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

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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.