key: cord-0761467-6ph3ykfc authors: Brojakowska, Agnieszka; Narula, Jagat; Shimony, Rony; Bander, Jeffrey title: Clinical Implications of SARS-Cov2 Interaction with Renin Angiotensin System date: 2020-04-16 journal: Journal of the American College of Cardiology DOI: 10.1016/j.jacc.2020.04.028 sha: da87d746da07b29ae9513e4a0b5ed4867f8cca35 doc_id: 761467 cord_uid: 6ph3ykfc Abstract SARS-CoV2 host cell infection is mediated by the binding to angiotensin-converting enzyme 2 (ACE2). Systemic dysregulation observed in SARS-CoV was previously postulated to be due to ACE2/Ang1-7/Mas axis downregulation, increased ACE2 activity was shown to mediate disease protection. Since angiotensin II receptor blockers (ARBs), ACE inhibitors, and mineralocorticoid receptor antagonists (MRAs) increase ACE2 receptor expression, it has been tacitly believed that the use of these agents may facilitate viral disease, thus they should not be used in high-risk patients with cardiovascular disease. Based on the anti-inflammatory benefits of the upregulation of the ACE2/Ang1-7/Mas axis and previously demonstrated benefits of lung function improvement in SARS-CoV infections, we hypothesize that the benefits of treatment with renin-angiotensin system inhibitors in SARS-COV2 may outweigh the risks and at the very least should not be withheld. The novel coronavirus outbreak, COVID-19 caused by SARS-CoV2, originated from the Wuhan, Hubei providence in central China in December 2019 and was declared a pandemic by the WHO on March 11 th 2020 [1] . Compared to SARS-CoV which caused the [2002] [2003] outbreak, SARS-CoV2 appears to have a stronger rate of transmission. Whereas the SARS infection exhibits a prolonged clinical course predominantly involving respiratory manifestations, the clinical course of the novel coronavirus is unclear. Further clinical insights from Wuhan suggest that some patients with COVID-19 exhibit severe cardiovascular damage, and those with underlying cardiovascular disease appear to have an increased risk of death [1, 2] . Both SARS-CoV and CoV2 belong to the beta-coronavirus phylogeny [3] . Although bats may be natural reservoirs for SARS-like coronavirus [3] , interspecies transfer of SARS-CoV and SARS-CoV2 could have occurred through civets [4] and pangolins [5] , respectively. Both SARS-CoV strains have been identified to use angiotensin converting enzyme II (ACE2) receptor as the portal of entry into the affected cell [1, 4] . ACE2 is a key modulator of the renin-angiotensin system (RAS) which is a signaling pathway involved in the regulation of vascular function including the regulation of blood pressure, natriuresis, and blood volume control [6] . Normally, the RAS system involves the formation of angiotensin II (Ang II) through ACE, which contributes to multiple cardiovascular physiological and pathophysiological functions including hypertension, myocardial hypertrophy, cardiac fibrosis, inflammation, vascular remodeling, and atherosclerosis [7] [8] [9] . Given adverse cardiovascular effects of RAS system upregulation, its inhibition through ACE inhibitors, angiotensin II receptor blockers (ARBs), and mineralocorticoid receptor antagonists (MRAs) has been critical for the management of various cardiovascular diseases. In the last two decades, the identification of ACE2 and its involvement in the counter regulation of the classic RAS system has offered a potentially new therapeutic target [10] [11] [12] . ACE2 exists both as a membrane-bound and soluble form, the former of which mediates SARS-CoV2 infection via S protein binding [13, 14] . It is unclear whether SARS-CoV2 interferes with ACE2 in a manner that contributes to the pathogenesis of SARS or the cardiovascular damage observed [1, 2] . This raises the question of whether RAS inhibition in cardiovascular patients should be reassessed in the setting of this novel coronavirus. Classically, the RAS system involves the conversion of angiotensinogen by renin into angiotensin I (Ang I). Ang I is metabolized to angiotensin II (Ang II) via the dipeptide carboxypeptidase angiotensin-converting enzyme (ACE). The proinflammatory effects of Ang