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在机制上与梗死后心脏的机械和电重构的密切相关过程相关。不良重塑的标志物被广泛用于对MI后患者进行风险分层，以进行药物或器械治疗。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MI后的不良结局，以适当且具有成本效益地应用这些先进疗法。细胞微小RNA（micro-RNAs，miRNAs）调控着人类心血管疾病的整个基因网络，循环miRNAs可作为整合性生物标志物。 我们现在提出鉴定新的循环miRNA特征，其可以明确心肌梗死后心律失常/SCA和HF的易感性，并将这些生物标志物整合到基于数字PCR的检测中，该检测易于转化为临床。我们的研究小组跨越心血管研究中的多个学科，将测试中心假设，即（1）使用RNA-seq的循环血浆的无偏分析将在广泛表型化的MI后患者队列中鉴定与不良机械和电重构的发展相关的新miRNA;（2）机械动物和细胞培养模型将通过帮助优先考虑在疾病病理生物学中发挥功能作用的那些标志物来补充临床发现工作，和（3）评估不良重构的miRNA特征将能够在患有CAD和MI的大队列患者中准确预测临床结果，特别是SCA和HF。我们相信，我们的研究结果将为心肌梗死后患者的风险分层新策略奠定基础，该策略将允许识别不良电刺激风险高的患者。 和机械重塑，他们可能受益于更积极的监测和药物和ICD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.