Author + information
- Received May 5, 2020
- Revision received June 17, 2020
- Accepted June 17, 2020
- Published online September 28, 2020.
- Michael R. Bristow, MD, PhDa,b,c,∗ (, )
- Lawrence S. Zisman, MDd,
- Natasha L. Altman, MDa,c,
- Edward M. Gilbert, MDe,
- Brian D. Lowes, MD, PhDf,
- Wayne A. Minobe, BSa,
- Dobromir Slavov, PhDa,
- Jessica A. Schwisow, BSa,
- Erin M. Rodriguez, BAa,
- Ian A. Carroll, PhDa,b,
- Thomas A. Keuer, MSb,
- Peter M. Buttrick, MDa,c and
- David P. Kao, MDa,c
- aDivision of Cardiology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, Colorado
- bARCA Biopharma, Westminster, Colorado
- cUniversity of Colorado Cardiovascular Institute Pharmacogenomics, Aurora, Colorado
- dGossamer Bio, San Diego, California
- eDivision of Cardiology, University of Utah Medical Center, Salt Lake City, Utah
- fDivision of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska
- ↵∗Address for correspondence:
Dr. Michael R. Bristow, Division of Cardiology, University of Colorado, Denver/Anschutz Medical Campus, B-139 Research 2, 12700 East 19th Avenue, Aurora, Colorado 80045.
• The CoV-2 cellular receptor ACE2 and 5 proteases implicated in fusion of virus and cell membranes that are vital to cell entry were expressed at the mRNA level in RNA extracted from septal EmBx of patients with F/NDC and NF control patients.
• ACE2 was up-regulated by 1.97 fold in 46 patients with F/NDC compared with NF control patients, but proteases showed similar degrees of expression.
• On LV reverse remodeling effected by beta-blocking agents, ACE2 expression, in the presence of unchanged doses of ACE inhibitors or ARBs, down-regulated into the normal range.
• ITGA5, which encodes an integrin that binds to ACE2 and to a motif in the CoV-2 spike protein binding domain, was expressed in both NF control subjects and subjects with F/NDC, was up-regulated in the latter at baseline, was decreased in expression on reverse remodeling similar to ACE2, and is a candidate for facilitating CoV-2 binding and cell entry in LV myocardium.
Using serial analysis of myocardial gene expression employing endomyocardial biopsy starting material in a dilated cardiomyopathy cohort, we show that mRNA expression of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) cardiac myocyte receptor ACE2 is up-regulated with remodeling and with reverse remodeling down-regulates into the normal range. The proteases responsible for virus-cell membrane fusion were expressed but not regulated with remodeling. In addition, a new candidate for SARS-CoV-2 cell binding and entry was identified, the integrin encoded by ITGA5. Up-regulation in ACE2 in remodeled left ventricles may explain worse outcomes in patients with coronavirus disease 2019 who have underlying myocardial disorders, and counteracting ACE2 up-regulation is a possible therapeutic approach to minimizing cardiac damage.
This work was supported by National Heart, Lung, and Blood Institute grants 2R01 HL48013 (awarded to Dr. Bristow), 1R01 HL71118 (awarded to Drs. Bristow and Lowes), K23 HL068875 (awarded to Dr. Lowes), and K08 HL125725 (awarded to Dr. Kao); American Heart Association grant 16SFRN31420008 (awarded to Drs. Buttrick and Bristow); and an American Heart Association COVID-19 Rapid Response grant awarded to Dr. Bristow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received May 5, 2020.
- Revision received June 17, 2020.
- Accepted June 17, 2020.
- 2020 The Authors