key: cord-0789570-j0gi07wj
authors: Ventura, Davide; Carr, Amy L; Davis, R Duane; Silvestry, Scott; Bogar, Linda; Raval, Nirav; Gries, Cynthia; Hayes, Jillian E; Oliveira, Eduardo; Sniffen, Jason; Allison, Steven L; Herrera, Victor; Jennings, Douglas L; Page, Robert L; McDyer, John F; Ensor, Christopher R
title: Renin Angiotensin Aldosterone System Antagonism in 2019 Novel Coronavirus Acute Lung Injury
date: 2021-04-04
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofab170
sha: f853eb6fd5e122de922ab76464db3d9392acce4f
doc_id: 789570
cord_uid: j0gi07wj

It has been established SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2), a membrane-bound regulatory peptide, for host cell entry. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been reported to increase ACE2 in type 2 pneumocytes pulmonary tissue. Controversy exists for the continuation of ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) in the current pandemic. ACE2 serves as regulatory enzyme in maintaining homeostasis between proinflammatory Angiotensin II and anti-inflammatory Angiotensin 1,7 peptides. Derangements in these peptides are associated with cardiovascular disease and are implicated in the progression of acute respiratory distress syndrome (ARDS). Augmentation of the ACE2/Ang1,7 axis represent a critical target in the supportive management of COVID-19 associated lung disease. Observational data describing the use of RAAS inhibitors in the setting of SARS-CoV-2 have not borne signals of harm to date. However, equipoise persists requiring an analysis of novel agents including recombinant human-ACE2 and existing RAAS inhibitors while balancing ongoing controversies associated with increased coronavirus infectivity and virulence.

The therapeutic use of renin-angiotensin-aldosterone inhibitors remains a contentious question during the COVID-19 pandemic. In mid-March, major societies including the American Heart Association, American College of Cardiology, Heart Failure Society of America, European Society of Cardiology, and International Society of Hypertension, had unanimously recommended continuation of therapy for existing indications. However, these organizations acknowledged the scant evidence supporting either approach in the setting of COVID-19. Since the publication of these consensus statements, important observational data have been published advancing the position on RAAS inhibitors as they relate to cardiovascular care in infected patients 1 . Epidemiologic data suggests hypertension, amongst other cardiometabolic disorders, is not only pervasive in up to 30% of patients but portends more severe illness and is associated with a three-fold increase in mortality [2] [3] [4] [5] .

consistency in cardiovascular management. The co-existence of RAAS and COVID-19, however, may traverse beyond chronic management and serve as a central target for ARDS itself.

The natural history of COVID-19 can be separated into three overlapping stages including a viral, pulmonary, and hyperinflammatory phase 6 . As an extensive neurohormonal network, RAAS plays an intrinsic role spanning all three phases of COVID-19 and may serve as an additional therapeutic focus. In contrast, anti-viral and immunomodulatory therapies may be confined to a specific phase, namely the viral and hyperinflammatory phase respectively.

A c c e p t e d M a n u s c r i p t COVID-19 exploits the RAAS system to gain access, proliferate, and inflict multisystem organ damage, notably respiratory in nature. SARS-CoV-2 has been reported to use ACE2 as a portal of tissue entry. This has generated a theoretical concern that RAAS blockers may upregulate ACE2 and increase infectivity questioning continued or de-novo use of this therapeutic class 7 . In order to evaluate the role of RAAS in COVID-19, we performed a balanced and thorough review.

RAAS is divided into classical and alternative pathways. The classical pathway (Ang II/AT-1 axis) is dependent on two main enzymes including renin, which cleaves angiotensinogen into Ang I. This substrate is further reduced to Ang II via ACE. Ang II is an agonist at the AT-1 receptor which is known to exhibit vasoconstrictive, fibroproliferative, pro-inflammatory, and fluid retaining properties. In 2000, an ACE homolog was identified and designated as ACE2. Though this enzyme shares approximately 42% of its catalytic residues with ACE, its role in RAAS serves as a counterregulatory glycoprotein found in various tissues including lungs, heart, vascular endothelium, kidneys and intestinal tract 8 . This homolog is a vital component of the alternative pathway also known as the Ang 1-7,1-9/Mas axis.

The primary purpose of the Ang1-7,1-9/Mas axis is to counteract the classical, Ang II/AT-1 axis. Upstream AngI has two fates, either direct metabolism to Ang1,7 via neprilysin or conversion to Ang1,9 via ACE2. Ang 1,9 has activity on the AT-2 receptor and offers reported protective benefits. Ang1,9 can also be converted to Ang1,7 through ACE, but catalytic output is low.

A c c e p t e d M a n u s c r i p t Though ACE2 has catalytic activity on AngI, it has a 400-fold greater efficiency targeting Ang II as a substrate. By metabolizing and reducing plasma Ang II, less substrate is available to activate the deleterious effects of the Ang II/AT-1 axis. Ang 1,7 is the main byproduct of ACE2-Ang II metabolism. Ang 1,7 peptides have activity on both the MrgD and Mas receptors providing anti-inflammatory, anti-fibrotic, vasodilatory, and natriuretic effects which directly oppose Ang II/AT-1 receptor activity 7-9 ( Figure 1 ).

