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Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China
Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China
Editorial
IMPORTANCE Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity Supplemental content
and mortality worldwide since December 2019. However, information on cardiac injury in
patients affected by COVID-19 is limited.
OBJECTIVE To explore the association between cardiac injury and mortality in patients with
COVID-19.
DESIGN, SETTING, AND PARTICIPANTS This cohort study was conducted from January 20,
2020, to February 10, 2020, in a single center at Renmin Hospital of Wuhan University,
Wuhan, China; the final date of follow-up was February 15, 2020. All consecutive inpatients
with laboratory-confirmed COVID-19 were included in this study.
MAIN OUTCOMES AND MEASURES Clinical laboratory, radiological, and treatment data were
collected and analyzed. Outcomes of patients with and without cardiac injury were
compared. The association between cardiac injury and mortality was analyzed.
RESULTS A total of 416 hospitalized patients with COVID-19 were included in the final analysis;
the median age was 64 years (range, 21-95 years), and 211 (50.7%) were female. Common
symptoms included fever (334 patients [80.3%]), cough (144 [34.6%]), and shortness of
breath (117 [28.1%]). A total of 82 patients (19.7%) had cardiac injury, and compared with
patients without cardiac injury, these patients were older (median [range] age, 74 [34-95] vs
60 [21-90] years; P < .001); had more comorbidities (eg, hypertension in 49 of 82 [59.8%] vs
78 of 334 [23.4%]; P < .001); had higher leukocyte counts (median [interquartile range
(IQR)], 9400 [6900-13 800] vs 5500 [4200-7400] cells/μL) and levels of C-reactive protein
(median [IQR], 10.2 [6.4-17.0] vs 3.7 [1.0-7.3] mg/dL), procalcitonin (median [IQR], 0.27
[0.10-1.22] vs 0.06 [0.03-0.10] ng/mL), creatinine kinase–myocardial band (median [IQR], 3.2
[1.8-6.2] vs 0.9 [0.6-1.3] ng/mL), myohemoglobin (median [IQR], 128 [68-305] vs 39 [27-65]
μg/L), high-sensitivity troponin I (median [IQR], 0.19 [0.08-1.12] vs <0.006 [<0.006-0.009]
μg/L), N-terminal pro-B-type natriuretic peptide (median [IQR], 1689 [698-3327] vs 139
[51-335] pg/mL), aspartate aminotransferase (median [IQR], 40 [27-60] vs 29 [21-40] U/L),
and creatinine (median [IQR], 1.15 [0.72-1.92] vs 0.64 [0.54-0.78] mg/dL); and had a higher
proportion of multiple mottling and ground-glass opacity in radiographic findings (53 of 82
patients [64.6%] vs 15 of 334 patients [4.5%]). Greater proportions of patients with cardiac
injury required noninvasive mechanical ventilation (38 of 82 [46.3%] vs 13 of 334 [3.9%];
P < .001) or invasive mechanical ventilation (18 of 82 [22.0%] vs 14 of 334 [4.2%]; P < .001)
than those without cardiac injury. Complications were more common in patients with cardiac
injury than those without cardiac injury and included acute respiratory distress syndrome (48
of 82 [58.5%] vs 49 of 334 [14.7%]; P < .001), acute kidney injury (7 of 82 [8.5%] vs 1 of 334
[0.3%]; P < .001), electrolyte disturbances (13 of 82 [15.9%] vs 17 of 334 [5.1%]; P = .003),
hypoproteinemia (11 of 82 [13.4%] vs 16 of 334 [4.8%]; P = .01), and coagulation disorders (6
of 82 [7.3%] vs 6 of 334 [1.8%]; P = .02). Patients with cardiac injury had higher mortality
than those without cardiac injury (42 of 82 [51.2%] vs 15 of 334 [4.5%]; P < .001). In a Cox Author Affiliations: Author
regression model, patients with vs those without cardiac injury were at a higher risk of death, affiliations are listed at the end of this
article.
both during the time from symptom onset (hazard ratio, 4.26 [95% CI, 1.92-9.49]) and from
Corresponding Author: Bo Yang,
admission to end point (hazard ratio, 3.41 [95% CI, 1.62-7.16]).
MD, PhD (yybb112@whu.edu.cn), and
CONCLUSIONS AND RELEVANCE Cardiac injury is a common condition among hospitalized He Huang, MD, PhD (huanghe1977@
whu.edu.cn), Cardiovascular
patients with COVID-19 in Wuhan, China, and it is associated with higher risk of in-hospital Research Institute, Department of
mortality. Cardiology, Renmin Hospital of
Wuhan University, 238 Jiefang Rd,
JAMA Cardiol. doi:10.1001/jamacardio.2020.0950 Wuchang District, Wuhan 430060,
Published online March 25, 2020. Hubei, China.
