Proteomics profiling in hypertrophic cardiomyopathy and cardiac event prediction

项目总结 肥厚型心肌病(HCM)是最常见的遗传性心脏病及其病因 主要心血管不良事件(MACE)--例如，心律失常、心力衰竭和突发事件 心源性死亡。预防MACE的侵入性干预措施是可用的，但可能会导致 并发症。当前的风险分层策略预测哪些患者的能力有限 会发展成Mace，并从预防性干预中获益最多。此外，几乎没有什么是 已知基因突变介导肥厚性心肌病发病的信号通路 还有梅斯。这些重大的知识差距阻碍了在HCM中预防Mace的努力。这个 哈佛-哥伦比亚多中心肥厚型心肌病(HCM2)生物信息库是一家 正在进行的三中心队列研究在2014-2020年间招募了560名肥厚型心肌炎患者。在这 大型多中心HCM生物库，研究人员收集了高质量的生物标本- 例如血浆、左心室心肌。随访数据包括一年两次的访谈、体检 记录审查和每年的面对面检查，到目前为止&gt；85%的跟进(中位数跟进， 3.1年)。目前的R01项目将扩展这个大型的、特征良好的HCM生物储存库 通过蛋白质组学分析血浆和心肌样本，并通过检测它们的 与肥厚型心肌炎病情和MACE的关系。在目标1中，我们将研究 应用分子生物学方法研究肥厚性心肌病心肌细胞信号转导途径异常 生物学方法(例如，信使核糖核酸的RT-PCR、酶联免疫吸附试验)和蛋白质组学图谱。在目标2中，我们将 用蛋白质组学方法确定信号通路失调与MACE的关系 分析，并指定预测突发事件Mace的信号通路。最后，使用一个系统 生物学方法，目标3将通过整合蛋白质组、遗传学和临床来定义HCM亚型 数据，并确定它们与MACE的关联。我们先前的研究和前期工作出借给 令人信服地支持我们的假设。目前的R01项目将提供一个独特的机会 从分子水平揭示肥厚性心肌炎发生发展为MACE的分子机制 使用蛋白质组学图谱研究血浆和心肌中的信号通路。 此外，拟议的研究还将发明一种新的HCM风险分层系统，它 将使我们能够准确识别将受益于以下方面的高危HCM亚群 预防性干预。该项目将为有针对性的开发提供强有力的证据基础 通过特异性调节预防肥厚性心肌病发病机制和MACE的药物治疗 信号通路。调查人员在所有领域都拥有综合和互补的专业知识 相关字段。这项研究与NHLBI的HCM研究战略计划很好地匹配。

PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac disease and causes major adverse cardiovascular events (MACE) – e.g., arrhythmias, heart failure, and sudden cardiac death. Invasive interventions to prevent MACE are available but can cause complications. Current risk stratification strategy has limited power to predict which patient would develop MACE and benefit most from preventive interventions. Furthermore, little is known about the signaling pathways through which gene mutations mediate HCM pathogenesis and MACE. These major knowledge gaps have hindered efforts to prevent MACE in HCM. The Harvard-Columbia Multi-center Hypertrophic Cardiomyopathy (HCM2) Biorepository is an ongoing 3-center cohort study that enrolled 560 patients with HCM during 2014-2020. In this large multi-center HCM biorepository, investigators have collected high-quality biospecimens – e.g., plasma, left ventricular myocardium. Follow-up data include biannual interviews, medical record reviews, and in-person exam every year, with >85% follow-up to date (median follow-up, 3.1 years). The present R01 project will extend this large well-characterized HCM biorepository by proteomically profiling both plasma and myocardium samples, and by examining their relations to both HCM disease status and MACE. In Aim 1, we will examine the association of signaling pathway dysregulation in the myocardium with HCM disease status using molecular biology approach (e.g., RT-PCR of mRNA, ELISA) and proteomics profiling. In Aim 2, we will determine the association of signaling pathway dysregulation with MACE using proteomics profiling, and specify signaling pathways that predict incident MACE. Finally, using a systems biology approach, Aim 3 will define HCM subtypes by integrating proteomic, genetic, and clinical data, and determine their associations with MACE. Our prior study and preliminary work lend compelling support to our hypotheses. The present R01 project will provide a unique opportunity to reveal the molecular mechanisms of HCM pathogenesis and progression to MACE through examining signaling pathways using proteomics profiling in both plasma and myocardium. Furthermore, the proposed study will also invent a novel risk stratification system in HCM, which will allow us to precisely identify high-risk HCM subpopulations that would benefit from preventive interventions. The project will provide a strong evidence base for developing targeted pharmacotherapies to prevent HCM pathogenesis and MACE through the modulation of specific signaling pathways. The investigators have integrated and complementary expertise in all relevant fields. The study matches well with the NHLBI strategic plan for HCM research.