What biochemistry facts and clinical outcomes really say.
Prior 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.
An 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.
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 the 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, such as 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 the 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 asserted. 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.
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.
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.
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.
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.
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 remarked.
Will RASB antihypertensive worsens COVID-19 symptoms? Clinical outcomes and biochemical facts both say no.
In a May 15 published paper in Pharmacological Research, a meta-analysis confirms the verdict. Chinese researchers at Zhejiang University synthesized data from 14 studies with a pooled sample size of >19000 COVID-19 patients.
They found that RASB antihypertensive — ACEI/ARB — is not associated with COVID-19 severity or mortality. In fact, its use “was associated with a [52%] lower risk of mortality compared those with non-ACEI/ARB antihypertensive drugs.” This means that patients taking RASB fares better against COVID-19 than those taking non-RASB antihypertensive. “Current evidence did not confirm previous concern regarding the harmful role of ACEI/ARB in COVID-19 patient,” the authors concluded.
This article was originally published in Microbial Instincts with minor modifications.