COVID-19

Clinical Features of COVID-19 in Patients With Essential

Hypertension and the Impacts of Renin-angiotensin-aldosterone
System Inhibitors on the Prognosis of COVID-19 Patients
Wei Pan,* Jishou Zhang,* Menglong Wang,* Jing Ye,* Yao Xu,* Bo Shen, Hua He, Zhen Wang,
Di Ye, Mengmeng Zhao, Zhen Luo, Mingxiao Liu, Pingan Zhang, Jian Gu, Menglin Liu,
Dan Li, Jianfang Liu, Jun Wan

See Editorial, pp 665–669

Abstract—Hypertension is one of the most common comorbidities in patients with coronavirus disease 2019 (COVID-19). This
study aimed to clarify the impact of hypertension on COVID-19 and investigate whether the prior use of renin-angiotensin-
aldosterone system (RAAS) inhibitors affects the prognosis of COVID-19. A total of 996 patients with COVID-19 were
enrolled, including 282 patients with hypertension and 714 patients without hypertension. Propensity score-matched analysis
(1:1 matching) was used to adjust the imbalanced baseline variables between the 2 groups. Patients with hypertension were
further divided into the RAAS inhibitor group (n=41) and non-RAAS inhibitor group (n=241) according to their medication
history. The results showed that COVID-19 patients with hypertension had more severe secondary infections, cardiac and renal
dysfunction, and depletion of CD8+ cells on admission. Patients with hypertension were more likely to have comorbidities
and complications and were more likely to be classified as critically ill than those without hypertension. Cox regression
analysis revealed that hypertension (hazard ratio, 95% CI, unmatched cohort [1.80, 1.20–2.70]; matched cohort [2.24,
1.36–3.70]) was independently associated with all-cause mortality in patients with COVID-19. In addition, hypertensive
patients with a history of RAAS inhibitor treatment had lower levels of C-reactive protein and higher levels of CD4+ cells.
The mortality of patients in the RAAS inhibitor group (9.8% versus 26.1%) was significantly lower than that of patients
in the non-RAAS inhibitor group. In conclusion, hypertension may be an independent risk factor for all-cause mortality
in patients with COVID-19. Patients who previously used RAAS inhibitors may have a better prognosis.  (Hypertension.
Downloaded from http://ahajournals.org by on May 25, 2021

2020;76:732-741. DOI: 10.1161/HYPERTENSIONAHA.120.15289.) Data Supplement •

Key Words: comorbidity ◼ coronavirus ◼ mortality ◼ prognosis ◼ risk factor

R ecently, a new coronavirus, named severe acute respira-

tory syndrome coronavirus 2 (SARS-CoV-2), was identi-
fied and quickly spread around the world.1–3 As of March 26,
2020, >82 078 cases of coronavirus disease 2019 (COVID-19)
had been confirmed in China, and 509 164 cases had been con-
firmed worldwide.3 This global public health emergency is
attracting substantial concern throughout the world.
Studies of SARS-CoV-2 have found that several fac-
tors are associated with the prognosis of infected people.
Comorbidities, older age, high sequential organ failure assess-
ment score, and higher D-dimer level are risk factors for a
worse prognosis of COVID-19.4–8 One study, including 1099
patients with COVID-19, revealed that the most common
underlying disease in patients with severe COVID-19 was
hypertension.9 Another study analyzed 140 confirmed cases,
and the results showed that 30% had comorbid hypertension
and 12% had diabetes mellitus.10 However, the clinical charac-
teristics and outcomes of COVID-19 patients with hyperten-
sion are still unclear.
ACE (angiotensin-converting enzyme)-2 is considered a
receptor for SARS-CoV-2. A previous study suggested that
ACE-2 enzyme activity may have a protective effect against
cardiovascular disease.11 Renin-angiotensin-aldosterone
system (RAAS) inhibitors, such as ACE inhibitors and ARBs
(angiotensin receptor blockers), play a protective role by
activating the ACE-2/angiotensin 1–7/Mas axis, which may
be associated with an elevated ACE-2 level in patients.12,13
However, evidence showing the association between ACE

Received April 14, 2020; first decision May 1, 2020; revision accepted June 6, 2020.
From the Department of Cardiology (W.P., J.Z., M.W., J.Y., Y.X., Z.W., D.Y., M.Z., Z.L., J.L., J.W.), Department of Medical Affairs (B.S., H.H.), Medical
Quality Management Office (Mingxiao Liu), Department of Clinical Laboratory (P.Z., J.G.), Department of Emergency (Menglin Liu), and Department of
Pediatrics (D.L.), Renmin Hospital of Wuhan University, China; Cardiovascular Research Institute, Wuhan University, China (W.P., J.Z., M.W., J.Y., Y.X.,
Z.W., D.Y., M.Z., Z.L., J.L., J.W.); and Hubei Key Laboratory of Cardiology, Wuhan, China (W.P., J.Z., M.W., J.Y., Y.X., Z.W., D.Y., M.Z., Z.L., J.L., J.W.).
*These authors contributed equally to this work.
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.120.15289.
Correspondence to Jun Wan, Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Rd, Wuhan 430060, China. Email wanjun@
whu.edu.cn
© 2020 American Heart Association, Inc.
Hypertension is available at https://www.ahajournals.org/journal/hyp DOI: 10.1161/HYPERTENSIONAHA.120.15289

