key: cord-0799383-za4x9igf
authors: Wang, James Jiqi; Edin, Matthew L.; Zeldin, Darryl C.; Li, Chenze; Wang, Dao Wen; Chen, Chen
title: Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities
date: 2020-07-09
journal: Pharmacol Ther
DOI: 10.1016/j.pharmthera.2020.107628
sha: e4de29180db9ca02de1311fe7d53250f6d86db9f
doc_id: 799383
cord_uid: za4x9igf

The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin–angiotensin–aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.

clinical outcomes observed with RAAS inhibitors in COVID-19 patients.

Human CoVs (HCoVs) belong to the Coronavirinae subfamily that are classified into 4 phylogenic clusters: α, β, γ, and δ CoVs (S. F. Zhang, et al., 2018) . Among all CoVs, 7 prominant strains from the α and β subgroups can infect humans (Madjid, Safavi-Naeini, Solomon, & Vardeny, 2020) . Of these 7 human-infectious CoVs, 4 (HCoV-NL63, HCoV-HKU1, HCoV-OC43 and HCoV-229E) cause self-resolving upper respiratory tract infections that are the second-most common cause (15%-30%) of the common cold (Killerby, et al., 2018; Su, et al., 2016) . Clinical manifestation vary in different strains of CoVs.

HCoV-NL63, HCoV-HKU1, HCoV-OC43 and HCoV-229E mainly cause mild symptoms, but can cause organ damage in some individuals. For example, Giacomo et al. reported that HCoV-OC43 triggered fulminant myocarditis in a 51-year-old woman (Veronese, et al., 2020) . van Doremalen, Falzarano, & Munster, 2016) . While these three viruses can induce respriratory distress, they each have distinctive properties (Table 1) . SARS-CoV-2 is most infectious, with a reproductive number (R 0 ) estimated by the WHO of 2.0-2.5. By comparison, SARS-CoV and MERS-CoV have respective R 0 estimates of 1.7-1.9 and 0.7, respectively (Petrosillo, SARS-CoV-2 binds to the same surface protein (ACE2) while MERS-CoV enters host cells via binding to dipeptidyl peptidase 4 (DPP4) (Petrosillo, et al., 2020) . Relative to the SARS-CoV spike protein, the SARS-CoV-2 spike protein contains several amino acid changes which increase salt bridge formation and hydrophobic interactions and strengthen ACE2 binding (Gheblawi, et al., 2020) .

These changes may contribute to virulence and the considerably larger global spread of SARS-CoV-2 compared to SARS-CoV (Gheblawi, et al., 2020) .

ACE2 is a transmembrane protein that plays a central role in downregulation of RAAS (Gheblawi, et al., 2020) . When co-expressed with transmembrane protease serine 2 (TMPRSS2), ACE2 acts as receptor for SARS-CoV-2 cell entry (Guzik, et al., 2020) . ACE2 expression is considerably reduced after SARS-CoV and SARS-CoV-2 infection (Jung, Choi, You, & Kim, 2020) . Interaction between ACE2 and the receptor binding domain (RBD) of the S1 subunit on the viral spike protein facilitates virus entrance. Endocytosis of SARS-CoV-2 along with ACE2 into endosomes reduces surface ACE2 expression (K. Wang, Gheblawi, & Oudit, 2020) . Viral entry of SARS-CoV-2 subsequently upregulates ADAM metallopeptidase domain 17 (ADAM-17), which mediates ectodomain shedding of ACE2 (Patel, et al., 2014) . ADAM-17 activation also mediates liberation of membrane bound cytokine precursors, including IL-4 and IFN-γ which repress ACE2 mRNA expression (K. . SARS-CoV-2 activation of RAAS combined with reduced ACE2-mediated conversion of angiotensin II (Ang II) to Ang-(1-7) results in increased AngII accumulation. Ang II activates the angiotensin receptor type 1 J o u r n a l P r e -p r o o f receptor (AT1R) to trigger a signaling cascade whereby activation of ERK/p38 MAP kinase signaling results in upregulation of ADAM-17 to initiate a positive feedback loop that limits ACE2 expression (Patel, et al., 2014) . In addition, inflammation-induced lung injury leads to apoptosis of Clara cells and type II alveolar epithelial cells, which are major ACE2-expressing cell subsets.

Reduced survival of these cells also contributes to the down-regulation of ACE2 ( Figure 2) (Wiener, Cao, Hinds, Ramirez, & Williams, 2007) .

