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Abstract

Coronavirus disease 19 (COVID-19) originated in Wuhan, China, in December 2019 has been declared pandemic by World Health Organization due to an exponential rise in the number of infected and deceased persons across the globe. Emerging reports suggest that susceptibility and mortality rates are higher in patients with certain comorbidities when compared to the average population. Cardiovascular diseases and diabetes are important risk factors for a lethal outcome of COVID-19. Extensive research ensuing the outbreak of coronavirus-related severe acute respiratory syndrome in the year 2003, and COVID-19 recently revealed a role of renin–angiotensin system (RAS) components in the entry of coronavirus wherein angiotensin-converting enzyme 2 (ACE2) had garnered the significant attention. This raises the question whether the use of RAS inhibitors, the backbone of treatment of cardiovascular, neurovascular, and kidney diseases could increase the susceptibility for coronavirus infection or unfortunate outcomes of COVID-19. Thus, currently, there is a lack of consensus regarding the effects of RAS inhibitors in such patients. Moreover, expert bodies like American Heart Association, American College of Cardiology, and so on have now released official statements that RAS inhibitors must be continued, unless suggested otherwise by a physician. In this brief review, we will elaborate on the role of RAS and ACE2 in pathogenesis of COVID-19. Moreover, we will discuss the potential effect of the use and disuse of RAS inhibitors in patients having COVID-19 with cardiometabolic comorbidities.

Keywords

COVID-19 SARS ACE2 renin–angiotensin system cardiovascular disease hypertension

Introduction

Coronavirus disease 19 (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹ It was first reported in Wuhan city of the Hubei province in China. Within a few months, it reached pandemic proportions with registered cases in almost every country on earth. By March 30, the number of reported tested positive cases was 746 112 with 35 347 deaths across all continents and most territories.² Although the genetic sequence of SARS-CoV-2 and severe acute respiratory syndrome coronavirus (SARS-CoV), the coronavirus that caused the 2002 to 2003 outbreak in Asia, shares only 79.5% of sequence homology, the 2 viruses differ significantly in the way they spread. They share the same receptor for entry into the host cell, that is, angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme 2 is an essential component of the renin–angiotensin system (RAS) that has a central role in maintaining cardiovascular homeostasis. Its different components include ACE, angiotensin II, angiotensin II receptor type 1 (AT1R), and angiotensin II receptor type 2 (AT2R). It is well known that in patients with cardiovascular disease (CVD) or chronic kidney disease (CKD), there is RAS overactivation that is commonly addressed by long-term therapy with RAS modulators. In view of the fact that COVID-19 per se can lead to acute cardiac injury,⁶ the risk-benefit assessment for continuing RAS inhibition in patients with CVD or CKD is under debate.

The reports regarding the usage of RAS inhibitors (AT1R blocker [ARBs] and ACE inhibitors [ACEi]) in patients having COVID-19 with cardiometabolic disorders are conflicting. Some reports reveal increased ACE2 expression after RAS inhibitors usage,^3,4 which is the receptor used by the COVID-19 virus for the entry, hence advocating its discontinuation. Contrarily reports also suggest that ARBs do not have any significant effect on ACE2 expression.⁵ Moreover, ongoing clinical trials are exploring the usage of the ARB losartan for treating patients with COVID-19.⁶ Patients having COVID-19 with cardiorenal comorbidities have a high baseline risk for cardiovascular or renal events and an immediate withdrawal of RAS inhibitors may also precipitate cardiovascular and renal injury. Thus, some advocate to discontinue RAS modulators in patients with COVID-19. This review intends to discuss in detail the use or disuse of RAS modulators and significant implications in cardiorenal-COVID-19 comorbidity.

