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

• 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
• 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

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 分子机制和威胁生命心律失常的临床预测因子， 非缺血性心肌病（DCM）仍然难以捉摸，阻碍了足够的预防和治疗 该人群中的心脏死亡（SCD）和恶性室性心律失常（VA）。我们的申请将解决 这个未满足的需求。我们科罗拉多大学和斯坦福大学的成熟调查员团队 已经组装了初步数据和概念验证实验，以解决三个完整目标，这 DCM中威胁生命的VA和SCD风险的关键知识差距将全面填补。我们假设 DCM中的VA/SCD涉及两种主要机制：遗传因素（“心律失常”基因）和 心脏纤维化。我们将以三个独立但完整的特定目的来解决这些假设 （临床，翻译和机械）旨在翻译机制的发现和描述 预后为精确的医学方法。特定目标1将定义基因型和表型 DCM中恶性VA和SCD的预测指标。我们的初步研究表明表型，例如 心肌纤维化和基因突变大大增加了VA/SCD的风险。那，我们假设 包括基因型和高级成像在内的临床多学科方法可以准确识别DCM患者 有SCD的风险。在家庭中使用深层表型，结局测量和NextGen测序 心肌病注册中心（1,316名DCM受试者），我们将为临床使用产生SCD风险预测评分。 具体目标2将确定VA的转录组签名。我们发现患者的心脏 心律失常DCM具有独特的转录特征。那我们假设这是在先进的 DCM期，致命的心律不齐是由遗传确定的转录特征驱动的。我们将利用 来自我们的NIH/NHLBI顶部项目的全基因组和转录组测序数据（X01 HL139403：1078 外植的心脏，504 DCM，140个对照），以识别基因特异性失调的途径，预测高危 VA。特定的目标3将阐明心律失常基因的分子机制。我们的初步 突变人类诱导多能干细胞衍生的心肌细胞（HIPSC-CM）中的数据显示了证据 固有的电不稳定性。但是，心脏成纤维细胞和CM/CF串扰在心律失常发生中的作用 仍然未知。我们假设心律失常DCM基因激活成纤维细胞并诱导心律不齐， 通过与心肌细胞的相互作用直接或间接。 HIPSC-CM和心脏成纤维细胞 （HIPSC-CF）将从我们的注册表中的60名患者（AIM 1）和基因组编辑的模型中生成 心律失常基因（LMNA，FLNC，DSP）和20岁/性别/种族匹配健康的突变 个人。使用工程心脏组织支架（EHT），我们将阐明CFS激活的机制 和心律失常，比较IPSC衍生模型中的改变的信号通路与在外植的心脏中的模型 队列（AIM 2），并在药物上拯救表型。