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Prognostic Value of Troponin Elevation in COVID-19 Hospitalized Patients

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(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates the respiratory epithelium through angiotensin-converting enzyme-2 (ACE2) binding. Myocardial and endothelial expression of ACE2 could account for the growing body of reported evidence of myocardial injury in severe forms of Human Coronavirus Disease 2019 (COVID-19). We aimed to provide insight into the impact of troponin (hsTnI) elevation on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with the SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 772 adult, symptomatic COVID-19 patients were hospitalized for more than 24 h in our institution, of whom 375 had a hsTnI measurement and were included in this analysis. The median age was 66 (55–74) years, and there were 67% of men. Overall, 205 (55%) patients were placed under mechanical ventilation and 90 (24%) died. A rise in hsTnI was noted in 34% of the cohort, whereas only three patients had acute coronary syndrome (ACS) and one case of myocarditis. Death occurred more frequently in patients with hsTnI elevation (HR 3.95, 95% CI 2.69–5.71). In the multivariate regression model, a rise in hsTnI was independently associated with mortality (OR 3.12, 95% CI 1.49–6.65) as well as age ≥ 65 years old (OR 3.17, 95% CI 1.45–7.18) and CRP ≥ 100 mg/L (OR 3.62, 95% CI 1.12–13.98). After performing a sensitivity analysis for the missing values of hsTnI, troponin elevation remained independently and significantly associated with death (OR 3.84, 95% CI 1.78–8.28). (4) Conclusion: Our study showed a four-fold increased risk of death in the case of a rise in hsTnI, underlining the prognostic value of troponin assessment in the COVID-19 context.
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Journal of
Clinical Medicine
Brief Report
Prognostic Value of Troponin Elevation in COVID-19
Hospitalized Patients
Elena-Mihaela Cordeanu 1, *, Nicolas Duthil 1, Francois Severac 2, Hélène Lambach 1,
Jonathan Tousch 1, Lucas Jambert 3, Corina Mirea 1, Alexandre Delatte 4, Waël Younes 5,
Anne-Sophie Frantz 1, Hamid Merdji 6, Valérie Schini-Kerth 7, Pascal Bilbault 8,
Patrick Ohlmann 9, Emmanuel Andres 10 and Dominique Stephan 1
1
Department of Hypertension, Vascular Disease and Clinical Pharmacology, Strasbourg Regional University
Hospital, 67091 Strasbourg, France; nicolas.duthil@chru-strasbourg.fr (N.D.);
helene.lambach@chru-strasbourg.fr (H.L.); jonathan.tousch@chru-strasbourg.fr (J.T.);
corina.mirea@chru-strasbourg.fr (C.M.); anne-sophie.frantz@chru-strasbourg.fr (A.-S.F.);
dominique.stephan@chru-strasbourg.fr (D.S.)