Coronavirus Disease 19 and Associated Cardiorenal Comorbidities

Studies suggest that individuals with underlying diseases are more susceptible to COVID-19. Such cases require special monitoring since the majority of the COVID-19 mortality is attributed to either old age or presence of one or more underlying diseases such as hypertension, diabetes, CVD, and so on. Huang et al reported that of 41 admitted patients, 20% had diabetes and 15% had hypertension and a cardiovascular disorder.⁷ Zhou et al analyzed a larger set of patients (191) among which 91 (48%) people had a comorbidity with hypertension (30%) being the most prevalent succeeded by diabetes (19%) and coronary artery disease (8%).⁸ McMichael et al in an epidemiological study in Washington found that kidney diseases (25.7%) were as common as to cardiac diseases and hypertension.⁹ Similar trends were reported by other authors as well (Table 1). As per a report from Italy, the most common co-morbidities amongst a total 3200 death cases due to COVID-19 were ischemic heart disease 145 (30.1%), atrial fibrillation 106 (22.0%), stroke 54 (11.2%), hypertension 355 (73.8%), chronic kidney disease (20.2%) and diabetes 163 (33.9 %).²¹ Another report revealed that CVD (10.5%) and diabetes (7.3%) were the top 2 contributors to the global case fatality rates.²² Cheng et al found that kidney disease including precipitation of acute kidney injury is a significant and independent factor of mortality in patients with COVIID-19.²³ Further emerging reports suggest that SARS-CoV-2 infection accelerates kidney abnormalities as evidenced by elevated creatinine, blood urea nitrogen along with hematuria, proteinuria, and albuminuria in such patients.²⁴ The possible reason behind the high level of mortality could be the ability of COVID-19 to cause direct injury to the heart, kidneys, liver, and so on beyond viral pneumonia. In a research letter, Shi et al developed a host risk score and found that CVDs are host risk factors to develop severe COVID-19 stressing upon the potential role of the RAS in the pathogenesis of this malady.²⁵

Table 1.

Coronavirus Disease 19 and Cardiometabolic Comorbidities.

Authors	Total No. of Patients	N (%)				Ref
Authors	Total No. of Patients	Comorbidities	Diabetes	Hypertension	Cardiovascular Disease	Ref
Cao et al	198	69 (34.8)	15 (7.6)	42 (21.2)	12 (6.0)	¹⁰
Huang et al	41	13 (31.7)	8 (19.5)	6 (14.6)	6 (14.6)	⁷
Chen et al	99	50 (50.5)	12 (12.1)	–	40 (40.4)	¹¹
Chen et al	29	16 (55.2)	5 (17.2)	8 (27.6)	–	¹²
Guan et al	1099	255 (23.2)	81 (7.4)	164 (14.9)	27 (2.5)	¹³
Kui et al	137	27 (19.7)	14 (10.2)	13 (9.5)	10 (7.3)	¹⁴
Liang et al	1590	18 (1.1)	2 (0.1)	2 (0.1)	–	¹⁵
Song et al	51	11 (22)	3 (6.0)	5 (10)	1 (2.0)	¹⁶
Wang et al	138	64 (46.4)	14 (10.1)	43 (31.2)	20 (14.5)	¹⁷
Wang et al	69	–	7 (10)	9 (13)	8 (12)	¹⁸
Yang et al	52	21 (40.4)	9 (17.3)	–	5 (9.6)	¹⁹
Zhang et al	9	1 (11.1)	1 (11.1)	–	–
Zhang et al	140	90 (64.3)	17 (12.1)	42 (30.0)	7 (5.0)	²⁰

Coronavirus Disease 19 and the RAS

Coronavirus disease 19 takes a severe course in patients with CVD and diabetes.^26,27 In a recent survey of 45 000 confirmed cases in China, case fatality rate was 10.5% and 7.3% for CVD and diabetic patients, respectively. The underlying pathophysiology of these disorders is highly associated with an altered RAS that is of particular interest to clinicians as well as investigators.²⁸ In general, the RAS is comprised of 2 arms: conventional and nonconventional axis, in which one exerts comparatively opposite functions to the other.²⁹ In the conventional axis, ACE facilitates the conversion of angiotensin I to angiotensin II, a vasoactive peptide which exert its vasoconstrictive action via AT1R (Figure 1). In contrary, the nonconventional axis contains ACE2, which converts angiotensin I to angiotensin 1 to 9 and angiotensin II to angiotensin 1 to 7. Both biologically active downstream peptides contribute to vasodilatory property, which is further accompanied by antifibrotic, antiproliferative, and anti-inflammatory effects.^30,31

Figure 1.

Interplay between SARS-CoV-2 and renin–angiotensin system: Representative figure shown the conversion of angiotensin II to angiotensin 1 to 7 and angiotensin I to angiotensin 1 to 9 via (ACE2). Angiotensin-converting enzyme 2 also binds and internalizes the SARS-CoV-2 into the type II pneumocytes, via its functional receptor ACE2, which leads to net rise in inflammation, fibrosis, apoptosis, and vasoconstriction. However, after ACEi/ARBs usage leading to attenuate inflammation, fibrosis, apoptosis, and cause vasodilation. ACE2 indicates, angiotensin-converting enzyme 2AT1R, angiotensin II type 1 angiotensin receptor; AT2R, angiotensin II type 2 angiotensin receptor; MasR, Mas receptor; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Coronavirus Disease 19 and ACE2 Pathogenicity

