Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 283e287

Contents lists available at ScienceDirect

Diabetes & Metabolic Syndrome: Clinical Research & Reviews

journal homepage: www.elsevier.com/locate/dsx

Comorbidities in COVID-19: Outcomes in hypertensive cohort and

controversies with renin angiotensin system blockers
Awadhesh Kumar Singh a, *, Ritesh Gupta b, Anoop Misra b, c, d
a
G. D Hospital & Diabetes Institute, Kolkata, India
b
Fortis CDOC Hospital for Diabetes and Allied Sciences, New Delhi, India
c
National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India
d
Diabetes Foundation (India), New Delhi, India

a r t i c l e i n f o a b s t r a c t

Article history: Background and aims: COVID-19 is already a pandemic. Emerging data suggest an increased association
Received 28 March 2020 and a heightened mortality in patients of COVID-19 with comorbidities. We aimed to evaluate the
Accepted 28 March 2020 outcome in hypertensive patients with COVID-19 and its relation to the use of renin-angiotensin system
blockers (RASB).
Keywords: Methods: We have systematically searched the medical database up to March 27, 2020 and retrieved all
COVID-19
the published articles in English language related to our topic using MeSH key words.
Comorbidities
Results: From the pooled data of all ten available Chinese studies (n ¼ 2209) that have reported the
Hypertension
Angiotensin-converting enzyme inhibitors
characteristics of comorbidities in patients with COVID-19, hypertension was present in nearly 21%,
Angiotensin-receptor blockers followed by diabetes in nearly 11%, and established cardiovascular disease (CVD) in approximately 7% of
patients. Although the emerging data hints to an increase in mortality in COVID-19 patients with known
hypertension, diabetes and CVD, it should be noted that it was not adjusted for multiple confounding
factors. Harm or benefit in COVID-19 patients receiving RASB has not been typically assessed in these
studies yet, although mechanistically and plausibly both, benefit and harm is possible with these agents,
given that COVID-19 expresses to tissues through the receptor of angiotensin converting enzyme-2.
Conclusion: Special attention is definitely required in patients with COVID-19 with associated comor-
bidities including hypertension, diabetes and established CVD. Although the role of RASB has a mech-
anistic equipoise, patients with COVID-19 should not stop these drugs at this point of time, as
recommended by various world organizations and without the advice of health care provider.
© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.

1. Introduction in particular more susceptible, compared to general populations

and have higher mortality. Therefore, it is necessary to re-look into
Coronavirus disease 2019 (COVID-19) has been declared as a these subgroups of COVID-19 patients with associated co-
pandemic by Word Health Organization on March 11, 2020, as soon morbidities.
as it satisfied the epidemiological criteria (infection in more than In this review article, we have collated all the available evidence
100,000 people in 100 countries) [1]. As of March 27, 2020, world that has emerged so far on outcomes and comorbidities in patients
has witnessed more than half a million cases of COVID-19 with with COVID-19. Here, we have focused on outcomes in patients of
more than 24,000 deaths [2]. This suggests the magnitude of its COVID-19 with hypertension and analyzed the controversies sur-
spread across the world, since it was first reported on December 31, rounding the use of renin-angiotensin system blockers (RASB).
2019 from Wuhan, Hubei province in China. Emerging data sug-
gests that older COVID-19 patients with other comorbid conditions
2. Methods
such as diabetes, hypertension, cardiac and pulmonary disease are

We have systematically searched the PubMed medical database

up till March 27, 2020 using MeSH key words that include Covid-19,
* Corresponding author. coronavirus, hypertension, diabetes, cardiovascular disease,
E-mail address: [email protected] (A.K. Singh). angiotensin receptor blockers, angiotensin converting enzyme

https://doi.org/10.1016/j.dsx.2020.03.016
1871-4021/© 2020 Diabetes India. Published by Elsevier Ltd. All rights reserved.
284 A.K. Singh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 283e287

