Clinical and Experimental Hypertension

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iceh20

Is the use of ACE inb/ARBs associated with higher

in-hospital mortality in Covid-19 pneumonia
patients?

Murat Selçuk , Tufan Çınar , Muhammed Keskin , Vedat Çiçek , Şahhan Kılıç
, Behruz Kenan , Selami Doğan , Süha Asal , Nuran Günay , Ersin Yıldırım ,
Ümran Keskin & Ahmet Lütfullah Orhan

To cite this article: Murat Selçuk , Tufan Çınar , Muhammed Keskin , Vedat Çiçek , Şahhan Kılıç ,
Behruz Kenan , Selami Doğan , Süha Asal , Nuran Günay , Ersin Yıldırım , Ümran Keskin & Ahmet
Lütfullah Orhan (2020) Is the use of ACE inb/ARBs associated with higher in-hospital mortality
in Covid-19 pneumonia patients?, Clinical and Experimental Hypertension, 42:8, 738-742, DOI:
10.1080/10641963.2020.1783549

To link to this article: https://doi.org/10.1080/10641963.2020.1783549

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CLINICAL AND EXPERIMENTAL HYPERTENSION
2020, VOL. 42, NO. 8, 738–742
https://doi.org/10.1080/10641963.2020.1783549

Is the use of ACE inb/ARBs associated with higher in-hospital mortality in Covid-19
pneumonia patients?
Murat Selçuka, Tufan Çınara, Muhammed Keskina, Vedat Çiçeka, Şahhan Kılıça, Behruz Kenana, Selami Doğana, Süha Asala,
Nuran Günayb, Ersin Yıldırımb, Ümran Keskinc, and Ahmet Lütfullah Orhana
a
Department of Cardiology, Sultan Abdülhamid Han Training and Research Hospital, Health Science University, Istanbul, Turkey; bDepartment of
Cardiology, Ümraniye Training and Research Hospital, Health Science University, Istanbul, Turkey; cDepartment of Internal Medicine, Haydarpaşa
Numune Training and Research Hospital, Health Sciences University, Istanbul, Turkey

ABSTRACT ARTICLE HISTORY

Introduction: The present research aimed to determine the relation between the use of angiotensin- Received 31 May 2020
converting enzyme inhibitors (ACE inh) and angiotensinogen receptor blockers (ARBs) and in-hospital Revised 8 June 2020
mortality of hypertensive patients diagnosed with Covid-19 pneumonia. Accepted 11 June 2020
Material and method: In this retrospective study, we included 113 consecutive hypertensive patients KEYWORDS
admitted due to Covid-19 infection. In all patients, Covid-19 infection was confirmed with using reverse- Covid-19; ACE inh/ARBs;
transcription polymerase chain reaction. All patients were on ACE inh/ARBs or other antihypertensive mortality; SARSCoV-2
therapy unless no contraindication was present. The primary outcome of the study was the in-hospital all-
cause mortality.
Results: In total, 113 hypertensive Covid-19 patients were included, of them 74 patients were using ACE
inh/ARBs. During in-hospital follow up, 30.9% [n = 35 patients] of patients died. The frequency of
admission to the ICU and endotracheal intubation were significantly higher in patients using ACE inh/
ARBs. In a multivariable analysis, the use of ACE inh/ARBs was an independent predictor of in-hospital
mortality (OR: 3.66; 95%CI: 1.11–18.18; p= .032). Kaplan–Meir curve analysis displayed that patients on ACE
inh/ARBs therapy had higher incidence of in-hospital death than those who were not.
Conclusion: The present study has found that the use of ACE inh/ARBs therapy might be associated with
an increased in-hospital mortality in patients who were diagnosed with Covid-19 pneumonia. It is likely
that ACE inh/ARBs therapy might not be beneficial in the subgroup of hypertensive Covid-19 patients
despite the fact that there might be the possibility of some unmeasured residual confounders to affect the
results of the study.