732
 Pan et al   Impacts of Hypertension and ACE Inhibitors/ARBs on COVID-19   733
inhibitors/ARBs and COVID-19 has been less reported. In
this study, we aimed to clarify the impact of hypertension on
COVID-19 and observe whether the prior use of ACE inhibi-
tors/ARBs affected the prognosis of patients with COVID-19.
Methods
The data that support the findings of this study are available from the
corresponding author upon reasonable request.
Study Population
This was a single-center, retrospective study. From January 4, 2020,
to February 14, 2020, consecutive patients diagnosed with COVID-19
were recruited at Renmin Hospital of Wuhan University. All patients
were diagnosed and classified based on the Diagnosis and Treatment
of Novel Coronavirus Pneumonia (sixth edition) guidelines published
by the National Health Commission of China.14 Confirmed cases were
those who had a positive result on a pathology test (real-time fluo-
rescent RT-polymerase chain reaction detection of novel coronavirus
nucleic acid or gene sequencing highly homologous with a known co-
ronavirus). The exclusion criteria included patients with mild COVID-
19 who were admitted to the cabin hospitals, patients who were
clinically diagnosed, patients with repeated admissions and patients
with incomplete records. Finally, 996 patients were enrolled in the
study. According to their medical history, patients were divided into the
nonhypertension group (n=714) and the hypertension group (n=282).
The identification of hypertensive patients was based on a clearly docu-
mented medical history of hypertension with a systolic blood pressure
≥140 mm Hg or a diastolic blood pressure ≥90 mm Hg.15 Among the
patients with hypertension, 41 patients had used ACE inhibitors/ARBs
regularly before admission (RAAS inhibitor group), and 241 patients
had not (non-RAAS inhibitor group). The past medical history was
reported by the patients, which may have resulted in missing some
patients with underlying diseases and patients with a history of taking
Downloaded from http://ahajournals.org by on May 25, 2021
ACE inhibitors/ARBs. This study was reviewed and approved by the
Medical Ethics Committee of Renmin Hospital of Wuhan University.
Data Collection
The retrospective analysis was based on case reports, nursing records,
and test results extracted from electronic medical records. All data
were collected using standardized forms, including the clinical symp-
toms, vital signs, other basic diseases (diabetes mellitus, coronary
heart disease, arrhythmia, chronic obstructive pulmonary diseases,
asthma, cerebrovascular disease, chronic kidney disease, chronic liver
disease, malignancy, and organ transplant), complications, therapy
strategies, results of the first laboratory examinations of admitted
patients and clinical outcomes. The therapy strategies included an-
tiviral treatment, antibacterial treatment, antifungal therapy, cortico-
steroid treatment, immunotherapy, artificial liver support, continuous
renal replacement therapy, and extracorporeal membrane oxygena-
tion. The clinical outcomes were recorded until February 24, 2020.
Criteria for Target Organ Injuries
Plasma hypersensitivity troponin I levels above the 99% reference
line were considered to indicate acute heart injury. Alanine amino-
transferase ≥150 U/L was considered as acute liver injury. Patients
with one of the following conditions could be diagnosed with acute
kidney injury: (1) the highest serum creatinine level increased by
>26.5 μmol/L (0.3 mg/dL) within 48 hours and (2) serum creatinine
exceeded the baseline value by 1.5-fold (confirmed or estimated to
occur within 7 days). The diagnosis of shock was mainly based on
the evidence: hypotensive patients with failed volume resuscitation
who were administered vasopressors to maintain blood pressure.
Propensity Score-Matched Analysis
The variables potentially confounding the associations between hy-
pertension and the outcomes of COVID-19 were addressed using
the propensity score-matching method according to a previous pub-
lication.16 The propensity score-matching cohorts were generated by
balancing age, sex, chronic obstructive pulmonary diseases, asthma.
and arrhythmia. Since diabetes mellitus, coronary artery disease, and
cerebrovascular disease are diseases that coexist with hypertension,
these variables were not adjusted for in the propensity score-matching
analysis. The matching ratio was 1:1 for patients with and without hy-
pertension (n=256 each). Exact matching with a caliper size of 0.05
was applied for all matched pairs according to the propensity scores.
Evaluation of the balance between covariates was conducted by esti-
mating standardized differences before and after matching. Only those
with small absolute values <0.1 were considered qualified.
Statistical Analysis
We made no assumptions regarding missing data. Continuous vari-
ables are represented as the median and the interquartile range, and
categorical variables are presented the number (percentage) based on
the available data. Chi-square tests or Fisher exact tests were used
for categorical variables, and the Mann-Whitney test was used for
continuous data. Kaplan-Meier curves were used to compare the cu-
mulative risk rate. Cox proportional hazard regression models were
applied to determine the potential risk factors associated with all-
cause mortality, and the results are reported as the hazard ratio and
95% CI. R 3.6.3 (R Foundation for Statistical Computing, Austria)
and SPSS 22.0 (IBM) were used for the analysis. SD>0.1 and P<0.05
were considered statistically significant.
Results
Basic Clinical Characteristics of COVID-19 Patients
With or Without Hypertension
Of the 996 patients with COVID-19, 282 patients (28.3%) had
hypertension, and 714 patients (71.7%) did not have hyper-
tension according to their medical history. COVID-19 patients
with hypertension had a higher proportion of males (50.7%
versus 45.1%), more advanced age (median, 69 versus 56
years), higher systolic blood pressure (median, 132 versus
124 mm Hg), and higher diastolic blood pressure (median, 78
versus 74 mm Hg) than patients without hypertension.
The hypertension group had more patients with comor-
bidities than the nonhypertension group. The proportions of
patients with diabetes mellitus (27.7% versus 5.6%), coronary
heart disease (15.6% versus 2.2%), cerebrovascular disease
(7.8% versus 1.4%), arrhythmia (4.3% versus 1.7%), chronic
liver disease (4.3% versus 2.4%), and chronic kidney disease
(4.6% versus 1.5%) were significantly higher in the hyperten-
sion group than in the nonhypertension group.
In addition, more patients with severe complications dur-
ing hospitalization were observed in the hypertension group.
The hypertension group had more patients with acute cardiac
injury (20.9% versus 7.9%), shock (13.5% versus 6.0%), and
acute kidney injury (6.0% versus 1.7%) than the nonhyperten-
sion group. In addition, 33 patients (11.7%) were admitted to
the intensive care unit in the hypertension group due to wors-
ening condition during hospitalization, while a smaller pro-
portion of patients (4.2%) were admitted to the intensive care
unit in the nonhypertension group. These results indicated that
patients with hypertension were more likely to develop severe
illness.
Among all patients, most received antiviral therapy, many
received antibiotic therapy, and some received immunoglob-
ulin therapy and glucocorticoid therapy. The main treatments
were not significantly different between the 2 groups, although
more patients received antifungal therapy (6.0% versus 2.1%)
in the hypertension group than in the nonhypertension group.
 734  Hypertension  September 2020

