New Focus on Renin-Angiotensin System Role
in COVID-19

May 13, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's  Coronavirus Resource Center.

Two new studies have been published that further focus attention on how the renin–angiotensin system — and specifically the ACE2 receptor — may be involved in COVID-19 infection.

Leading experts suggest that effects of the virus on the renin–angiotensin system may be the key to understanding why men and individuals with underlying cardiovascular diseases appear to have worse outcomes from COVID-19. 

One study, published in the European Heart Journal, found higher plasma levels of the ACE2 receptor/enzyme in men vs women in two large samples of patients with heart failure.

Noting that the SARS-CoV-2 virus that causes COVID-19 interacts with the ACE2 receptor, the authors suggest that their findings may explain why men have worse outcomes with the virus.

The study also shows that neither ACE inhibitors nor angiotensin-receptor blockers (ARBs) were associated with higher plasma ACE2 concentrations.

A second study, published as a letter to the New England Journal of Medicine, studied the relationship between ACE-inhibitor and ARB use and influenza A infection in a large United Kingdom patient database.

The authors note that influenza A has been shown to use the ACE2 receptor to mediate lung damage, similar to that seen in severe acute respiratory syndrome (SARS) with COVID-19.  

"Understanding the shared mechanism between SARS and influenza may help to address the question as to how ACE inhibitors and ARBs may modulate the manifestations of certain viral respiratory infections," they write.

Results showed that during a median 8.7 years of follow-up, individuals who had received a prescription for an ACE inhibitor had a lower risk of influenza than those who had not (adjusted hazard ratio, 0.66).

A second analysis found that the longer the duration of ACE-inhibitor use, the lower the risk of influenza infection. Similar results were found for ARBs.

"These associations regarding observed susceptibility to influenza may reflect mechanisms that are shared with coronaviruses, including SARS-CoV-2," the researchers conclude.

Is COVID-19 Activating the Renin–Angiotensin System?

In an editorial accompanying the European Heart Journal publication, Gavin Oudit, MD, University of Alberta, Edmonton, Canada, and Mark Pfeffer, MD, Brigham and Women's Hospital, Boston, Massachusetts, suggest that further work should measure plasma angiotensin peptides and plasma ACE2 levels and activity in COVID-19 patients to provide a direct evaluation of the state of the renin–angiotensin system, which could guide therapeutic interventions.

In comments to Medscape Medical News, Oudit, who has researched extensively on ACE2, put forward a hypothesis that the COVID-19 virus could be bringing about its harmful effects by causing an over-activation of the renin–angiotensin system.

He explained that higher plasma levels of ACE2 may actually reflect lower tissue levels. "Tissue ACE2 is beneficial. It is nature's own inhibitor of the renin–angiotensin system, breaking down harmful angiotensin II to the protective angiotensin 1-7," he said. 

"The enzyme ADAM-17 is the key to regulating tissue and plasma ACE2 levels. This enzyme, which is thought to be more active in men than women, cleaves tissue ACE2 to form plasma ACE2, and it is believed that the virus responsible for COVID-19 activates ADAM-17," he noted.  

Activation of ADAM-17 is detrimental on two levels, Oudit says. "It directly causes a super inflammatory response, and it also reduces cardioprotective ACE2 in tissue." 

Oudit believes ACE2 has been wrongly cast as the villain regarding COVID-19 infection. "Yes, the virus does bind to ACE2 to enter cells, but only a small amount of ACE2 is needed for this. Higher levels are needed to protect from cardiovascular disease."

"By activating ADAM-17 the virus causes shedding of ACE2 from tissue into plasma, and the reduction of ACE2 in tissue leads to over-activation of the renin–angiotensin system in tissues, which causes cardiovascular disease to get worse," Oudit explained.

He believes there has been a lot of misinformation surrounding COVID-19, which has included speculation about ACE inhibitors and ARBs. "The science that we know suggests that these drugs are more likely to be beneficial than harmful. Observational clinical studies reported so far support this view.

"As we believe the renin–angiotensin system is being over-activated by the virus, this could also explain why patients with underlying cardiovascular diseases are having worse outcomes and would suggest that taking an ACE inhibitor or ARB would actually be protective." 

On the influenza study, Oudit said: "The influenza virus may well also activate the renin–angiotensin system. That study suggests that ACE inhibitors and ARBs may be protective here as well."

Eur Heart J. Published online May 10, 2020.  Full text, Editorial

N Eng J Med. Published online May 8, 2020. Letter

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