Clinical outcomes in COVID-19 patients are strongly associated with the pre-existing health status of infected patients. CVD comorbidities increase mortality of patients with COVID-19 (Shahid, et al., 2020) . CVD comorbidities have direct consequences upon SARS-CoV2 infection. For example, patients with abnormally high blood pressure may exhibit increased apoptosis, not only in the heart but also in the kidney, which may be exacerbated by the additional stress of SARS-CoV2 infection (A. Gonzalez, et al., 2003; Hamet, et al., 1995) .

Over the course of severe COVID-19, biomarkers indicating heart injury become elevated (Mehta, et al., 2020; . In a Washington state case series of 21 critically ill COVID-19 patients, 7 patients (33%) developed cardiomyopathy and 4 (19%) developed acute renal injury (Arentz, et al., 2020) . ACE2 expression in human heart might be one potential mechanism underlying heart injury during infection with SARS-CoV-2; however, SARS-CoV-2 infection-induced cytokine storm may also contribute to cardiovascular injury (L. Chen, Li, Chen, Feng, & Xiong, 2020) .

Tissue kallikrein produces kinin and bradykinin peptides by cleaving its J o u r n a l P r e -p r o o f substrate kininogen. In addition to its role in production of angiotensin II, ACE mediates bradykinin degradation. Thus, both kinin and bradykinin are increased with use of ACE inhibitors ( Figure 3 ). Increased bradykinin levels are believed to be responsible for the dry cough adverse effect observed in some patients on ACE inhibitors. Moreover, kinin and bradykinin peptides can also participate in shock and respiratory allergy. Thus, well-known side effects suggest that ACE inhibitors may aggravate lung inflammation and cause lung dysfunction during COVID-19.

Despite the potential adverse effect of dry cough on respiratory tract, the kallikrein/kinin system (KKS) has many positive functions which may ameliorate CVD ( Figure 3 ). In experimental models, the expression of human tissue kallikrein caused significant reduction of blood pressure in fructose-induced hypertension rats, but did not affect blood pressure of non-fructose-fed normal rats (Yao, Yin, Shen, Chao, & Chao, 2007) .

Accumulating evidence indicates that the KKS is capable of exerting organ protection apart from its blood pressure-lowing effect. An in vivo study showed that the infusion of kinin improved renal function of hypertensive rats and lowered the corresponding increase in capase-3 activity .

Recombinant adeno-associated virus (rAAV) mediated human tissue kallikrein exerted a protective effect on myocardial apoptosis in spontaneous hypertensive rats (SHRs), specifically by modulating the activity of caspase-3 through the B2 receptor (Yan, Wang, & Wang, 2009 ). Tissue kallikrein not only reduced blood pressure, but also attenuated remodeling of the myocardium, large blood vessels and kidney (T. Wang, et al., 2004) . In addition, tissue kallikrein efficiently protected against diabetic nephropathy and chronic renal J o u r n a l P r e -p r o o f failure (Tu, et al., 2008; Yuan, et al., 2007; Zhao, et al., 2003) . It has also been suggested that tissue kallikrein prevents apoptosis and ventricular remodeling after myocardial infarction (Yao, et al., 2007) .

In summary, bradykinin may improve blood pressure regulation and provide organ protection in hypertensive patients. Since organ injury often determines mortality in hypertensive patients infected with SARS-CoV-2, we hypothesize that the 'by product' of increased bradykinin levels induced by ACE inhibition may provide more benefit than harm in CVD-comorbid COVID-19 patients.

Many studies have demonstrated that Ang II-induced hypertension and the accompanying vascular inflammation result in organ damage (D. Chen, et al., 2019; F. Chen, et al., 2017; G. E. Gonzalez, et al., 2015; Yang, et al., 2018) .

Il6 markedly attenuates the cardiac injury and inflammation induced by Ang II, which suggests that IL-6 acts downstream of the Ang II effector (D. Chen, et al., 2019; F. Chen, et al., 2017; G. E. Gonzalez, et al., 2015; Yang, et al., 2018) .

Ang II also induces the production of other pro-inflammatory cytokines, such as TNF-α and IL-1β (Guo, et al., 2011) . Several studies suggest that Ang II not only acts as a vasoactive peptide that regulates blood pressure but also works as an inflammatory cytokine causing cardiovascular remodeling (Gibbons, Pratt, & Dzau, 1992; Griendling, Minieri, Ollerenshaw, & Alexander, 1994; Sadoshima & Izumo, 1993) . During the immune response activated by SARS-CoV-2, a cytokine storm is often observed. In severe cases, serum J o u r n a l P r e -p r o o f levels of pro-inflammatory cytokines including IL-6, IL-2R, and IL-1β are elevated Qin, et al., 2020; Xu, et al., 2020) . Increased markers of this cytokine storm, such as serum IL-6, predict poor outcome in patients with severe COVID-19 (Cao, 2020) . COVID-19 patients also have elevated Ang II levels which are positively associated to viral load and lung injury . Thus, SARS-CoV-2 infection dysregulates Ang II, over-activates the immune response and augments the cytokine storm that causes organ damage. The inhibition or the blockage of RAAS may be helpful to attenuate the inflammatory storm and prevent end-organ damage.