Introduction first choice to treat such clinical conditions, the increased

mortality risk might be due to adverse effects of such drugs.
Severe acute respiratory syndrome coronavirus 2 (SARSCoV-
In contrast, it has been found that ACE-2 receptor expression
2) is a newly identified coronavirus that is responsible for
is downregulated after SARS-CoV-1 infection, thereby result­
Covid-19 disease. The virus was first isolated from the patients
ing in a disproportionate renin-angiotensinogen-aldosterone
with pneumonia in December 2019 in Wuhan, China (1). After
system (RAAS) activation and the progression of pneumonia
that, SARSCoV-2 spread globally, and in March 2020, the
(7). Hence, it has been speculated that the use of ACE inh/
World Health Organization declared it as an ongoing pan­
ARBs might in turn be useful by inhibiting the RAAS hyper­
demic. SARS-CoV-2 has similar features with SARSCoV-1
activation and preventing the progressive acute lung injury (7).
and Middle Eastern respiratory syndrome (MERS) coronavirus
Currently, there is a limited data about whether the use of
and enters the cell through angiotensin-converting enzyme-2
ACE inh/ARBs is beneficial or harmful in patients with Covid-
(ACE-2) receptor, a main entry point to infect the cells (2,3).
19 infection. Therefore, the present research aimed to
Because studies showed that ACE-2 receptor expression is
determine the relation between the use of ACE inh/ARBs and
substantially increased in hypertensive patients who are
in-hospital mortality of hypertensive patients diagnosed with
chronically treated with angiotensin-converting enzyme inhi­
Covid-19 pneumonia.
bitors (ACE inh) and angiotensinogen receptor blockers
(ARBs), it has been considered that such receptor upregulation
may facilitate massive infection and increase the risk of devel­ Material and methods
oping severe Covid-19 pneumonia (4,5). In addition, the cur­
Data collection
rent data suggest that hypertension, coronary artery disease,
and diabetes are associated with an increased mortality risk in This research was approved by both the Scientific Research
Covid-19 patients (6). Because ACE inh/ARBs are usually the Board and the Local Ethic Committee (approval number:

CONTACT Tufan Çınar drtufancinar@gmail.com Department of Cardiology, Health Sciences University, Sultan Abdülhamid Han Training and Research Hospital,
Istanbul, Turkey
© 2020 Taylor & Francis