(Reprinted) E1
© 2020 American Medical Association. All rights reserved.
S
ince December 2019, coronavirus disease 2019 (COVID-
19) caused by the severe acute respiratory syndrome Key Points
coronavirus 2 (SARS-CoV-2) has resulted in consider-
Question What is the incidence and significance of cardiac injury
able morbidity and mortality in more than 30 countries world- in patients with COVID-19?
wide. Recently, COVID-19–associated clusters of severe respi-
Findings In this cohort study of 416 consecutive patients with
ratory illness have been independently associated with risk of
confirmed COVID-19, cardiac injury occurred in 19.7% of patients
mortality, and mounting evidence substantiates the pres-
during hospitalization, and it was one independent risk factor for
ence of cardiac injury in patients with COVID-19.1,2 Although in-hospital mortality.
a recent study reported that 12% of patients had COVID-19–
Meaning Cardiac injury is a common condition among patients
associated acute cardiac injury,1 manifesting as an ejection frac-
hospitalized with COVID-19, and it is associated with higher risk of
tion decline and troponin I elevation, and the American Col-
in-hospital mortality.
lege of Cardiology clinical bulletin has highlighted the cardiac
implications of COVID-19,3 the association between COVID-
19–associated cardiac injury and risk of mortality remains un- electrocardiography and echocardiography. Acute respira-
clear. The present study therefore retrospectively analyzed data tory distress syndrome (ARDS) was defined according to the
from a single center in Wuhan, China, to examine the poten- Berlin definition.5 Acute kidney injury was identified accord-
tial association between cardiac injury and mortality among ing to the Kidney Disease: Improving Global Outcomes
patients with COVID-19. definition.6 The clinical outcomes (ie, discharges, mortality,
and length of stay) were monitored up to February 15, 2020,
the final date of follow-up.
To confirm COVID-19, the Viral Nucleic Acid Kit (Health)
Methods was used to extract nucleic acids from clinical samples accord-
Study Participants ing to the kit instructions. A 2019-nCoV detection kit (Bioper-
Consecutive patients admitted to Renmin Hospital of Wuhan fectus) was used to detect the ORF1ab gene (nCovORF1ab) and
University with laboratory-confirmed COVID-19 were in- the N gene (nCoV-NP) according to the manufacturer’s instruc-
cluded in this retrospective cohort study, which was con- tions, using real-time reverse transcriptase–polymerase chain
ducted from January 20, 2020, to February 10, 2020. Renmin reaction.7 An infection was considered laboratory-confirmed
Hospital of Wuhan University, located in Wuhan, Hubei Prov- if the nCovORF1ab and nCoV-NP tests both showed positive re-
ince, China, was assigned responsibility for the treatment of sults.
patients with severe COVID-19 by the Wuhan government. The
patients with COVID-19 enrolled in this study were diag- Statistical Analysis
nosed according to World Health Organization interim Descriptive statistics were obtained for all study variables. All
guidance.4 The cases without cardiac biomarkers, including categorical variables were compared for the study outcome by
values of high-sensitivity troponin I (hs-TNI) and creatinine ki- using the Fisher exact test or χ2 test, and continuous vari-
nase–myocardial band (CK-MB), were excluded. ables were compared using the t test or the Mann-Whitney U
This study was approved by the National Health Commis- test, as appropriate. Continuous data are expressed as mean
sion of China and the institutional review board at Renmin Hos- (SD) or median (interquartile range [IQR]) values. Categorical
pital of Wuhan University (Wuhan, China). Written informed data are expressed as proportions. Survival curves were plot-
consent was waived by the ethics commission of the desig- ted using the Kaplan-Meier method and compared between pa-
nated hospital for patients with emerging infectious dis- tients with vs without cardiac injury using the log-rank test.
eases. Multivariate Cox regression models were used to determine
the independent risk factors for death during hospitalization.
Data Collection Data were analyzed using SPSS version 25.0 (IBM). Statistical
The demographic characteristics (age and sex), clinical data charts were generated using Excel 2016 (Microsoft) or Prism 5
(symptoms, comorbidities, laboratory findings, treatments, (Graphpad). For all the statistical analyses, P < .05 was con-
complications, and outcomes), laboratory findings, and re- sidered significant.
sults of cardiac examinations (cardiac biomarkers and electro-
cardiography) for participants during hospitalization were col-
lected from electronic medical records by 2 investigators (S.S.