ACE2 plays an important role in the regulation of angiotensin signaling.

The generation of Ang II is well understood. Liver-derived angiotensinogen (ATG) is cleaved by renin into Ang I, which is further processed by ACE to Ang II, and is converted by ACE2 into Ang-(1-7). Ang-(1-7) is generally considered CVD-protective; it counters the action of Ang II through a G protein-coupled SARS-CoV-2 uses ACE2, abundantly expressed in pulmonary epithelium, kidney and heart, for intracellular entry (Figure 3 ). After infection by SARS-CoV-2, ACE2 expression is reduced (Crackower, et al., 2002; Kuba, et al., 2005) . Animal models of infection with SARS-CoV showed that ACE2 downregulation resulted in pro-inflammatory responses, including lung injury and cardiac contractility impairment (Crackower, et al., 2002; Imai, et al., 2005; Kuba, et al., 2005) . If SARS-CoV-2 infections progress similarly to SARS-CoV, the virus may deteriorate a patient's condition via two production and contribute to tissue damage in COVID-19. Although ACE inhibitors and ARBs do not directly affect ACE2, they can indirectly lead to increased ACE2 activity and Ang-(1-7) expression (Hanff, Harhay, Brown, Cohen, & Mohareb, 2020) . A study by Ferrario and co-workers showed that ACE inhibitor caused a 2.5-fold rise of plasma Ang-(1-7) concentrations and an approximately 25% increase of ACE2 expression in the left ventricle (Ferrario, et al., 2005) . Thus, the usage of ACE inhibitors and ARBs may have a potential benefit in preventing COVID-19-triggered organ damage via its upregulation of Ang-(1-7) and depletion of Ang II.

In conclusion, dysregulation of RAAS due to increased Ang II and decreased ACE2 can lead to a harmful inflammatory response and worsening J o u r n a l P r e -p r o o f of elevated blood pressure. ACE inhibitors and ARBs may have a potential role in preventing the harmful effects by directly countering Ang II and upregulating ACE2.

Acute respiratory distress syndrome (ARDS) is a common and devastating (Orfanos, et al., 2000) . ACE activity is considerably elevated in the bronchoalveolar lavage fluid (BALF) of J o u r n a l P r e -p r o o f patients with ARDS (Idell, et al., 1987) . A polymorphic insert that reduces ACE expression and activity is associated with reduced ARDS severity (Marshall, et al., 2002) . ACE expression activates macrophage function and stimulates interleukin (IL) formation . COVID-19 is associated with an increased proportion of mononuclear phagocytes which are regulated by the RAAS (Merad & Martin, 2020) . In addition, alveolar macrophages are associated with tissue repair and fibrosis generation in COVID-19 patients (Ramachandran, et al., 2019) . Lastly, ACE inhibitors decrease oxygen free radical production generated by lung alveolar macrophages (Suzuki, et al., 1999 (Yamamoto, et al., 1997) .

Ang II can also induce endothelial expression of IL-8, E-selectin, P-selectin, CC-chemokine ligand-5 (CCL5) and CCL2 which increase pulmonary leukocyte recruitment and retention (Bernstein, et al., 2018) . Moreover, Ang II induces nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in vascular smooth muscle cells and endothelial cells to increase reactive oxygen species (ROS) and cause vascular injury (Bernstein, et al., 2018) . In addition, Ang II reduces alveolar epithelial cell survival by accelerating cellular J o u r n a l P r e -p r o o f apoptosis with an EC 50 of just 10 nM (R. Wang, et al., 1999) . Epithelial apoptosis is linked to subsequent fibrotic responses (Shetty, et al., 2017) . (Uhal, et al., 2012) . Finally, during the severe ARDS or COVID-19, patients often suffer from septic shock.

Prolonged Ang II signaling induces AT1R phosphorylation and desensitization which is a major cause of the vascular hyporesponsiveness that leads to pulmonary vasoplegia (Levy, et al., 2018) . Together, this data suggests that Ang II may be a potential therapeutic target for the treatement many vascular pathophysiologies of COVID-19.

