key: cord-0744459-86ex3gxt
authors: Gersh, Felice L.
title: Angiotensin-Converting Enzyme 2 and the Resolution of Inflammation: In Support of Continuation of Prescribed Angiotensin-Converting Enzyme Inhibitors and Angiotensin-Receptor Blockers
date: 2020-05-21
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.05.001
sha: 93230653241118f412fbf58f3bcb5b6e980c1935
doc_id: 744459
cord_uid: 86ex3gxt

nan

To the Editor: The COVID-19 pandemic has resulted in a debate over potential risks vs benefits of certain pharmaceuticals -"angiotensin-converting enzyme inhibitors" (ACEIs) and "angiotensin-receptor blockers" (ARBs). A recent letter to the editor, published online on March 23 in the Journal of Travel Medicine 1 outlined a hypothesis stating that use of ACEIs and ARBs may increase the risk of severe disease in COVID-19 patients. Data showed that intravenous infusion of ACEIs and ARBs to experimental animals increased the numbers of angiotensinconverting enzyme 2 (ACE2) receptors in the cardiopulmonary circulation. It is acknowledged that ACE2 receptors are widely dispersed, including lung alveolar epithelial cells, gastrointestinal tract enterocytes, the vascular system, the nasopharynx, kidney, and brain. 2 (2) Based on that preclinical data, recognizing that ACE2 receptors are binding sites for COVID-19 entry into the body, an increased number of ACE2 receptors was hypothesized to heighten the risk for severe pulmonary disease, by increasing the number of binding sites available to the virus. Though that conclusion is persuasive at first glance, the data and recommendations presented in the accompanying article by Sanchis-Gomar et al, 3 

Vaduganathan et al, 4 are more compelling. Further analysis of the ACE2 mechanisms supports the hypothesis that ACEIs and ARBs are more likely to benefit than harm patients infected with COVID-19. COVID-19 binds viral S protein to ACE2, reducing receptor expression, enabling viral and cell membrane fusion and viralreplication, with the potential for inflammatory tissue damage, and the severe inflammatory response, a cytokine storm.

At infection onset, an initial inflammatory response is triggered with the production of Angiotensin II (Ang II), via Renin-Angiotensin-Aldosterone System (RAAS) activation (nicely reviewed in the article). This inflammatory response is normally moderated by the activation of ACE2 receptors. ACE2 is a key player in minimizing and reversing the inflammatory response, by converting Angiotensin II to angiotensin 1-7 (Ang 1-7), which after binding to the Mas receptor (MasR), results in a wide array of anti-inflammatory actions. 5 The inflammatory state is a critical organismal response to an invader, but ultimately healing requires inflammation resolution, a process blocked by COVID-19's binding to and disabling ACE2 receptors, leading to unrelenting inflammation.

The proposal that increased numbers of ACE2 receptors, due to ACEIs and ARBs, would signal an increase in viral binding and severe disease is unsupported by clinical data. The alternative view, that the presence of more functional ACE2 receptors could facilitate inflammation resolution by increasing production of anti-inflammatory Ang 1-7 is reasonable. More Ang 1-7 would promote and support healthy vascular, pulmonary, myocardial, and renal function and suppress inflammatory cytokine production. If ACEIs and ARBs increase functional ACE2 receptors, the activation of anti-inflammatory pathways may save lives.

Pending more research on this topic, and lacking evidence of harm to patients infected by COVID-19 while taking ACEIs and ARBs, the discontinuation of these medications is unjustified and could result in more negative outcomes. 

