key: cord-0780816-fghtbph6 authors: Amano, Tetsuya title: Angiotensin‐Converting Enzyme 2 as a Versatile Player in the Management of Coronavirus Disease 2019 date: 2020-07-13 journal: J Diabetes Investig DOI: 10.1111/jdi.13346 sha: 5dc649651302cb73a05209147015c8ff40de9d66 doc_id: 780816 cord_uid: fghtbph6 In view of the global coronavirus disease 2019 (COVID‐19) pandemic, there are ongoing efforts aimed at predicting potential factors causing clinical exacerbation of COVID‐19 and at seeking effective therapies for COVID‐19.Recent studies have indicated that severe acute respiratory coronavirus 2 (SARS‐CoV‐2) uses angiotensin‐converting enzyme 2 (ACE2) as a receptor for cellular invasion and subsequent replication. In view of the global coronavirus disease 2019 (COVID-19) pandemic, there are ongoing efforts aimed at predicting potential factors causing clinical exacerbation of COVID-19 and at seeking effective therapies for COVID-19. Recent studies have indicated that severe acute respiratory coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular invasion and subsequent replication 1 . Furthermore, some reports suggest that the renin-angiotensin-aldosterone system (RAAS) inhibitors increase expression of ACE2 2 . These findings gave rise to the hypothesis that the use of RAAS inhibitors may increase might enhance the cellular invasion of SARS-CoV-2 and predispose patients to develop infection and increase the severity of COVID-19. In the first clinical case series, age, the presence of hypertension, diabetes and cardiovascular disease coronary heart disease, which are relevant to associated with the use of RAAS inhibitors, were identified as potential risk factors for severe conditions and mortality due to COVID-19 3 . However, as RAAS inhibitors are commonly used drugs worldwide for indications such as cardiovascular diseases including hypertension, heart failure, myocardial infarction, and diabetic complication of kidney kidney complications of diabetes, their discontinuation due to COVID-19 should be carefully considered until sound evidence is available. Recently, in an epidemiological study, Abajo et al. 4 reported on the relationship between the use of RAAS inhibitors and risk of COVID-19 requiring admission in hospital 4 . In this case-population study, a total of consecutive 1,139 patients, the authors consecutively selected patients (1139 patients) who were diagnosed with COVID-19 on the basis of polymerase chain reaction and required admission to hospital in Madrid were studied. As a reference group, 11,390 patients, who they randomly sampled This article is protected by copyright. All rights reserved ten patients per case (11390 patients) and individually matched the potential confounding factors were sampled. As compared to other antihypertensive drugs, RAAS inhibitors were not associated with an increased risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to an intensive care unit (ICU) (adjusted odds ratio [OR], 0.94; 95% confidence interval [CI], 0.77-1.15). Sex, age, and background potential confounding cardiovascular risks did not modify the adjusted OR between the use of RAAS inhibitors and COVID-19 requiring admission to hospital. These results were consistent with those of two other epidemiological studies, and none of these studies found an increased risk of severe outcomes related to associated with RAAS inhibitors. It is noteworthy that Notably, in both studies, the authors considered exposure to ACE inhibitors before (7 days) or at admission to hospital, and during hospital stay in both studies. Thus, these findings suggest that RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and as well as those admitted to ICUs, and hence, RAAS inhibitors should not be discontinued in order to prevent a severe COVID-19 case. Diabetes is the leading cause of morbidity, and its prevalence is predicted to increase exclusively in developed countries over the next few decades. Several reports indicated that diabetic individuals had a higher susceptibility to some infectious diseases, presumably because of lower immunity than their healthy counterparts. In the past decade, plasma glucose level and diabetes were proved to be independent predictors for mortality and morbidity in patients with SARS. Although diabetes has been reported as a risk factor for severe COVID-19, the underlying mechanism of this clinical observation is unknown. Experimental studies using diabetic mice have shown an increased activity of ACE exclusively in the lungs. Therefore, if this is the case in humans as well, the increased severity of COVID-19 in diabetes diabetic patients might be caused by an imbalance in the ACE:ACE2 ratio. In addition, this might explain the beneficial protective effect of RAAS inhibitors. In this context, This article is protected by copyright. All rights reserved another interesting finding by Abajo et al. 4 was a decreased risk of COVID-19 requiring admission to hospital among patients with diabetes who used RAAS inhibitors (adjusted OR, 0.53; 95% CI, 0.34-0.80). It is noteworthy that the use of RAAS inhibitors by diabetic outpatients did not facilitate or aggravate infection, but rather improved the prognosis in this population. Further studies will be needed to identify the biological mechanism for this clinical observation. Among various risk factors of severe COVID-19, elderly male older men with accompanied by chronic illnesses may be more severely affected than their counterparts. A recent report indicates that 70% of patients who died of COVID-19 in Italy were elderly men. Furthermore, the increased risk of elderly men vulnerability of older people with cardiovascular diseases and concomitant comorbid conditions could be associated with related to increased concentrations of ACE2. Therefore, this may suggest that there are higher concentrations of ACE2 in men than in women. Recently, Sama et al. 5 investigated the association between circulating plasma concentrations of ACE2 in men and women with heart failure and the effects of RAAS inhibitors 5 . They measured ACE2 concentrations in 1,485 men and 537 women with heart failure as an index cohort. The results were validated in 1,123 men and 575 women as a validation cohort. They found that the strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively) was the strongest predictor of elevated concentrations of ACE2 in both cohorts and that the use of RAAS inhibitors was not associated with high plasma ACE2 concentrations. They concluded that plasma concentrations of ACE2 were higher in men than in women in two independent cohorts of patients with heart failure and that RAAS inhibitors did not increase the risk vulnerability for COVID-19 through increased plasma ACE2 concentrations. These findings could explain the increased susceptibility of men to SARS-CoV-2 and support the continued use of RAAS inhibitors in patients with This article is protected by copyright. All rights reserved heart failure even during the COVID-19 pandemic. Given the recent study results that ACE2 is a human cell receptor with a binding affinity to SARS-CoV-2 and that ACE2 is expressed in a variety of organs ( Figure 1 ) 5 , it is rational to hypothesize that COVID-19-induced organ damages might be mediated by ACE2. However, a recent pathological study found some inflammatory mononuclear infiltrates in a tissue suggesting that COVID-19 might not directly impar the organs 6 . The equilibrium between plasma concentrations of ACE2 and membrane-bound ACE2 might influence COVID-19 pathogenesis and treatment options. These findings give rise to the question whether of ACE2 could just be a trigger for the SARS-CoV-2 infectivity or the therapeutic target in patients with various diseases as well as heart failure during the current SARS-CoV-2 pandemic. Further work is needed to answer this question. Disclosure nothing to disclose. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. The Lancet Published Online Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of reninangiotensin-aldosterone inhibitors Pathological findings of COVID-19 associated with acute respiratory distress syndrome Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors The original image/content is not covered by the terms of the Creative Commons license of this publication. For permission to reuse This article is protected by copyright. All rights reserved