Molecular Phenotyping for Autopsy-Defined Sudden Cardiac Death

项目摘要/摘要 心脏性猝死(SCD)的传统定义假定是心脏原因。4我们的NHLBI资助正在进行 自2011年以来，对连续1000例SCD患者进行了97%的尸检，这是第一次也是唯一一次SCD后研究 未经选择的预期成人SCD队列，捕获社区中的全部SCD，使用尸检进行提炼 5最近的SCD风险6和遗传学研究7报告的结果不一致，可能是由于 依赖于推测的SCD表型。指南8和最近的研究3支持有针对性的尸检 心血管疾病(CVD)尸检基因检测阴性猝死&35年，但没有指南 存在用于对较老的SCD(35岁)进行死后基因测试，也不存在具有结构性病理的SCD。在POST中 SCD，98%的患者有常见的病理改变，如冠状动脉疾病(CAD)、左心室肥厚 或扩张型心肌病(DCM)。临床上可操作的单基因心血管疾病的作用尚未得到证实 在尸检定义的成人SCD中进行研究，具有此类常见心脏病理的背景。我们的试点数据 证明有可能阐明已建立的致病结构基因变异与 心律失常风险为尸检指南提供信息，并扩展和改进表型。我们已经成功地 让绝大多数后SCD家庭部署基于Web的新型高效工具，以解决 SCD预防中一个尚未得到满足的主要需求-确定SCD患者的共同隔离的一级亲属 处于最高风险。最后，SCD预防的新方法的关键障碍之一是缺乏 在获得性或非获得性心律失常的背景下，对易发生致命性心律失常的急性细胞环境的理解 遗传性结构病理，例如左心室肥厚、纤维化、扩张或疤痕。我们提出了一种创新的方法来 询问死后心肌RNA转录本-反映所有可能因素在 SCD前几小时：遗传、表观遗传、缺血、神经体液和潜在的心肌病理-作为 洞察造成致命性心律失常的脆弱底物的急性细胞变化。 我们将利用尸检定义的SCD的家庭同意、血液和左心室样本以及 配对对照以解决以下具体目标：(1)确定致病变异体的产量 具有尸检亚型的成人SCD的临床可操作的CVD基因；(1B)精炼基因-表型 SCD伴左室肥厚患者HCM基因致病变异与心脏扩大患者DCM基因的相关性 和所有SCD中的经络病基因；(2)阐明基因-表型相关性，以确定一级 有共同分离的单基因心血管易患SCD的亲属；(3)心肌RNA图谱的特征 针对SCD亚型设置中的致死性心律失常。我们预计这个项目将使 所有成人SCD的死后基因测试指南，精炼精确的基因型-表型相关性 群体SCD，过滤不确定意义的变异到潜在的致病变异，并提供对 急性细胞环境易患SCD。

PROJECT SUMMARY/ABSTRACT Conventional definitions of sudden cardiac death (SCD) presume cardiac cause.4 Our NHLBI-funded ongoing POST SCD Study, which has autopsied 97% of >1000 consecutive SCDs since 2011, is the first and only prospective unselected adult SCD cohort, capturing the entirety of SCDs in a community, to use autopsy to refine SCD to true cardiac causes.5 Recent SCD risk6 and genetic studies7 have reported inconsistent results likely due to reliance on the presumed SCD phenotype. Guidelines8 and recent studies3 support postmortem targeted cardiovascular disease (CVD) genetic testing of autopsy-negative sudden deaths < 35 years, but no guidelines exist for postmortem genetic testing of older SCDs (> 35 years), nor SCDs with structural pathology. In POST SCD, 98% of cases have common pathology such as coronary artery disease (CAD), left ventricular hypertrophy (LVH), or dilated cardiomyopathy (DCM). The contribution of clinically actionable monogenic CVD has not been studied in autopsy-defined adult SCD with a background of such common cardiac pathology. Our pilot data demonstrate the potential to elucidate associations of established, pathogenic structural gene variants with arrhythmic risk to inform postmortem testing guidelines and extend and refine phenotypes. We have successfully engaged the large majority of POST SCD families to deploy a novel, highly efficient web-based tool to address a major unmet need in SCD prevention – identifying co-segregating first degree relatives of SCD victims who are at highest risk. Finally, one of the key barriers to new approaches in SCD prevention is a lack of understanding of the acute cellular milieu that predisposes to fatal arrhythmias in the context of acquired or inherited structural pathology, e.g., LVH, fibrosis, dilation, or scar. We propose an innovative method to interrogate postmortem myocardial RNA transcripts – reflecting the sum total effect of all possible factors in the hours prior to SCD: genetic, epigenetic, ischemia, neurohumoral, and underlying myocardial pathology – as an insight into the acute cellular alterations that create vulnerable substrate for fatal arrhythmia. We will leverage family consent, blood, and left ventricular samples from our autopsy-defined SCDs and matched controls to address the following Specific Aims: (1A) Determine the yield of pathogenic variants in clinically actionable CVD genes in adult SCDs with autopsy sub-phenotypes; (1B) Refine genotype-phenotype correlations with pathogenic variants in HCM genes for SCDs with LVH, DCM genes for SCDs with dilated hearts, and channelopathy genes in all SCDs; (2) Elucidate genotype-phenotype correlation to identify first degree relatives with co-segregating monogenic CVD predisposing to SCD; (3) Characterize the myocardial RNA profile specific to fatal arrhythmias in the setting of sub-phenotypes of SCD. We anticipate that this project will inform guidelines for postmortem genetic testing in all adult SCDs, refine precision genotype-phenotype correlations in population SCD, filter variants of uncertain significance to potentially causative ones, and offer insights into the acute cellular milieu vulnerable to SCD.