Although numerous studies reported that SARS-CoV-2 utilizes the identical membrane-bound ACE2 to enter into the target cells,^32

-35 studies also suggest that receptors and cofactors other than ACE2 could also play a role in viral infection.^36,37 Basically, ACE2 is a carboxypeptidase that specifically eliminates carboxy-terminal hydrophobic or basic amino acids.³⁸ With respect to the high expression of ACE2 in epithelia of the mouth and tongue, it is the most accessible path for the entry of SARS-CoV-2.³⁹ In normal physiology, ACE2 is also expressed on type I and II alveolar epithelial cells in lower lung areas. Upon contagion, the spike glycoprotein of SARS-CoV-2 binds to the ACE2 present on alveolar surface (Figure 1). This binding further triggers the clathrin-dependent endocytosis of the entire SARS-CoV-2 and ACE2 complex and fused to the cell membrane. Low pH and the pH-dependent endosomal cysteine protease cathepsins avoid the energetically adverse membrane fusion reaction and promote endosomal cell entry of SARS-CoV-2.^40,41 In alveolar cells, SARS-CoV-2 emprises the anterior transcriptional machinery to multiply and proliferate throughout the lung.⁴¹ Targeting the essential role of pH for SARS-CoV-2 processing and internalization, the antimalarial drug hydroxychloroquine seems to exert an effective antiviral activity via increasing the endosomal pH.⁴² During COVID-19, the continue accumulation of debris and fluids in the lungs hinders the physiological role of ciliated cells within airway, that is, clearing the airways. Studies considered the ACE2-binding affinity as the critical determinant in the SARS-CoV-2 contagion, therefore, identification of the detailed receptor-binding domain (RBD) of the spike glycoprotein on the virion envelope has been given high priority.^43
-45 Studies have found that the arrangement of the SARS-CoV-2 RBD motif exerts similar pattern to that of SARS-CoV. Coronavirus S glycoprotein is surface exposed and interposes its entry to host cells. The compact binding to human ACE2 might partially explain the effective transmission of SARS-CoV-2 in humans, similar to the case of SARS-CoV, and hence confirming ACE2 as entry receptor for SARS-CoV-2.^45,46 In addition, single mutation at RBD that notably increased its binding affinity to ACE2, signifying the drastic evolution of SARS-CoV-2 to spread infection amid large populations.⁴⁵ Due to the presence of higher number of contacts, broad interface area of SARS-CoV-2–ACE2 complex, scientists have explored an extraordinary evolutionary path chosen by coronaviruses toward host recognition. Thus, the adaptability of cell receptor binding approaches has instant inferences on the development of therapeutic strategies.⁴⁷ An investigation has been carried out on altered ACE2 expression with respect to individual race, age, sex, and smoking status that one may identify the differences in patients susceptibility toward COVID-19.⁴⁸ Five large-scale transcriptomic data sets of normal lung tissue and 2 single-cell transcriptomic data sets were conducted on behalf of COVID-19 and revealed the higher ACE2 gene expression in former smokers’ lungs in comparison to nonsmokers’ lungs, signifying that smoking might serve as a major risk factor for COVID-19 susceptibility. However, differences in ACE2 gene expression did not associated with individual age (young vs old), race (Asian vs Caucasian), age and sex (male vs female).⁴⁸

Pharmacologically, the production of angiotensin II could be reduced by ACEi and ARBs via hindering the binding of angiotensin II with AT1R,⁴⁹ whereas, many studies demonstrated that ACEi and ARBs indirectly increased the ACE2 expression that might be beneficial for controlling blood pressure.⁵⁰ At present, it has been recognized that the effect of RAS inhibitors on ACE2 is due to increased systemic, cardiac, and renal ACE2 expression. However, it is not clearly known whether RAS inhibitors exert any effect on ACE2 in airway epithelial cells.³⁶ Angiotensin-converting enzyme 2 is known to participate in normal cardiac function and the progression of CVD.^51,52 Thus, in patients with SARS-CoV-2 infection, underlying cardiovascular and renal disease might aggravate the pneumonia and upsurge the severity of symptoms by increased expression of ACE2 in the epithelium of the respiratory tract.⁵³ Therefore, usage of ACEi and ARBs in heart and kidney function compromised patients with COVID-19 should be carefully examined. Other drug classes like glitazones (thiazolidinediones) and nonsteroidal anti-inflammatory drugs (ibuprofen) were also reported to increase ACE2 levels but the data are very limited.