inhibitors. We have retrieved all the available literature published neither of these studies were adjusted for all confounding variables.
in English language on COVID-19, that reported the outcomes in Nevertheless, a study of 187 patients with COVID-19, Guo et al.
different co-morbidities. reported nearly a twice increase in mortality in patients with
established CVD and raised troponin T (TnT), compared to patients
without CVD and raised TnT (69.4% vs. 37.5% respectively) [14].
3. Results
The Chinese Center for Disease Control and Prevention in a
summary report of COVID-19, reported a case fatality rate (CFR) of
3.1. Hypertension as a significant comorbidity with COVID-19
2.3% (1023 deaths among 44,672 confirmed cases). However, CFR
was elevated to 6.0% for hypertension, 7.3% for diabetes, and 10.5%
The association of hypertension and diabetes in patients with
for presence of CVD [15]. Unsurprisingly, based on the above find-
COVID-19 is not unexpected, given the rising prevalence of both of
ings, researchers have recently proposed that the course of treat-
these chronic diseases, globally. Interestingly, in the pooled data
ment and prognosis of COVID-19 should be stratified based on the
from the ten Chinese studies (n ¼ 2209) that have reported the
absence or presence of co-morbidities in to type A, B and C. Type A
characteristics of comorbidities in patients with COVID-19; asso-
denotes COVID-19 patients with pneumonia but without comor-
ciations of hypertension, diabetes and presence of established
bidities, Type B denotes COVID-19 pneumonia and comorbidities,
cardiovascular disease (CVD) are larger, varying from 15 to 30%
whereas, Type C denotes COVID-19 patients with multi-organ
(average 21%), 5e20% (average 11%) and 2e40% (average 7%)
dysfunction [16].
respectively (Table 1). Established CVD was also present in nearly
Nonetheless, it still remains unclear whether these increased
43% in Italian study of 355 patients with COVID-19.
association of hypertension with COVID-19 and heightened risk of
Table summarizes the prevalence of these comorbidities in all
mortality is directly related to hypertension or other associated
available studies to-date in patients with COVID-19 [3e14].
comorbidities, or, anti-hypertensive treatment. There has been a
growing concern that this association with hypertension and or
3.2. Hypertension as a prognostic indicator for severity and CVD may be confounded by the treatment with certain antihy-
mortality in COVID-19 pertensive medications such as RASB. Although a recent paper has
proposed to stop RASB and suggested to replace it with the calcium
While consistent association of hypertension in patients with channel blocker, while treating hypertension in patients with
COVID-19 across all these studies is unique, the concern which COVID-19 [17], this hypothesis has been questioned by several
needs a serious attention is the increase in mortality. Two Chinese other colleagues [18e22].
studies have worked in this direction to-date. In 191 patients with
COVID-19, Zhou et al. found hypertension to have an odds ratio (OR)
of 3.05 (95% CI, 1.57 to 5.92; p < 0.006), diabetes with OR of 2.85 3.3. Role of renin angiotensin system and its inhibitors in SARS
(95% CI, 1.35 to 6.05; p < 0.001), whereas presence of coronary ar- CoV2 infection
tery disease had an OR of 21.40 (95% CI, 4.64 to 98.76; p < 0.0001)
for in-hospital mortality, in an univariate analysis [8]. However, the The entry of coronavirus into the cell is facilitated by the spike
association between these disorders and COVID-19 mortality were (S) protein. Before attachment to the receptor on host cell, the S
no longer significant after a multivariate regression analysis. protein needs to be primed by a serine protease named TMPRSS2.
Similarly, in an analysis of 201 patients with COVID-19, Wu et al. The S proteins of different coronaviruses may utilise different re-
found hypertension to have a hazard ratio (HR) of 1.82 (95% CI, 1.13 ceptors; MERS utilises CD26 while SARS CoV and SARS CoV2 utilise
to 2.95; p ¼ 0.01) for acute respiratory distress syndrome (ARDS) Angiotensin Converting Enzyme-2 (ACE-2) [23]. The efficiency of
and 1.70 (95% CI, 0.92 to 3.14, p ¼ 0.09) for death. The diabetic the interaction between S-protein and ACE-2 may be a key deter-
patients had a HR of 2.34 (95% CI, 1.35 to 4.05; p ¼ 0.002) for ARDS minant of the transmissibility of the virus, viral replication and the
and HR of 1.58 (95% CI, 0.80 to 3.13, p ¼ 0.19) for death, in a bivariate severity of disease. In theory, this efficiency could be influenced by
cox regression analysis [11]. It should be noted however, that changes or amino acid substitutions in either the viral S-protein or

Table 1
Hypertension, diabetes and other co-morbidities in COVID-19, world-wide data.