Table 1.  The Basic Clinical Characteristics of Patients With or Without Hypertension

Hypertension (Unmatched) Hypertension (Matched, 1:1)

Characteristics Yes (n=282) No (n=714) SD Yes (n=256) No (n=256) SD
Ages, median (IQR), y 69 (62–76) 56 (41–67) 0.996 68 (60–75) 68 (60–75) 0.003
Gender
 Male 143 (50.7) 322 (45.1) 0.112 125 (48.8) 134 (52.3) 0.07
Systolic blood pressure,* mm Hg 132 (121–147) 124 (112–135) 0.584 132 (123–147) 128 (117–140) 0.385
Diastolic blood pressure,* mm Hg 78 (71–87) 74 (68–81) 0.356 78 (72–87) 75 (68–83) 0.362
Comorbidities
 Diabetes mellitus 78 (27.7) 40 (5.6) 0.62 73 (28.5) 22 (8.6) 0.53
 Coronary heart disease 44 (15.6) 16 (2.2) 0.482 36 (14.1) 11 (4.3) 0.343
 Arrhythmia 12 (4.3) 12 (1.7) 0.152 9 (3.5) 6 (2.3) 0.07
 COPD 8 (2.8) 15 (2.1) 0.047 7 (2.7) 8 (3.1) 0.023
 Asthma 3 (1.1) 9 (1.3) 0.018 3 (1.2) 3 (1.2) <0.001
 Cerebrovascular disease 22 (7.8) 10 (1.4) 0.309 16 (6.2) 4 (1.6) 0.244
 Chronic kidney disease 13 (4.6) 11 (1.5) 0.178 12 (4.7) 6 (2.3) 0.128
 Chronic liver disease 12 (4.3) 17 (2.4) 0.105 12 (4.7) 7 (2.7) 0.103
 Malignancy 7 (2.5) 21 (2.9) 0.028 6 (2.3) 11 (4.3) 0.109
 Organ transplant 1 (0.4) 1 (0.1) 0.043 1 (0.4) 0 (0.0) 0.089
Complications
 Shock 38 (13.5) 43 (6.0) 0.253 36 (14.1) 18 (7.0) 0.23
 Acute cardiac injury 59 (20.9) 57 (7.9) 0.374 51 (19.9) 35 (13.7) 0.168
 Acute kidney injury 17 (6.0) 12 (1.7) 0.227 16 (5.9) 12 (1.54) 0.164
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 Acute liver injury 9 (3.2) 55 (7.7) 0.20 8 (3.1) 18 (7.0) 0.179

 Only one complication 42 (14.9) 83 (11.6) 0.097 34 (13.3) 34 (13.3) <0.001
 More than one complication 33 (11.7) 33 (4.6) 0.261 31 (12.1) 18 (7.0) 0.173
Admission to ICU 33 (11.7) 30 (4.2) 0.28 33 (12.9) 13 (5.1) 0.276
 Duration of ICU, d 6.5 (3.8–11.3) 8.0 (3.0–10.3) 0.018 6.5 (3.8–11.3) 7.5 (1.5–9.0) 0.112
Treatment
 Antiviral therapy 259 (91.8) 666 (93.3) 0.055 235 (91.8) 240 (93.8) 0.075
 Antibacterial therapy 227 (80.5) 554 (77.6) 0.071 210 (82.0) 205 (80.1) 0.05
 Antifungal therapy 17 (6.0) 15 (2.1) 0.20 16 (6.2) 8 (3.1) 0.148
 Glucocorticoid therapy 146 (51.8) 340 (47.4) 0.083 139 (54.3) 142 (55.5) 0.024
 Immunoglobulin therapy 151 (53.5) 361 (50.6) 0.06 141 (55.1) 148 (57.8) 0.055
 Artificial liver support 2 (0.7) 8 (1.1) 0.043 2 (0.8) 3 (1.2) 0.04
 ECMO 0 2 (0.3) 0.075 0 0 -
 CRRT 6 (2.1) 9 (1.3) 0.067 6 (2.3) 6 (2.3) <0.001
Values are number (percentage) or Medium (IQR) unless stated otherwise. COPD indicates chronic obstructive pulmonary disease; COVID-19, coronavirus
disease 2019; CRRT, continuous renal replacement therapy; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; and IQR, interquartile
range.
The total number of patients with available data in different groups (n1 and n2 indicate the number in COVID-19 patients with and without hypertension before
matching, n3 and n4 indicate the number in COVID-19 patients with and without hypertension after matching): *: n1=241, n2=566, n3=219, and n4=223.

In the propensity score-matching analysis, we matched 256
patients from the hypertension group with 256 patients from the
nonhypertension group at a ratio of 1:1. Similar results with regard
to the basic clinical characteristics, complications, and treatments
were observed between the hypertension group and the nonhyper-
tension group after matching. All data are shown in Table 1.
Hypertensive Patients With COVID-19 Had Worse
Initial Laboratory Tests
The proportion of hypertensive patients with abnormal lab-
oratory indicators was significantly higher than that of those
without hypertension. Patients with hypertension had higher
white blood cell counts (median, 6.25 versus 5.26×109/L) and
 Pan et al   Impacts of Hypertension and ACE Inhibitors/ARBs on COVID-19   735

Table 2.  Profile of Laboratory Findings in Patients With or Without Hypertension

Hypertension (Unmatched) Hypertension (Matched, 1:1)

