As Covid-19 cases mount, some have raised concern about the use of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) because SARS-CoV-2 (the virus that causes Covid-19) uses the ACE2 receptor to gain entry to targeted cells, and this receptor is “predominantly expressed by epithelial cells of the lung, intestine, kidney, heart, and blood vessels.”
The question then became, could treatment with ACEIs or ARBs increase the availability of ACE2 and thus the increase the risk of Covid-19? Media coverage of this issue has raised the possibility that patients may discontinue use of their medications, which would then increase the risk of cardiovascular events, including worsening heart failure or stroke.
JAMA Cardiology addressed these concerns in a pair of viewpoint articles — and both make the case that persons taking ACEIs and/or ARBs should continue taking their meds as prescribed, while also supporting the hypothesis that ACEI/ARBs may prove to be beneficial in Covid-19.
In their paper, Chirag Bavishi, MD, MPH of Brown University, Thomas M. Maddox, MD, MSc of Washington University School of Medicine in St. Louis, and Franz H. Messerli, MD of the University of Bern, Bern, Switzerland, Jagiellonian University, Krakow, Poland, and Mount Sinai Health Medical Center/Icahn School of Medicine in New York, noted that “hypertension, diabetes, and cardiovascular diseases were the most frequent comorbidities in affected patients, and case fatality rates tended to be high in these individuals.”
Moreover, patients with those comorbidities are likely to be treated with ACEI and ARBs.
“Both ACE and ACE2 belong to the ACE family of dipeptidyl carboxydipeptidases and exert distinct physiological functions. ACE cleaves angiotensin I to angiotensin II, which in turn binds and activates angiotensin II receptor type 1. This activation leads to vasoconstrictive, proinflammatory, and pro-oxidative effects,” they wrote. “In contrast, ACE2 also degrades angiotensin II to angiotensin 1-7 and angiotensin I to angiotensin 1-9. When angiotensin 1-9 binds to the Mas receptor, it leads to anti-inflammatory, antioxidative, and vasodilatory effects [emphasis added].”
Additionally, there are two forms of ACE2: “a structural transmembrane protein with extracellular domain that serves as a receptor for spike protein of SARS-CoV-2 and a soluble form that represents the circulating ACE2.”
Bavishi et al make the case that understanding “the relationship between SARS-CoV-2 and membranous and soluble ACE2” is key to understanding the role, if any, of ACEIs and ARBs in Covid-19.
“Animal (mice) studies have shown that expression of ACE2 is substantially increased in patients treated with ACEIs/ARBs. Similar to these observations, higher urinary ACE2 levels were seen in patients with hypertension treated with the ARB olmesartan. In another study, circulating ACE2 levels were increased in patients with diabetes treated with ACEIs.”
Those studies, they wrote, led some to hypothesize that ACEI or ARB use could “facilitate infection with Covid-19 “
But another study reported that serum angiotensin II levels were elevated in patients with Covid-19 pneumonia and those levels were “linearly associated with viral load and lung injury. Based on this, it can be postulated that SARSCoV-2 binding to ACE2 may attenuate residual ACE2 activity, skewing the ACE/ACE2 balance to a state of heightened angiotensin II activity leading to pulmonary vasoconstriction and inflammatory and oxidative organ damage, which increases the risk for acute lung injury (ALI). Conceivably, renin angiotensin system modulation, either by ACEIs/ARBs or recombinant ACE2, leading to increased expression of ACE2 may help mitigate some of these deleterious effects of angiotensin II [emphasis added].”
What about soluble ACE2? Bavishi et al noted that some have suggested it “may act as a competitive interceptor of SARSCoV-2 and slow virus entry into the cells and protect from lung injury.”
They cited a mixed bag of meta-analyses and small studies that suggested a benefit for ACEI/ARB therapy in patients with pneumonia or ARDS but no statistically significant evidence to back-up what looks like a benefit.
They noted that there are reports of hyperinflammation and cytokine storm syndrome leading to ARDS in some Covid-19 patients, but the driver of “such intense hyperinflammation is not yet known; however, through up-regulation of ACE2, ACEIs/ARBs can exert anti-inflammatory and antioxidative effects, which may be beneficial in preventing ALI and ARDS.”
In the second opinion piece, Majd AlGhatrif, MD, MA, of the National Institute on Aging (NIA) and Johns Hopkins School of Medicine in Baltimore, Oscar Cingolani, MD, also of Johns Hopkins, and Edward G. Lakatta, MD, of the Laboratory of Cardiovascular Science at NIA, point out that age must also be considered when trying to unravel the ACE2 role.
For example, in animal studies, age is associated with a decrease in ACE2 expression in the lungs.
“The up-regulation of ACE2 in individuals with diabetes and hypertension treated with ACEIs/ARBs is, in a way, restorative of physiological function. Hence, these observations raise an apparent paradox: given ACE2 itself is the gateway of SARS CoV-2 entry into cells, how can the reduction in ACE2 levels in older persons and those with CVD predispose for greater Covid-19 severity?
“This apparent paradox becomes clear if we distinguish the role of ACE2 as a gateway for SARS-CoV-2 facilitating the infection from its pivotal anti-inflammatory function in RAS signaling that is compromised in individuals with Covid-19, contributing to its severity,” they wrote.
This may, they wrote, explain why in South Korea, where the most extensive testing has taken place, most Covid-19 cases are among younger people with greater ACE2 expression. “However, when it comes to Covid-19 severity, reduction in ACE2 levels with aging and CVD and its associated up-regulation of angiotensin II proinflammatory pathway likely predispose older individuals with cardiovascular comorbidities to severe forms of Covid, as has been observed in Italy.”
AlGhatrif et al concluded that older persons, especially those with diabetes and/or hypertension, would boost their ACE2 levels with ACEI/ARB treatment, which they said would be “corrective.”
Authors of both viewpoints urged individuals to continue to take ACEI/ARBS as prescribed, and they await results from the “multicenter, double-blind, placebo controlled phase II randomized clinical trial of starting losartan in patients with COVID-19 in outpatient settings (ClinicalTrials.gov identifier: NCT04311177) and in in-patient settings (ClinicalTrials.gov identifier: NCT04312009)” which is currently being planned.
Be aware that there are scant data to support the suggestion that ACEI/ARB treatment increases risk of Covid-19 infection.
Note that SARS-CoV-2 enters target cells by the ACE2 receptor and the expression of ACE2 decreases with age.
Peggy Peck, Editor-in-Chief, BreakingMED™
Maddox has received grants from the National Center for Advancing Translational Sciences, consulting fees from Creative Educational Concepts and Atheneum Partners, and honoraria and personal fees from the University of Utah, NewYork-Presbyterian, Westchester Medical Center, Sentara Heart Hospital, Henry Ford Health System, and University of California, San Diego; is the Executive Director of the Healthcare Innovation Lab at BJC HealthCare/Washington University School of Medicine in St Louis; advises Myia Labs through his institution, which receives equity compensation; and is the director of JF Maddox Foundation.
Messerli has received personal fees from Menarini, Medtronic, and Pfizer.
AlGhatrif, Cingolani, and Lakatta had no disclosures.
Cat ID: 3
Topic ID: 74,3,282,494,931,730,933,3,6,190,926,192,255,927,925