First author n Smokers, HTN, % Diabetes, % CVD, % COPD, % CKD, % CLD, Ref.
% %

COVID-19 in China
Liu et al. 61 6.6 19.7 8.2 1.6 8.2 NR NR 3
Guan et al. 1099 12.6 15.0 7.4 3.8 1.1 0.7 NR 4
Huang et al. 41 7.3 14.6 19.5 15.0 2.4 NR 2.4 5
Chen et al. 99 NR NR 12.1 40.0 1.0 NR NR 6
Wang et al. 138 NR 31.2 10.1 19.6 2.9 2.9 2.9 7
#
Zhou et al. 191 6.0 30 19 8.0 3.0 1.0 NR 8
Zhang et al. 140 NR 30 12.1 8.6 1.4 1.4 NR 9
Yang et al. 52 4.0 NR 17.0 23.0 8.0 NR NR 10
Wu et al. 201 NR 19.4 10.9 4.0 2.5 1.0 3.5 11
Guo et al. 187 9.6 32.6 15.0 11.2# 2.1 3.2 NR 14
Overall, China, 10.7% 20.7% 10.5% 7.4% 2.0% 1.2% 3.2%
N ¼ 2209
COVID-19 in Italy
Onder et al. 355 NR NR 35.5 42.5 NR NR NR 12
COVID-19 in Singapore
Young et al. 18 NR NR NR NR NR NR NR 13
# reported coronary heart disease only, HTN- hypertension, CVD- cardiovascular disease, COPD- chronic obstructive pulmonary disease, CKD- chronic kidney disease, CLD-
chronic liver disease, NR- not reported, Ref.- references
 A.K. Singh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 283e287 285

the ACE-2 receptor on host cell. expression in lungs of smokers compared to non-smokers,
which could explain the higher risk of infection in smokers [30].
a) Changes in S-protein: Molecular studies and the elucidation of
the atomic and crystal structure of ACE-2/S protein interface of
SARS CoV have provided important insights [24]. The major 3.4. Physiological role of ACE-2 and its relationship with
outbreak of SARS CoV occurred in 2002e2003 with a minor coronavirus infection
localised outbreak with mild symptoms in 2003e2004. It was
observed that the S-protein of SARS CoV in the 2002e2003 The role of ACE-2 on vascular bed is opposite to that of angio-
outbreak bound to ACE-2 receptor much more efficiently than tensin converting enzyme (ACE). ACE converts angiotensin I to
that of SARS CoV in the 2003e2004 outbreak, consistent with angiotensin II, which is a vasoconstrictor. ACE-2 converts angio-
the absence of human-to-human transmission during the latter tensin II to angiotensin (1e7) which causes vasodilatation after
outbreak. Several molecular changes in the S-protein influence binding to the Mas receptor in the vascular bed [31]. Down-
the binding with human ACE-2; for example, the substitution of regulation of ACE-2 was observed in animal models of lung injury
threonine by serine at position 487 in S protein reduces the induced by SARS CoV [32]. Recombinant ACE-2 improved pulmo-
binding [25]. Similarly, asparagine at position 479 increased the nary blood flow and oxygenation in animals with lung injury,
binding affinity [26]. Methylation at position 487 has also been indicating that ACE-2 may be the main determinant of lung injury
shown to influence binding. Recently, S-protein of SARS CoV2 caused by SARS CoV [33]. However, there is lack of human data
has been shown to be similar to that of SARS CoV, barring a few except a small study in 10 patients with acute respiratory distress
gains of function mutations. The most important of these is a syndrome which showed that recombinant ACE-2 was well toler-
glutamine at position 493 at the receptor binding domain, ated and led to an increase in angiotensin (1e7) [34].
which explains its increased transmissibility compared to SARS
CoV [27].
3.5. Effects of ACE inhibitors and angiotensin receptor blockers
b) Changes in ACE-2 Receptor: With regard to MERS-CoV, which
employs CD26 (DPP-4) as its receptor for cellular entry, there are
There has been considerable interest regarding the role of RAS
naturally-occurring polymorphisms in DPP4 that impact cellular
blockers in COVID-19 infection. Both benefit and harm have been
entry of MERS-CoV and might thus modulate MERS develop-
postulated. Figure 1 illustrates the interactions between the effect
ment in infected patients [28]. There is a possibility that similar
of RASB and COVID-19. Fig. 1
variations or polymorphisms in ACE-2 could affect the viral
entry and disease course. Polymorphisms of ACE-2 gene have
a) Rationale and Evidence for Harm: There is evidence that ACE-
been identified; however, there is no evidence that they affect
2 expression increases with the use of ACE inhibitors and
susceptibility to or severity of SARS CoV2 infection [29]. A recent
ARB, especially in heart and kidney [35,36]. This has raised a
study found differential ACE-2 gene expression in human lung
theoretical concern that by increasing ACE-2 expression,
tissue with no racial/gender differences, but a higher gene
ACEIs and ARBs could facilitate the entry of virus into the