2Division of Public Health, Methodology and Biostatistics, University Hospitals of Strasbourg,
67091 Strasbourg, France; francois.severac@chru-strasbourg.fr
3Department of Vascular Medicine, Mulhouse Regional Hospital, 68100 Mulhouse, France;
jambertlucas@gmail.com
4
Department of Cardiology, Haguenau Regional Hospital, 67500 Haguenau, France; delatte.alex@gmail.com
5Department of Vascular Medicine, Colmar Regional Hospital, 68000 Colmar, France;
wael.younes@ch-colmar.fr
6Intensive Care and Reanimation Department, Strasbourg Regional University Hospital,
67091 Strasbourg, France; hamid.merdji@chru-strasbourg.fr
7UMR 1260 INSERM Regenerative Nanomedecine, Faculty of Pharmacy, Strasbourg University,
67400 Illkirch, France; valerie.schini-kerth@unistra.fr
8Emergency Department, Strasbourg Regional University Hospital, 67091 Strasbourg, France;
pascal.bilbault@chru-strasbourg.fr
9Cardiology Department, Strasbourg Regional University Hospital, 67091 Strasbourg, France;
patrick.ohlmann@chru-strasbourg.fr
10 Internal Medicine Department, Strasbourg Regional University Hospital, 67091 Strasbourg, France;
emmanuel.andres@chru-strasbourg.fr
*Correspondence: elena-mihaela.cordeanu@chru-strasbourg.fr; Tel.: +33-0369-551-520
Received: 10 November 2020; Accepted: 15 December 2020; Published: 17 December 2020


Abstract:
(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates
the respiratory epithelium through angiotensin-converting enzyme-2 (ACE2) binding. Myocardial
and endothelial expression of ACE2 could account for the growing body of reported evidence of
myocardial injury in severe forms of Human Coronavirus Disease 2019 (COVID-19). We aimed to
provide insight into the impact of troponin (hsTnI) elevation on SARS-CoV-2 outcomes in patients
hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult
patients with the SARS-CoV-2 infection admitted to a university hospital in France. The observation
period ended at hospital discharge. (3) Results: During the study period, 772 adult, symptomatic
COVID-19 patients were hospitalized for more than 24 h in our institution, of whom 375 had a hsTnI
measurement and were included in this analysis. The median age was 66 (55–74) years, and there
were 67% of men. Overall, 205 (55%) patients were placed under mechanical ventilation and 90 (24%)
died. A rise in hsTnI was noted in 34% of the cohort, whereas only three patients had acute coronary
syndrome (ACS) and one case of myocarditis. Death occurred more frequently in patients with hsTnI
elevation (HR 3.95, 95% CI 2.69–5.71). In the multivariate regression model, a rise in hsTnI was
independently associated with mortality (OR 3.12, 95% CI 1.49–6.65) as well as age
65 years old
(OR 3.17, 95% CI 1.45–7.18) and CRP
100 mg/L (OR 3.62, 95% CI 1.12–13.98). After performing a
sensitivity analysis for the missing values of hsTnI, troponin elevation remained independently and
J. Clin. Med. 2020,9, 4078; doi:10.3390/jcm9124078 www.mdpi.com/journal/jcm
J. Clin. Med. 2020,9, 4078 2 of 9
significantly associated with death (OR 3.84, 95% CI 1.78–8.28). (4) Conclusion: Our study showed a
four-fold increased risk of death in the case of a rise in hsTnI, underlining the prognostic value of
troponin assessment in the COVID-19 context.
Keywords: COVID-19; troponin; myocardial injury; SARS-CoV-2; cardiovascular; biomarker
1. Introduction
Human Coronavirus Disease 2019 (COVID-19), resulting from a newly described respiratory
viral infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was originally
identified in December 2019 in Wuhan, China, before becoming a global pandemic. Cardiovascular risk
factors and underlying cardiovascular diseases were associated with worse prognosis [
1
]. Moreover,
cardiovascular involvement in COVID-19 has been related to the viral infective mechanism through the
binding of the spike envelope protein to cell membrane angiotensin-converting enzyme-2 (ACE2) [
2
,
3
].
ACE2 is physiologically implicated in balancing the deleterious eects of renin–angiotensin system
activation, being highly expressed by the lungs, kidneys, gut, and brain and has also been identified
in the cardiovascular system [
4
]. Endothelial and myocardial expression of ACE2 could account
for myocardial injury, defined by a rise in troponin (Tn) associated with some severe forms of
COVID-19 [
5
,
6
]. In March 2020, the American College of Cardiology suggested Tn measurement in the
context of COVID-19 only if myocardial infarction was suspected [
7
]. Since then, myocardial injury
has been described in approximately one-third of COVID-19 patients [
8
13
]. Recent publications have
associated an elevation in cardiac and inflammatory biomarkers with infection severity and worse
prognosis [
13
,
14
]. Whether cardiac biomarkers such as Tn could have a prognostic value in SARS-CoV-2
is still under debate, and Tn measurement is not systematically performed in infected patients. We report
herein a retrospective analysis of hospitalized adult patients, in whom a high-sensitivity troponin I
(hsTnI) test was performed, from a university hospital in Eastern France, one of the most aected areas
in Europe during the first wave of the COVID-19 pandemic.