Laboratory Parameters Normal Range Yes (n=282) No (n=714) SD Yes (n=256) No (n=256) SD
Blood routine
 White blood cell count,* ×109/L 3.5–9.5 6.25 (4.60–8.20) 5.26 (4.02–6.93) 0.381 6.45 (4.62–8.56) 5.29 (4.14–7.45) 0.341
 Neutrophil count,* ×10 /L 9
1.8–6.3 4.52 (3.00–6.75) 3.40 (2.33–5.18) 0.418 4.65 (3.01–7.24) 3.57 (2.51–5.93) 0.339
 Lymphocyte count,* ×109/L 1.1–3.2 0.93 (0.61–1.31) 1.07 (0.76–1.52) 0.287 0.92 (0.61–1.33) 0.94 (0.64–1.34) 0.057
 Platelet count,* ×109/L 125–350 198.5 212.0 0.051 200.5 213.0 0.025
(157.0–259.3) (162.0–271.5) (157.3–260.0) (156.0–270.5)
Liver function
 ALT,† U/L 9–50 245 (17.0–35.8) 24.0 (16.0–44.0) 0.124 24.5 (17.0–35.3) 26.0 (17.0–44.3) 0.101
 AST,† U/L 15–40 29.0 (21.0–42.0) 27.0 (20.0–40.0) 0.045 28.0 (20.0–42.0) 30.0 (21.8–46.0) 0.026
Renal function
 Creatinine,‡ μmol/L F<60 y, 41–73 68.0 (54.0–87.8) 57.0 (48.0–69.0) 0.262 67.0 (54.0–85.0) 60.0 (49.0–73.0) 0.17
F≥60 y, 41–81;
M<60 y, 57–97
M≥60 y, 57–111
 eGFR,‡ mL/min >90 89.0 (69.3–97.1) 103.2 (93.0–116.4) 0.916 90.2 (70.7–98.2) 94.5 (86.9–101.8) 0.4
Myocardial injury
 Creatine kinase,§ ng/mL 50–310 67.50 58.00 0.134 69.50 63.00 0.089
(43.75–127.50) (37.00–100.00) (46.25–128.50) (40.00–109.00)
 CK-MB,‖ ng/mL 0–5 1.35 (0.85–2.48) 0.88 (0.59–1.46) 0.338 1.34 (0.82–2.47) 1.15 (0.73–1.89) 0.132
 hs-TnI,¶ ng/mL 0–0.04 0.011 0.006 0.148 0.009 0.006 0.1
(0.006–0.036) (0.006–0.011) (0.006–0.033) (0.006–0.020)
Coagulation function
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 D-dimer,# mg/L 0–0.55 1.17 (0.56–3.95) 0.70 (0.37–1.99) 0.142 1.19 (0.54–3.95) 1.01 (0.50–3.16) 0.015
Inflammation
 C-reactive protein,** mg/L 0–10 47.1 (11.4–101.4) 22.2 (5.0–60.3) 0.461 48.7 (11.0–102.8) 43.9 (11.9–79.5) 0.224
 hs-C-reactive protein,†† mg/L 0–5 5.0 (5.0–5.0) 5.0 (3.6–5.0) 0.124 5.0 (5.0–5.0) 5.00 (5.0–5.0) 0.038
 ESR,‡‡ mm/h 0–26 59.0 (34.0–88.0) 52.5 (31.3–70.0) 0.29 59.0 (35.5–90.5) 53.5 (27.3–70.0) 0.337
 Procalcitonin,§§ ng/mL <0.5 0.09 (0.04–0.21) 0.06 (0.03–0.11) 0.225 0.09 (0.04–0.22) 0.07 (0.04–0.13) 0.263
Cytokine
 γ-IFN,‖‖ pg/mL ≤18 4.00 (3.05–5.94) 3.72 (2.57–5.3.8) 0.054 4.00 (3.15–5.27) 4.23 (2.73–6.75) 0.067
 IL-6,¶¶ pg/mL ≤20.0 10.42 5.93 0.119 10.18 8.11 0.145
(5.65–26.58) (2.10–14.54) (5.55–25.89) (2.19–21.61)
 IL-10,‖‖ pg/mL ≤5.9 5.90 (4.68–7.33) 5.71 (4.76–7.26) 0.262 6.02 (4.65–7.33) 5.63 (4.83–7.91) 0.282
Cellular immunity
 CD16+56 count,## /μL 84–724 116.0 118.0 0.049 115.5 117.5 0.017
(73.0–189.0) (73.0–180.0) (73.3–185.0) (71.0–184.8)
 CD16+56,## % 5–26 14.7 12.8 0.277 14.4 13.8 0.094
(9.5–22.3) (8.1–19.6) (9.4–21.8) (9.3–21.4)
 CD19 count,## /μL 80–616 130.0 138.0 0.085 137.0 129.0 0.05
(78.0–199.0) (93.5–201.0) (83.5–203.0) (83.3–192.0)
 CD19,## % 5–22 16.6 15.1 0.17 17.1 15.2 0.128
(12.2–22.7) (10.9–20.2) (12.5–23.6) (11.0–21.4)
 CD3 count,## /μL 723–2737 519.0 630.0 0.289 518.5 547.5 0.055
(305.0–780.0) (408.3–944.5) (305.0–783.0) (328.0–831.5)
 CD3,## % 56–86 63.5 68.0 0.389 63.4 65.7 0.206
(52.0–71.9) (59.0–74.8) (51.9–71.8) (56.3–72.7)

(Continued )
 736  Hypertension  September 2020

Table 2.  Continued

Hypertension (Unmatched) Hypertension (Matched, 1:1)

Laboratory Parameters Normal Range Yes (n=282) No (n=714) SD Yes (n=256) No (n=256) SD