B.10.1.TKH.4.34.H.GP.0.01/149), and it was performed
according to the Declaration of Helsinki of 1975, as revised in
2008. An informed consent was not needed because of the
retrospective design of the study.
In this retrospective study, we included 113 consecutive
hypertensive patients admitted to our centers due to Covid-
19 infection. The patients with the absence of in-hospital
clinical data were excluded from the study. Also, heart failure
patients with hypertension were not included in the study. In
all patients, Covid-19 infection was confirmed with using
reverse-transcription polymerase chain reaction (RT-PCR) in
addition to specific signs and symptoms and imaging findings.
The majority of patients who were hospitalized due to Covid-
19 infection had specific viral pneumonia findings on
computerized thoracic tomography. Per hospital’s protocol,
all Covid-19 patients following admission to the emergency
department had a standard work-up, which was consisted of
a detailed history, a complete physical examination, an electro­
cardiography, and standard biochemical and hematologic tests.
The patients enrolled in the study were treated according to the
National Health Ministry Covid-19 guidelines. Briefly, patients
with Covid-19 infection receive a hydroxychloroquine and/or
azithromycin as a first-line therapy. Favipiravir or remdesivir is
the second line available options after the failure of first-line
therapy. Biologic agents (tocilizumab, anakinra, etc.), Jak inhi­
bitors and corticosteroids are used if hemophagocytic lympho-
histiocytosis occurs due to cytokine storm.
For each patient, the clinical data, including gender, age, risk
factors (coronary artery disease, chronic obstructive lung disease,
etc.), and drug therapies, were collected from hospital electronic
database. We also collected the data regarding to the in-hospital
course of Covid-19 patients, such as admission to the intensive
care unit (ICU), and the need for endotracheal intubation.
In our study, hypertension was accepted as undergoing
anti-hypertensive treatment and a systolic pressure of
>140 mmHg, and/or a diastolic pressure of >90 mmHg in
at least two separate measurements during hospitalization
(8). All patients included in the study were on ACE inh/
ARBs or other antihypertensive therapy unless no contra­
indication was present.
Laboratory analysis
The blood samples, including creatinine, hemoglobin,
D-dimer, C-reactive protein (CRP), fibrinogen, etc., were
measured in all patients following admission to hospital.
A Beckman Coulter LH 780 hematology analyzer (Beckman
Coulter, FL, USA) was used for the complete blood count
analysis of the samples and Beckman Coulter LH 780
device (Beckman Coulter Ireland Inc., Mervue, Galway,
Ireland) was used to analyze the standard biochemical
parameters.
Primary outcome
The primary outcome of the study was the in-hospital all-cause
mortality. A trained study coordinator evaluated all electronic
medical records and confirmed in-hospital mortality.
CLINICAL AND EXPERIMENTAL HYPERTENSION 739
Statistical analysis
Statistical analyses were performed by using the SPSS software
(Version 23.0, SPSS, Inc., Chicago, IL, USA). Shapiro-Wilk’s test
was used to determine the normality of the data. The categorical
variables were expressed as numbers and percentages and the Chi-
square test was used to compare it. The independent sample t test
was used to compare the differences for variables with normally
distributed, while the Mann–Whitney U test was used to compare
the differences for variables without normally distributed. To
determine independent predictors of in-hospital mortality, the
possible factors identified with univariable analyses were further
entered into the multivariable logistic regression analysis. Kaplan–
Meir curve was drawn to show the cumulative survival of patients
with and without ACE inh/ARBs use and it was differentiated
using the log-rank test. The odds ratios (ORs) and 95% confidence
intervals (CIs) were calculated. P-values less than 0.05 were con­
sidered statistically significant.
Results
In our study, 113 hypertensive patients were included, of them
74 patients were using ACE inh/ARBs. The frequency of female
gender was 52.2% [n = 59 patients]. During in-hospital follow
up, 30.9% [n = 35 patients] of patients died.
We divided the study population into two groups; ACE inh/
ARBs and non-ACE inh/ARBs group. Baseline demographic
data, laboratory findings, and in-hospital course of patients
receiving or not receiving ACE inh/ARBs are given in Table 1.
The patients in the ACE inh/ARBs group were older. The fre­
quency of coronary artery disease was significantly higher in
patients using an ACE inh/ARBs as anti-hypertensive treatment
(p = .009). The other baseline features and medical treatments
were indifferent between the groups (p > .05, for each). In terms
of laboratory results, patients in the ACE inh/ARBs group had
significantly higher white blood cell (WBC) and neutrophils
count. The other laboratory findings were fairly similar in both
groups (p > .05, for each). The frequency of admission to the
ICU, endotracheal intubation, and death was significantly higher
in patients using ACE inh/ARBs [37 cases (50.0%) vs. 7 cases
(17.9; p = .001, 33 cases (44.6%) vs. 4 cases (10.3%); p < .001, and
31 cases (41.9%) vs. 4 cases (10.3%); p = .001, respectively].
Additionally, the study population was divided into two
groups; survivor and non-survivor group (Table 2). The patients
in the non-survivor group were older, had higher coronary
artery disease, and dementia (p < .05, for each). The use of
ACE inh/ARBs were significantly higher in the non-survivor
group compared those in the survivor group [31 cases (88.6%)
vs. 43 cases (55.1%), p< .001]. Comparison of laboratory findings
revealed that patients who did not survive following Covid-19
infection had higher WBC and neutrophils count, plasma glu­
cose, lactate dehydrogenase, D-dimer, and creatinine, while their
lymphocytes levels were significantly lower.
The independent predictors associated with in-hospital mor­
tality were evaluated by univariable and multivariable logistic
regression analysis. At the end of the univariable analysis, eight
variables were found to be statistically significant with in-
hospital mortality; age, coronary artery disease, ACE inh/ARBs
use, D-dimer, WBC count, creatinine, plasma glucose, and
740 M. SELÇUK ET AL.