II [7] [8] [9] are mediated through Ang II type I (AT1) receptors. Recently, the ACE2 receptor and its signaling pathway have been identified as an important counter regulatory mechanism to the classic RAS system. ACE2 is a type I integral membrane glycoprotein [15] expressed predominantly in the bronchus, lung parenchyma, heart, endothelium, kidneys, duodenum, and small intestine [16] . ACE2 is a monocarboxypeptidase unlike its homolog ACE which is a dipeptidase, and ACE2 is not antagonized by ACE inhibitors [17] . Whereas ACE contains two active catalytic domains, ACE2 has a single catalytic domain with 42% identical residues [18, 19] . The major substrate of ACE2 is Ang II which upon C-terminus cleavage produces angiotensin 1-7 (Ang1-7) and Lphenylalanine [20] . Other substrates for ACE2 include Ang I, apelin-13, and dynorphin-13, which are catalyzed at much lower affinities [21] . The non-catalytic C-terminal domain of ACE2 shares a 48% sequence homology to collectrin, a protein involved in neutral amino acid reabsorption from the intestine and the kidney [22, 23] . In the presence of a disintegrin and metalloproteinase 17 (ADAM17), also known as TNFα-converting enzyme (TACE), ACE2 exhibits ectodomain shedding [24] resulting in the formation of a soluble enzyme. ACE2 also contains a calmodulin domain on its cytoplasmic tail which influences ectodomain shedding [25] . Ang I is a decapeptide that is converted into the octapeptide Ang II by ACE. Unlike ACE, Ang I can be converted to Ang1-9 by ACE2, and more importantly Ang II is converted to Ang 1-7 through ACE2 [17] . Ang1-7 has a range of anti-inflammatory, antioxidant, vasodilatory, and natriuretic effects that are mediated by GPCR Mas receptor [26] [27] [28] . Ang1-7 may be produced directly from Ang I through the alternative pathways involving a zinc metallopeptidase neprilysin (NEP) or conversion of Ang1-9 to Ang 1-7 via ACE, though at a significantly lower efficiency [17] . Genetic deletion studies have established ACE2 as an essential regulator of cardiovascular function [29] . Studies focused on the regulation of ACE2 in cardiac myocytes and cardiac fibroblasts have demonstrated that whereas Ang II significantly reduced ACE2 activity and downregulated ACE2 mRNA in cardiac myocytes, it only reduced ACE2 activity in fibroblasts [30] . In myocytes, endothelin-1 [ET-1] also significantly decreased ACE2 mRNA production. This reduction in ACE2 mRNA by Ang II or ET-1 was blocked by inhibitors of mitogen-activated protein kinase kinase 1 (MAPK1), suggesting Ang II and ET-1 activate extracellular signal-regulated kinase ERK1/ERK2 to reduce ACE2 [31] . Further in vivo murine studies showed Ang II mediated loss of membrane-bound cardiomyocyte ACE2 correlated with the upregulation of TACE/ADAM17 activity which was prevented with AT1 receptor blockade [32] . Cardiac fibroblasts and coronary endothelial cells also express ACE2 and TACE and this reciprocal relationship extends to these cell types as well [32, 33] . Ang II activates several other signaling cascades such as PKC and JAK2-STAT3 signaling pathways, which results in myocardial hypertrophy and increased fibrosis [34] . The binding of Ang1-7 to the C-terminal domain also inhibits the proteolytic function of ACE enzyme and promotes bradykinin function [35] . Studies in human vascular and cardiac tissue and plasma show Ang1-7 has a higher affinity to ACE than Ang I, suggesting Ang1-7's inhibitory effects on ACE may contribute to its protective effects [36] . The treatment of ACE2 knock out mice with Ang II infusion and recombinant ACE2 (rhACE2) eliminated ERK1/2, JAK2-STAT3, and PKC signaling by rhACE2 and was at least partially responsible for attenuation of Ang II induced myocardial hypertrophy and fibrosis and improvement in diastolic dysfunction [37] . Other studies have highlighted the role of ACE2/Ang-(1-7)/Mas axis in modulating the expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, MCP-1 and TGF-β in cardiac/lung fibrosis, pulmonary hypertension, and vascular remodeling [38] [39] [40] [41] [42] (Figure 1 ). Given the importance of the RAS system in cardiovascular