 CD4 count,## /μL 404–1612 328.0 375.0 0.177 329.5 329.0 0.009
(191.0–507.0) (237.8–575.3) (191.0–506.5) (197.0–533.0)
 CD4,## % 33–58 39.7 39.5 0.067 40 40.1 0.101
(31.2–46.1) (31.8–46.0) (31.4–46.1) (31.2–47.8)
 CD8 count,## /μL 220–1129 163.0 227.5 0.352 161.5 189.5 0.121
(90.0–261.0) (125.0–354.0) (90.3–262.0) (91.3–296.8)
 CD8,## % 13–39 19.8 (14.5–24.3) 23.4 (16.6–30.0) 0.382 19.7 (14.4–24.3) 20.6 (14.3–28.0) 0.178
 CD4/CD8## 0.9–2.0 2.0 (1.4–2.8) 1.7 (1.2–2.5) 0.2 2.0 (1.4–2.8) 1.9 (1.3–3.1) 0.04
Values are number (percentage) or medium (IQR) unless stated otherwise. γ-IFN indicates γ-interferon; ALT, alanine aminotransferase; AST, aspartate
aminotransferase; CK-MB, creatine kinase-MB; COVID-19, coronavirus disease 1029; eGFR, estimated glomerular filtration rate; ESR, erythrocyte sedimentation rate;
hs-TnI, hypersensitive troponin I; IL, interleukin; and IQR, interquartile range.
The total number of patients with available data in different groups (n1 and n2 indicate the number in COVID-19 patients with and without hypertension before
matching, n3 and n4 indicate the number in COVID-19 patients with and without hypertension after matching): *: n1=280, n2=695, n3=254, and n4=251; †: n1=278,
n2=696, n3=252, and n4=252; ‡: n1=278, n2=695, n3=252, and n4=252; §: n1=276, n2=680, n3=250, and n4=251; ‖: n1=253, n2=508, n3=231, and n4=208; ¶:
n1=254, n2=506, n3=231, and n4=210; #: n1=268, n2=578, n3=244, and n4=234; **: n1=274, n2=671, n3=248, and n4=246; ††: n1=272, n2=665, n3=246, and
n4=247; ‡‡: n1=33, n2=74, n3=31, and n4=30; §§: n1=269, n2=563, n3=243, and n4=231; ‖‖: n1=55, n2=126, n3=51, and n4=46; ¶¶: n1=123, n2=274, n3=112,
and n4=113; and ##: n1=249, n2=600, n3=226, and n4=230.

neutrophil counts (median, 4.52 versus 3.40×109/L) and lower
lymphocyte counts (median, 0.93 versus 1.07×109/L). In addi-
tion, D-dimer levels (median, 1.17 versus 0.70 mg/L) were
significantly higher in patients with hypertension than in those
without hypertension (Table 2).
Compared with those without hypertension, COVID-19
patients with hypertension had higher rates of organ damage
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In the matched cohort, similar results were also observed for
most of these variables, although no significant differences were
observed in lymphocyte counts, levels of creatine kinase, hyper-
sensitive troponin I, D-dimer, and hs-CRP, CD3+, and CD4+ counts
between COVID-19 patients with and without hypertension.
COVID-19 Patients With Hypertension Had a

on admission. Although the results for liver function were
similar in both groups, patients with hypertension had signif-
icantly more renal impairment at admission, which was indi-
cated by higher creatinine levels (median, 68.0 versus 57.0
μmol/L) and lower estimated glomerular filtration rate (me-
dian, 89.0 versus 103.2 mL/min) in the hypertension group.
Similarly, the hypertensive group had a higher proportion of
patients with cardiac injury on admission, with elevated lev-
els of creatine kinase (median, 67.50 versus 58.00 ng/mL),
creatine kinase-MB (median, 1.35 versus 0.88 ng/mL), and
hypersensitive troponin I (median, 0.011 versus 0.006 ng/
mL). Laboratory results also showed that patients in the hy-
pertension group had higher levels of indicators of bacterial
infections, such as CRP (C-reactive protein), high sensitivity
(hs)-CRP and procalcitonin, than the nonhypertension group
on admission, which suggested that patients with hyperten-
sion were more susceptible to secondary infections (Table 2).
Most importantly, patients with hypertension had worse
immune dysfunction and inflammatory cytokine storms. The
counts of CD3+ cells (median, 519.0 versus 630.0/μL), CD4+
cells (median, 328.0 versus 375.0/μL), and CD8+ cells (median,
163.0 versus 227.5/μL) were lower in the hypertension group
than in the nonhypertension group (Table 2), suggesting that
infected patients with hypertension had more severe depletion of
immune cells. In addition, the plasma levels of IL (interleukin)-6
(median, 10.42 versus 5.93 pg/mL) and IL-10 (median, 5.90
versus 5.71 pg/mL) were significantly higher in the hypertension
group than in the nonhypertension group (Table 2).
Worse Prognosis
As of February 24, 2020, the proportion of patients assessed as
critically ill was significantly higher in the hypertension group
than in the nonhypertension group (Table 3). The proportion
of patients assessed as having mild to moderate COVID-19
was significantly lower in the hypertension group than in
the nonhypertension group (24.5% and 43.8%). Compared
with the nonhypertension group, the hypertension group had
smaller proportions of patients who were discharged (10.6%
versus 23.0%) and a greater proportion of patients who died
(23.8% versus 7.3%; Table 3). More importantly, the mortality
risk increased with age, both in patients with and without hy-
pertension (Table S1 in the Data Supplement). These results
indicated that COVID-19 patients without hypertension
had a better prognosis. The Kaplan-Meier curves showed
that patients with hypertension were more likely to die than
patients without hypertension, both in the unmatched cohort
and matched cohort (P<0.05, respectively; Figure [A and B]).
In the unmatched cohort, after adjusting for age, sex, diabetes
mellitus, coronary artery disease, cerebrovascular disease,
chronic kidney disease, chronic liver disease, shock, acute
cardiac injury, acute renal injury, and acute liver injury, Cox
regression analysis revealed that hypertension was an inde-
pendent risk factor (hazard ratio, 1.80; [95% CI, 1.20–2.70])
for all-cause mortality in patients with COVID-19, and age,
shock and acute cardiac injury may also be positively asso-
ciated with all-cause mortality (Table 4 and Table S2). In
addition, in the matched cohort, hypertension was also an in-
dependent risk factor (hazard ratio, 2.24 [95% CI, 1.36–3.70])
 Pan et al   Impacts of Hypertension and ACE Inhibitors/ARBs on COVID-19   737

