Molecular Phenotyping for Autopsy-Defined Sudden Cardiac Death

尸检定义的心脏性猝死的分子表型分析

• 批准号: 9884445
• 负责人: ZIAN H TSENG
• 金额: $ 80.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884445
• 关键词: Acute; Address; Adult; Arrhythmia; Autopsy; Biological Assay; Blood; CLIA certified; Cardiac; Cardiovascular Diseases; Cardiovascular Manifestation; Cells; Cellular Infiltration; Cessation of life; Cicatrix; Communities; Consent; Coronary Arteriosclerosis; Data; Diagnosis; Dilated Cardiomyopathy; Epigenetic Process; Exhibits; Expression Profiling; Family; Family member; Fibrosis; First Degree Relative; Funding; Future; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genotype; Guidelines; Heart; Heritability; Hour; Individual; Inherited; Ischemia; Left; Left Ventricular Hypertrophy; Measures; Messenger RNA; Methods; MicroRNAs; Myocardial; National Heart, Lung, and Blood Institute; Pathogenicity; Pathology; Phenotype; Population; Prevention; RNA; Relative Risks; Reporting; Risk; Risk Factors; Sampling; Severities; Structural Genes; Structure; Sudden Death; Sum; Techniques; Testing; Therapeutic Intervention; Tissues; Transcript; Trauma; Untranslated RNA; Variant; Ventricular; cardiovascular disorder prevention; clinically actionable; cohort; genetic testing; genetic variant; high risk; in silico; innovation; insight; molecular phenotype; mortality risk; novel; novel strategies; prospective; segregation; sudden cardiac death; variant of unknown significance; web-based tool

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.

项目总结/摘要 心源性猝死（SCD）的传统定义假定为心源性。4我们的NHLBI资助的正在进行的 自2011年以来，POST SCD研究已经对>1000例连续SCD中的97%进行了尸检，这是第一个也是唯一一个 前瞻性成人SCD队列，捕获社区中的全部SCD，使用尸检来完善 5最近的SCD风险6和遗传研究7报告了不一致的结果，可能是由于 依赖于假定的SCD表型。指南8和最近的研究3支持死后目标 心血管疾病（CVD）基因检测尸检阴性猝死< 35岁，但没有指导方针 存在用于较老SCD（> 35岁）的死后基因检测，也不存在具有结构病理学的SCD。员额 98%的SCD患者有冠心病、左室肥厚等共同病理 (LVH)或扩张型心肌病（DCM）。临床上可操作的单基因CVD的贡献还没有被证实。 在尸检定义的成人SCD中研究，具有这种常见心脏病理学背景。我们的试点数据 证明了阐明已建立的致病性结构基因变异与 告知死后检测指南并扩展和完善表型的潜在风险。我们已经成功 让绝大多数POST SCD家族参与部署一种新颖、高效的基于Web的工具， 在SCD预防方面的一个主要未满足的需求-确定共同隔离的SCD受害者的一级亲属， 处于最高风险。最后，SCD预防新方法的关键障碍之一是缺乏 了解急性细胞环境，易患致命性心律失常的背景下获得性或 遗传性结构病理学，例如，LVH、纤维化、扩张或瘢痕。我们提出了一种创新方法， 询问死后心肌RNA转录本-反映了所有可能因素的总影响， SCD前14小时：遗传、表观遗传、缺血、神经体液和基础心肌病理学-作为 深入了解急性细胞变化，创造致命的心律失常脆弱的基板。 我们将利用尸检定义的SCD中的家属同意书、血液和左心室样本， （1A）确定在小鼠中致病性变体的产率， 具有尸检亚表型的成人SCD中的临床上可操作的CVD基因;（1B）细化基因型-表型 与HCM基因致病性变异的相关性（SCD伴LVH），与DCM基因致病性变异的相关性（SCD伴心脏扩张）， （2）阐明基因型-表型相关性，以确定一级 有SCD易感性的共分离单基因CVD的亲属;（3）表征心肌RNA谱 在SCD亚表型的情况下，特异于致死性心律失常。我们预计，该项目将告知 在所有成人SCD中进行死后基因检测的指南， 人口SCD，过滤不确定的重要性的潜在致病的变种，并提供洞察力， 急性细胞环境易受SCD影响。