Reports Advocating the Use of RAS Modulators in Patients With COVID-19

Angiotensin-converting enzyme 2 inhibitors/ARBs are the most extensively used classes of antihypertensive agents, with clinically proven advantages in patients with hypertension, diabetes, heart failure, and CKD. The use of ARBs such as telmisartan or valsartan and ACEi such as enalapril and ramipril could be promising therapeutic strategies to control blood pressure also in patients with COVID-19 pneumonia.⁵⁴ In a concise review, Kuster et al concluded that the use of ACEi and ARBs therapy in the patients having COVID-19 with CVDs such as myocardial infarction, heart failure, or hypertension is helpful and should be maintained.³⁷ Furthermore, one recent clinical study has suggested the use of ARBs for potential repurposing treatment of COVID-19.⁵⁵ Additionally, the European Society of Hypertension and the European Society of Cardiology released official statements and recommended that treatment with RAS inhibitor should be as conservative as possible in those patients who are diagnosed with COVID-19 or at high risk of COVID-19 infection.⁵⁶

In 2008, Penninger et al filed the patent application under the title of use of RAS inhibitors for the treatment of lung injuries and also for lung edema’s associated with SARS-CoV-1 infection.⁵⁷ In that, the combination of 1 or 2 RAS inhibitors along with ACE2 (recombinant plasmid form, directly or as part of a recombinant virus or bacterium) and bradykinin inhibitors such as ARBs + ACE2, ACEi + ACE2, and renin inhibitor + ACE2 + bradykinin inhibitor were utilized for synergistic effects. They used this combination for treating SARS-CoV-1 associated lung injuries, hence it might have a potential also for treating COVID-19-related lung injuries.⁵⁷ In 2010, Imai et al reviewed the role of ACE2 in SARS-CoV-mediated acute respiratory distress syndrome and demonstrated that administration of recombinant ACE2 together with an AT1R inhibitor or ACEi can have beneficial effects.⁵⁸ Moreover, an experimental study reported that inhibition of the AT1R attenuated SARS-CoV-mediated pulmonary edema and acute severe lung injury in mice.⁵⁹ Also, studies suggest that ACE2 is downregulated after interacting with SARS-CoV-2, which leads to uncontrolled angiotensin II activity. Reduced ACE2 was reported to cause acute lung injury in SARS-CoV infection which was ameliorated by RAS blockade.⁶⁰ Renin–angiotensin system inhibitors keeps angiotensin II level in check and protect the renal and cardiovascular system.^60,61 Till date, there is no clinical evidence to strongly recommend the use or disuse of RAS modulators for patients with SARS-CoV-19. In fact, United Kingdom had to release 2019 national consensus guidelines for continuation of these drugs in patients with heart disease unless stated otherwise by a physician.⁶² The effect of RAS inhibitor cessation also depends on the condition for which it is prescribed and the current status of the disease. For instance, it is highly possible that initially the RAS inhibitors were prescribed for hypertension. But over the time, another heart complication such as left ventricular dysfunction may have developed. In these scenarios, sudden withdrawal of drugs may lead to quick deterioration in patient health.^62,63 For the lack of data proving otherwise, medical associations like Heart Failure Society of America, America Heart Association, and American College of Cardiology recommended the continuation of RAS antagonists in patients having COVID-19 with conditions like heart failure, hypertension, or ischemic heart disease. In addition, individualized treatment decision should be made according to each patient’s hemodynamic status and clinical presentation. Decision to add or remove any RAS-related treatment should be guided by standard clinical practice.⁶⁴ Furthermore, European Medicines Agency also advised to continue the treatment with RAS modulators in patients with hypertension, heart, or kidney disease during COVID-19 pandemic.⁶⁵ Thus, the abovementioned data raise hope that RAS modulators like ACEi, ARBs, or ACE2 might actually reduce the mortality and morbidity associated with SARS-COVID-19 infection in patients with CVD. Obviously, trials are needed to verify this assumption.