Table 3.  The Clinical Types and Outcomes of COVID-19 Patients With or Without Hypertension

Hypertension (Unmatched) Hypertension (Matched, 1:1)

Parameters Yes (n=282) No (n=714) SD Yes (n=256) No (n=256) SD
Typing
 Mild-moderate 69 (24.5) 313 (43.8) 0.417 66 (25.8) 74 (28.9) 0.07
 Severe 96 (34.0) 251 (35.2) 0.023 85 (33.2) 110 (43.0) 0.202
 Critically ill 117 (41.5) 150 (21.0) 0.453 105 (41.0) 72 (28.1) 0.273
Prognosis
 Death 67 (23.8) 52 (7.3) 0.467 61 (23.8) 28 (10.9) 0.345
 Onset of symptom to death (day) 16.5 (12–21) 17 (13–21.75) 0.11 16.5 (13–21) 18 (14–22) 0.05
 Transferred 2 (0.7) 9 (1.3) 0.056 2 (0.8) 2 (0.8) <0.001
 Discharged 30 (10.6) 164 (23.0) 0.334 29 (11.3) 46 (18) 0.188
 Still in hospital 183 (64.9) 489 (68.5) 0.076 164 (64.1) 180 (70.3) 0.133
Values are numbers (percentages) or medium (IQR) unless stated otherwise. COVID-19 indicates coronavirus disease 2019; and IQR,
interquartile range.

for all-cause mortality in the Cox regression after adjusting for
the above covariates (Table 4).
Prior Use of RAAS Inhibitors May Be Associated
With a Better Prognosis in COVID-19 Patients With
Hypertension
Of the 282 patients with hypertension, 41 patients re-
ported taking RAAS inhibitors. There were no significant
Downloaded from http://ahajournals.org by on May 25, 2021
differences in basic clinical features between patients with
hypertension who had and had not used RAAS inhibitors.
Patients receiving RAAS inhibitor treatment had higher
lymphocyte counts (median, 1.06 versus 0.89×109/L) than
patients without RAAS inhibitor treatment (Table S3).
At the same time, the levels of CRP (median, 32.5 versus
48.7 mg/L) and hs-CRP (5.0 [2.3–5.0] versus 5.0 [5.0–
5.0] mg/L) were lower in the RAAS inhibitor treatment
group than in the non-RAAS inhibitor treatment group
(Table S3). The most important difference was the CD4+

cell count, which was significantly higher (median, 420.0

versus 311.5/μL) in the RAAS inhibitor treatment group
than in the non-RAAS inhibitor treatment group. A similar
trend was observed for the CD8+ cell count (median, 204.0
versus 156.5/μL), although the difference was not signifi-
cant (Table S3).
In terms of in-hospital complications and treatment, the
proportions of patients with complications were similar in the
2 groups, but the proportion of patients receiving glucocorti-
coids (34.1% versus 54.8%) was lower in the RAAS inhibitor
treatment group than in the non-RAAS inhibitor treatment
group (Table 5).
Disease severity was similar between the 2 groups,
and the proportions of critically ill patients were 31.7%
and 43.2% in the RAAS inhibitor and non-RAAS inhibitor
treatment groups, respectively (Table 5). However, the all-
cause mortality rate was significantly lower in the RAAS
inhibitor treatment group (9.8%) than in the non-RAAS in-
hibitor treatment group (26.1%; Table 5), which may indi-
cate that the prior use of RAAS inhibitors has a beneficial
effect on prognosis.

Figure.  Comparison of the time-dependent risks for death in patients with
or without hypertension. (A) Comparison before matching; (B) Comparison
after matching. Red curve (95% CI) indicates COVID-19 patients combined
with hypertension; Blue curve (95% CI) indicates coronavirus disease 2019
(COVID-19) patients without hypertension. Number of deaths indicates
cumulative number of deaths at each time points.
Discussion
Our study showed that COVID-19 patients with hyper-
tension were more likely to develop complications and
be classified as critically ill. COVID-19 patients with
hypertension had a higher mortality rate, and hyperten-
sion was an independent risk factor for a poor prognosis.
In addition, patients with hypertension who have used
 738  Hypertension  September 2020

Table 4.  COX Regression Analysis on the Risk Factors Associated With Mortality in Patients With COVID-19

Unmatched Matched*
Parameters HR 95% CI P Value HR 95% CI P Value
Hypertension 1.80 1.20–2.70 0.005† 2.24 1.36–3.70 0.002†
Age 1.04 1.02–1.05 <0.001† 1.04 1.02–1.07 <0.001†
Sex 1.05 0.72–1.52 0.803 1.16 0.75–1.80 0.502
Diabetes mellitus 1.25 0.76–2.04 0.385 1.34 0.78–2.29 0.285
Coronary artery disease 0.91 0.51–1.61 0.743 0.90 0.48–1.70 0.755
Cerebrovascular disease 1.33 0.73–2.45 0.353 1.43 0.69–2.99 0.34
Chronic kidney disease 1.23 0.59–2.55 0.587 1.09 0.46–2.59 0.849
Chronic liver disease 0.69 0.27–1.74 0.432 0.89 0.31–2.55 0.833
Shock 3.85 2.43–6.08 <0.001† 3.62 2.09–6.28 <0.001†
Acute cardiac injury 4.50 2.82–7.20 <0.001† 4.32 2.47–7.55 <0.001†
Acute renal injury 0.57 0.32–1.04 0.068 0.46 0.23–0.92 0.028†
Acute liver injury 1.35 0.70–2.60 0.371 1.16 0.47–2.84 0.746
Age was explained as per year. COVID-19 indicates coronavirus disease 2019; and HR, hazard ratio.
*In the matched cohort (1:1) performed by PSM analysis, COX regression analysis was used to investigate the association between
hypertension and all-cause mortality, after adjusting age, sex, diabetes mellitus, et al.
†P<0.05.

