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The Verdict of Recent Academic Paper

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The Verdict of Recent Academic Paper

What biochemistry facts and clinical outcomes really say.

[Modified and Redesigned] Image by Clker-Free-Vector-Images from Pixabay

PPrior studies and meta-analyses have shown that medical comorbidities — like diabetes, hypertension, cardiac and pulmonary diseases — increase the risk of disease progression and mortality from COVID-19.

Antihypertensive and COVID-19

A recent academic review — written by Awadhesh Kumar Singh, MD, a senior consultant endocrinologist at G.D. Hospital & Diabetes Institute in India, and his colleagues — further probed the relationship between hypertension and COVID-19.

Specifically, they wanted to resolve the controversies about the use of renin-angiotensin system blockers (RASB; an anti-hypertensive) making COVID-19 symptoms worse. There’re two types of RASB — angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs).

“There has been a growing concern that this association with hypertension and/or cardiovascular diseases may be confounded by the treatment with certain antihypertensive medications such as RASB,” Dr. Singh remarked.

Source: Open-access publication from ScienceDirect.

There’s evidence that the use of RASB antihypertensive raises the levels of ACE-2 receptors, especially in the heart and kidneys. “This has raised a theoretical concern that by increasing ACE-2 expression, ACEIs and ARBs could facilitate the entry of virus into the host cell and increase the chances of infection or its severity,” Dr. Singh said.

There’s even a paper in the Lancet Respiratory Medicine that suggested replacing RASD with calcium channel blocker when treating hypertensive patients with COVID-19. But several other researchers have questioned this idea (Patel et al., 2020; Gurwitz, 2020; Tiganelli et al., 2020; Brown, 2020; Lo et al., 2020), Dr. Singh highlighted.

What Clinical Outcomes Say

The only clinical evidence supporting the potential harm of RASB antihypertensive is the data of Guo et al. (2020). “The mortality rates of patients with and without use of ACEIs/ARBs was 36.8% (7 of 19) and 25.6% (43 of 168) [respectively],” the authors reported.

But this doesn’t prove causation, Dr. Singh asserts. It could be that people with severe COVID-19 are more likely to be taking RASB, compared to the general population, due to their hypertensive or cardiovascular condition. In other words, maybe it’s hypertension, rather than antihypertensive medications, that increase mortality from COVID-19.

Another clinical outcome involving 112 COVID-19 patients found “there was no significant difference in the proportion of ACEI/ARB [antihypertensive] medication between the critical group and the general group or between non-survivors and survivors.” As per the study authors’ conclusion,

“ACEI/ARB use does not affect the morbidity and mortality of COVID-19 combined with cardiovascular diseases.”

What Biochemistry Says

Reason 1: ACE-2 receptor is not the sole determinant of SARS-CoV-2 — the causative agent of COVID-19 — entry into cells. Before binding to the receptor, the spike protein of SARS-CoV-2 needs to be activated by a protein called TMPRSS2. This means that it’s only bad news if ACE-2 receptors and TMPRSS2 are BOTH upregulated. As Dr. Singh explains,

“Increased ACE-2 expression may not result in more viral entry into the cell because of the limited availability of the serine protease TMPRSS2.”

Reason 2: If a drug increases ACE-2 levels, then there’s no reason that it only does so in specific cells. In other words, the effects of increased ACE-2 levels should be more generalized. For this reason, Dr. Singh says,

“Increased ACE-2 expression on the cell membrane may also lead to increased soluble ACE-2 in blood, which may actually bind to most of SARS-CoV-2 and prevent its interaction with the membrane-bound receptor.

Reason 3: RASB not only increases ACE-2 but its product, angiotensin II as well. This means that the increased angiotensin II could bind to ACE-2 receptors — occupying more ACE-2 receptors and, thus, limiting the availability for SARS-CoV-2. As Dr. Singh puts it,

“[RASB] increase angiotensin II, which is a substrate for ACE-2. The interaction of ACE-2 with angiotensin II could induce a conformational change in the receptor-binding domain of ACE-2, limiting its ability to bind with SARS-CoV-2.”

Reason 4: Children and young adults have higher levels of ACE2 receptors in their lungs compared to older individuals. It’s somewhat farfetched but the idea is that RASB could also support the lung function this way. Quoting the hypothesis of Dr. Singh et al.,

“ACE-2 receptors by the use of RASB over time in older people may emulate ACE expression in young people… that might provide resilience against target-mediated destruction and development of pulmonary failure in patients with COVID-19.”

The Verdict

While it’s true that RASB antihypertensive increases the levels/expression of ACE-2 receptors, what’s happening in the cellular environment is much more complex. Many different biochemical reactions can happen in a single cell, and one reaction can influence the other. How complex, you may ask?

Source: Open-access publication from ScienceDirect.

Furthermore, discontinuing RASB might pose harms that outweigh the minor (or non-existent) risk of increased ACE-2 receptors for SARS-CoV-2 entry. “Indiscriminate discontinuation of RASB in patients with heart failure may also lead to readmission to hospital and increase in mortality,” Dr. Singh remarks.

Will RASB antihypertensive worsens COVID-19 symptoms? Clinical outcomes and biochemical facts both say no.

Finally, to end with the excerpt from the concluding paragraph of Dr. Singh,

“In view of lack of robust evidence for either benefit or harm, and with bulk of the experimental evidence in favour of benefit, it is reasonable for patients to continue using ACE inhibitors and ARB, as recommended by the European Society of Cardiology, Hypertension Canada, The Canadian Cardiovascular Society, UK Renal Association, the International Society of Hypertension, and European Society of Hypertension and American Heart Association.”

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