Reports Advocating Discontinuation of RAS Modulators in Patients With COVID-19

Because SARS-CoV and SARS-CoV-2 use ACE2 for host entry, it should be a major factor in the morbidity and mortality of SARS and COVID-19, respectively.⁶⁶ Oudit et al studied heart tissue samples from patients who died due to SARS-CoV as well as of mice infected with the human strain of the SARS-CoV. They found that SARS-CoV pulmonary infection also led to myocardial inflammation and damage associated with downregulation of ACE2 in the heart. The expression of ACE2 was also significantly reduced in the human heart samples.⁶⁶ Owing to the fact that SARS-CoV-2 also utilizes ACE2 receptors for host entry led to speculations regarding the usage of ACE2-enhancing drugs. The ACE2 levels significantly increase in patients with hypertension and diabetes on ACEi and ARB therapy. Fang et al hypothesized that ACEi and ARBs have a potential to upregulate ACE2 expression, which might facilitate COVID-19 in patients with CVD, hypertension, diabetes, and CKD.⁵³ A similar hypothesis was put forward by Diaz based on a previous study reporting that intravenous administration of ACEi and ARBs in experimental animals increased plasma ACE2 expression in cardiopulmonary circulation. Based on their own data as well as by analyzing the clinical characteristics of patients with COVID-19, they suggested that RAS inhibitors may negatively affect outcomes in COVID-19.⁶⁷ A recent report revealed that pericytes of microvessels in the human heart express abundant ACE2, suggesting susceptibility of the heart to direct COVID-19 infection. They also revealed that deceased patients heart expressed high level of ACE2 both at messenger RNA and protein level which could be attributed to COVID-19 infection but viral inclusion bodies in hearts of patients with COVID-19 were not reported. However, more studies are needed to test whether drugs enhancing the ACE2 expression (RAS inhibitors) could worsen the COVID-19 outcomes in CVD.⁶⁸ Li et al also suggested that there exists a theoretical risk of aggravating COVID-19 infection on usage of ACEi/ARBs.³⁶ Other authors arrived at similar conclusions.⁶⁹ A recent correspondence letter reported that patients with CVD from Spain, South America, and Central America either discontinued taking ACEi and ARBs or were planning to do so based on the theory that this could upregulate ACE2 expression thus favoring the internalization of SARS-CoV-2 into cells.⁷⁰ Further randomized clinical trials are required to substantiate the above discussion.

Discussion and Perspectives

At this point, there exists confusion regarding the usage of RAS modulators in patients with COVID-19. As per the abovementioned reports and the gathered data, it is difficult to arrive at a consensus for mandating the use or withdrawal of such drugs in patients with CVD at risk or patients with COVID-19. The reasons being lack of sufficient clinical trials, vulnerability of comorbid patients to adverse effects of COVID-19, and chances of precipitating the underlying CVD on cessation of therapy or a sudden change in therapy. However, the current situation offers research opportunities for an indepth exploration of these questions. Clinical trials are already initiated where ARBs and recombinant human ACE2 are being tested as a potential therapy in COVID-19. The role of ACE2 in maintaining the cardiovascular system is evident for long. Although, ACE2 was found not to be the only entry receptor for coronavirus during and after SARS-CoV in 2003 as discussed above. Moreover, we still do not have any clinically approved directly acting ACE2 activator at our disposal. For now, the objective should be to collect and evaluate clinical characteristics, medication history (RAS inhibitors), and possible disease outcome of patients having COVID-19 with hypertension, diabetes, CVD, and CKD. Such data mining could give a fair idea regarding the usage and potential effect of RAS inhibitors in progression of COVID-19–CVD comorbidity. Also, different expert bodies such as European Society of Hypertension, American Heart Association, American College of Cardiology, The Renal Association, United Kingdom, International Society of Hypertension, Hypertension Canada, Australian Diabetes Society, and so on encourage continuation of ACEi and ARBs unless there is concrete evidence against using those.

In conclusion, data suggest that SARS-CoV-2 enters the cell via ACE2 and that COVID-19 is associated with significant deleterious effects on the cardiovascular system. Therefore, patients with precedent CVD and renal disorders are at high risk for unfortunate outcomes of COVID-19 and should be carefully looked after. Future preclinical and clinical research should focus on exploring the mechanistic relationship between RAS modulators including ACE2 in COVID-19 entry, pathogenesis, and prevention and safety of their continuation in patients with underlying diseases.

Footnotes

Author Contribution

H.S., A.K., and N. S. conducted literature research, designed and wrote the manuscript. H. J. A. participated to design the manuscript, edited and prepared it for submission. A. B. G. designed and drafted the manuscript. All authors read and approved the final manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: A.B.G. sincerely acknowledges Science and Engineering Research Board- Department of Science and Technology, Government of India [SERB/ECR/2017/000317] and [EEQ/2019/000308] for their financial support. HJA was supported by the Deutsche Forschungsgemeinschaft (AN372/24-1).