disease, its regulation via ACE inhibitors, ARBs, and MRAs has played an essential role in the management of cardiovascular diseases (Central Illustration). Several studies have elucidated the role of these drug classes on the modulation of the ACE2/Ang1-7/Mas axis. Mouse peritoneal macrophages (MPMs) treated in vitro with aldosterone, demonstrated significantly increased ACE activity as well as ACE mRNA, and significantly reduced ACE2. However, in MPMs treated with NADPH oxidase inhibitor, aldosterone could not increase ACE or decrease ACE2 suggesting these effects to be mediated in part by NADPH oxidase [43] . These effects were also attenuated with treatment with an MRAeplerenone [43] . Human monocyte-derived macrophages obtained from patients with heart failure before and after one month of treatment with another MRA-spironolactone (25 mg/d), showed 47% reduction in ACE activity and 53% reduction in ACE mRNA expression; at the same time, ACE2 activity increased by 300% and ACE2 mRNA expression increased by 654% [43] . In mice treated for two weeks with eplerenone, cardiac ACE2 activity increased two-fold and was paralleled by increased ACE2 activity in macrophages [43] . This study demonstrated that the MRA reduced oxidative stress, decreased ACE activity, and increased ACE2 activity/expression, suggesting their protective role played by increased generation of Ang 1-7 and decreased formation of Ang II. Overall, aldosterone decreased ACE2 transcription through a nicotinamide adenine dinucleotide phosphate oxidase-mediated pathway [43] and in vascular smooth muscle cells, potentiated Ang II signaling with increased phosphorylation of extracellular signal-regulated kinase (ERK1/2) and c-Jun kinase (JNK) which are also dependent on reactive oxygen species generation [44] . Thus, the beneficial effects of MRAs are likely associated with reduction of oxidative stress and differential control of these angiotensinases. MRAs appeared to promote membrane ACE2 expression and suppress the peripheral effects of Ang II; however, the effect of MRAs on soluble ACE2 remains unclear. Similar upregulation of ACE2 was observed in studies focused on the effects of ARB treatment. Spontaneously hypertensive rats (SHR) treated with olmesartan demonstrated a 5-fold greater expression of ACE2 mRNA and increased Ang1-7 in thoracic aorta, while those treated with atenolol and hydralazine exhibited no change in ACE2 expression or Ang1-7 [45] . Comparison of vessel wall dimensions showed that olmesartan selectively reduced the thoracic aorta media-to-lumen ratio, while vascular hypertrophy was unchanged in SHR given atenolol or hydralazine [45] . There was no change in ACE2/Ang1-7 expression/activity in the carotid arteries of the treated animals. The possibility that the effects of olmesartan on vascular ACE2 gene and protein expression were the result of reduced arterial blood pressure was ruled out given the comparative effect observed in mice treated with atenolol or hydralazine [45] . Sprague-Dawley rats treated on a 4-week course of Ang II infusion showed Ang II upregulated AT1 receptor, downregulated AT2 receptor, ACE2 activity, eNOS expression and increased CD44 expression and hyaluronidase [46] . However, rats treated with telmisartan exhibited significantly increased ACE2 activity and eNOS expression in intracardiac vessels and intermyocardium as well as downregulated local expression of AT1 receptor. Treatment with telmisartan also inhibited membrane CD44 expression and reduced TGFβ and Smad expression [46] . Studies in normotensive rats with post coronary artery ligation left ventricular remodeling and dysfunction, exhibited partial resolution following losartan and olmesartan treatment while augmenting plasma concentrations of the angiotensins [47] . This was associated with recovery of cardiac AT1 receptor mRNA and increased ACE2 mRNA post myocardial infarction, implying the beneficial effects of ARBs on cardiac remodeling were accompanied by direct blockade of AT1 receptors and increased ACE2 expression/activity [47] . The literature offers conflicting results pertaining to ARB use and the level