Table 1. Characteristics of ACE inh/ARBs group compared with the non-ACE inh/ Table 2. Characteristics of survivor and non-survivor hypertensive patients hospi­
ARBs group in hypertensive patients hospitalized with the diagnosis of Covid-19 talized with the diagnosis of Covid-19 pneumonia.
pneumonia. Survivor Non-survivor
Non-aCE inh/ ACE inh/ Characteristics (n = 78) (n = 35) P value
ARBs ARBs Age 52 ± 14 68 ± 13 <.001
Characteristics (n = 39) (n = 74) P value Gender, n (%)
Age 58 ± 10 67 ± 11 <.001 Male 37 (47.4) 22 (62.9) .129
Gender, n (%) Female 41 (52.6) 13 (37.1)
Male 23 (59.0) 36 (48.6) .296 Comorbidities, n (%)
Female 16 (41.0) 38 (51.4) Diabetes mellitus 33 (42.3) 15 (42.9) .956
Admission systolic blood 132 ± 26 135 ± 24 .055 Smoking 5 (6.4) 4 (11.4) .362
pressure, mm Hg Chronic lung disease 15 (19.2) 8 (22.9) .658
Admission diastolic blood 70 ± 15 72 ± 13 .270 Chronic kidney disease 7 (9.0) 6 (17.1) .208
pressure, mm Hg Coronary artery disease 14 (17.9) 14 (40.0) <.001
Comorbidities, n (%) Heart failure 4 (5.1) 5 (14.3) .096
Diabetes mellitus 17 (43.6) 31 (41.9) .862 Stroke 4 (5.1) 2 (5.7) .898
Smoking 4 (10.3) 5 (6.8) .514 Dementia 0 (0.0) 3 (8.6) .009
Chronic lung disease 5 (12.8) 18 (24.3) .149 Cancer 4 (5.1) 1 (2.9) .587
Chronic kidney disease 3 (7.7) 10 (13.5) .357 Antihypertensive medications, n (%)
Coronary artery disease 4 (10.3) 24 (32.4) .009 ACE inh/ARBs 43 (55.1) 31 (88.6) <.001
Heart failure 2 (5.1) 7 (9.5) .419 Beta blockers 24 (30.8) 11 (31.4) .944
Stroke 1 (2.6) 5 (6.8) .345 Calcium channel blockers 20 (25.6) 14 (40.0) .124
Dementia 0 (0.0) 3 (4.1) .203 Other medications, n (%)
Cancer 2 (5.1) 3 (4.1) .792 Aspirin 19 (24.4) 16 (45.7) .023
Antihypertensive medications, n (%) Anticoagulant therapy 3 (3.8) 2 (5.7) .655
Beta blockers 10 (25.6) 25 (33.8) .373 Furosemide 1 (1.3) 5 (14.3) .004
Calcium channel blockers 8 (20.5) 26 (35.1) .107 Statins 11 (14.1) 10 (28.6) .068
Other medications, n (%) Insulin 7 (9.0) 4 (11.4) .684
Aspirin 7 (17.9) 28 (37.8) .030 Oral anti-hyperglycemic agents 24 (30.8) 11 (31.4) .944
Anticoagulant therapy 3 (7.7) 2 (2.7) .220 Laboratory data
Furosemide 1 (2.6) 5 (6.8) .345 White blood cell count, cells/µL 6.18 ± 2.64 8.75 ± 4.47 .003
Statins 5 (12.8) 16 (21.6) .253 Neutrophils, 4.28 ± 2.22 7.00 ± 4.31 <.001
Insulin 4 (10.3) 7 (9.5) .892 Lymphocytes 1.46 ± 0.82 1.13 ± 0.70 .013
Oral anti-hyperglycemic agents 16 (41.0) 19 (25.7) .093 Platelets, cells/µL 202 ± 61 231 ± 82 .113
Laboratory data Hemoglobin, g/dL 12.8 ± 1.5 12.4 ± 2.0 .418
White blood cell count, cells/µL 5.94 ± 2.61 7.53 ± 3.81 .038 Glucose, mg/dL 126 ± 54 167 ± 99 .016
Neutrophils, 4.25 ± 2.32 5.60 ± 3.59 .048 Lactate dehydrogenase, U/L 439 ± 176 759 ± 861 <.001
Lymphocytes 1.31 ± 0.90 1.39 ± 0.75 .211 Fibrinogen, mg/L 565 ± 135 477 ± 221 .075
Platelets, cells/µL 200 ± 56 217 ± 74 .346 D-dimer, μg/mL 656 ± 644 1720 ± 1595 <.001
Hemoglobin, g/dL 12.7 ± 1.3 12.7 ± 1.8 .856 C-reactive protein, mg/dL 54.1 ± 61.7 44.7 ± 65.2 .388