ORCID iD

Anil Bhanudas Gaikwad

References

Zheng

Zhang

Xie

. COVID-19 and the cardiovascular system [published online ahead of print March 5, 2020]. Nat Rev Cardiol. 2020. doi:10.1038/s41569-020-0360-5

World Health Organization. Coronavirus disease 2019 (COVID-19) Situation report—70. 2020. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200320-sitrep-70-covid-19.pdf?sfvrsn=8894045a_2. Accessed April 1, 2020.

Carey

. Angiotensin type-1 receptor blockade increases ACE 2 expression in the heart. Hypertension. 2004;43(2):943–944. doi:10.1161/01.HYP.0000124669.02394.72

Ocaranza

Godoy

Jalil

, et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48(4):572–578. doi:10.1161/01.HYP.0000237862.94083.45

Ramchand

Patel

Srivastava

Farouque

Burrell

. Elevated plasma angiotensin converting enzyme 2 activity is an independent predictor of major adverse cardiac events in patients with obstructive coronary artery disease. PLoS One. 2018;13(2):e0198144. doi:10.1371/journal.pone.0198144

University of Minnesota. Losartan for Patients With COVID-19 Requiring Hospitalization. 2020. https://clinicaltrials.gov/ct2/show/NCT04312009. Accessed March 28, 2020.

Huang

Wang

, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(2):497–506. doi:10.1016/S0140-6736(20)30183-5

Zhou

, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(4):1054–1062. doi:10.1016/S0140-6736(20)30566-3

McMichael

Currie

Clark

, et al. Epidemiology of covid-19 in a long-term care facility in king county, Washington [published online ahead of print March 27, 2020]. N Engl J Med. 2020. doi:10.1056/NEJMoa2005412

10.

Cao

Zhang

Wang

, et al. Clinical features of patients infected with the 2019 novel coronavirus (COVID-19) in Shanghai, China [published online ahead of print March 6, 2020]. medRxiv. 2020. doi:10.1101/2020.03.04.20030395

11.

Chen

Zhou

Dong

, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(1):507–513. doi:10.1016/S0140-6736(20)30211-7

12.

Chen

Liu

, et al. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi. 2020;43(0):E005. doi:10.3760/cma.j.issn.1001-0939.2020.0005

13.

Guan

, et al. Clinical characteristics of 2019 novel coronavirus infection in China [published online ahead of print February 9, 2020]. MedRxiv. 2020. doi:10.1101/2020.02.06.20020974

14.

Kui

Fang

Deng

, et al. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province [published online ahead of print February 7, 2020]. Chin Med J. 2020. doi:10.1097/CM9.0000000000000744

15.

Liang

Guan

Chen

, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol. 2020;21(3):335–337. doi:10.1016/S1470-2045(20)30096-6

16.

Song

Shi

Shan

, et al. Emerging 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology. 2020;295(1):210–217. doi:10.1148/radiol.2020200274

17.

Wang

, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China [published online ahead of print February 7, 2020]. JAMA. 2020. doi:10.1001/jama.2020.1585

18.

Wang

Yang

Wen

Zhang

. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020:ciaa272. doi:10.1093/cid/ciaa272

19.

Yang

, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study [published online ahead of print]. Lancet Respir Med. 2020. pii: S2213-2600(20)30079-5. doi:10.1016/S2213-2600(20)30079-5

20.

Zhang

Dong

Cao

, et al. Clinical characteristics of 140 patients infected by SARS-CoV-2 in Wuhan, China [published online ahead of print February 19, 2020]. Allergy. 2020. doi:10.1111/all.14238

21.

Characteristics of COVID-19 patients dying in Italy Report based on available data on March 20th, 2020. 2020. https://www.epicentro.iss.it/coronavirus/bollettino/Report-COVID-2019_20_marzo_eng.pdf. Accessed March 28, 2020.

22.

Global Covid-19 Case Fatality Rates. 2020. https://www.cebm.net/covid-19/global-covid-19-case-fatality-rates/. Accessed March 28, 2020.

23.

Cheng

Luo

Wang

, et al. Kidney disease is associated with in-hospital death of patients with COVID-19 [published online ahead of print March 20, 2020]. Kidney Int. 2020. doi:10.1016/j.kint.2020.03.005

24.

Naicker

Yang

Hwang

Liu

Chen

Jha

. The novel coronavirus 2019 epidemic and kidneys [published online ahead of print March 20, 2020]. Kidney Int. 2020. doi:10.1016/j.kint.2020.03.001

25.

Shi

Zhao

Wang

Zhao

Sheng

. Host susceptibility to severe COVID-19 and establishment of a host risk score: findings of 487 cases outside Wuhan. Crit Care 2020;24(5):108. doi:10.1186/s13054-020-2833-7

26.