Ang II. Lower ACE2 has deleterious cardiovascular consequences and also worsens lung functional decline. Compared to WT mice, Ace2-deficient mice had impaired lung function and higher mortality in sepsis-induced lung injury . Severe lung failure in Ace2-deficient mice could be rescued J o u r n a l P r e -p r o o f by inactivation of ACE and AT1R blockage . ARBs can prevent downregulation of ACE2 during LPS-induced ARDS, suggesting that RAAS inhibitors may also protect against lung damage in patients with SARS (Wosten-van Asperen, et al., 2011) . Furthermore, downregulation of ACE2 can lead to elevated activation of ACE and Ang II (Li, et al., 2008; Simoes e Silva, et al., 2013) , which can exacerbate the physiological progression of ARDS in COVID-19. Thus, despite acting as the receptor for SARS-CoV-2, ACE2 activity is likely protective during COVID-19 disease progression.

In conclusion, elevation of ACE and Ang II and down-regulation of ACE2

can exacerbate SARS-CoV-2 induced ARDS. Drugs that target ACE and Ang II, ACE inhibitors and ARBs, may play an important role in abrogating the inflammatory response, vasoconstriction and V/Q mismatching that causes clinical deterioration in patients with COVID-19.

Animal models and clinical experience suggest both beneficial and deleterious effects of ACE inhibitors and ARBs in patients suffering from COVID-19. This uncertainty raises concerns regarding the overall effect of RAAS inhibitors after SARS-CoV-2 infection (Sriram & Insel, 2020) . Such concerns should not be ignored. Examination of clinical outcomes of RAAS inhibitor application in COVID-19 patients should be a top priority (G. L. Zhou, et al., 2013) .

Accumulated clinical data demonstrates that hypertension is associated with higher mortality in patients with COVID-19, SARS and Middle East Respiratory Syndrome (MERS) (D. . inhibitors in COVID-19-related outcomes in South Korea (Jung, et al., 2020) .

Among the 5,179 confirmed SARS-CoV-2 patients, RAAS inhibitor use did not alter mortality (adjusted OR, 0.88; 95% CI, 0.53-1.44; p=0.60) (Jung, et al., 2020) . Among hospitalized COVID-19 patients with hypertension, in-hospital mortality was lower (9%) in patients given RAAS inhibitors than those not treated with RAAS inhibitors (13%) although this difference was not statisticaly significant (p=0.14) (Jung, et al., 2020) . Multivariate analysis that adjusted for baseline co-morbidities revealed no independent association between RAAS inhibitor use and risk mortality among hypertensive COVID-19 patients (adjusted OR, 0.71; 95% CI, 0.40-1.26; p=0.25) (Jung, et al., 2020 (Mancia, et al., 2020) . These data suggest that treatment with ACE inhibitors/ARBs did not increase the inhibitor-treated subjects may seek more routine or intensive medical care or have heightened awareness that leads to more diligent hygiene and/or social distancing. In addition, these findings may not replicate in other populations.

Geographically and ethnically diverse cohorts and randomized, controlled clinical trials are needed to better understand the specific effect of RAAS inhibitors in COVID-19 patients.

Two recent studies suggest the interesting finding that, while ACE inhibitors might reduce COVID-19 morbidity, ARBs have a less pronounced effect. Khera et al. reported that of 2,263 hypertensive SARS-CoV-2 patients, those treated with ACE inhibitors were 40% less likely to be hospitalized than those not treated with ACE inhibitors, while there was no reduction in hospitalization in patients treated with ARBs (Khera, et al., 2020) . Milne et al. J o u r n a l P r e -p r o o f analyzed gene expression of 1,051 lung tissue samples and discovered that ACE inhibitor treatment was associated with significantly lower expression of the ACE2 co-receptor TMPRSS2. In contrast, TMPRSS2 expression was not altered in patients treated with ARBs (Milne, Yang, Timens, Bosse, & Sin, 2020) . These data provide a potential mechanistic explanation for a protective role of ACE inhibitors, but not ARBs, in COVID-19 treatment.

Our review of the recent literature suggests potential for protective effects of continued treatment of CVD COVID-19 subjects with ACE inhibitors and/or 

The authors have declared that no competing interests exist. and ARB, angiotensin-receptor blocker. 

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We thank all our colleagues from the Division of Cardiology, Tongji Hospital, as well as all the medical staff fighting against COVID-19, for their tremendous efforts.J o u r n a l P r e -p r o o f Journal Pre-proof