Glucose, mg/dL 131 ± 54 143 ± 82 .845 Alanine aminotransferase, U/L 35 ± 27 37 ± 36 .684
Lactate dehydrogenase, U/L 450 ± 160 584 ± 262 .300 Aspartate aminotransferase, U/L 31 ± 21 38 ± 32 .253
Fibrinogen, mg/L 509 ± 172 556 ± 168 .448 Creatinine, mg/dL 1.02 ± 0.29 1.42 ± 0.81 <.001
D-dimer, μg/mL 636 ± 681 1223 ± 1326 .002 Potassium, mEq/L 137 ± 3.3 136 ± 4.3 .201
C-reactive protein, mg/dL 49 ± 55 52 ± 66 .887 Sodium, mEq/L 4.2 ± 0.4 4.1 ± 0.8 .709
Alanine aminotransferase, U/L 34 ± 26 51 ± 123 .706 Hospital stay, d 8±4 10 ± 6 .089
Aspartate aminotransferase, U/L 39 ± 35 33 ± 27 .935 Continuous variables are presented as mean ± SD, nominal variables presented as
Creatinine, mg/dL 1.06 ± 0.31 1.20 ± 0.63 .368 frequency (%).
Potassium, mEq/L 137 ± 2.7 137 ± 4.1 .593
Sodium, mEq/L 4.2 ± 0.35 4.1 ± 0.69 .690
In-hospital course, n (%)
Admitted to intensive care unit 7 (17.9) 37 (50.0) .001 hospital mortality in patients who were diagnosed with Covid-
Endotracheal intubation 4 (10.3) 33 (44.6) <.001 19 pneumonia. Also, the frequency of admission to the ICU
Death 4 (10.3) 31 (41.9) .001
Hospital stay, d 8±4 9±6 .524
and endotracheal intubation was more common in patients on
ACE inh/ARBs therapy.
Continuous variables are presented as mean ± SD, nominal variables presented as
frequency (%). In previous outbreaks from SARS and MERS infection,
hypertension was demonstrated to be a major risk factor for
higher mortality in patients suffering from these infections
lactate dehydrogenase. These variables, which were included in (9,10). Similarly, existing data provide evidence that Covid-19
the multivariable analysis, are shown in Table 3. The multi­ patients with hypertension have usually higher mortality rates
variable analysis showed that the independent predictors of in- than those without it (6). Although the underlying mechanisms
hospital mortality were ACE inh/ARBs use (OR: 3.66; 95%CI: linked hypertension with the severity of Covid-19 infection
1.11–18.18; p= .032), age, D-dimer, and lactate dehydrogenase. remain to be unknown, it has been considered that an excessive
Kaplan-Meir curve analysis displayed that patients on ACE inh/ RAS activation can cause to acute lung injury by aggravating
ARBs therapy had higher incidence of in-hospital death than the inflammatory response (cytokine storm) and triggering an
those who were not [log rank test p value <.001, Figure 1]. excessive vasoconstriction as well as cell contraction (11,12).
ACE-2 in the human body is a potent inhibitor of RAAS,
and it has a critical role for maintaining a healthy physiologic
Discussion system (13,14). Because ACE-2 is demonstrated to be vital for
The present study has found that the use of ACE inh/ARBs the SARS-CoV-2 entry to the host cells, the use ACE inh/ARBs
therapy and older age might be associated with an increased in- therapy in Covid-19 patients with hypertension has become
 CLINICAL AND EXPERIMENTAL HYPERTENSION 741

