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

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. [Display omitted] •Cellular expression and composition are altered in ischemic cardiomyopathy•LAMININ signaling from endothelial cells to other cell types increases in disease•Cell-type transcriptional profiles converge across multiple cardiomyopathy subtypes•Potential druggable targets identified for end-stage heart failure Simonson et al. compare non-failing and ischemic cardiomyopathy human left ventricles using snRNA-seq and identify an increase in lymphatic and angiogenic endothelial cells in disease. Transcriptionally, ischemic cardiomyopathy is similar to other cardiomyopathies. Gene targets from this shared expression profile could be explored for therapeutic benefit in end-stage heart failure.