key: cord-0872260-8sd1jahh
authors: Patel, Ankit B; Verma, Ashish
title: Renin-angiotensin-aldosterone system inhibitors impact on COVID-19 mortality: What’s next for ACE2?
date: 2020-05-22
journal: Clin Infect Dis
DOI: 10.1093/cid/ciaa627
sha: 0b2568b8178c37cf931ed7d9aae1f7c0a8476dfc
doc_id: 872260
cord_uid: 8sd1jahh

nan

M a n u s c r i p t As clinicians and researchers look to identify optimal treatments for COVID-19 and prevent its spreading, they have focused on 2 questions; 1) What risk factors lead to increased susceptibility of SARS-CoV-2 infection? and 2) What factors predict worse prognosis and increased severity of COVID- 19 ? The answer to these questions can enlighten our ability to provide prophylactic interventions to limit transmissions of SARS-CoV-2 as governances look to reopen society and effectively treat patients that have contracted SARS-CoV-2 to limit their progression to acute respiratory distress syndrome that has been a hallmark of SARS-CoV-2 infection in the lung.

Hypertension has been shown to be associated with COVID-19 and its severity in a number of early demographic studies of COVID-19 [1, 2] . It remains unclear if this association is due to the pathogenesis of hypertension or confounded by an associated co-morbidity or medication. In this setting, angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), medications commonly used to treat hypertension amongst other disease such as diabetes mellitus and heart failure have also been associated with COVID-19 and its severity. ACEi and ARBs have garnered particular interest given previous studies demonstrating its regulation of the carboxymonopeptidase enzyme, angiotensin converting enzyme 2 (ACE2), which has been shown to facilitate SARS-CoV-2 entry into human cells [3, 4] . ACE2 expression is seen throughout the body including the respiratory tract, heart, kidney, endothelium, and intestines. Studies in rats have shown upregulation of ACE2 in cardiac [5, 6] and renal tissues [6, 7] with ACEi and/or ARB therapy, with mixed results in humans [8, 9] . Recent data evaluating gene expression in human lung samples suggest that ACEis lower ACE2 expression further clouding our understanding [10] . Though ACE2 facilitates SARS-CoV-2 entry into human cells, it also serves a protective role in the setting of lung injury through its effect on generating angiotensin 1-7 from angiotensin II and counterbalancing effects of angiotensin II signaling [11] . This leads to the question; "Is ACE2 expression a risk factor for susceptibility to SARS-CoV-2 infection and/or protective in limiting COVID-19 severity? M a n u s c r i p t Jung et al. evaluated in-hospital mortality and found mortality rates of 9% in RAASi users and 3% in non-RAASi users but this difference was not present after adjustment for confounders. Given hypertension is noted to be associated with COVID-19 severity and mortality, Jung et al. did a subgroup analysis of hypertensive patients and found in-hospital mortality in this group to be 9% amongst RAASi users and 13% amongst non-RAASi users demonstrating the influence of hypertension and its pathogenesis. A large cohort in Spain evaluating hospital admission with COVID-19 found no impact of RAASi use but upon sub-group analysis found diabetic patients had a lower rate of hospital admission when on RAASi suggesting certain sub-groups could gain benefit from RAASi in setting of COVID-19 [13] .

The authors noted most of the RAASi use in their study was from ARB with minimal use of ACEi in Korea limiting the extension of the findings to ACEi use. A recent, multinational, retrospective study identified outpatient ACEi use as protective for in-hospital COVID-19 mortality [14] though other A c c e p t e d M a n u s c r i p t studies have not confirmed the same finding. As a number of different retrospective analysis evaluating the effect of RAASi use on COVID-19 severity have been recently published, it is important to identify the distinguishing characteristics. The authors are able to control for in-hospital medication exposures and particular interventions including vasopressor use and mechanical ventilation which has yet to be done in other studies. The authors also note that their study is the only retrospective analysis looking at outpatient RAASi use impacting COVID-19 mortality in a predominantly Asian population, which is relevant given noted variation in ACE2 expression amongst different ethnicities. There has been significant racial disparity in COVID-19 infection and mortality [15] , ACE2 biology could be a piece of the puzzle.