Guan

, et al. Clinical characteristics of coronavirus disease 2019 in China [published online ahead of print February 28, 2020]. N Engl J Med. 2020. doi 10.1056/NEJMoa2002032

27.

Ganatra

Hammond

Nohria

. The novel coronavirus disease (COVID-19) threat for patients with cardiovascular disease and cancer. ACC J. 2020. doi:10.1016/j.jaccao.2020.03.001

28.

Danser

AHJ

Epstein

Batlle

. Renin-angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers [published online ahead of print March 25, 2020]. Hypertension. 2020. doi:10.1161/HYPERTENSIONAHA.120.15082

29.

Sharma

Anders

Gaikwad

. Fiend and friend in the renin angiotensin system: an insight on acute kidney injury. Biomed Pharmacother. 2019;110(2):764–774. doi:10.1016/j.biopha.2018.12.018

30.

De Farias Lelis

de Freitas

Machado

Crespo

Santos

SHS

. Angiotensin-(1-7), adipokines and inflammation. Metab Clin Exp. 2019;95(1):36–45. doi:10.1016/j.metabol.2019.03.006

31.

Santos

RAS

Sampaio

Alzamora

, et al. The ACE2/angiotensin-(1–7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7). Physiol. Rev. 2018;98(3):505–553. doi:10.1152/physrev.00023.2016

32.

Hoffmann

Kleine-Weber

Schroeder

, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor [published online ahead of print March 4, 2020]. Cell. 2020. doi:10.1016/j.cell.2020.02.052

33.

Yan

Zhang

Xia

Guo

Zhou

. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020;367(6485):1444–1448. doi:10.1126/science.abb2762

34.

Liu

Xiao

Wei

, et al. Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2 [published online ahead of print February 26, 2020]. J Med Virol. 2020 doi:10.1002/jmv.25726

35.

Zhou

Yang

Wang

, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579:270–273. doi:10.1038/s41586-020-2012-7

36.

Zhang

. Antihypertensive treatment with ACEI/ARB of patients with COVID-19 complicated by hypertension [published online ahead of print March 30, 2020]. Hypertens Res. 2020.

37.

Kuster

Pfister

Burkard

, et al.

SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? [published online ahead of print March 20, 2020]

Eur Heart J. 2020. doi:10.1093/eurheartj/ehaa235

38.

Donoghue

Hsieh

Baronas

, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87(4):e1–e9. doi:10.1161/01.res.87.5.e1

39.

Peng

Cheng

Zhou

Ren

. Transmission routes of 2019-nCoV and controls in dental practice. Int J Oral Sci. 2020;12(1):1–6.

40.

Gierer

Bertram

Kaup

, et al. The spike protein of the emerging betacoronavirus EMC uses a novel coronavirus receptor for entry, can be activated by TMPRSS2, and is targeted by neutralizing antibodies. J Virol. 2013;87(4):5502–5511. doi:10.1128/JVI.00128-13

41.

Qian

Dominguez

Holmes

. Role of the spike glycoprotein of human Middle East respiratory syndrome coronavirus (MERS-CoV) in virus entry and syncytia formation. PloS One. 2013;8(10):e76469. doi:10.1371/journal.pone.0076469

42.

Liu

Cao

, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. doi:10.1038/s41421-020-0156-0

43.

Struck

Axmann

Pfefferle

Drosten

Meyer

. A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2. Antiviral Res. 2012;94(3):288–296. doi:10.1016/j.antiviral.2011.12.012

44.

Brielle

Schneidman

Linial

. The SARS-CoV-2 exerts a distinctive strategy for interacting with the ACE2 human receptor. Biorxiv. 2020. doi.org/10.1101/2020.03.10.986398

45.

Wan

Shang

Graham

Baric

. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol. 2020;94(7):e00127–e001320. doi:10.1128/JVI.00127-20

46.

Walls

Park

Tortorici

Wall

McGuire

Veesler

. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein [published online ahead of print March 6, 2020]. Cell. 2020. doi:10.1016/j.cell.2020.02.058

47.

Kruse

. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res. 2020;9:72. doi:10.12688/f1000research.22211.2

48.

Cai

. Bulk and single-cell transcriptomics identify tobacco-use disparity in lung gene expression of ACE2, the receptor of 2019-nCov. medRxiv. 2020. doi:10.20944/preprints202002.0051.v2

49.

Zhang

Zhuo

. The vasoprotective axes of the renin-angiotensin system: physiological relevance and therapeutic implications in cardiovascular, hypertensive and kidney diseases. Pharmacol Res. 2017;125(4):21–38. doi:10.1016/j.phrs.2017.06.005

50.

