key: cord-0847825-7lonkj5p
authors: Sanchis-Gomar, Fabian; Lavie, Carl J.; Perez-Quilis, Carme; Henry, Brandon M.; Lippi, Giuseppe
title: Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019
date: 2020-04-04
journal: Mayo Clin Proc
DOI: 10.1016/j.mayocp.2020.03.026
sha: 47931ee3b584a1e47aa31715c9f6bc2775173198
doc_id: 847825
cord_uid: 7lonkj5p

Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection. In agreement with current guidelines, patients with hypertension should continue taking antihypertensive medications as prescribed without interruption. Because ACEIs and ARBs are also used to retard the progression of chronic kidney disease, we suggest that these recommendations also apply to the use of these agents in chronic kidney disease. No differences generally exist between ARBs and ACEIs in terms of efficacy in decreasing blood pressure and improving other outcomes, such as all-cause mortality, cardiovascular mortality, myocardial infarction, heart failure, stroke, and end-stage renal disease. The ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, and withdrawal rates due to adverse events are lower with ARBs. Given their equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in patients with COVID-19 at higher risk for severe forms of disease.

March 30, 2020 HTN prevalence increases in parallel with aging, this pattern may represent the expected prevalence for the given age group. Therefore, although the number of fatal COVID-19 positive patients treated with ACEIs was more than twice the number of those treated with ARBs, one cannot definitely conclude risks or benefits of these therapies due to confounding variables of age, HTN, as well as the impact of yet unidentified comorbidities on outcome with the COVID-19 pandemic.

In a recent study, in which potential drugs targeting SARS-CoV-2 were evaluated, the authors reported that ARBs (e.g., irbesartan) may associate with some human coronaviruses-associated host proteins in the human interactome. 34 Irbesartan targets the SLC10A1 gene (solute carrier family 10 member 1), which interacts with C11orf74 gene, a potential transcriptional repressor that interacts with the non-structural protein 10 (NSP10) of SARS-CoV and participates in CoV replication fidelity. 35 Crackower and co-workers 36 reported that disruption of ACE2 results in increased Ang II levels and impaired cardiac function, whereas other authors showed that ACE2 overexpression reduced left ventricular hypertrophy and myocardial fibrosis in HTN rats. 37 Deshotels et al. 50 investigated the compensatory reduction of ACE2 expression and activity in response to Ang II-mediated HTN. Elevated levels of Ang II decreased ACE2 activity on the cell surface via an AT 1 Rdependent internalization mechanism. 50 Moreover, in vitro treatment of HEK293T cells with Ang II enhanced ACE2 ubiquitination also mediated by AT 1 R, which ultimately stimulates ACE2 lysosomal degradation (which might prevent interaction of the SARS-Co-V2 with ACE2 catalytic site). 50 This is reported to be prevented by AT 1 R antagonist losartan which may block internalization, proteolytic degradation and ubiquitination of ACE2. 50 As such, this latter pathway represents another mechanism by which ACEIs or ARBs could prevent COVID-19 viral entry. If the viral protein interaction with ACE2 is reduced in the presence of stabilized ACE2-AT 1 R complexes, then ARBs could prove beneficial by stabilizing ACE2-AT 1 R interaction and preventing viral protein-ACE2 interaction and internalization. Based on this mechanism of action, Gurwitz recently suggests ARBs (losartan and telmisartan) as a tentative therapy for COVID-19 patients prior to the development of ALI/acute respiratory failure. 51 However, it remains unknown whether preventing ACE2 internalization would be effective at attenuating infections by SARS coronaviruses, and further studies are urgently needed to clarify this mechanism.

