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      Understanding the Renin-Angiotensin-Aldosterone-SARS-CoV-Axis: A Comprehensive Review

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          Abstract

          Importance:

          Coronavirus Disease 19 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been declared a global pandemic with significant morbidity and mortality since first appearing in Wuhan, China, in late 2019. As many countries are grappling with the onset of their epidemics, pharmacotherapeutics remain lacking. The window of opportunity to mitigate downstream morbidity and mortality is narrow but remains open. The renin-angiotensin-aldosterone system (RAAS) is crucial to the homeostasis of both the cardiovascular and respiratory systems. Importantly, SARS-CoV-2 utilises and interrupts this pathway directly, which could be described as the renin-angiotensin-aldosterone-SARS-CoV-2-axis (RAAS-SCoV-axis). There exists significant controversy and confusion surrounding how anti-hypertensive agents might function along this pathway. This review explores the current state of knowledge regarding the RAAS-SCoV-axis, informed by prior studies of SARS-CoV, how this relates to our currently evolving pandemic, and how these insights might guide our next steps in an evidence-based manner.

          Observations:

          This review discusses the role of the RAAS-SCoV-axis in acute lung injury and the effects, risks, and benefits of pharmacologic modification of this axis. There may be an opportunity to leverage the different aspects of RAAS inhibitors to mitigate indirect viral-induced lung injury. Concerns have been raised that such modulation might exacerbate the disease. While relevant preclinical, experimental models to date favor a protective effect of RAAS-SCoV-axis inhibition on both lung injury and survival, clinical data related to the role of RAAS modulation in the setting of SARS-CoV-2 remains limited.

          Conclusion:

          Proposed interventions for SARS-CoV-2 predominantly focus on viral microbiology and aim to inhibit viral cellular injury. While these therapies are promising, immediate use may not be feasible, and the time window of their efficacy remains a major unanswered question. An alternative approach is the modulation of the specific downstream pathophysiologic effects caused by virus that lead to morbidity and mortality. We propose a preponderance of evidence that supports clinical equipoise regarding the efficacy of RAAS-based interventions, and the imminent need for a multisite randomised controlled clinical trial to evaluate the inhibition of the RAAS-SCoV-axis on acute lung injury in COVID-19.

          Abstract

          SARS-CoV-2’s interplay with the Renin-Angiotensin-Aldosterone-System likely accounts for much of its unique pathology. Appreciating the degree and mechanism of this interaction highlights potential therapeutic options, including blockade (ARBs).

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          Most cited references 44

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          Updated Approaches against SARS-CoV-2

          Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in virology, epidemiology, and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing to develop a treatment for COVID-19. Recent studies have revealed many attractive therapeutic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials.
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            Angiotensin II Mediates Angiotensin Converting Enzyme Type 2 Internalization and Degradation Through an Angiotensin II Type I Receptor–Dependent MechanismNovelty and Significance

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              Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease

              Background Angiotensin converting enzyme 2 (ACE2) is an endogenous regulator of the renin angiotensin system. Increased circulating ACE2 predicts adverse outcomes in patients with heart failure (HF), but it is unknown if elevated plasma ACE2 activity predicts major adverse cardiovascular events (MACE) in patients with obstructive coronary artery disease (CAD). Methods We prospectively recruited patients with obstructive CAD (defined as ≥50% stenosis of the left main coronary artery and/or ≥70% stenosis in ≥ 1 other major epicardial vessel on invasive coronary angiography) and measured plasma ACE2 activity. Patients were followed up to determine if circulating ACE2 activity levels predicted the primary endpoint of MACE (cardiovascular mortality, HF or myocardial infarction). Results We recruited 79 patients with obstructive coronary artery disease. The median (IQR) plasma ACE2 activity was 29.3 pmol/ml/min [21.2–41.2]. Over a median follow up of 10.5 years [9.6–10.8years], MACE occurred in 46% of patients (36 events). On Kaplan-Meier analysis, above-median plasma ACE2 activity was associated with MACE (log-rank test, p = 0.035) and HF hospitalisation (p = 0.01). After Cox multivariable adjustment, log ACE2 activity remained an independent predictor of MACE (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.24–4.72, p = 0.009) and HF hospitalisation (HR: 4.03, 95% CI: 1.42–11.5, p = 0.009). Conclusions Plasma ACE2 activity independently increased the hazard of adverse long-term cardiovascular outcomes in patients with obstructive CAD.
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                Author and article information

                Journal
                Eur Respir J
                Eur. Respir. J
                ERJ
                erj
                The European Respiratory Journal
                European Respiratory Society
                0903-1936
                1399-3003
                27 April 2020
                27 April 2020
                Affiliations
                [1 ]Department of Medicine, University of Minnesota, Division of Pulmonary and Critical Care, Minneapolis, MN
                [2 ]Department of Anesthesiology, University of Minnesota, Minneapolis, MN
                [3 ]Department of Pharmacy, Fairview Pharmacy Services, Minneapolis, MN
                [4 ]Department of Medicine, University of Minnesota, Division of Medicine and Infectious Disease, Minneapolis, MN
                [5 ]Department of Surgery, University of Minnesota Division of Acute Care Surgery, Minneapolis, MN
                [6 ]Institute for Health Informatics, University of Minnesota, Minneapolis, MN
                [7 ]Department of Emergency Medicine, University of Minnesota, Minneapolis, MN
                [8 ]Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis, MN
                Author notes
                Nicholas Ingraham, MMC 276, 420 Delaware St SE, Minneapolis, MN 55455. E-mail: ingra107@ 123456umn.edu
                Article
                ERJ-00912-2020
                10.1183/13993003.00912-2020
                7236830
                32341103
                Copyright ©ERS 2020

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                Funding
                Funded by: National Heart, Lung, and Blood Institute , open-funder-registry 10.13039/100000050;
                Award ID: T32HL07741
                Categories
                State of the Art

                Respiratory medicine

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