of ACE2 expression on myocardium; most of the controversy arises from the difference in the ACE2 cell surface expression and the plasma ACE2 levels. In the Sprague-Dawley rats with left coronary artery ligation and myocardial infarction, plasma Ang II and Ang 1-7 were not elevated but plasma ACE2 was elevated along with enhanced cardiac ACE2 and AT1 receptor mRNA at the infarct border [48] . Receptor upregulation was not observed in the remote myocardium [48] . Treatment with ramipril and valsartan resulted in increased plasma Ang I and Ang II and suppression in plasma ACE and ACE2 activity, however, neither monotherapy nor combination therapy affected ACE2 or AT1 receptor expression, both of which remained at levels comparable to non-myocardial infarction control [48] . However, a prior study in the same murine model showed ACE and ACE2 upregulation in the border, infarct zones and in viable myocardium after myocardial infarction, and treatment with ramipril reduced ACE expression while ACE2 remained elevated compared to non-infarcted control [49] . A recent study in the same murine model demonstrated that treatment with olmesartan or telmisartan increased both cardiac ACE2 mRNA and protein expression while augmenting plasma Ang 1-7/Ang II ratios resulting in improved cardiac function and alleviated collagen disposition [40] . These experiments suggest that both ACE inhibitors and ARBs variably upregulated ACE2 expression [50] . ARBs inhibit binding of Ang II to AT1 receptor, permitting circulating Ang II to be shunted to ACE2 for conversion to Ang1-7. These studies suggest the ACE2/Ang1-7 axis collaborates with or is regulated by AT1 receptor and may be important in mediating vascular and cardiac remodeling effects of Ang II. The mechanisms by which ACE inhibitors act are complex. Although ACE2 is not inhibited by ACE inhibitors [19] , an increase in Ang 1-7 suggests their clinical effects are partly mediated by the angiotensinases. ACE inhibitors inhibit the conversion of Ang I to Ang II and inhibit the hydrolysis of bradykinin. ACE inhibition promotes the vasodilatory effects of bradykinin, improved endothelium-dependent vasodilation through increased prostaglandin and nitric oxide production, and down regulation of AT1 receptor [51] [52] [53] . Studies elucidating the effect of ACE inhibition on the ACE2 gene have shown that the inhibition of Ang II synthesis regulated ACE2 mRNA, but not ACE2 activity [54] . However, ACE inhibition alone or in combination with losartan has demonstrated to increase plasma Ang1-7 while reducing plasma Ang II [54] . Compared to the degree of ACE2 mRNA upregulation seen post losartan monotherapy, combination of losartan and lisinopril resulted in suppressed upregulation of ACE2 mRNA suggesting ACE inhibitors may override a signal which regulates ACE2 transcription [54] . Although Ang II is the predominant substrate, ACE2 can also convert Ang I into Ang 1-9 which in turn could be converted to Ang 1-7 via ACE; Ang I can be directly converted into Ang 1-7 via NEP [17] , though with less favorable kinetics at baseline. Thus, one can assume ACE inhibitors disrupt the balance between catalytically active ACE and ACE2, resulting in favored activation of the ACE2/Ang1-7/Mas axis. Overall, given the demonstrated anti-inflammatory, anti-fibrotic, anti-thrombotic effects associated with ACE2/Ang1-7/Mas axis upregulation could serve as a valuable therapeutic target. Multiple murine studies demonstrated rhACE2 modulates the RAS pathway, though it is unclear if these effects translate to humans. A clinical study (NCT00886353) assessing the pharmacokinetics and pharmacodynamics of soluble rhACE2 treatment in healthy volunteers with no known comorbidities showed a decrease in plasma Ang 1-8 and increased Ang 1-7 and Ang 1-5 with no effect on blood pressure and heart rate [55] . Common side effects included diarrhea and headache. No antibodies to rhACE2 developed, suggesting there was no elicit immune response to single or repeated dosing [55] ; however, further studies investigating the immunogenicity of rhACE are required. In patients with ARDS and sepsis, serum