Interestingly, Liu et al. 52 reported serum Ang II levels were significantly higher in COVID-19 infected than non-infected individuals and linearly associated with viral load and lung damage. It is suspected that Ang II, via pulmonary vasoconstriction leading to decrease flow and ventilation/perfusion mismatch and via increased vascular permeability and its proinflammatory and pro-oxidative properties, may induce or perpetuate ARDS in a variety of pathologies. 53 The findings by Liu et al. 52 would support the hypothesis that elevated levels of Ang II may foster ARDS in COVID-19 patients. Nevertheless, this study has important limitations as it was performed in a limited sample and, as such, require confirmation. 52 The role of RAAS peptides in acute lung injury has been also investigated in other ARDS patients (diagnosed within 24 hours) by using a targeted metabolomics approach. 54 Ang I concentrations were significantly higher in non-survivors at study entry and at 72 hours, while ARDS survival was associated with lower Ang I levels but higher Ang 1-9 concentration (a precursor to Ang 1-7 significantly higher average Ang 1-9/Ang I and Ang 1-7/Ang I ratios, which suggests that ACE2 activity is higher in survivors than non-survivors. 54 Therefore, ACE2 activities seems to be reduced in patients who succumb from ARDS.

Further downstream, high levels of Ang II, which may be due to attenuated ACE2, such as that potentially caused by the SARS-CoV-2 interaction with ACE2, stimulates increased production of aldosterone. Aldosterone in turn increases ACE activity inducing further production of Ang II, leading to a potentially vicious cycle which perpetuates ARDS. 55 Moreover, aldosterone decreases expression of the MasR, minimizing the antagonizing benefits of any Ang 1-7 produced by ACE2. As such, aldosterone receptor blockers or aldosterone synthase inhibitors may have a potential role in COVID-19 therapy;

however, careful evaluation of any influence on corticosteroids synthesis and signaling is required. 55 Since SARS-CoV-2 invades alveolar epithelial cells, respiratory symptoms are often the most common reported, and is reported to be more severe in patients with CVD. 23 This might be associated with higher ACE2 levels, which has been suggested to be increased in patients maintained on RAAS inhibitors. 23 However, in a study conducted in rats by Xudong et al., 56 ACE2 expression dramatically decreased with age in both genders, while older male rats also had lower ACE2 concentrations than did older female rats.

Whether such altered profiles of ACE2 are similarly observed in humans, or if ACE2 expression is altered in disease, requires further investigation.

It has also been recently demonstrated that recombinant ACE2 administration in mice with ARDS protects from development of ALI and severe lung disease, thus strongly suggesting that ACE2 mediates a cytoprotective role in ALI; 57 whether such effects are also observed in ARDS caused by COVID-19 is unknown at this time Thus extrapolating from these and previously discussed findings, one may speculate that the administration of recombinant ACE2 or its product Ang 1-7, which directly opposes Ang II, may offer potentially beneficial effects in SARS-CoV-2-associated ARDS. 57 Moreover, specifically with SARS- ARDS. Such an approach in preclinical studies of ARDS specifically due to COVID-19 is especially important and timely.

SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, further tipping the ACE/ACE2

balance to a predominant ACE/AngII/AT1 axis signaling, in which AngII may then foster pulmonary vasoconstriction, and inflammatory and oxidative organ damage, ultimately progressing towards ALI/ARDS. 53 We speculate that RAAS dysregulation may play a central role in the pathophysiology of (Table 1 ). In this article, we review the evidence on the relationship between the Renin-Angiotensin-Aldosterone system (RAAS) and COVID-19 infection.

Healthcare professionals, physicians, researchers, and patients are actively debating the potential influence of J o u r n a l P r e -P r o o f interstitial pneumonia and ARDS) and lymphopenia. Moreover, ACE2 is observed on the surface of many other cell types, such as those of the heart, kidney, liver, gastrointestinal tract (especially esophagus, stomach, colon, ileum, rectum) and bladder (Figure 1 ). 9-11

Kuba et al. 12 first showed that ACE2 is essential for SARS-CoV infection, acting as its effective host receptor in vivo. SARS-CoV infection, through binding of viral S protein to ACE2, seems to reduce receptor expression. Injecting SARS-CoV Spike into mice induces acute lung injury (ALI) in vivo, which can be mitigated by blocking the RAAS. Wrapp et al. 13 have recently reported that SARS-CoV-2 binds to ACE2

with 10-to 20-fold higher affinity compared to SARS-CoV. Specifically, the S protein of SARS-CoV-2 virus binds to the catalytic domain of ACE2 inducing internalization of the virus by the cell.

