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Pathogenic variants in genes that cause dilated (DCM) and arrhythmogenic cardiomyopathies (ACM) convey high risks for the development of heart failure (HF) through unknown mechanisms. Using single nucleus RNA sequencing (snRNAseq), we characterized the transcriptome of 880,000 nuclei from 18 control and 61 failing, non-ischemic human hearts with pathogenic variants in DCM and ACM genes or idiopathic disease. We performed genotype-stratified analyses of the ventricular cell lineages and transcriptional states. The resultant DCM and ACM ventricular cell atlas demonstrated distinct right and left ventricular responses, highlighting genotype-associated pathways, intercellular interactions, and differential gene expression at single cell resolution. Together these data illuminate both shared and distinct cellular and molecular architectures of human HF and suggest novel candidate therapeutic targets. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Chan Zuckerberg FoundationLeducq Foundation

Background Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are disorders of the myocardium that affect the structure and function of the heart. Purpose The primary aim of this study was to discover damaging genetic variants in myocardial tissue from patients with DCM or HCM, who underwent heart transplantation. Methods Whole exome sequencing was performed on myocardial tissue from 103 explanted hearts with diagnosis of cardiomyopathy; 80 DCM and 13 HCM. Sanger sequencing was performed to confirm the loss-of-function variants in genes known to be linked to cardiomyopathy. RNA sequencing was conducted to confirm copy number variation deletions detected in the cohort. Burden analysis was performed by comparing the frequency of variants found in the study cohort to the frequency in the population database gnomAD. Results Rare (minor allele frequency Conclusions The frequency of damaging variants that are likely pathogenic (46.3%) is higher in DCM cases in this cohort compared to previous studies. These data indicate that patients with end-stage DCM are more likely to have a genetic cause for their disease. As read depth of variant and normal alleles were, these are likely germline and not mosaic variants, and can enable cascade testing in family members. Moreover, our study demonstrates that CNVs in TTN that alter the reading frame can cause DCM. Funding Acknowledgement Type of funding source: None