levels of ACE and Ang II are elevated [56, 57] . Studies focused on microvascular dysfunction in sepsis showed that the degree of elevation in plasma renin and Ang II correlated with the extent of organ failure and degree of microvascular dysfunction, especially in patients receiving exogenous vasoconstrictors [57] ; there was also a negative correlation between reoxygenation rates and both concentrations of plasma renin and Ang II [57] . In a pilot clinical trial (NCT01597635), patients with ARDS that were treated with rhACE2 exhibited decreased plasma Ang II and elevated plasma Ang 1-7 and surfactant protein-D, which is involved in innate immunity [58] . IL-6 concentrations in treated patients were also reduced, albeit statistically insignificantly which was owed to intrasubject variability and baseline imbalance. Although rhACE2 attenuated RAS mediators, infusions of the medication did not show improvement in physiological or clinical measures of ARDs in this study [58] . An additional pilot study (NCT101884051) investigated the effects of rhACE2 in human pulmonary arterial hypertension which is characterized by reduced ACE2 activity [59] . Treatment with rhACE2 showed improved cardiac output which coincided with maximum suppression of plasma cytokines and reduction in nitrotyrosine levels, improved peripheral vascular resistance as well as improved renal perfusion [59] . Ongoing clinical studies assessing the modulation of RAS axis include 1) the assessment of the relative activity of ACE and ACE2 in diabetic patients following treatment with candesartan (NCT00192803) and 2) the overexpression of ACE2/Ang 1-7 in cardiac progenitor cells to assesses for enhancement in reparative function and potential to attenuate myocardial ischemia-induced cardiac damage (NCT02348515). It is evident that targeting the ACE2/Ang1-7/Mas axis is going to be interesting in clinical settings given the observed cardioprotective effects in the in vivo murine and in vitro cell culture models. However, further investigation is required to demonstrate whether these favorable experimental effects could be translated into clinical benefit. Several reports have noted COVID-19 is associated with cardiac involvement. In cohort studies of hospitalized patients with confirmed COVID-19, several patients presented with elevated troponin I, C-reactive protein, and NT-proBNP suggestive of myocardial injury [60] [61] [62] . Anecdotal studies have reported patients presenting with cardiac magnetic resonance imaginingverified acute myopericarditis with systolic dysfunction masquerading as diffuse ST-elevation myocardial infarction with elevated cardiac markers in the absence of obstructive coronary disease [60] . In a cohort study of 139 COVID-19 confirmed hospitalized patients in Wuhan, China, 7.2% had acute myocardial injury, 8.7% had shock, and 16.7% had an arrhythmia [63] . Of the observed patients, those with cardiac injury were found to have a high risk of death both from time of symptom onset and time of admission [62] . As more epidemiological studies emerge from China, Italy, and other affected areas, more data will be available to elucidate the clinical presentation of patients and the cardiovascular damage associated with this novel coronavirus. With regard to COVID-19, there are currently several clinical studies investigating the effects of RAS inhibition and ACE2 regulation. An ongoing study will assess the impact of ACE inhibitor and ARB treatment on the severity and prognosis of patients with COVID-19 (NCT04318301, NCT04318418). Along these lines, there are two recently launched trials testing the effects of losartan among patients hospitalized with COVID-19 (NCT04312009) and those who are ambulatory (NCT04311177). Further studies have been launched to evaluate the effect of continuation verses replacement (NCT04330300) or withdrawal (NCT04329195) of RAS inhibitors on the clinical outcomes in patients with cardiovascular disease and COVID-19. There is also an ongoing pilot study assessing the effects of rhACE2 treatment in patients with COVID-19 (NCT04287686). Currently, there is no data to support any