Plasma miRNA predictors of adverse mechanical and electrical remodeling after MI

描述(由申请人提供)： 心肌梗死的并发症每年导致55万例心力衰竭(HF)和30万例心脏骤停(SCA)。HF和SCA在力学上与心肌梗死后心脏的机械和电学重塑密切相关。不良重构的标记物被广泛用于对心肌梗死后患者进行药物或设备治疗的风险分层。然而，目前的风险分层策略缺乏足够的敏感性和特异性。因此，需要开发互补的生物标志物来预测心肌梗死后的不良结果，以适当和经济有效地应用这些先进的治疗方法。细胞微小RNAs(MiRNAs)调控人类心血管疾病的整个基因网络，循环中的miRNAs可作为综合生物标志物。我们现在建议识别新的循环miRNA信号，这些信号可以预测心肌梗死后心律失常/SCA和心力衰竭的易感性，并将这些生物标记物整合到基于数字PCR的分析中，易于翻译到临床上。我们的研究小组跨越心血管研究中的多个学科，将检验这一中心假设：(1)使用RNA-SEQ对循环血浆进行无偏分析将确定与一组广泛表型的MI后患者发生不利机械和电气重构相关的新型miRNA；(2)机械性动物和细胞培养模型将有助于优先处理那些在疾病病理生物学中发挥作用的标记物，从而补充临床发现工作；(3)在一大批CAD和MI患者中，对不利重构的miRNA特征的评估将能够准确预测临床结果，尤其是SCA和HF。我们相信，我们的结果将为心梗后患者风险分层的新策略奠定基础，该策略将允许识别具有不良电信号高风险的患者。 以及机械重塑，他们可能受益于更积极的监测和药物和ICD的干预。

DESCRIPTION (provided by applicant): The complications of myocardial infarction contribute to 550,000 cases of heart failure (HF) and 300,000 cases of sudden cardiac arrest (SCA) annually. HF and SCA are mechanistically linked to the closely related processes of mechanical and electrical remodeling of the heart following infarction. Markers of adverse remodeling are widely used to risk-stratify post-MI patients for medical or device therapies. However, current risk-stratification strategies lack adequate sensitivity and specificity. Thus, development of complementary biomarkers to predict adverse outcomes post-MI is needed for the appropriate and cost-effective applications of these advanced therapies. Cellular micro-RNAs (miRNAs) regulate entire gene networks in human cardiovascular diseases and circulating miRNAs can be used as integrative biomarkers. We now propose to identify novel circulating miRNA signatures that can prognosticate susceptibility to arrhythmia/SCA and HF post-MI and to integrate these biomarkers into a digital PCR-based assay readily translatable into the clinic. Our group of investigators spanning multiple discipline within cardiovascular research will test the central hypothesis that (1) unbiased profiling of circulating plasma using RNA-seq will identify novel miRNAs associated with the development of adverse mechanical and electrical remodeling in a cohort of extensively-phenotyped post-MI patients; (2) mechanistic animal and cell culture models will complement the clinical discovery efforts by helping prioritize those markers that play a functional role in disease pathobiology, and (3) the assessment of miRNA signatures of adverse remodeling will enable accurate prediction of clinical outcomes, notably SCA and HF, in a large cohort of patients with CAD and MI. We believe that our results will lay the foundation for a novel strategy of risk-stratificationfor post-MI patients that would allow for identification of patients at high risk of adverse electrical and mechanical remodeling, who may benefit from more aggressive monitoring and interventions with medications and ICDs.