Dynamic Regulation of SARS-CoV-2 Binding and Cell Entry Mechanisms in Remodeled Human Ventricular Myocardium

Abstract

Objectives: In intact Nonfailing (NF) and failing/remodeled left ventricles (LVs) in patients with nonischemic dilated cardiomyopathies (F/NDC), measure gene expression of elements required for SARS-CoV-2 cell binding and entry, to determine: 1) whether the CoV-2 binding cell membrane receptor ACE2 is up-regulated; 2) if host cell proteases required for CoV-2 cell entry are expressed and/or up-regulated; and 3) whether ACE2 interacting integrins that may play a role in viral internalization are present and upregulated.Background: Cardiac involvement in COVID-19 infection appears to worsen outcomes, but to date there is no histopathologic evidence of cardiac myocyte CoV-2 involvement and no information on whether myocardial cells contain the biologic machinery for CoV-2 binding and cell entry.Methods: We measured serial analysis of gene expression in 46 F/NDC patients, using serial endomyocardial biopsies for RNA extraction and mRNA measurements by microarray and RNA-sequencing at baseline and after institution of beta-blocker therapy to effect reverse remodeling. Baseline measurements were compared to 4 NF controls.Results: ACE2 mRNA was upregulated vs. controls by nearly two-fold at baseline and then downregulated with reverse remodeling, five proteases previously shown to participate in SARS-Co-V or CoV-2 cell membrane fusion were expressed but not regulated with remodeling, and multiple integrins known to participate in viral endocytosis were expressed, with one (ITGA5) that binds to ACE2 and contains a CoV-2 binding motif upregulated in remodeling.Conclusions: Failing, remodeled human ventricular myocardium contains the biologic elements necessary for CoV-2 cell binding and entry, some of which are enhanced in remodeling.Funding: This work was supported by NHLBI grants 2R01 HL48913 (awarded to MRB), 1R01 HL71118 (awarded to MRB and BDL), K23 HL068875 (awarded to BDL), K08 HL125725 (awarded to DPK), AHA grant 16SFRN31420008 (awarded to PMB and MRB), and an AHA COVID-19 Rapid Response grant awarded to MRB.Conflict of Interest: No author has any conflict of interest with any aspect of the data or its interpretation.Ethical Approval: All patients signed written consent for this multi-center study conducted at the University of Colorado Anschutz Medical Campus and the University of Utah Medical Center. The study included a Data and Safety Monitoring Board and was approved by the Institutional Review Boards at both sites.