In brief, the RAAS is the central regulatory system for BP control. 14 Additionally, RAAS activation plays a crucial pathogenic role in HTN, through hemodynamic actions and cytokines and intracellular signaling pathways, which ultimately promote many adverse cellular processes implicated in systemic damage. 14 In the RAAS, Angiotensin I (Ang I) is converted to angiotensin II (Ang II) by ACE. Ang II mediates vasoconstrictive, pro-inflammatory and pro-oxidative effects through agonism at Ang II type 1 receptor (AT 1 R). 15 ACE2 converts Ang II to angiotensin 1-7 (Ang1-7), which finally binds to Mas receptor (MasR) and mediates many beneficial actions, including vasodilation and anti-inflammatory, anti-oxidant and antiapoptotic effects. 15 Thus, ACE2/Ang1-7/MasR axis has opposite actions to ACE/AngII/AT 1 R axis ( Figure   2 ).

ACE2, a homologue of ACE, is an integral cell membrane protein with a catalytic domain on the extracellular surface exposed to vasoactive peptides. 16 ACE2 is a monocarboxypeptidase whose major role is converting Ang II to Ang 1-7, 16 with vasodilatory and antifibrotic actions 17 when it activates MasR. 18 Moreover, ACE2 also converts Ang I to Ang 1-9 which can be further converted by ACE into Ang 1-7.

Thus, ACE2 limits the adverse vasoconstrictor and profibrotic effects of Ang II through its degradation and by counteracting its actions through the formation of Ang 1-7. The high expression of ACE2 in heart, type II 

It has been hypothesized that increased levels of ACE2 may facilitate COVID-19 infection, such that administering ARBs or ACEIs might increase the risk of developing severe and fatal COVID-19. [24] [25] [26] As discussed later in this section, this premise is based in part on the findings in some, but not all, studies that ARBs and ACEIs may increase ACE2 levels. According to the most recent studies on COVID-19, it appears that HTN is one of the most important factors associated with poor prognosis at an early stage of COVID-19

infection. 27-32 HTN, however, has also been found to be associated with decreased baseline levels of ACE2 expression. Unfortunately, most of these early COVID-19 studies have not been adjusted for age or other co- In a recent study, in which potential drugs targeting SARS-CoV-2 were evaluated, the authors reported that ARBs (e.g., irbesartan) may associate with some human coronaviruses-associated host proteins in the human interactome. 34 Irbesartan targets the SLC10A1 gene (solute carrier family 10 member 1), which interacts with C11orf74 gene, a potential transcriptional repressor that interacts with the non-structural protein 10 (NSP10) of SARS-CoV and participates in CoV replication fidelity. 35 Crackower and co-workers 36 Deshotels et al. 50 investigated the compensatory reduction of ACE2 expression and activity in response to Ang II-mediated HTN. Elevated levels of Ang II decreased ACE2 activity on the cell surface via an AT 1 Rdependent internalization mechanism. 50 Moreover, in vitro treatment of HEK293T cells with Ang II enhanced ACE2 ubiquitination also mediated by AT 1 R, which ultimately stimulates ACE2 lysosomal degradation (which might prevent interaction of the SARS-Co-V2 with ACE2 catalytic site). 50 This is reported to be prevented by AT 1 R antagonist losartan which may block internalization, proteolytic degradation and ubiquitination of ACE2. 50 As such, this latter pathway represents another mechanism by which ACEIs or ARBs could prevent COVID-19 viral entry. If the viral protein interaction with ACE2 is reduced in the presence of stabilized ACE2-AT 1 R complexes, then ARBs could prove beneficial by stabilizing ACE2-AT 1 R interaction and preventing viral protein-ACE2 interaction and internalization. Based on this mechanism of action, Gurwitz recently suggests ARBs (losartan and telmisartan) as a tentative therapy for COVID-19 patients prior to the development of ALI/acute respiratory failure. 51 However, it remains unknown whether preventing ACE2 internalization would be effective at attenuating infections by SARS coronaviruses, and further studies are urgently needed to clarify this mechanism.