Table 3. Univariable analysis and multivariable model for in-hospital mortality.

Univariable analysis P value OR (95% CI) Multivariable analysis P value OR (95% CI)
Age <0.001 1.09 (1.04–1.14) Age 0.003 1.10 (1.04–1.16)
Coronary artery disease 0.014 3.04 (1.25–7.42) - - -
ACE inh/ARBs 0.001 6.30 (2.03–19.58) ACE inh/ARBs 0.032 3.66 (1.11–18.18)
D-Dimer <0.001 1.00 (1.00–1.00) D-Dimer 0.006 1.00 (1.00–1.00)
White blood cell 0.001 1.09 (1.09–1.40) - - -
Creatinine 0.002 7.74 (2.14–28.01) - - -
Glucose 0.014 1.00 (1.00–1.00) - - -
Lactate dehydrogenase 0.001 1.00 (1.00–1.00) Lactate dehydrogenase 0.002 1.00 (1.00–1.00)
All clinically relevant parameters were included in the model.
OR, Odds ratio; CI, confidence interval.
Abbreviations; ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers

should be interpreted cautiously. Because only moderate and

Figure 1. Kaplan-Meir curve survival analysis of ACE inh/ARBs user and ACE inh/
ARBs non-user.
severe Covid-19 pneumonia cases were followed and hospita­
lized in our institution, the study findings cannot be general­
ized to all Covid-19 patients, especially for asymptomatic and
mild hypertensive Covid-19 cases who were on ACE inh/ARBs
therapy. In our study, patients who were on ACE inh/ARBs
therapy were older and more likely to have coronary artery
disease comparing to those who were not. In addition to the
ACE inh/ARBs possible adverse effects, we thought that older
Covid-19 patients with chronic disease might have a weak
immunity and poor respiratory tract functions, thereby having
a higher mortality rate. Based on our results, we could not
definitely recommend discontinuing the use of ACE inh/ARBs
therapy in all Covid-19 patients. However, the study findings
highlighted that ACE inh/ARBs therapy might not be beneficial
in the subgroup of hypertensive Covid-19 patients, particularly
those with moderate to severe Covid-19 pneumonia.
Therefore, the present study results yielded that more research
is needed to draw a definitive conclusion about whether the use
of ACE inh/ARBs therapy is beneficial or harmful in hyperten­
sive Covid-19 pneumonia cases.

Limitations of the study

a contentious issue. Experimental studies showed that ACE
inh/ARBs therapy can increase ACE-2 expression in the cardi­
opulmonary circulation (15,16). Hence, the main hypothesize
is that Covid-19 patients who are treated with ACE inh/ARBs
may be at increased risk of severe disease outcomes because of
Covid-19 infection.
In the current literature, there are a few clinical studies
investigating the relation between ACE inh/ARBs therapy
and in-hospital mortality in hypertensive Covid-19 patients.
In a retrospective, single-center case series of 362 hypertensive
cases, of whom 115 (31.8%) were on ACE inh/ARBs therapy, Li
et al. reported that the use of ACE inh/ARBs was not associated
with an increased mortality in such Covid-19 patients (17).
Moreover, in a recent retrospective, multi-center cohort study
of adult hypertensive patients, including 188 taking ACE inh/
ARBs, Zhang et al. found that the use of ACE inh/ARBs was
not associated with higher risk of all-cause mortality compared
with ACE inh/ARBs non-users (18). In our study, contradic­
tory to the current knowledge, which recommends
a continuation of ACE inh/ARBs therapy in hypertensive
Covid-19 patients (19,20), we found that the use of ACE inh/
ARBs might be associated with a higher mortality in such
patients. However, we believed that the results of our study
The present research had the following limitations. The retro­
spective design of the study and a relatively low number of
patients were major limitations. However, all consecutive
hypertensive Covid-19 patients were included in the study.
Despite the use of multivariate logistic regression analysis, we
acknowledged that there might be the possibility of unmea­
sured confounders in the study. Although we checked all anti­
hypertensive treatments form the electronic prescription
database, some patients might stop their medications because
of well-controlled blood pressure. Because our study was con­
ducted in a one geographic region, geographically diverse
cohorts are necessary to confirm our findings. Finally, large
prospective cohort studies are needed to determine the exact
relation between ACE inh/ARBs therapy and survival in
Covid-19 patients.
Conclusions
In the present study, we found that ACE inh/ARBs therapy was
associated with higher risk of in-hospital mortality in hyper­
tensive patients who were hospitalized with Covid-19 pneu­
monia. Although there might be the possibility of some
742 M. SELÇUK ET AL.
unmeasured residual confounders to affect study’s results, it is
likely that ACE inh/ARBs therapy might not be beneficial in
the subgroup of hypertensive Covid-19 patients, particularly
those with moderate to severe Covid-19 pneumonia.
Compliance with ethical standards
All authors declare that he has no conflict of interest. All procedures
performed in studies involving human participants were in accordance
with the ethical standards of the institutional research committee and with
the 1964 Helsinki declaration and its later amendments or comparable
ethical standards. This article does not contain any studies with animals
performed by any of the authors. The ethics committee approved the
design of the present study. Informed consent was waived due to the
retrospective design of the study.
Disclosure statement
All authors declare that they do not have conflict of interest.
Funding
The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-for-profit sectors.
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