Some heart medications may facilitate SARS-CoV-2 infection through increasing ACE2 receptor levels

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has continued to ravage much of the world since it first emerged in December 2019.

An interesting poster, just presented at the annual meeting of the American Society for Pharmacology and Experimental Therapeutics 2021, reports an association between the use of certain heart medications and the risk of COVID-19.

The virus engages host cells via an interaction between its spike glycoprotein and the angiotensin converting enzyme 2 (ACE2) receptor, which also mediates viral entry via fusion with the host cell membrane. At present, the ACE2 receptor is distributed widely on human lung alveolar cells, and on enterocytes in the small bowel, besides arterial and venous endothelium.

Many scientists have explored the possibility that the use of medications commonly prescribed in hypertensive patients, such as ACE inhibitors (ACEi), and angiotensin receptor blockers (ARBs), would change the distribution of these receptors, and that this could result in an altered risk of COVID-19 or an aggravated clinical profile.

The current study led by Hans Ackerman, MD, DPhil, at the National Institute of Allergy and Infectious Diseases, aimed to assess the use of these two drug categories with respect to their effects on the receptor distribution in various tissues, in a mouse study.

The study used male and female mice, exposing them to the ACEi lisinopril, the ARB losartan, singly and in combination, as well as to controls, at 8 weeks of age. They were exposed for 21 days, and then tested for ACE2 levels in different organs, including the kidney, lung, liver and small intestine.

The lungs and the small intestine are the chief sites of viral entry, but the brain and kidneys were also examined because of the high frequency of neurological and renal complications in these organs in COVID-19 patients.

What were the results?

The findings showed that control mice and female mice had similar organ-specific ACE2 levels. The expression profile of ACE2 was ten times higher in the small intestine compared to the kidney, while in the brain and the lung, it was a hundred times less than in the small intestine.

In the ACEi treatment group, the levels of ACE2 in the brain, kidney, small intestine and lung were raised after 21 days, compared to controls. The ARB-treated mice showed an increase in ACE2 only in the small intestine.

At follow-up, after 21 days from the cessation of treatment, the ACE2 levels had returned to normal in all treatment groups, suggesting that if treatment with either ACEi or ARB is discontinued, the effect wanes to baseline.

What are the implications?

Our findings that ACE inhibitor treatment increases tissue expression of ACE2 are in agreement with a previous study in rats that showed ACE2 increased in heart tissue, and a separate study in rats that showed ACE2 increased in lung tissue, following treatment with ACE inhibitor.”

The findings indicate a differential expression of ACE2, the viral receptor, in the various mouse tissues.

These results require to be validated in other animals and in clinical studies in humans. Currently, preclinical studies are seeking to measure the expression of the ACE2 protein and the gene at earlier treatment points and after cessation of the drugs.

These results will provide valuable insight into the risk or potential benefit of starting or stopping ACEi, ARB, or combination therapy during the COVID-19 pandemic.”

Evidence for any adverse or beneficial clinical impact of either ACEi or ARB, together or separately, when used in COVID-19 patients either as part of an ongoing protocol or as a newly initiated treatment, is lacking. Thus, patients should consult with their doctors before stopping any medication they are already taking for hypertension or heart disease.  

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.