Interestingly, Liu et al. 52 reported serum Ang II levels were significantly higher in COVID-19 infected than non-infected individuals and linearly associated with viral load and lung damage. It is suspected that Ang II, via pulmonary vasoconstriction leading to decrease flow and ventilation/perfusion mismatch and via increased vascular permeability and its proinflammatory and pro-oxidative properties, may induce or perpetuate ARDS in a variety of pathologies. 53 The findings by Liu et al. 52 would support the hypothesis that elevated levels of Ang II may foster ARDS in COVID-19 patients. Nevertheless, this study has important limitations as it was performed in a limited sample and, as such, require confirmation. 52 The role of RAAS peptides in acute lung injury has been also investigated in other ARDS patients (diagnosed within 24 hours) by using a targeted metabolomics approach. 54 Ang I concentrations were significantly higher in non-survivors at study entry and at 72 hours, while ARDS survival was associated with lower Ang I levels but higher Ang 1-9 concentration (a precursor to Ang 1-7). Survivors showed a

SARS-CoV-2 binding to ACE2 may attenuate residual ACE2 activity, further tipping the ACE/ACE2

balance to a predominant ACE/AngII/AT1 axis signaling, in which AngII may then foster pulmonary vasoconstriction, and inflammatory and oxidative organ damage, ultimately progressing towards ALI/ARDS. 53 We speculate that RAAS dysregulation may play a central role in the pathophysiology of COVID-19 associated ALI/ARDS, but definitive studies that address this issue are needed. Whether RAAS modulation may have a beneficial effect in selected patients with severe COVID-19 at risk for ALI/ARDS is entirely unknown at the present time. Moreover, the effects of other agents that may interrupt the RAAS by inhibiting renin, such as renin inhibitors and beta-blockers, would also be of interest regarding their effects on COVID-19 and attendant ALI.

In agreement with current guidelines, patients with HTN should continue taking anti-HTN medications as prescribed without interruption. Current evidence shows that RAAS inhibitors, i.e., ACEIs and ARBs, significantly reduce mortality in CVD, reduce the progression of CKD, and are the cornerstone of HF and HTN treatment. ACEIs or ARBs therapy should be maintained or initiated, as indicated, in patients with HF, HTN, or myocardial infarction, regardless of SARS-CoV-2. No differences exist between ARBs and ACEIs in terms of efficacy to decrease BP and improve other outcomes, such as all-cause mortality, CVD mortality, myocardial infarction, HF, stroke, and end-stage renal disease. 58 ACEIs are associated with cough secondary to accumulation of bradykinin and angioedema, while withdrawal rates due to adverse events are lower with ARBs. 58 Given the equal efficacy but fewer adverse events, ARBs could potentially be a more favorable treatment option in COVID-19 patients at higher risk of developing severe forms of disease ( 

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World Health Organization. Coronavirus disease 2019 (COVID-19) Situation Report -62

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention

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© 2020 Mayo Foundation for Medical Education and Research

Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors

Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan

Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats

Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implications for future therapeutic directions

Myocardial infarction increases ACE2 expression in rat and humans

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Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

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Both aldosterone and spironolactone can modulate the intracellular ACE/ANG II/AT1 and ACE2/ANG (1-7)/MAS receptor axes in human mesangial cells

Here is the permission to use table 1 (see below). The authors would prefer we cite it as