SARS-CoV-2 is associated with a myriad of multi-system manifestations ranging from neurological deficits to renal dysfunction. Given that RAAS and its accompanying peptides are ubiquitously expressed throughout the human body, this may offer an important link in the pathophysiologic derangements associated with COVID-19. Liu and colleagues reported epidemiologic and biomarker data associated with disease severity compared to healthy controls. Though only hypothesis generating, results by Liu, et al. indicated marked elevations in Ang II which were linearly associated with viral load and specifically lung injury.

Acute Respiratory Distress Syndrome (ARDS) survivors have also been noted to have higher average Ang 1,7 and Ang 1,9 compared to ARDS non-survivors 36 . Anatomical ACE expression may offer a logical explanation for these findings. ACE expression in most organ systems including the heart, is at most 20%. In contrast, pulmonary vasculature is exclusively dominated by ACE, making the lungs particularly sensitive to RAAS 41 .

Excess ACE activation in pulmonary capillaries promotes vasoconstriction, vascular permeability, cytokine production, edema, hypoxemia and extensive alveolar damage 41, 42 .

Specifically located in type II alveolar epithelium, the counterregulatory mechanisms A c c e p t e d M a n u s c r i p t provided by ACE2 are compromised. Left unchecked, ACE accelerates apoptosis and drives fibroproliferation 41,42 .

The RAAS system is an intricate balance of regulatory and counterregulatory pathways.

Disruption by SARS-CoV-2 may detrimentally impact pulmonary tissue and influence each stage of lung disease progression spanning from the viral to the hyperinflammatory phase 43 .

In the viral phase, viral spikes, or S-proteins, located on the surface of SARS-CoV-2 form hydrophobic and salt bridge interactions with transmembrane ACE2. Once docked, the Sproteins undergo a conformational change enhancing interactions with TMPRSS2, a principal serine protease. TMPRSS2 cleaves S-proteins and merges viral and pulmonary tissue membranes which leads to cytoplasmic infiltration. Ultimately, the virus uses ACE2 to gain tissue entry, becomes endocytosed, envelopes itself in a protein vesicle resembling normal tissue phospholipid bilayers, and downregulates ACE2 activity post tissue entry 7, 8, 10 .

As the viral phase progresses, ACE2 continues to become downregulated. Though ACE2 is the primary port of entry for SARS-CoV-2, viral proliferation persists despite downregulation. This suggests the virus uses concealed methods of spreading. Fehr and colleagues postulate that once the initial virion transcribes S-proteins, these migrate to the host cell membrane, creating a hybrid cell membrane with both host and viral fusion proteins, known as a syncytium. This initially allows the virus to evade detection by coronavirus specific antibodies. Such a mode of viral transmission would explain how SARS-CoV-2 is able to propagate despite ACE2 downregulation. The plausibility of a syncytial A c c e p t e d M a n u s c r i p t mode of infectious spreading independent of ACE2 may invalidate concerns surrounding the continuation of ARB/ACE-I beyond the viral phase 11 .

Once SARS-CoV-2 has infiltrated host cells and replicated, tissue dysfunction along with a cytokine storm ensues. A dysregulated RAAS parallels hyperactivated innate immunity contributing to damaging downstream effects. RAAS dysregulation is a culmination of ACE2 downregulation, Ang 1-7,1-9/Mas axis quiescence, and unopposed Ang II/AT-1 activity.

Initial As ACE2 continues to become depleted, Ang II metabolism to Ang 1,7 is depressed. With no ACE2 to metabolize Ang II as substrate for the Ang1-7/MAS axis, counterregulatory measures are crippled. Experimental models indicate that in the presence of ARDS, ACE2 deficiency magnifies IL-1B, IL-6, and TNF-alpha contributing to a hyperactive immune system 12, 13, 39 . These inflammatory markers augment kinases (MAPK) and ROS to further upregulate ADAM17 and insidiously participate in ACE2 shedding and collectively produce a positive feedback loop (Figure 3) .

A c c e p t e d M a n u s c r i p t Ectodomain shedding and elevated plasma concentrations of ACE2 are associated with the extent of tissue damage in acute lung injury data 14, 15, 16 . Though plasma ACE2 remains catalytically active, enzymatic efficiency in metabolizing Ang II may be diminished compared with membrane bound ACE2.

Given the intrinsic connection between RAAS and ARDS pathophysiology, exploring RAAS inhibitors is warranted. Various pharmacologic and genetic techniques have been explored ranging from gene therapy, rhACE2 infusions, and direct ACE2 agonists in both the heart failure and ARDS arenas. Though all experimental agents, promising surrogate results have been noted including decreases in IL-6 production, enhanced Ang1-7,1-9/Mas axis and overall improvement in acute lung injury caused by SARS-CoV 7,8 .

