Pathogenic variants damage cell composition and single-cell transcription in cardiomyopathies

Daniel Reichart, Eric L. Lindberg, Henrike Maatz, Antonio M.A. Miranda, Anissa Viveiros, Nikolay Shvetsov, Anna Gärtner, Emily R. Nadelmann, Michael Lee, Kazumasa Kanemaru, Jorge Ruiz-Orera, Viktoria Strohmenger, Daniel M. DeLaughter, Giannino Patone, Hao Zhang, Andrew Woehler, Christoph Lippert, Yuri Kim, Eleonora Adami, Joshua M. GorhamSam N. Barnett, Kemar Brown, Rachel J. Buchan, Rasheda A. Chowdhury, Chrystalla Constantinou, James Cranley, Leanne E. Felkin, Henrik Fox, Ahla Ghauri, Jan Gummert, Masatoshi Kanda, Ruoyan Li, Lukas Mach, Barbara McDonough, Sara Samari, Farnoush Shahriaran, Clarence Yapp, Caroline Stanasiuk, Pantazis I. Theotokis, Fabian J. Theis, Antoon van den Bogaerdt, Hiroko Wakimoto, James S. Ware, Catherine L. Worth, Paul J.R. Barton, Young Ae Lee, Sarah A. Teichmann, Hendrik Milting, Michela Noseda, Gavin Y. Oudit, Matthias Heinig, Jonathan G. Seidman, Norbert Hubner, Christine E. Seidman

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Pathogenic variants in genes that cause dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) convey high risks for the development of heart failure through unknown mechanisms. Using single-nucleus RNA sequencing, we characterized the transcriptome of 880, 000 nuclei from 18 control and 61 failing, nonischemic 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 heart failure and suggest candidate therapeutic targets.

Original languageEnglish
Article numberabo1984
JournalScience
Volume377
Issue number6606
DOIs
StatePublished - 5 Aug 2022
Externally publishedYes

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