Author + information
- Received May 5, 2020
- Revision received June 17, 2020
- Accepted June 17, 2020
- Published online June 29, 2020.
- Michael R. Bristow, MD, PhD;1,2,3,∗ (, )
- Lawrence S. Zisman, MD;4,
- Natasha L. Altman, MD;1,3,
- Edward M. Gilbert, MD;5,
- Brian D. Lowes, MD, PhD;6,
- Wayne A. Minobe, BS;1,
- Dobromir Slavov, PhD;1,
- Jessica A. Schwisow, BS;1,
- Erin M. Rodriguez, BA;1,
- Ian A. Carroll, PhD;1,2,
- Thomas A. Keuer, MS;2,
- Peter M. Buttrick, MD;1,3 and
- David P. Kao, MD.1,3
- 1Division of Cardiology, University of Colorado, Denver/Anschutz Medical Campus, Aurora, Colorado, United States of America
- 2ARCA biopharma,, Westminster, Colorado, United States of America
- 3University of Colorado Cardiovascular Institute Pharmacogenomics, Boulder and Aurora, Colorado, United States of America
- 4Gossamer Bio, San Diego, CA, United States of America
- 5Division of Cardiology, University of Utah Medical Center, Salt Lake City, Utah, United States of America
- 6Division of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America
- ↵∗Corresponding author: Michael R. Bristow MD, PhD; B-139 Research 2, 12700 E. 19th Ave, Aurora, CO 80045;
1. The SARS-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 endomyocardial biopsies of F/NDC and nonfailing (NF) control patients.
2. ACE 2 was upregulated by 1.97 fold in 46 F/NDC patients compared to NF, but proteases showed similar degrees of expression.
3. On LV reverse remodeling effected by beta-blocking agents, ACE2 expression, in the presence of unchanged doses of ACE inhibitors or ARBs, downregulated into the normal range.
4. ITGA5, an integrin that binds to ACE2 and to a motif in the CoV-2 spike protein binding domain, was expressed in both NF and F/NDC, upregulated in the latter at baseline and 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 the SARS-CoV-2 cardiac myocyte receptor ACE2 is upregulated 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 CoV-2 cell binding and entry was identified, the integrin ITGA5. The upregulation in ACE2 in remodeled LVs may explain worse outcomes in COVID-19 patients with underlying myocardial disorders, and counteracting ACE2 upregulation is a possible therapeutic approach to minimizing cardiac damage.
The authors thank Rachel Rosenberg, MS, MBA and Laura Hofstatter for manuscript proofing and handling.
No author has any conflict of interest with any aspect of the data or its interpretation.
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.
- Received May 5, 2020.
- Revision received June 17, 2020.
- Accepted June 17, 2020.
- 2020 The Authors