and B.S.). Cardiac biomarkers measured on admission were col-
Results
lected, including hs-TNI, CK-MB, and myohemoglobin. The ra- Patient Characteristics
diologic assessments included chest radiography or com- Figure 1 shows a flowchart for patient recruitment. Briefly, of
puted tomography. All data were independently reviewed and all 1004 patients in the medical record system who were
entered into the computer database by 2 analysts (T.L. and Y.C.). screened initially from January 20, 2020, to February 10, 2020,
Patients were categorized according to the presence or ab- 218 patients whose cases were not confirmed, 141 patients with-
sence of cardiac injury. Cardiac injury was defined as blood lev- out available medical information and duplicated records, and
els of cardiac biomarkers (hs-TNI) above the 99th-percentile 229 patients with missing core results of laboratory examina-
upper reference limit, regardless of new abnormalities in tion (hs-TNI and CK-MB) were excluded. The median age of
Table 1. Baseline Characteristics and Laboratory and Radiographic Findings of 416 Patients With COVID-19
Abbreviation: IQR, interquartile range. aminotransferase to μkat/L, multiply by 0.0167; to convert albumin to g/L,
SI conversion factors: To convert leukocytes or lymphocytes to ×109/L, multiply multiply by 10; to convert creatinine to μmol/L, multiply by 88.4; to convert
by 0.001; to convert platelets to ×109/L, multiply by 1.0; to convert potassium and sodium to mmol/L, multiply by 1.0.
erythrocytes to ×1012/L, multiply by 1.0; convert hemoglobin to g/L, multiply by a
Indicated that the lowest value of troponin actually measured is <0.006
10.0; to convert C-reactive protein to mg/L, multiply by 10.0; to convert ng/mL in our hospital, although the range of reference values is 0.00 to 0.04
creatinine kinase–myocardial band to μg/L, multiply by 1.0; to convert troponin I ng/mL.
to ng/mL, multiply by 1.0; to convert alanine aminotransferase or aspartate
Table 2. Treatment, Complications, and Clinical Outcome of 416 Patients With COVID-19
Table 2). A total of 399 patients (95.9%) were treated with oxy- (13 [15.9%] vs 17 [5.1%]; P = .003), hypoproteinemia (11 [13.4%]
gen, and the percentages of use of oxygen inhalation, vs 16 [4.8%]; P = .01), and coagulation disorders (6 [7.3%] vs
noninvasive ventilation, and invasive mechanical ventilation 6 [1.8%]; P = .02) (Table 2).
were 76.0% (316 patients), 12.3% (51 patients), and 7.7% (32 pa-
tients), respectively. The proportion of antiviral therapy use Cardiac Injury and Mortality
was the highest (403 [96.9%]), followed by glucocorticoids (304 Patients with cardiac injury vs those without cardiac injury
[73.1%]), intravenous immunoglobulin therapy (259 [62.3%]), had shorter durations from symptom onset to follow-up
and antibiotic therapy (235 [56.5%]). Only 2 patients (0.5%) (mean, 15.6 [range, 1-37] days vs 16.9 [range, 3-37] days;
among all participants were given continuous kidney therapy. P = .001) and admission to follow-up (6.3 [range, 1-16] days
Overall, 97 patients (23.3%) had ARDS, and 8 patients (1.9%) vs 7.8 [range, 1-23] days; P = .039). The mortality rate was
had acute kidney injury during hospitalization; other com- higher among patients with vs without cardiac injury (42
mon complications included electrolyte disturbance (30 pa- [51.2%] vs 15 [4.5%]; P < .001) as shown in Table 2 and the
tients [7.2%]), hypoproteinemia (27 [6.5%]), anemia (13 [3.1%]), Kaplan-Meier survival curves in Figure 2. The mortality rate
and coagulation disorders (12 [2.9%]). During follow-up, a total increased in association with the magnitude of the refer-
of 57 patients (13.7%) died, 40 patients (9.6%) were dis- ence value of hs-TNI (eFigure 3 in the Supplement). After
charged, and the rest (319 [76.7%]) remained hospitalized. adjusting for age, preexisting cardiovascular diseases (hy-
Compared with those without cardiac injury, patients with car- pertension, coronary heart disease, and chronic heart fail-
diac injury required more noninvasive ventilation (38 [46.3%] ure), cerebrovascular diseases, diabetes mellitus, chronic
vs 13 [3.9%]; P < .001) and invasive mechanical ventilation (18 obstructive pulmonary disease, renal failure, cancer, ARDS,
[22.0%] vs 14 [4.2%]; P < .001) (Table 2). The use of antibiotic creatinine levels greater than 133 μmol/L, and NT-proBNP
treatment (68 [82.9%] vs 167 [50.0%]), glucocorticoids (72 levels greater than 900 pg/mL, the multivariable adjusted
[87.8%] vs 232 [69.5%]), and intravenous immunoglobulin Cox proportional hazard regression model showed a signifi-
treatment (68 [82.9%] vs 191 [57.2%]) was also significant cantly higher risk of death in patients with cardiac injury
higher in patients with cardiac injury than in those without car- than in those without cardiac injury, either during time
diac injury (all P < .001; Table 2). In addition to anemia, other from symptom onset (hazard ratio [HR], 4.26 [95% CI, 1.92-
complications were more common among patients with car- 9.49]) or time from admission to study end point (HR, 3.41