conclusive effects of the use of RAS inhibitors in patients with COVID-19. SARS-CoV which emerged in the Guangdong province, China and SARS-CoV2 which emerged in Wuhan, China are closely related beta-coronaviruses whose affected receptor is ACE2 [1, 3, 4] . At this time, it is unknown if the approximate 76% sequence similarity between strains of viruses translates into similar biological properties [14] . Recent studies have confirmed COVID-19 exploits ACE2 for entry and thus may target a similar spectrum of cells as SARS-CoV [14] . SARS-CoV2 binds to ACE2 via its spike (S) protein [13, 14] . The surface unit S1, of the S protein binds to ACE2, which facilitates viral attachment to target cells. Following receptor binding, the virus must gain access to host cytosol, which is accomplished by acid-dependent proteolytic cleavage of the S protein by cellular serine protease TMPRSS2, which is similar to S protein priming in SARS-CoV [14, Figure 2 ]. Given the sequence similarity between SARS-CoV and SARS-CoV2, their affected receptor, and recently confirmed TMPRSS2-mediated viral entry, it is reasonable to hypothesize that SARS-CoV2 may act similarly with respect to utilizing host endocytosis machinery, subsequent virus propagation and further infection. Upon binding to ACE2, cleavage of the S protein at the S1/S2 sites and S2 allows for fusion of viral and cellular membranes. SARS-CoV is then internalized and penetrates early endosomes in a clathrin-dependent manner [64] . Viral binding to ACE2 appears to affect TNFα activity, which in the presence of calmodulin inhibitors promotes ectodomain cleavage [65] . In the case of SARS-CoV2, it is possible this shedding is also mediated by TNFα given one of the clinical features noted in COVID-19 patients was the presence of a cytokine storm with increased plasma concentrations of IL2, IL7, IL10, GCSF, IP10, MCP1, MIP1A, and TNFα [61] . It is also possible that ACE2 shedding may be mediated by other cytokines dysregulated in COVID-19. This shedding contributes to the down-regulation of membrane-bound ACE2 observed in severe acute lung injury [66] . Ectodomain shedding increases the concentration of plasma ACE2, which remains catalytically active, though the function of soluble ACE2 remains unclear. In patients with advanced heart failure, plasma ACE2 activity is increased in direct proportion with worsening clinical status and reduction in ejection fraction and correlates with adverse clinical outcomes [67] . Since down-regulation of bound ACE2 is observed in severe acute lung injury [67] and post myocardial infarction [47] , and concentrations of soluble ACE2 appears to correlate with clinical outcomes of heart failure patients [31] , it is possible to suggest that concentrations of soluble ACE2 may correlate to the extent of tissue damage sustained and may correlate to the degree by which systemic inflammatory pathways are upregulated. There is some evidence to suggest soluble ACE2 is able to regulate systemic Ang II. Clinical trials have shown rhACE2 could convert systemic Ang II to Ang 1-7 [58, 59] , and play some pathological, compensatory, or counter regulatory roles. If SARS-CoV2 does induce ACE2 ectodomain shedding resulting in the reduction of ACE2 entry sites on the infected cell, it is possible that following transcription S proteins fuse directly at the host cell membrane and directly promote infection of neighboring cells resulting in the formation of multinucleated syncytia [68] . Formation of multinucleated cells would allow the virus to spread without being detected or neutralized by virus-specific antibodies [68] . Otherwise, following replication and transcription, complete virion assembly in the Golgi would result in transportation of the virus in vesicles and release by exocytosis [68] . In the setting of full virion assembly and exocytosis, it is unclear if ACE2 ectodomain shedding would be favorable for further propagation and infection. Regardless of how SARS-CoV2 completes virion assembly, it is clear that membranebound ACE2 would play a physiological role in the replication of the novel virus. The question remains whether