RAAS inhibitors before SARS-CoV2 infection may have
a better prognosis than patients who have used other
antihypertensive drugs.
Severe acute respiratory syndrome (SARS)17 was a
global epidemic in 2003, and it was reported that preex-
Downloaded from http://ahajournals.org by on May 25, 2021
secrete proinflammatory cytokines such as IL-6, γ-IFN
(interferon), and GM-CSF (granulocyte-macrophage col-
ony-stimulating factor); this can eventually develop into
a cytokine storm, which can cause progression to acute
respiratory distress syndrome (ARDS), multiple organ

isting comorbid diseases, such as hypertension, led to se-
vere complications and were associated with the prognosis
of patients infected with SARS-CoV.18–20 Significantly
higher mortality was reported in 2012 Middle East respira-
tory syndrome-infected patients with hypertension than in
those without hypertension,21,22 which indicated that under-
lying diseases damaged the host’s immune system and led to
an increased risk of severe complications. Current literature
reports showed that the proportion of COVID-19 patients
with cardiovascular diseases, such as hypertension and cor-
onary artery disease, was higher than that of patients without
comorbidities,8,23,24 suggesting that patients with hyperten-
sion may be prone to SARS-CoV-2 infection. According
to the report published by the Chinese Center for Disease
Control and Prevention, basic cardiovascular diseases such
as hypertension constituted an important risk factor for a
poor prognosis in patients with COVID-19. Interestingly,
our study found that hypertension in patients with COVID-
19 was associated with a higher incidence of complications,
more severe illness, lower discharge rate, and higher mor-
tality rate. After adjusting for age, sex, other comorbidities
and complications, hypertension was an independent risk
factor for all-cause mortality in patients with COVID-19.
These results support the idea that COVID-19 patients with
hypertension have a worse prognosis than patients without
hypertension.
A previous study suggested that SARS-CoV-2 rec-
ognizes ACE-2 through spike proteins, thereby infect-
ing cells25; this leads to the activation of CD4+ T cells,
which proliferate and differentiate into Th1 cells that
failure, and even death. Therefore, IL-6 and GM-CSF
released by T lymphocytes and monocytes may be the key
factor inducing cytokine storms in patients with COVID-
19.26 The mechanism by which COVID-19 triggers cyto-
kine storms may be closely related to the destruction of
the balance between specific and nonspecific immunity.
Substantial evidence suggests that hypertension could
skew T cells toward the Th1 phenotype,27 which indi-
cates that hypertension may contribute to cytokine storms
in patients with COVID-19. In addition, the depletion of
CD4+ and CD8+ T cells has been observed in critically ill
patients with COVID-19, which may be associated with a
poor prognosis.28 In our study, we found that patients with
hypertension were more likely to have immune dysfunc-
tion, which was supported by the findings of higher levels
of CRP, procalcitonin, IL-10 and IL-6 and lower CD8+ cell
counts. In addition, patients with hypertension had higher
levels of white blood cells and neutrophils and lower lev-
els of lymphocytes. These results suggested that immune
dysfunction may contribute to severe illness and poor out-
comes in COVID-19 patients with hypertension.
Recent studies have shown that human ACE-2 recep-
tors are key receptors for SARS-CoV-229 and that SARS-
CoV-2 does not use other coronavirus receptors, such as
aminopeptidase N and dipeptidyl peptidase 4, to infect
cells.30 Therefore, blocking the ACE-2 receptor and deliv-
ering an excessive amount of the soluble form of ACE-2
may be a potential strategy.31 The administration of RAAS
inhibitors is a critical means to protect against heart
failure, myocardial infarction, and hypertension. Previous
 Pan et al   Impacts of Hypertension and ACE Inhibitors/ARBs on COVID-19   739

Table 5.  Characteristics and Outcomes of Hypertensive Patients With or studies have shown that RAAS inhibitors upregulate the
Without RAAS Inhibitors in COVID-19 Patients
expression of the ACE-2 receptor,12,13,32,33 which may fa-
RAAS Inhibitors cilitate the cellular invasion of SARS-CoV-2. However,
Parameters Yes (n=41) No (n=241) P Value current research suggests that targeting the RAS system is
important for treating lung diseases.34,35 In recent weeks,
Age, y 70 (63–76) 69 (62–76) 0.889
several studies focused on the effect of RAAS inhibitors
Male 16 (39.0) 127 (52.7) 0.105 on patients with COVID-19 have been published. Zhang et
Systolic blood pressure,* mm Hg 132 132 0.941 al36 reported the association of the inpatient use of RAAS
(121–147) (121–147) inhibitors with mortality among COVID-19 patients with
Diastolic blood pressure,* mm Hg 77 (72–86) 78 (71–87) 0.729 hypertension. They found that the inpatient use of RAAS
Comorbidity except hypertension 17 (41.5) 123 (51.0) 0.499
inhibitors was associated with a reduced risk of all-cause
mortality. Mancia et al37 found that RASS inhibitors were
Complications 8 (19.5) 67 (27.8) 0.267
unlikely to affect the risk of SARS-CoV-2 infection and
 Shock 3 (7.3) 35 (14.5) 0.316 were not associated with severe or fatal infections. In
 Acute cardiac injury 8 (19.5) 51 (21.2) 0.810 addition, the use of RAAS inhibitors was not associated
 Acute kidney injury 3 (7.3) 14 (5.8) 0.984
with an increased risk of in-hospital death.38,39 Similarly,
Yang et al40 reported that the RAAS inhibitor group had a
 Acute liver injury 0 9 (3.7) 0.366
lower proportion of critically ill patients and a lower mor-
Admission to ICU 3 (7.3) 30 (12.4) 0.495 tality rate than the non-RAAS inhibitor group, although
Treatment the differences were not statistically significant. In our
 Antiviral therapy 37 (90.2) 222 (92.1) 0.686
study, lower levels of CRP and hs-CRP and higher CD4+
cell counts were observed in patients treated with RAAS
 Antibacterial therapy 29 (70.7) 198 (82.2) 0.088
inhibitors. We found that patients regularly treated with
 Antifungal therapy 2 (4.9) 15 (6.2) 1.000 RAAS inhibitors before admission may have a better prog-
 Glucocorticoid therapy 14 (34.1) 132 (54.8) 0.015† nosis than patients who were not previously treated with
RAAS inhibitors. Although it is necessary to consider the
 Immunoglobulin therapy 17 (41.5) 134 (55.6) 0.093
potential for residual confounders, it is unlikely that the
 Artificial liver support 0 2 (0.8) 1.000
previous use of RAAS inhibitors is associated with an
Downloaded from http://ahajournals.org by on May 25, 2021