Fig. 1. Components of Renin-Angiotensin System pathway and possible interaction of Angiotensin Converting Enzyme inhibitors (ACE-I), Angiotensin-Receptor Blockers (ARB) and
COVID-19.
286 A.K. Singh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 283e287

host cell and increase the chances of infection or its severity in SARS CoV2 infection is very scarce. The only indirect evidence of
[17]. Also, there is increased ACE-2 expression in elderly [37]. RAS activation in COVID-19 is high incidence of hypokalaemia [46].
To what extent this predisposes the elderly to infection with With regards to the use of RASB, a retrospective analysis of 112
SARSCoV2 is not known. In a study of 187 patients with COVID-19 hospitalised patients with cardiovascular disease in
COVID-19, Guo et al. reported an increased trend in mortality Wuhan, there was no significant difference in the proportion of
with those receiving RASB, compared to those not receiving. ACEI/ARB medication between non-survivors and survivors [47].
Mortality was 36.8% (6 of 19) and 25.6% (43 of 168) in pa- However, a study of 187 patient reported by Guo et al., there was a
tients with or without RASB, respectively [14]. Indeed, trend of increase in mortality in patients with COVID-19 receiving
increased association and heightened mortality with COVID- RASB (36.8%), compared to those not receiving (25.6%) [14].
19 have been observed consistently across the studies in
elderly, hypertensive, diabetics and known CVD; however, it 4. Conclusion
is not exactly known whether it has any causal relation with
the use of RASB or these subgroups are more on RASB due to COVID-19 is increasingly associated with comorbidities that
these illness, compared to the rest of population. Moreover, include hypertension and diabetes. Special care is required in pa-
there is no solid evidence to back this concern either in tients with COVID-19 with associated comorbidities, given the
COVID-19 or in infection by other coronaviruses. heightened risk of in-hospital death.
b) Rationale and Evidence for Benefit: As discussed above, In view of lack of robust evidence for either benefit or harm, and
increasing ACE-2 levels in coronavirus infection could reduce with bulk of the experimental evidence in favour of benefit, it is
lung injury. In an experimental study with mice, Kuba et al. reasonable for patients to continue using ACE inhibitors and ARB, as
found that losartan showed significantly diminished lung recommended by the European Society of Cardiology, Hyperten-
injury and pulmonary edema after acid aspiration-induced sion Canada, The Canadian Cardiovascular Society, UK Renal Asso-
acute lung injury (with addition of SARS-CoV spike protein) ciation, the International Society of Hypertension, and European
compared to placebo [32]. Similarly, severe lung injury and Society of Hypertension and American Heart Association [48e50].
pulmonary edema were prevented by both recombinant Future studies reporting the outcome stratified on the basis of
human ACE-2 infusions or losartan in ACE2-knockout mice different anti-hypertensive agents in COVID-19 may further
[38]. Mice with coronavirus induced lung injury showed enlighten us in this regard.
improvement when treated with losartan [39]. Moreover, a
retrospective analysis found reduced rates of death and
Declaration of competing interest
endotracheal intubation in patients with viral pneumonia
who were continued on ACE inhibitors [40]. Treatment with
We hereby declare that we have no conflict of interest related to
ARBs was reported to reduce mortality in Ebola virus infec-
this article.
tion [41]. The exact mechanism of apparent benefit of these
drugs in coronavirus infection is not yet clear. However, there
References
could be several explanations [42].
i. Increased ACE-2 expression may not result in more viral [1] Callaway E. Time to use the p-word? Coronavirus enter dangerous new phase.