Ferrario

Jessup

Chappell

, et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111(20):2605–2610. doi:10.1161/CIRCULATIONAHA.104.510461

51.

Goru

Kadakol

Malek

Pandey

Sharma

Gaikwad

. Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes. Br J Pharmacol. 2017;174(1):3118–3130. doi:10.1111/bph.13946

52.

Malek

Sharma

Sankrityayan

Gaikwad

. Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy. Life Sci. 2019;221:159–167. doi:10.1016/j.lfs.2019.02.027

53.

Fang

Karakiulakis

Roth

. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8(4):e12. doi:10.1016/S2213-2600(20)30116-8

54.

Sun

Yang

Sun

. Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2020;433(1):E014. doi:10.3760/cma.j.issn.1001-0939.2020.0014

55.

Liu

Yang

Zhang

, et al. Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury. Sci China Life Sci. 2020;63(3):364–374. doi:10.1007/s11427-020-1643-8

56.

Perico

Benigni

Remuzzi

. Should COVID-19 concern nephrologists? Why and to what extent? The emerging impasse of angiotensin blockade [published online ahead of print March 23, 2020]. Nephron. 2020. doi:10.1159/000507305

57.

Penninger

Imai

Kuba

Jiang

U.S. Patent No. US20080159962A1. Washington, DC: U.S. Patent and Trademark Office; 2008.

58.

Imai

Kuba

Ohto-Nakanishi

Penninger

. Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis. Circ J. 2010;74(3):405–410. doi:10.1253/circj.cj-10-0045

59.

Kuba

Imai

Rao

, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11(2):875–879. doi:10.1038/nm1267

60.

Vaduganathan

Vardeny

Michel

McMurray

JJV

Pfeffer

Solomon

. Renin–angiotensin–aldosterone system inhibitors in patients with covid-19 [published online ahead of print March 30, 2020]. N Engl J Med. 2020. doi:10.1056/NEJMsr2005760

61.

Bavishi

Maddox

Messerli

. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers [published online ahead of print April 3, 2020]. JAMA Cardiology. 2020. doi:10.1001/jamacardio.2020.1282

62.

South

Tomlinson

Edmonston

Hiremath

Sparks

. Controversies of renin–angiotensin system inhibition during the COVID-19 pandemic [published online ahead of print April 3, 2020]. Nat Rev Nephrol. 2020. doi:10.1038/s41581-020-0279-4

63.

Aronson

Ferner

. Drugs and the renin-angiotensin system in covid-19. BMJ 2020;369(1):m1313. doi:10.1136/bmj.m1313

64.

Sun

Wang

, et al. COVID-19: Epidemiology, evolution, and cross-disciplinary perspectives [published online ahead of print March 21, 2020]. Trends Mol Med. 2020. doi:10.1016/j.molmed.2020.02.008

65.

Rothan

Byrareddy

. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020;109:102433. doi:10.1016/j.jaut.2020.102433

66.

Oudit

Kassiri

Jiang

, et al. SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS. Eur J Clin Invest. 2009;39(10):618–625. doi:10.1111/j.1365-2362.2009.02153.x

67.

Diaz

. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19 [published online ahead of print March 18, 2020]. J Travel Med. 2020. doi:10.1093/jtm/taaa041

68.

Chen

Feng

Xiong

. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2 [published online ahead of print March 30, 2020]. Cardiovasc Res. 2020. doi:10.1093/cvr/cvaa078

69.

Esler

. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens. 2020;38(5):781–782; Publish Ahead of Print. doi:10.1097/HJH.0000000000002450

70.

Marin

. Facts and reflections on COVID-19 and anti-hypertensives drugs [published online ahead of print Mach 26, 2020]. Drug Discov Ther. 2020. doi:10.5582/ddt.2020.01017

Evidence for Use or Disuse of Renin–Angiotensin System Modulators in Patients Having COVID-19 With an Underlying Cardiorenal Disorder

Abstract

Keywords

Introduction

Coronavirus Disease 19 and Associated Cardiorenal Comorbidities

Coronavirus Disease 19 and the RAS

Coronavirus Disease 19 and ACE2 Pathogenicity

Reports Advocating the Use of RAS Modulators in Patients With COVID-19

Reports Advocating Discontinuation of RAS Modulators in Patients With COVID-19

Discussion and Perspectives

Footnotes

Author Contribution

Declaration of Conflicting Interests

Funding

ORCID iD

References