 CRRT 0 6 (2.5) 0.598 increased mortality risk, which is consistent with the find-
Typing ings of previous studies.
There are certain limitations in this study. First, this
 Mild-moderate 10 (24.4) 59 (24.5) 0.990
was a single-center, retrospective study. Second, past med-
 Severe 18 (43.9) 78 (32.4) 0.150
ical history was reported by the patients, which may have
 Critically ill 13 (31.7) 104 (43.2) 0.169 resulted in missing some patients with underlying diseases
Prognosis and patients with a history of taking ACE inhibitors/ARBs.
Finally, the observation period was short, and longer ob-
 Death 4 (9.8) 63 (26.1) 0.037†
servation periods and larger sample sizes may be needed to
 Onset of symptom to death (day) 20.0 16.0 0.781 validate the results.
(15.5–20.5) (12.5–21.0)
 Transferred 0 2 (0.8) 1.000 Perspectives
 Discharged 6 (14.6) 24 (10) 0.369 COVID-19 patients with hypertension had more severe inflam-
Still in hospital 31 (75.6) 152 (63.1) 0.120 mation, a greater degree of depletion of CD8+ cells and more
organ damage than those without hypertension. Hypertension
Previous drug history
may be an independent risk factor for all-cause mortality in
 Calcium channel blocker 24 (58.5) 105 (43.6) 0.075 patients with COVID-19. Hypertensive patients with a history
 β-blocker 9 (22.0) 37 (15.4) 0.290 of ACE inhibitors/ARBs use may have a better prognosis than
 Diuretics 3 (7.3) 26 (10.8) 0.690 patients who used other antihypertensive drugs.
 Other antihypertension drugs 2 (4.9) 16 (6.6) 0.936
Acknowledgments
Values are numbers (percentages) or medium (IQR) unless stated otherwise. We acknowledge all the health care workers for their help to Wuhan.
P values indicate differences between hypertensive patients with and without
ACE inhibitors/ARBs history. ACE indicates angiotensin-converting enzyme;
ARB, angiotensin receptor blocker; COVID-19, coronavirus disease 2019; CRRT,
Sources of Funding
continuous renal replacement therapy; ICU, intensive care unit; IQR, interquartile None.
range; and RAAS, renin-angiotensin-aldosterone system.
The total number of patients with available data: *: n1=36 and n2=205. Disclosures
†P<0.05. None.
 740  Hypertension  September 2020
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Huang X, Lin L, et al. Association of inpatient use of angiotensin-
converting enzyme inhibitors and angiotensin II receptor block-
ers with mortality among patients with hypertension hospitalized
with COVID-19. Circ Res. 2020;126:1671–1681. doi: 10.1161/
CIRCRESAHA.120.317134
 Pan et al   Impacts of Hypertension and ACE Inhibitors/ARBs on COVID-19   741
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Novelty and Significance
What Is New
• This study used the largest cohort to date to evaluate the effects of hy-
pertension on the prognosis of coronavirus disease 2019 (COVID-19) in
a single-center.
• Patients with hypertension had more severe inflammation, lower CD8+
cell counts and higher levels of IL (interleukin)-6 and IL-10 on admission.
• Patients with hypertension were more likely to have comorbidities and
complications and were more likely to be classified as critically ill.
• Hypertension may be independently associated with all-cause mortality
in patients with COVID-19.
• Hypertensive patients with a history of RAAS inhibitor use may have a
better prognosis than patients who used other antihypertensive drugs.
Downloaded from http://ahajournals.org by on May 25, 2021
39. Jarcho JA, Ingelfinger JR, Hamel MB, D’Agostino RS, Harrington DP.
Inhibitors of the renin-angiotensin-aldosterone system and covid-19. N
Engl J Med. 2020. doi: 10.1056/NEJMe2012924
40. Yang G, Tan Z, Zhou L, Yang M, Peng L, Liu J, Cai J, Yang R, Han J,
Huang Y, He S. Effects of ARBs and ACEIs on virus infection, inflam-
matory status and clinical outcomes In COVID-19 patients with hyper-
tension: a single center retrospective study. Hypertension. 2020;76:51-58.
doi: 10.1161/HYPERTENSIONAHA.120.15143
What Is Relevant?
• Immune dysfunction may contribute to severe illness and poor outcomes
in COVID-19 patients with hypertension.
• RAAS inhibitors may have a beneficial effect on the prognosis of CO-
VID-19 patients with hypertension. While it is important to consider the
potential for residual confounders, it is unlikely that the previous use of
RAAS inhibitors is associated with an increased mortality risk.
Summary
The most common comorbidity in COVID-19 patients, hypertension,
may be independently associated with all-cause mortality. Patients
with hypertension regularly treated with RAAS inhibitors before severe
acute respiratory syndrome coronavirus 2 infection may have a bet-
ter prognosis than patients treated with other antihypertensive drugs.