diac injury than those without cardiac injury; these included [95% CI, 1.62-7.16]) (Table 3). Under this hazard regression
ARDS (48 [58.5%] vs 49 [14.7%]; P < .001), acute kidney in- model, ARDS was another independent risk factor for mor-
jury (7 [8.5%] vs 1 [0.3%]; P < .001), electrolyte disturbances tality with COVID-19, with a high HR (7.89 [95% CI, 3.73-
Table 3. Multivariate Cox Regression Analysis on the Risk Factors Associated With Mortality in Patients
With COVID-19
of cardiac injury. Thus, because of the current limited evi- lar comorbidities, it is rational to presume that patients with
dence, the question of whether the SARS-CoV-2 virus can di- coronary artery disease or heart failure are susceptible to car-
rectly injure the heart requires further demonstration. diac injury, and once such patients are infected with severe
In contrast, a previous study found that reversible, subclini- pneumonia, myocardial ischemia or cardiac dysfunction are
cal diastolic left ventricular impairment appears to be common more likely to occur, ultimately leading to a sudden deterio-
in acute SARS infection, even among those without underlying ration. On the other hand, acute inflammatory responses can
cardiac disease,14 suggesting that left ventricular dysfunction in also lead to ischemia in the presence of preexisting cardiovas-
the acute phase might be attributable to the cytokine storm syn- cular diseases. The inflammatory activity within coronary ath-
drome. This is a serious life-threatening disease with clinical fea- erosclerotic plaques is exacerbated during systemic inflam-
tures of systemic inflammation, methemoglobinemia, hemody- mator y response, making them prone to rupture. 1 8
namic instability, and multiple organ failure.15,16 The hallmark of Inflammation also causes endothelial dysfunction and in-
cytokine storm syndrome is an uncontrolled and dysfunctional creases the procoagulant activity of the blood, which can con-
immune response involving the continuous activation and pro- tribute to the formation of an occlusive thrombus over a rup-
liferation of lymphocytes and macrophages. Huang et al1 found tured coronary plaque.19 Based on these lines of evidence, we
that patients with COVID-19 who were admitted to the intensive hypothesize that an intense inflammatory response superim-
care unit had higher plasma levels of cytokines, including inter- posed on preexisting cardiovascular disease may precipitate
leukin (IL)–2, IL-7, IL-10, granulocyte-colony stimulating factor, cardiac injury observed in patients with COVID-19 infections.
IgG-induced protein 10 (also known as C-X-C motif chemokine
10), monocyte chemoattractant protein-1, macrophage inflam- Limitations
matory protein 1-alpha (also known as chemokine ligand 3), and Some limitations existed in the present study. First, because
tumor necrosis factor α. In the present study, we also found that of the logistical limitations at the onset of these emerging in-
markers of inflammatory response, such as C-reactive protein, fections in Wuhan, some data, such as echocardiography data,
procalcitonin, and leukocytes, were significantly increased among electrocardiography data, and cytokine level measurements,
patients who suffered from cardiac injury. The activation or en- were lacking from clinical examinations of patients in isola-
hanced release of these inflammatory cytokines can lead to apop- tion wards or the intensive care unit, which limits the deter-
tosis or necrosis of myocardial cells. mination of potential mechanisms of cardiac injury. Second,
In addition, preexisting cardiovascular diseases might also because the clinical observation of patients is still ongoing,
be more susceptible COVID-19–induced heart injury, as ap- many with and without cardiac injury have not reached clini-
proximately 30% and 60% of patients with cardiac injury in cal end points. Third, data from larger populations and mul-
the present study had a history of coronary heart disease and tiple centers are warranted to further confirm the outcomes
hypertension, respectively, which were significantly more of cardiac injury in COVID-19.
prevalent than in those without cardiac injury. Similarly, in a
recent report,2 25% and 58.3% of patients who were critically
ill with COVID-19 had underlying heart diseases and hyper-
tension, respectively. According to the “Diagnosis and Treat-
Conclusions
ment of Novel Coronavirus Pneumonia (Trial Version 4),”17 el- Cardiac injury is a common condition among patients hospi-
derly patients with underlying diseases are more likely to be talized with COVID-19, and it is associated with a higher risk
infected with SARS-CoV-2 and tend to be severely ill, espe- of in-hospital mortality. Although the exact mechanism of car-
cially those with hypertension, coronary heart disease, and dia- diac injury needs to be further explored, the findings pre-
betes. Although there are few pieces of evidence to establish sented here highlight the need to consider this complication
a direct association between cardiac injury and cardiovascu- in COVID-19 management.