the use of ACE inhibitors, ARBs, and MRAs should be avoided in the setting of SARS-CoV infection given each agent [43] [44] [45] [46] [47] 54] upregulates ACE2 expression and activity. Lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse models, exhibited decreased expression of ACE2, lung and inflammatory injury, however, this was ameliorated by the injection of cells transfected with ACE2 and results in the improvement of lung function and lung injury. Treatment of these mice with ACE inhibitors and ARBs also alleviated LPS-induced pneumonic injury [69] . Prior studies have shown the SARS-CoV S protein can exaggerate acute lung failure through deregulation of the renin-angiotensin system. However, SARS-CoV Spikemediated lung failure could be rescued by inhibition of AT1 receptor [69] . Again, adequate data on the effects of RAS inhibition in COVID-19 patients is not available, and the ongoing clinical/observations studies are being conducted (NCT04318301, NCT04318418, NCT04312009, NCT04311177, NCT04287686, NCT04330300, NCT04329195). If SARS-CoV2 downregulates membrane-bound ACE2 by promoting ADAM17 mediated ectodomain shedding resulting in increased concentrations of soluble ACE2 without compromising viral propagation, we hypothesize this would result in the overall downregulation of the ACE2/Ang1-7/Mas pathway which would contribute to the severity of inflammation and systemic dysregulation observed in SARS-CoV2. Thus, in patients with cardiovascular disease and SARS-CoV2, the use of ACE inhibitors, ARBs, or MRAs may be favorable as a method to endogenously upregulate ACE2 as a compensatory mechanism that provides anti-inflammatory, anti-fibrotic and anti-thrombotic support as well as reduction in progression of vascular/cardiac remodeling and heart failure. Several societies including the American College of Cardiology, American Heart Association, Heart Failure Society of America [70] , European Society of Cardiology [71] , have recommended continuing RAS system antagonists given the lack of conclusive data on a link between upregulation of systemic or tissue ACE2 and the increased susceptibility to COVID-19 in patients with cardiovascular disease. Based on our review, we hypothesize cardiovascular patients with COVID-19 should remain on RAS system inhibitors given the protective effects of the ACE2 pathway until RAS blockade is proven to increase the risk to COVID-19. • COVID-19 has been associated with cardiac involvement. SARS-Cov2 requires binding to ACE2 in the RAS system. • ACE2/Ang1-7/Mas pathway counterbalances the RAS system resulting in activation of antiinflammatory pathways. • ACE inhibitors, ARBs, and MRAs upregulate ACE2 activity and expression. • More data is required to determine if regulation of ACE2 in patients with cardiovascular disease and COVID-19 would help improve clinical outcomes. Central Illustration. The RAS system interaction with COVID-19. Normally, Ang I is converted to Ang II via ACE which could be inhibited by ACE inhibitors. 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We would like to thank Kristen Amodio for her contribution during discussions. other tissues stimulates pathways responsible for hypertrophy, fibrosis, oxidative stress, and apoptosis. These effects are attenuated by ARBs which block Ang II binding to AT1R. Ang II can also be converted to Ang 1-7 via ACE2 which stimulates the Mas receptor promoting antiinflammatory benefits. The ACE2/Ang1-7/Mas axis acts as a counter regulatory pathway to the traditional RAS system. AT1R and ACE2 are coupled. Ang II binding to AT1R allows dissociation of ACE2 and subsequent degradation. ARB prevents dissociation of ACE2 and renders it availability for unused Ang II conversion to Ang 1-7. ACE2 has been identified as the targeted receptor for both SARS-CoV2 and SARS-CoV. ACE2 mediates S protein binding which stimulates viral entry into the host cytosol resulting in infection and viral replication.Diversion of Ang II towards ACE2 could competitively inhibit viral binding, and also counter regulate the adverse effects caused by AT1R and improve outcomes by Mas R based favorable effects.