Single-nucleus RNA sequencing in ischemic cardiomyopathy reveals common transcriptional profile underlying end-stage heart failure

Bridget Simonson; Mark Chaffin; Matthew C Hill; Ondine Atwa; Yasmine Guedira; Harshit Bhasin; Amelia W Hall; Sikander Hayat; Simon Baumgart; Kenneth C Bedi Jr; Kenneth B Margulies; Carla A Klattenhoff; Patrick T Ellinor

doi:10.1016/j.celrep.2023.112086

Single-nucleus RNA sequencing in ischemic cardiomyopathy reveals common transcriptional profile underlying end-stage heart failure

Cell Rep. 2023 Feb 28;42(2):112086. doi: 10.1016/j.celrep.2023.112086. Epub 2023 Feb 14.

Authors

Affiliations

¹ Precision Cardiology Laboratory, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Precision Cardiology Laboratory, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
³ Precision Cardiology Laboratory, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Gene Regulation Observatory, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Precision Cardiology Laboratory, Bayer US, LLC, Cambridge, MA 02142, USA.
⁵ Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Precision Cardiology Laboratory, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: ellinor@mgh.harvard.edu.

Abstract

Ischemic cardiomyopathy (ICM) is the leading cause of heart failure worldwide, yet the cellular and molecular signature of this disease is largely unclear. Using single-nucleus RNA sequencing (snRNA-seq) and integrated computational analyses, we profile the transcriptomes of over 99,000 human cardiac nuclei from the non-infarct region of the left ventricle of 7 ICM transplant recipients and 8 non-failing (NF) controls. We find the cellular composition of the ischemic heart is significantly altered, with decreased cardiomyocytes and increased proportions of lymphatic, angiogenic, and arterial endothelial cells in patients with ICM. We show that there is increased LAMININ signaling from endothelial cells to other cell types in ICM compared with NF. Finally, we find that the transcriptional changes that occur in ICM are similar to those in hypertrophic and dilated cardiomyopathies and that the mining of these combined datasets can identify druggable genes that could be used to target end-stage heart failure.

Keywords: CP: Molecular biology; dilated cardiomyopathy; druggable genome; heart failure; hypertrophic cardiomyopathy; ischemic cardiomyopathy; single-nucleus RNA sequencing.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cardiomyopathies* / genetics
Cardiomyopathy, Dilated*
Endothelial Cells / metabolism
Heart Failure* / genetics
Heart Failure* / metabolism
Humans
Myocardial Ischemia* / genetics
Myocardial Ischemia* / metabolism
Sequence Analysis, RNA

Abstract

Publication types

MeSH terms

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