Turner To the Editor: The COVID-19 pandemic has resulted in a debate over potential risks vs benefits of certain pharmaceuticalsangiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs). A recent letter to the editor, published online on March 23 in the Journal of Travel Medicine 1 outlined a hypothesis stating that use of ACEIs and ARBs may increase the risk of severe disease in COVID-19 patients. Data showed that intravenous infusion of ACEIs and ARBs to experimental animals increased the numbers of angiotensin-converting enzyme 2 (ACE2) receptors in the cardiopulmonary circulation. It is acknowledged that ACE2 receptors are widely dispersed, including lung alveolar epithelial cells, gastrointestinal tract enterocytes, the vascular system, the nasopharynx, kidney, and brain. 2 Based on that preclinical data, recognizing that ACE2 receptors are binding sites for COVID-19 entry into the body, an increased number of ACE2 receptors was hypothesized to heighten the risk for severe pulmonary disease, by increasing the number of binding sites available to the virus. Though that conclusion is persuasive at first glance, the data and recommendations presented in the accompanying article by Sanchis-Gomar et al, 3 and the recent NEJM article by Vaduganathan et al, 4 are more compelling. Further analysis of the ACE2 mechanisms supports the hypothesis that ACEIs and ARBs are more likely to benefit than harm patients infected with COVID-19. COVID-19 binds viral S protein to ACE2, reducing receptor expression, enabling viral and cell membrane fusion and viral replication, with the potential for inflammatory tissue damage, and the severe inflammatory response, a cytokine storm.

At the onset of infection, an initial inflammatory response is triggered with the production of Angiotensin II (Ang II), via Renin-Angiotensin-Aldosterone System (RAAS) activation (nicely reviewed in the article). This inflammatory response is normally moderated by the activation of ACE2 receptors. ACE2 is a key player in minimizing and reversing the inflammatory response, by converting Angiotensin II to angiotensin 1-7 (Ang 1-7), which after binding to the Mas receptor (MasR), results in a wide array of anti-inflammatory actions. 5 The inflammatory state is a critical organismal response to an invader, but ultimately healing requires inflammation resolution, a process blocked by COVID-19's binding to and disabling ACE2 receptors, leading to unrelenting inflammation.

The proposal that increased numbers of ACE2 receptors, due to ACEIs and ARBs, would signal an increase in viral binding and severe disease is unsupported by clinical data. The alternative view, that the presence of more functional ACE2 receptors could facilitate inflammation resolution by increasing production of anti-inflammatory Ang 1-7 is reasonable. More Ang 1-7 would promote and support healthy vascular, pulmonary, myocardial, and renal function and suppress inflammatory cytokine production. If ACEIs and ARBs increase functional ACE2 receptors, the activation of anti-inflammatory pathways may save lives.

Pending more research on this topic, and lacking evidence of harm to patients infected by COVID-19 while taking ACEIs and ARBs, the discontinuation of these medications is unjustified and could result in more negative outcomes. 

Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2):631-637.

Sanchis-Gomar F, Lavie CJ, Perez-Quilis C, Henry BM, Lippi G. Angiotensinconverting enzyme 2 and anti-hypertensives (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) in coronavirus disease 2019 (COVID-19) . Mayo Clin Proc. 2020;95(6):xx-xx.

Vaduganathan 

Turner To the Editor: We thank Dr. Gersh for her interest and comments on our manuscript, as well as for taking the time to express her concerns on this subject. We agree with Dr. Gersh that discontinuation of anti-hypertensives angiotensinconverting enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of hypertension (HTN) is unjustified at this moment due to the lack of evidence on negative effects of these drugs in patients with coronavirus disease 2019 (COVID-19). However, in recent weeks, several important articles have been published, shedding new light in reference to the potential interplay of ACEIs and ARBs with COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus which causes COVID-19, penetrates the cells primarily through ACE2, its natural receptor at cell surface. Whether ACEIs and ARB administration would increase ACE2 levels or expression remains mostly speculative, as does whether increased ACE2 expression is beneficial or detrimental in COVID-19. As noted by Dr. Gersh, Diaz argued that as ACE2 levels increase after intravenous infusion of ACEIs and ARBs in animal models, taking ACEIs or ARBs may aggravate the infection severity in COVID-19 patients. 1 However, not all studies conducted in animals clearly shown increased ACE2 levels in response to ACEI/ARB administration. 2 Importantly, investigations analyzing changes in plasma or tissue ACE2 levels in humans are limited. In fact, two studies in patients with atrial fibrillation or coronary heart disease found no differences in plasma ACE2 levels between those taking ACEIs or ARBs versus those not taking these medications. 3, 4 Nonetheless, plasma levels may not reflect tissue ACE2 expression, and vice versa, and this topic requires further investigation.

