Elucidating the Origin of Sudden Cardiac Death in Dilated Cardiomyopathy: from Phenotype Predictors to Therapeutic Targets

阐明扩张型心肌病心脏性猝死的起源：从表型预测因子到治疗靶点

基本信息

批准号：
10658201
负责人：
Luisa Mestroni
金额：
$ 72.73万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658201
关键词：
Age Arrhythmia Basic Science Cardiac Cardiac Myocytes Cardiomyopathies Cells Circulation Clinical Clinical Data Clinical Sciences Cohort Studies Colorado Data Development Dilated Cardiomyopathy Disease Early identification Ethnic Origin FLNC gene Fibroblasts Fibrosis Foundations Gender Gene Expression Profile Gene Mutation Genes Genetic Genomics Genotype Goals Heart Human Image Implantable Defibrillators Individual Knowledge Left Ventricular Ejection Fraction Life Malignant - descriptor Modeling Molecular Morbidity - disease rate Mutation Myocardial dysfunction National Heart, Lung, and Blood Institute Nature Outcome Measure Pathogenicity Pathway interactions Patients Phenotype Population Prevention Preventive Prognosis Registries Reporting Research Personnel Risk Role Science Signal Pathway Signal Transduction Societies Tissue-Specific Gene Expression Trans-Omics for Precision Medicine Translating Translational Research United States National Institutes of Health Universities Variant Ventricular Arrhythmia Work cardiac tissue engineering clinical predictors cohort coronary fibrosis design experimental study filamin genetic predictors genome editing genome sequencing heart rhythm high risk implantation induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes interdisciplinary approach mortality mortality risk multidisciplinary mutant next generation sequencing novel novel therapeutic intervention pharmacologic precision medicine risk prediction risk stratification sudden cardiac death therapeutic target tissue support frame tool transcriptome transcriptome sequencing whole genome

项目摘要

Project Abstract The molecular mechanisms and the clinical predictors of life-threatening arrhythmias in patients with dilated, nonischemic cardiomyopathy (DCM) remain elusive, hampering adequate prevention and treatment of sudden cardiac death (SCD) and malignant ventricular arrhythmias (VA) in this population. Our application will address this unmet need. Our established team of investigators from the University of Colorado and Stanford University has assembled preliminary data and proof-of-concept experiments to tackle three complementary aims, which will comprehensively fill critical knowledge gaps in life-threatening VA and SCD risk in DCM. We hypothesize that two main mechanisms are involved in VA/SCD in DCM: genetic factors (“arrhythmogenic” genes) and cardiac fibrosis. We will address these hypotheses with three independent but complementary Specific Aims (clinical, translational and mechanistic) designed to translate the discovery of mechanisms and delineation of prognosis into a precision medicine approach. Specific Aim 1 will define genotype and phenotype predictors of malignant VA and SCD in DCM. Our preliminary studies show that phenotype, such as myocardial fibrosis, and gene mutations significantly increase the risk of VA/SCD. Thus, we hypothesize that a clinical multidisciplinary approach including genotype and advanced imaging can precisely identify DCM patients at risk of SCD. Using deep phenotyping, outcome measures, and NextGen sequencing in the Familial Cardiomyopathy Registry (1,316 DCM subjects), we will generate a SCD risk prediction score for clinical use. Specific Aim 2 will identify the transcriptome signature of VA. We found that explanted hearts of patients with arrhythmogenic DCM have a distinct transcriptional signature. Thus, we hypothesize that, in advanced- stage DCM, lethal arrhythmias are driven by genetically determined transcriptional signatures. We will leverage whole genome and transcriptome sequencing data from our NIH/NHLBI TOPMed project (X01 HL139403: 1078 explanted hearts, 504 DCM, 140 controls) to identify gene-specific dysregulated pathways predicting high-risk VA. Specific Aim 3 will elucidate the molecular mechanisms of arrhythmogenic genes. Our preliminary data in mutant human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) show evidence of intrinsic electrical instability. However, the role of cardiac fibroblasts and CM/CF cross-talk in arrhythmogenesis remains unknown. We hypothesize that arrhythmogenic DCM genes activate fibroblasts and induce arrhythmia, either directly or indirectly through their interaction with cardiomyocytes. hiPSC-CM and cardiac fibroblasts (hiPSC-CF) will be generated from 60 patients from our Registry (Aim 1) and genome edited models with mutations in arrhythmogenic genes (LMNA, FLNC, DSP), and 20 age/gender/ethnicity-matched healthy individuals. Using engineered heart tissue scaffolds (EHT), we will elucidate the mechanisms of CFs activation and arrhythmia, compare altered signaling pathways in iPSC-derived models with those in the explanted hearts cohort (Aim 2), and pharmacologically rescue the phenotype.

项目摘要扩张型、危及生命的心律失常的分子机制和临床预测因子非缺血性心肌病（DCM）仍然难以捉摸，妨碍了对突发性心脏病的充分预防和治疗我们的应用程序将解决该人群的心源性死亡（SCD）和恶性室性心律失常（VA）问题。我们建立了来自科罗拉多大学和斯坦福大学的研究团队。已经收集了初步数据和概念验证实验来解决三个互补的目标，将全面填补 DCM 中危及生命的 VA 和 SCD 风险的关键知识空白。 DCM 中的 VA/SCD 涉及两个主要机制：遗传因素（“致心律失常”基因）和我们将通过三个独立但互补的具体目标来解决这些假设。（临床、转化和机制）旨在转化机制的发现和描述具体目标 1 将定义基因型和表型。我们的初步研究表明，表型是 DCM 中恶性 VA 和 SCD 的预测因子。心肌纤维化和基因突变显着增加 VA/SCD 的风险。包括基因型和先进影像学在内的临床多学科方法可以精确识别 DCM 患者在家族中使用深度表型分析、结果测量和下一代测序。心肌病登记处（1,316 名 DCM 受试者），我们将生成 SCD 风险预测评分以供临床使用。具体目标 2 将鉴定 VA 的转录组特征我们发现患者的移植心脏。致心律失常性 DCM 具有独特的转录特征，因此，我们在高级阶段捕获了这一点。 DCM 阶段，致命性心律失常是由基因决定的转录特征驱动的。来自 NIH/NHLBI TOPMed 项目的全基因组和转录组测序数据 (X01 HL139403: 1078 外植心脏，504 个 DCM，140 个对照），以确定预测高风险的基因特异性失调途径 VA。具体目标 3 将阐明我们初步的致心律失常基因的分子机制。突变型人诱导多能干细胞衍生的心肌细胞 (hiPSC-CM) 的数据表明然而，心脏成纤维细胞和 CM/CF 串扰在心律失常发生中的作用。我们仍然未知致心律失常 DCM 基因激活成纤维细胞并诱发心律失常，直接或间接通过其与心肌细胞和心肌成纤维细胞的相互作用。 (hiPSC-CF) 将从我们注册中心（目标 1）的 60 名患者和基因组编辑模型中生成致心律失常基因（LMNA、FLNC、DSP）突变，以及 20 名年龄/性别/种族匹配的健康人使用工程心脏组织支架 (EHT)，我们将阐明 CF 激活的机制。和心律失常，比较 iPSC 衍生模型与外植心脏中改变的信号通路队列（目标 2），并从药理学上拯救表型。