entry into the cell because of the limited availability of the Nature 2020;579:12.
serine protease TMPRSS2. Camostat mesylate, which is a [2] WHO. https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20200326-sitrep-66-covid-19.pdf?sfvrsn¼81b94e61_2. [Accessed 27
TMPRSS2 inhibitor, has been shown to inhibit cellular entry March 2020].
of SARS CoV2 and could be a potential therapeutic option [3] Liu J, Liu Y, Xiang P, Pu L, Xiong H, Li C, et al. Neutrophil-to-lymphocyte ratio
[43]. predicts severe illness patients with 2019 novel coronavirus in the early stage.
https://www.medrxiv.org/content/10.1101/2020.02.10.20021584v1.
ii. Increased ACE-2 expression on the cell membrane may also
[4] Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of
lead to increased soluble ACE-2 in blood, which may actually coronavirus disease 2019 in China. https://www.nejm.org/doi/full/10.1056/
bind to most of SARS CoV2 and prevent its interaction with NEJMoa2002032.
[5] Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients
the membrane bound receptor.
infected with 2019 novel coronavirus in Wuhan, China. Lancet
iii. RAS blockers increase angiotensin II, which is a substrate for 2020;395(10223):497e506.
ACE-2. The interaction of ACE-2 with angiotensin II could [6] Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and
induce a conformational change in the receptor binding clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in
Wuhan, China: a descriptive study. Lancet 2020;395:507e13.
domain of ACE-2, limiting its ability to bind with SARS CoV2 [7] Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138
[44]. hospitalized patients with 2019 novel coronaviruseinfected pneumonia in
iv. ACE-2 receptors are present at a much higher density in lung wuhan, China. J Am Med Assoc 2020;323(11):1061e9.
[8] Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for
tissue of children and young adults, compared to older in- mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective
dividuals. Thus, the upregulation of ACE-2 receptors by the cohort study. Published Online March 2020;9. https://doi.org/10.1016/S0140-
use of RASB over time in older people may emulate ACE 6736(20)30566-3.
[9] Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al. Clinical charac-
expression in young people. It is also possible that having teristics of 140 patients infected with SARSCoV-2 in Wuhan, China. Allergy
more ACE-2 receptors and increased ACE-2 functions will 2020 Feb 19. https://doi.org/10.1111/all.14238 [Epub ahead of print].
likely produce more angiotensin (1e7) that might provide [10] Yang X, Yu Y, Shu H, Xia J, Liu H, Wu Y, et al. Clinical course and outcomes of
critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-
resilience against target-mediated destruction and devel-
centered, retrospective, observational study. Lancet Respir Med 2020. https://
opment of pulmonary failure in patients with COVID-19 [22]. doi.org/10.1016/S2213-2600(20)30079-5. Published Online February 21,
This postulated positive effects on lung can be also protective 2020, . [Accessed 27 March 2020].
during overwhelming infection with COVID-19. [11] Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with
acute respiratory distress syndrome and death in patients with coronavirus
v. Indiscriminate discontinuation of RASB in patients with disease 2019 pneumonia in wuhan, China. JAMA Intern Med. Published online
heart failure may also lead to readmission to hospital and March 13, 2020. doi:10.1001/jamainternmed.2020.0994 (Accessed on March
increase in mortality [45]. 27, 2020).
[12] Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of pa-
tients dying in relation to COVID-19 in Italy. J Am Med Assoc 2020 Mar 23.
Collectively, relationship between RAS activity and use of RASB https://doi.org/10.1001/jama.2020.4683 [Epub ahead of print].
 A.K. Singh et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 14 (2020) 283e287 287

