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

Bridget Simonson*1,2, Mark Chaffin*1,2, Matthew C. Hill1,2,3, Ondine Atwa1,2, Yasmine Guedira1,2, Harshit Bhasin1,2, Amelia W. Hall1,4, Sikander Hayat5, Simon Baumgart5, Kenneth C. Bedi Jr.6, Kenneth B. Margulies6, Carla A. Klattenhoff5  and Patrick T. Ellinor1-3

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

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.