Infusion of rhACE2 is designed to mimic soluble, plasma ACE2. Animal models infected with various respiratory viruses including RSV, H5N1, and H7N9, mimic similar RAAS derangements noted in SARS-Cov-2 along with histopathological damage consisted with ACE-I animal models are primarily limited to lisinopril, enalapril and ramipril (Table 1) . These agents, however, have shown variance in their capacity to increase ACE2 activity or mRNA expression 19, 21 . The discrepant actions between ACE-Is and ARBs may very well lie in differences between experimental methodology and modelling. Mechanistically, however, it merits some hypothetical acknowledgment. ACE-Is offer less consistency perhaps because they operate too far upstream in RAAS. Specifically, blocking the conversion of Ang 1 to Ang II, creates a dam-effect, siphoning Ang 1 toward Ang 1-9 conversion via ACE2. Though Ang 1-9 elicits tissue protective benefits on the AT-2 receptor, they may be less profound than those provided by Ang 1-7. Additionally, Ang 1-9 can be converted to Ang 1-7 however this requires functional, uninhibited ACE activity. Thus, ACE inhibitors may prevent conversion of Ang 1-9 to Ang 1-7 and significantly decrease Ang II substrate for ACE2. As mentioned earlier, ACE2 has a greater efficiency to convert Ang II to Ang 1-7 by 400-fold which may stunt Mas axis optimization 8,25-26 . In contrast, ARBs by design will increase Ang II substrate and magnify Ang 1-7 activity to promote anti-inflammatory and anti-proliferative tissue effects while blocking the damaging effects of the AT-1 receptor. The excess Ang II that is encouraged by ARBs promotes competition with SAR-CoV-2 for ACE2 attachment and catalysis. Finally, even if ARBs/ACE-Is A c c e p t e d M a n u s c r i p t only increase soluble, plasma ACE2 with variable effects on tissue-bound ACE2 activity, this may still serve the benefit of acting as decoy mechanisms or amplification of plasma conversions to Ang 1-7.

Direct infusion of Ang 1-7 in ARDS rat models were noted to have an improvement in oxygenation and decrease in white blood cell migration along with a decreasing in polymorphonuclear count with early Ang 1-7 administration. Additionally, late stage ARDS modeling noted a decrease in collagen formation despite delayed Ang 1-7 administration further substantiating Ang 1-7 as a pharmacologic prospect 47 .

COVID-19 specific data has been generated to inform the safety of these agents in hypertension specifically. One of the initial signals of safety published by Meng, et al. 

The influence of RAAS on pulmonary physiology and COVID-19 illustrate a complex link between SARS-CoV-2 and development of ARDS. Though histopathology and animal modeling offer viable pharmacologic targets, the capacity for RAAS inhibitors to modulate lung injury remains unknown. Animal models and tissue samples are mostly confined to non-pulmonary experiments. Further, a paucity of data exists for de-novo treatment with RAAS inhibitors in those without an established chronic condition. Expanded investigation into the implications of RAAS inhibition using readily available agents and novel compounds in the setting of ARDS must be further explored (Table 2 ). Finally, we suggest the burden of A c c e p t e d M a n u s c r i p t proof has been met to pursue randomized controlled trials of RAAS inhibitors for viral pneumonitis and would likely deliver important insights in the management of inflammatory conditions that manifest in ARDS.

In the interim, acknowledging the increased mortality amongst those with cardiovascular comorbidities and COVID-19 should dissuade RAAS therapy interruption. Discontinuing neurohormonal treatment leads to re-establishment of Ang II to pre-treatment levels and an increase in end diastolic volumes in four to 15 days, respectively and highlights the critical role of RAAS inhibition in maintaining cardiovascular homeostasis [27] [28] [29] .

The purported mechanisms of concern associated with ACE-Is/ARBs during the COVID-19 pandemic should be balanced by the therapeutic benefits that RAAS pathway manipulation has in treating cardiovascular diseases. The most recent observational data does not offer substantial scientific rigor to support superiority of these drug classes over alternative antihypertensives nor does it merit the widespread initiation of ACE-Is/ARBs across COVID-19

patients. There is an absolute void in data regarding if ACE-Is/ARBs increase vulnerability to infection. However, once infected, current data suggests ACE-Is/ARBs do not contribute to increased disease severity or progression. Furthermore, the importance of addressing uncontrolled hypertension indicates that initiation of ACE-Is/ARBs can be carefully considered and should not be immediately dismissed.

Amy L. Carr: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work R. Duane Davis: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Scott Silvestry: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work M a n u s c r i p t Linda Bogar: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Nirav Raval: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Cynthia Gries: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Jillian E. Hayes: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Eduardo Oliveira: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Jason Sniffen: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Steven L. Allison: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Victor Herrera: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Douglas L. Jennings: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Robert L. Page II: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work John F. McDyer: Substantial contribution to conception and interpretation for the work; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work Christopher R. Ensor: Substantial contribution to conception, design of the work; acquisition, analysis, and interpretation of data; critical revision for important critical content; final approval of the paper and agreement to be accountable for submitted work

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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