[13] Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al. Epidemiologic acute respiratory distress syndrome (ARDS) with angiotensin converting
features and clinical course of patients infected with SARS-CoV-2 in enzyme 2 (ACE2). Masui 2008;57(3):302e10.
Singapore. J Am Med Assoc. doi:10.1001/jama.2020.3204. Published online [32] Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2
March 3, 2020. (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11(8):875e9.
[14] Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al. Cardiovascular implications https://doi.org/10.1038/nm1267.
of fatal outcomes of patients with coronavirus disease 2019 (COVID-19). JAMA [33] Reml B, Neu N, Kleinsasser A, et al. Recombinant angiotensin-converting
Cardiol. doi:10.1001/jamacardio.2020.1017. Published online March 27, 2020. enzyme 2 improves pulmonary blood flow and oxygenation in
[15] Wu Z, McGoogan JM. Characteristics of and important lessons from the lipopolysaccharide-induced lung injury in piglets. Crit Care Med 2010
coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report Feb;38(2):596e601. https://doi.org/10.1097/CCM.0b013e3181c03009.
of 72 314 cases from the Chinese center for disease Control and prevention. [34] Khan A, Benthin C, Zeno B, et al. A pilot clinical trial of recombinant human
J Am Med Assoc 2020 Feb 24. https://doi.org/10.1001/jama.2020.2648 [Epub angiotensin converting enzyme 2 in acute respiratory distress syndrome. Crit
ahead of print]. Care 2017;21(1):234.
[16] Wang T, Du Z, Zhu F, Cao Z, An Y, Gao Y, Jiang B. Comorbidities and multi- [35] Li XC, Zhang J, Zhuo JL. The vasoprotective axes of the renin-angiotensin
organ injuries in the treatment of COVID-19. Published Online March 9, system:physiological relevance and therapeutic implications in cardiovascu-
2020. HYPERLINK "https://doi.org/10.1016/S0140-6736(20)30558-4" lar, hypertensive and kidney diseases. Pharmacol Res 2017;125:21e38.
(Accessed on March 27, 2020). [36] Ferrario CM, Jessup J, Chappell MC, et al. Effect of angiotensin-converting
[17] Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes enzyme inhibition and angiotensin II receptor blockers on cardiac
mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020. angiotensin-converting enzyme 2. Circulation 2005 May;111(20):2605e10.
https://doi.org/10.1016/S2213- 2600(20)30116-8. published online March 11. [37] Bukowska A, Spiller L, Wolke C, et al. Protective regulation of the ACE2/ACE
[18] Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors gene expression by estrogen in human atrial tissue from elderly men. Exp Biol
and angiotensin receptor blockers. What is the evidence? JAMA. Published Med 2017;242(14):1412e23. https://doi.org/10.1177/1535370217718808.
online March 2020;24. https://doi.org/10.1001/jama.2020.4812. [38] Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from
[19] Tiganelli CJ, Ingraham NE, Sparks MA, Benson B, Schacker T, Chipman J, severe acute lung failure. Nature 2005;436:112e6.
Puskarich MA. Antihypertensive drugs and risk of COVID-19? Lancet Respir [39] Yang P, Gu H, Zhao Z, et al. Angiotensin-converting enzyme 2 (ACE2) mediates
Med 2020. https://doi.org/10.1016/S2213-2600(20)30153-3. Published Online influenza H7N9 virus-induced acute lung injury. Sci Rep 2014;4:7027.
March 26, 2020. [40] Henry C, Zaizafoun M, Stock E, Ghamande S, Arroliga AC, White HD. Impact of
[20] Brown JD. Antihypertensive drugs and risk of COVID-19? Lancet Respir Med angiotensin-converting enzyme inhibitors and statins on viral pneumonia.
2020. https://doi.org/10.1016/S2213-2600(20)30158-2. Published Online SAVE Proc 2018;31(4):419e23.
March 26, 2020. [41] Fedson DS, Jacobson JR, Rordam OM, Opal SM. Treating the host response to
[21] Lo KB, Mc Cullogh PA, Rangaswami J. Antihypertensive drugs and risk of Ebola virus disease with generic statins and angiotensin receptor blockers.
COVID-19? Lancet Respir Med 2020. https://doi.org/10.1016/S2213-2600(20) mBio 2015 Jun 23;6(3):e00716. https://doi.org/10.1128/mBio.00716-15.
