (N=9 proteins) and stage D (N=18) HF; additionally, a core set of 5 shared HF proteins (NT-proBNP [N-terminal pro-B type natriuretic peptide], ESM [endothelial cell-specific molecule]-1, cathepsin L1, osteopontin, and MCSF-1) was also identified. For patients with stage D HF, moderate (δ, 0.40-0.60) and moderate-to-large (δ, 0.60-0.80) sized differences were observed in 8 of their 18 core proteins after left ventricular assist devices implantation. Additionally, specific protein groups reached concentration levels equivalent (<0.10) to stage C HF after initiation on ARNI therapy.
HF with reduced ejection fraction severity associates with distinct proteomic signatures that reflect underlying disease attributes; these core signatures may be useful for monitoring changes in cardiac function following initiation on ARNI or left ventricular assist device implantation.
蛋白质组学已经为射血分数降低的心力衰竭（HF）的病理生理学提供了新的见解。以前的研究已经评估了 HF 的横断面蛋白质特征，但很少有研究描述 ARNI（血管紧张素受体/脑啡肽酶抑制剂）治疗或左心室辅助装置治疗后射血分数降低的 HF 的蛋白质组变化。
在这项回顾性组学研究中，我们使用邻近延伸测定法对美国心脏病学会/美国心脏协会（ACC/AHA）D 期（n=29）和 C 期（n=12）HF 患者的全血血清进行了靶向蛋白质组学（n=625）。在左心室辅助装置植入（D 期；主要分析）和 ARNI 治疗开始（C 期；匹配参考）前后获得了样本（中位数=82 天）。偏主成分分析和点二项式相关用于特征提取和选择；标准化均数差用于评估组内和组间差异；富集分析用于生成和聚类基因本体术语。
确定了 C 期（n=9 种蛋白）和 D 期（n=18 种蛋白）HF 的核心蛋白集；此外，还确定了 5 种共同的 HF 蛋白（N 端前 B 型利钠肽[NT-proBNP]、内皮细胞特异性分子-1[ESM-1]、组织蛋白酶 L1、骨桥蛋白和巨噬细胞集落刺激因子-1[MCSF-1]）的核心集合。对于 D 期 HF 患者，在左心室辅助装置植入后，其 18 种核心蛋白中的 8 种蛋白的中等（δ，0.40-0.60）和中到大（δ，0.60-0.80）大小差异。此外，在开始 ARNI 治疗后，特定蛋白组的浓度水平达到（<0.10）与 C 期 HF 相当。
射血分数降低的 HF 严重程度与反映潜在疾病特征的独特蛋白质组学特征相关；这些核心特征可能有助于监测 ARNI 或左心室辅助装置植入后心脏功能的变化。