The role of ACE2 expression in COVID-19 morbidity and mortality is still unknown. As hypertension is a clear risk factor for COVID-19, 5 Dr. Gersh noted that many such patients are likely to be on ACEIs or ARBs, and, as such, these anti-HTN medications may be directly connected with infection severity. However, although a relatively high percentage of COVID-19 patients hospitalized have HTN, the percentage of HTN in adults is similar worldwide, increasing with age. In patients with COVID-19, the odds of disease severity with HTN was found in meta-regression to be associated with advancing age. 5 As Marin has also stated, an epidemiological association based simply on prevalence of HTN and ACEI/ARBs in COVID-19 is inappropriate. 6 Moreover, it has been previously reported that ACE2 expression is reduced in HTN animal models and, historically, HTN has not affect outcomes of other coronavirus infections. 7 Most concerning is the fact that Marin pointed out that many patients from South America, Central America and Spain have abruptly interrupted their treatments with ACEIs or ARBs over these hypothetical concerns, which might may be as equally dangerous to the patient as COVID-19 itself. 6 Thankfully, to address these concerns, new data are emerging. Mehra et al. 8 analyzed the factors associated with increased risk of in-hospital death in 8,910 COVID-19 patients included in an observational database of 169 worldwide hospitals. Among those factors, the authors found that ACEIs were independently associated with a significant 67% reduction in mortality in a subgroup with hypertension, whereas ARBs were associated with an insignificant 23% higher mortality. 8 Taking ACEIs or statins were associated with higher rates of survival after hospital discharge, while taking ARBs had no effect. Additionally, there was no increased risk of in-hospital death associated with either ACEIs (2.1% vs. 6.1%; odds ratio, 0.33; 95% CI, 0.20 to 0.54) or ARBs (6.8% vs. 5.7%; odds ratio, 1.23; 95% CI, 0.87 to 1.74). Likewise, Mancia et al. 9 carried out a case-control study involving 6,272 confirmed COVID-19 patients from the Lombardy region of Italy. They compared COVID-19 patients with 30,759 controls matched by age, sex, and municipality of residence. Neither ACEIs , nor ARBs, were associated with increased probability of being infected by SARS-CoV-2 in multivariate logistic-regression analysis. Moreover, no association was observed between these drugs and SARS-CoV-2 infection severity. Reynolds et al. 10 analyzed the data of 5,894 COVID-19 patients (tested positive) from the New York University (NYU) Langone Health electronic health record, 1,002 with severe disease (ICU admission, mechanical ventilation, or death). Through a Bayesian approach, no association between taking ACEIs or ARBs and positive test result or COVID-19 severity could be found.

In a retrospective, single-center case series of the 1178 COVID-19 patients with HTN hospitalized at the Central Hospital of Wuhan, China (January 15 to March 15, 2020), Li et al. 11 studied the association between ACEIs/ARB and severity of illness and mortality. There were no differences between the percentage of patients with HTN taking ACEIS/ARB with severe and non-severe infections (32.9% vs 30.7%; p=0.645), or between non-survivors and survivors (27.3%vs 33.0%; p=0.34). Unlike the Mehra et al. 8 data, which suggested more benefits with ACEIs, no differences were observed between patients taking ACEIs and those taking ARBs. These authors concluded that neither ACEIs nor ARBs may be associated with severity or mortality of COVID-19 patients. 8 In a retrospective, multicenter study including 1128 adult COVID-19 Chinese patients with HTN, 188 taking ACEIs/ARBs and 940 without these agents, Zhang et al. 12 reported that unadjusted mortality rate was lower in the ACEIs/ARBs group versus the non-ACEIs/ARBs group (3.7% vs. 9.8%; p=0.01). After adjusting for age, gender, comorbidities, and in-hospital medications, the risk for allcause mortality was still lower in the ACEIs/ARBs group versus the non-ACEIs/ARBs group (adjusted hazard ratio, 0.42; 95% CI, 0.19-0.92; p=0.03). Their results also demonstrated lower risk of COVID-19 mortality in patients who received ACEIs/ARBs versus those who did not (adjusted hazard ratio, 0.37; 95% CI, 0.15-0.89; P = 0.03) in a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model. Moreover, compared to other anti-HTN drugs, ACEIs/ARBs were associated with lower mortality (adjusted hazard ratio, 0.30; 95%CI, 0.12-0.70; P = 0.01) in COVID-19. Therefore, what can be reasonably concluded from the recently published large single and multi-center studies from multiple countries, is that there is no significant risk of disease severity or mortality associated with ACEI/ARB, with some even suggesting potential benefits in patient with COIVD-19.

