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
Affiliations
Bridget Simonson
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
Mark Chaffin
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
Matthew C. Hill
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
Ondine Atwa
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
Yasmine Guedira
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
Harshit Bhasin
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
Amelia W. Hall
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
Sikander Hayat
Precision Cardiology Laboratory, Bayer US, LLC, Cambridge, MA 02142, USA
Simon Baumgart
Precision Cardiology Laboratory, Bayer US, LLC, Cambridge, MA 02142, USA
Kenneth C. Bedi, Jr.
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
Kenneth B. Margulies
Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
Carla A. Klattenhoff
Precision Cardiology Laboratory, Bayer US, LLC, Cambridge, MA 02142, USA
Patrick T. Ellinor
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; Corresponding author
Summary: 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.