30156-9. Published Online March 26, 2020. [42] Perico L, Benigni A, Remuzzi G. Should COVID-19 concern nephrologists? Why
[22] Gurwitz D. Angiotensin receptor blockers as tentative SARS-CoV-2 thera- and to what extent? The emerging impasse of angiotensin blockade. Nephron
peutics. Drug Dev Res 2020. https://doi.org/10.1002/ddr.21656. published 2020 Mar 23:1e9. https://doi.org/10.1159/000507305.
online March 4. [43] Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry de-
[23] Hoffmann M, Kleine-Weber H, Krüger N, et al. The novel coronavirus 2019 pends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease
(2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular pro- inhibitor. Cell 2020 Mar 4. https://doi.org/10.1016/j.cell.2020.02.052. S0092-
tease TMPRSS2 for entry into target cells. bioRxiv 2020:2020. 01.31.929042. 8674(20)30229-4.
[24] Li F, Li W, Farzan M, Harrison SC. Structure of SARS coronavirus spike [44] Towler P, Staker B, Prasad SG, et al. ACE2 X-ray structures reveal a large hinge-
receptor-binding domain complexed with receptor. Science 2005;309: bending motion important for inhibitor binding and catalysis. J Biol Chem
1864e8. 2004 Apr;279(17):17996e8007.
[25] Li W, Zhang C, Sui J, et al. Receptor and viral determinants of SARS- [45] Oliveros E, Oni ET, Shahzad A, et al. Benefits and risks of continuing
coronavirus adaptation to human ACE2. EMBO J 2005;24(8):1634e43. angiotensin-converting enzyme inhibitors, angiotensin II receptor antago-
[26] Yuan Z, Nan Z, Pei H, et al. Reconstruction of the most recent common nists, and mineralocorticoid receptor antagonists during hospitalizations for
ancestor sequences of SARS-Cov S gene and detection of adaptive evolution in acute heart failure. Cardiorenal Med 2020;10:69e84.
the spike protein. Chin Sci Bull 2004;49:1311e3. https://doi.org/10.1360/ [46] Chen D, Li X, Song Q, Hu C, Su F, DaiJ, Ye Y, HuangJ, Zhang X. Hypokalemia and
04wc0153. Clinical Implications in Patients with CoronavirusDisease 2019 (COVID-19).
[27] Wan Y, Shang J, Graham R, et al. Receptor recognition by the novel corona- medRxiv preprint doi: https://doi.org/10.1101/2020.02.27.20028530.
virus from wuhan: an analysis based on decade-long structural studies of [47] Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX,
SARS coronavirus. J Virol 2020 Mar 17;94(7). https://doi.org/10.1128/ Huang K, Zeng QT. Clinical characteristics and outcomes of 112 cardiovascular
JVI.00127-20. e00127-20. disease patients infected by 2019-nCoV. Zhonghua Xinxueguanbing Zazhi
[28] Kleine-Weber H, Schroeder S, Krüger N, et al. Polymorphisms in dipeptidyl 2020 Mar 2;48:E004. https://doi.org/10.3760/cma.j.cn112148-20200220-
peptidase 4 reduce host cell entry of Middle East respiratory syndrome 00105. 0.
coronavirus. Emerg Microb Infect 2020 Jan 21;9(1):155e68. https://doi.org/ [48] Position statement of the ESC council on hypertension on ACE-inhibitors and
10.1080/22221751.2020.1713705. angiotensin receptor blockers. Mar 11 2020, https://www.escardio.org/
[29] Pan Y, Wang T, Li Y, Guan T, et al. Association of ACE2 polymorphisms with Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-
susceptibility to essential hypertension and dyslipidemia in Xinjiang, China. esc-council-on-hypertension-on-ace-inhibitors-and-ang.
Lipids Health Dis 2018 Oct 20;17(1):241. https://doi.org/10.1186/s12944-018- [49] ESH statement on COVID-19. March 12, https://www.eshonline.org/
0890-6. spotlights/esh-statement-on-covid-19/; 2020.
[30] Cai G. Bulk and single-cell transcriptomics identify tobacco-use disparity in [50] Sun ML, Yang JM, Sun YP, Su GH. Inhibitors of RAS might Be a good choice for
lung gene expression of ACE2, the receptor of 2019-nCov. Preprints 2020. the therapy of COVID-19 pneumonia. Zhonghua Jiehe He Huxi Zazhi 2020 Mar
https://doi.org/10.20944/preprints202002.0051.v2. 2020020051. 12;43(3):219e22. https://doi.org/10.3760/cma.j.issn.1001-0939.2020.03.016.
[31] Imai Y, Kuba K, Penninger JM. Lessons from SARS: a new potential therapy for