The mechanism behind any potential benefit of ACEI and ARB in COVID-19 is still enigmatic. Differences in inflammatory and immune biomarkers has been reported in COVID-19 patients taking ACEI and ARBs. Meng et al. 13 found a reduced rate of severe COVID-19 disease and lower levels of interleukin-6, increased CD3 and CD8 T-cell in peripheral blood, and decreased peak viral loads compared to those using other anti-HTN medication. Moreover, Yang et al. reported that COVID-19 patients with HTN taking ACEI and ARBs had significantly lower C reactive protein and procalcitonin, as well as decreased rate of critical illness and death. 14 ARBs may also exert beneficial effects in patients with sepsis, pneumonia and influenza. Moreover, a combination of statin and ARBs appeared to substantially reduce mortality during the recent Ebola outbreak dramatically, 15 similar to the reduction in mortality noted by Mehra et al. 8 with ACEIs/statin therapy in COVID-19. It has been suggested that higher doses of ARBs may protect COVID-19 patients from acute lung injury (ALI) via two complementary mechanisms: (i) by blocking excessive angiotensin II binding promoting vasoconstriction, inflammation, and oxidative damage; ii) by up-regulating ACE2 and increasing angiotensin 1-7 production. 16 In fact, trials using Losartan to reduce ALI in COVID-19 are currently underway in the United States. Interestingly, ACEI were reported by Mehra et al. 8 to reduce mortality, while a similar effect could not be noted for ARBs. This warrants immediate further investigation. We hypothesize that ACEI may not only attenuate the increase in angiotensin II, but via reduced endothelial dysfunction and decreased expression of tissue plasminogen activator-1 and increase tissue plasminogen activator levels (tPA) due to decreased bradykinin breakdown, may mitigate the reported COVID-19 associated coagulopathy; such coagulopathy may drive ALI and multiple organ dysfunction. 17 As the COVID-19 pandemic continues, the cardiovascular health of patients must not be neglected at the expense of outbreak. ACEIs and ARBs improve outcomes and increase survival in multiple cardiovascular diseases. While further investigation in prospective studies is warranted, the preponderance of current data and evidence makes it highly unlikely that the use of ACEIs/ARBs may be associated with increased severity or mortality risk. In summary, the newly reported data supports current guidelines and health professional recommendations for continuation of ACEI/ARBs for treating HTN during the COVID-19 pandemic.

Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Angiotensin-converting enzyme 2 and anti-hypertensives (angiotensin receptor blockers and angiotensin converting enzyme inhibitors) in coronavirus disease 2019 (COVID-19)

Hypothesis: angiotensin-Med

Myocardial infarction increases ACE2 expression in rat and humans

Hypertension and its severity or mortality in Coronavirus Disease 2019 (COVID-19): a pooled analysis

Facts and reflections on COVID-19 and anti-hypertensives drugs

CORONAVIRUS: What are the implications for cardiology?

Cardiovascular disease, drug therapy, and mortality in Covid-19

Renin-angiotensinaldosterone system blockers and the risk of Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19

Effects Of ARBs And ACEIs On Virus Infection, Inflammatory Status And Clinical Outcomes In COVID-19 Patients With Hypertension: A Single Center Retrospective Study

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

Angiotensin-Converting Enzyme 2 and Anti-Hypertensives (Angiotensin Receptor Blockers and Angiotensin Converting Enzyme Inhibitors) in Coronavirus Disease 2019 (COVID-19)

Hyperinflammation and Derangement of Renin-Angiotensin-Aldosterone System in COVID-19: a novel hypothesis for clinically suspected hypercoagulopathy and microvascular immunothrombosis