ACE Inhibitors & ARBs: Wading Into the Unknown of COVID-19


A study’s proposed findings of increased coronavirus risk shows how presenting half of a fact can influence our care during a pandemic.

Simon Murray

What is the role of ACE inhibition or angiotensin receptor blockers (ARBs) within regard to the novel coronavirus (COVID-19)?

There has been some dissent lately about the role angiotensin-converting enzyme plays in the COVID-19 infections. The chemistry can be quite confusing, making it easy to see why it has caused controversy.

A very elegant system exists in humans to regulate blood pressure when there are sudden drops in renal blood flow or reduced sodium excretion, which could lead to hypotension. The system is called the renin-angiotensin system (RAS), which keeps us from fainting when we stand up quickly or when we are dehydrated.

Angiotensinogen is a protein formed in the liver and activated when renin, an enzyme secreted by the kidney in response to a drop in renal blood flow, cleaves it. The resulting protein is called Angiotensin 1, which has no known function except as an intermediary in the process of maintaining blood pressure. Angiotensin 1 is converted by angiotensin-converting enzyme-1 or ACE1 in the lung into angiotensin II.

Angiotensin II can act on the adrenal to produce the hormone aldosterone, which increases sodium retention and promotes potassium excretion. Angiotensin II will bind a specific receptor in the heart, lung, and blood vessels called the AT1 receptor. There are 3 other receptors—AT2, AT3, AT4—but their roles remain unknown.

Once bound to AT1, angiotensin II causes vasoconstriction, fluid and sodium retention, stimulation of aldosterone, and cardiac stimulation. Free, unbound angiotensin II has direct proinflammatory properties in lung tissue.

There is a second angiotensin-converting enzyme called ACE2 that had remained rather obscure in literature until 2002 when it turned out to be the point of entry for SARS virus to enter lung cells.

The 2 angiotensin-converting enzymes, ACE1 and ACE2, are analogs of each other and structurally very similar. ACE2 protein exists as a soluble form but mainly resides on the epithelial surface of the lung, intestine, and heart. Not much was known about ACE2 until the SARS epidemic, but much has been learned since.

ACE2 plays a counterregulatory role in the classical RAS and causes vasodilation, reduction in sodium, and reduced levels of angiotensin II. It does so by reducing angiotensin II levels and converting angiotensin II into angiotensin (1,7), which are vasodilators. ACE2 levels are generally 200 times higher than ACE1 levels.

It also has a negative effect on aldosterone. The 2 proteins ACE1 and ACE2 each have very different actions on the RAS.

Chronic overactivity of the RAS is felt to be one cause of hypertension. It became logical to look for drugs to interfere with this system. In the late 70’s and 1980’s a class of drugs were developed called angiotensin-converting enzyme inhibitors after the discovery that cobra snakes have a large amount of angiotensin in their venom. The way that cobra snakes kill their prey is by causing shock from hypotension.

ACE inhibitors block the conversion of angiotensin 1 to angiotensin II by inhibiting ACE1. The inhibitors were not felt to have any role in blocking ACE2. But a few years later, the second class of drugs was developed, which blocked the action of angiotensin II further upstream at by preventing angiotensin II from binding to specific receptor sites on the blood vessel and heart.

These are ARBS, which have been shown to reduce the symptoms of congestive heart failure, lower blood pressure and protect the kidney from high blood pressure. They are often the first-line drugs used to treat these conditions.

And I said before: the role of ACE2 remained obscure until 2002, prior to the discovery that it binds SARS virus avidly and served as the point of entry of the virus into the cells that lined the surface of the lung.

Why is this important? We know that SARS-COV-2 is bound to ACE2 and serves as a portal of entry of the SARS-COV2 virus into cells—just as it was for the SARS and probably the MERS viruses. Theoretically, anything with increased ACE2 levels could make patients more susceptible to infection with coronavirus, and make their cases more severe.

A letter to the editor in The Lancet described the observation that Chinese patients who had high blood pressure or diabetes and who were taking ACE inhibitors and ARBS had worse outcomes, with more severe infections and more deaths.

The article implied that ARBS and ACE inhibitors elevated ACE2 levels and that increased ACE2 facilitated more viral penetration into lung tissue. The paper concluded that taking these medicines could increase the number and severity of infections. The authors suggested that people should stop taking these medications. On face value, it seemed like a logical conclusion.

For several days after publication, there was a firestorm of confusion about whether or not to take ACE inhibitors or ARBs. The European Society of Cardiology and several leading American cardiology societies all refuted the findings in The Lancet. They suggested that patients should continue their medications and that there was no proof that the COVID-19 infection was adversely affected by inhibition of the RAS. There is evidence that these medicines might make infections better.

It is complicated, but it has already been demonstrated that viral pneumonia improved faster when the patients were taking ACE inhibitors.

Did The Lancet article consider that the patients who did worse either had diabetes, hypertension, or obesity? That triad is part of the metabolic syndrome and would make any sick person worse, because the metabolic syndrome can produce the “cytokine storm” that generates damage to lung tissue.

I was drawn into this debate by several patients who had the quickly popularizing article. A few days later, when institutions refuted the findings, I saw more controversy stir.

This episode is an example of the ongoing issue we have during this pandemic—in which public announcements or declarations on the virus are later retracted. People in authority are making statements and decisions without certain and evidenced knowledge. The most present fact in this debate is that story is rapidly developing.

Of course, as we see the virus rapidly spread and take more lives, it is understandable to see people react quickly, rather than rationally.

Simon Murray, MD, is an internist based in Princeton, NJ. The piece reflects his views, not necessarily those of the publication.Healthcare professionals and researchers interested in responding to this piece or contributing to MD Magazine® can reach the editorial staff here.

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