Despite initial concern RAASi could be harmful in COVID-19, uncovering the potential protective effects of RAASi on viral lung injury that are independent of the regulation of ACE2 expression and the lack of clinical evidence led many hypertension and cardiology societies to encourage clinicians to continued RAASi for clinical indications [16] . As mounting retrospective evidence suggests that RAASi use does not impact COVID-19 infection incidence or severity, a better understanding of the regulation of the RAAS system in the lungs could shed light on timing and mechanism of effective RAAS targeting therapies in COVID-19.

The role of RAAS in the pathogenesis of acute lung injury appears to center around signaling through Angiotensin II type 1 receptors (AT1R). Previous work has shown that knockout and small molecule inhibition of AT1R mitigates acid-induced lung injury [11] . A key enzyme regulated by AT1R is a disintegrin and metalloproteinase 17 (ADAM17) [17] , which is known to cleave membrane bound ACE2 and release of soluble ACE2 (sACE2) lead to unopposed angiotensin II. ADAM17 can additionally cleave membrane bound tumor necrosis factor alpha (TNF-) and interleukin-6 receptor A c c e p t e d M a n u s c r i p t (IL-6R) releasing them into the plasma and stimulating a pro-inflammatory milieu [18] ; a hallmark of SARS-CoV-2 pathogenesis in the lung. The inflammatory cytokines can additionally affect the kallikrein-kinin system by increasing bradykinin B1 and B2 receptors that decrease vascular permeability allowing for inflammatory cell migration and increase pulmonary edema. Of note, ACE2 processes des-Arg 9 -bradykinin [19] which is a ligand for B1 receptors, while ACE process bradykinin, a ligand for B2 receptors ,and thus modulation of ACE2 and ACE activity can control potentially adverse responses to SARS-CoV-2 infection.

An understanding of the interaction of signaling cascades involving innate immunity and vascular physiology with ACE2 has been hampered by lack of quantitative measurement of ACE2 levels in humans. A recent study evaluated sACE2 levels in heart failure patients and found significantly higher sACE2 levels in men. They found no effect of ACEi or ARBs on sACE2 level in their index cohort but found lower sACE2 levels with both class of medications in their validation cohort [20] . This highlights the importance of understanding soluble versus tissue bound ACE2 expression as there is high spatial specificity for ACE2 regulation of the different pathways impacting SARS-CoV-2 pathogenesis.

Jung et al. found no association of RAASi use and in-hospital mortality in COVID-19 patients in this retrospective analysis and point to the need for prospective, randomized trials to evaluate the impact of RAASi on COVID-19 outcomes. Table 1 outlines current trials which look to ask two important questions; 1) Should RAASi be continued during hospitalization in COVID-19 patient? and 2) Can RAASi improve outcomes in COVID-19 patients not previously on RAASi? As we await the results of these trials, we should continue to better understand the pathophysiology of SARS-CoV-2 infection. A mouse model over-expressing human ACE2 that recapitulates the pulmonary pathology A c c e p t e d M a n u s c r i p t of SARS-CoV-2 infection in humans [3] was recently published and could serve as a tool to deconstruct the complex interactions between RAAS, inflammation, and vascular biology to provide insight into novel therapeutic approaches.

A.P. reports a Nephrology Fellowship Grant from Relypsa, and consulting fees from Third Rock Ventures and Goldfinch Bio, outside the submitted work. Dr. Verma has nothing to disclose.

Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the

Clinical Characteristics of Coronavirus Disease 2019 in China

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2

Olmesartan Is an Angiotensin II Receptor Blocker with an Inhibitory Effect on Angiotensin-Converting Enzyme

Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors

Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker

Urinary mRNA expression of ACE and ACE2 in human type 2 diabetic nephropathy

SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors

Angiotensin-converting enzyme 2 protects from severe acute lung failure

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

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

Variation in COVID-19 Hospitalizations and Deaths Across New York City Boroughs

COVID-19 and Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers: What Is the Evidence?

Clinical Relevance and Role of Neuronal AT1 Receptors in ADAM17-Mediated ACE2 Shedding in Neurogenic Hypertension

The shedding protease ADAM17: Physiology and pathophysiology

Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome

Circulating plasma concentrations of angiotensinconverting enzyme 2 in men and women with heart failure and effects of renin-angiotensinaldosterone inhibitors

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t