2. Experimental Section
2.1. Study Design and Patient Selection
We performed a retrospective analysis of electronic medical records of hospitalized COVID-19
patients admitted to the University Hospital of Strasbourg between 25 February 2020 (date of admission
of the first case) and 1 April 2020. The study was approved by the Strasbourg University Hospital Ethical
Committee. All patients aged more than 18 years old were selected on the basis of laboratory-confirmed
COVID-19 infection by positive reverse-transcriptase polymerase chain reaction (RT-PCR) on a
nasopharyngeal swab. A local RT-PCR kit was used to detect SARS-CoV-2. The observation period
ended at discharge. Vital status at discharge was known for all hospitalized patients. Thus, all patients
having had at least one measurement of hsTnI during hospitalization were included in the first analysis
and the entire cohort in the sensitivity analysis.
2.2. Baseline Variables
Data concerning medical history, chronic medication, clinical presentation, laboratory findings,
and low-dose pulmonary computed tomography (CT) lesions were collected. hsTnI test results were
retrieved from two hospital sites with site- and sex-specific 99th percentile upper reference limits
(URLs) (Hospital Site 1: Siemens Advia Centaur XP and XPT assay with URLs of 37 ng/L for women
and 57 ng/L for men; Hospital Site 2: Siemens Dimension Vista assay with URLs of 54 ng/L for women
and 79 ng/L for men). When several tests were performed for the same patient, maximum levels
of hsTnI were recorded. Given the infectivity risk and according to guidelines, echocardiography
J. Clin. Med. 2020,9, 4078 3 of 9
was only sporadically performed, and data were colligated. Antiviral, antibiotic, and anticoagulant
treatments during hospitalization were equally reported.
2.3. Outcome Assessment
For the purpose of this study, the observation period ended at hospital discharge, with a median
length of stay of 16.5 days (interquartile range (IQR): 8–29). All patient data were collected during
hospitalization. The main evaluation criterion was in-hospital death from any cause. Recourse to
high-flow nasal oxygen (HFNO) therapy, noninvasive ventilation (NIV), orotracheal intubation (OTI),
and occurrence of severe sepsis, arterial or venous thrombosis, and acute renal impairment were
colligated. Events were abstracted from clinical charts or discharge synopsis. The evaluation criteria
were adjudicated by senior physicians of the vascular medicine unit.
2.4. Statistical Analysis
This was a retrospective cohort study; therefore, no power calculation was performed. Continuous
variables were expressed as mean
±
standard deviation (SD) or median with interquartile range (IQR),
depending on their distribution. The normality of the distribution was assessed using the Shapiro–Wilk
test. Categorical variables were presented as numbers of cases (percentages/frequencies). Continuous
variables were compared using the Student’s t-test or Wilcoxon rank-sum test, for categorical variables,
Fisher’s exact tests were employed. In order to address potential sources of bias, clinically pertinent risk
factors associated with mortality in univariate analysis were selected as candidates for the multivariate
logistic regression analysis. Results were expressed as odds ratios (ORs) with 95% confidence intervals
(CI). A sensitivity analysis including patients without troponin measurement was performed using
multiple imputation by chained equation to handle missing values [
15
,
16
]. A value of p<0.05
was considered statistically significant. All analyses were performed using R software version 3.2.2
(R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).
3. Results
3.1. Patients Characteristics at Baseline
A total of 943 COVID-19 patients were admitted to the University Hospital of Strasbourg from
25 February 2020 to 1 April 2020, of whom 375 (67% of males, mean age of 66
±
14.4 ranging from 21
to 93 years) were included in this analysis after exclusion of patients hospitalized for less than 24 h
(n=145), minors (n=14), patients hospitalized for other medical reasons and incidentally found
positive for SARS-CoV-2 PCR (n=12), and patients without a hsTnI test (n=397) (Figure 1).
The remaining population was divided into two subgroups based on hsTnI elevation,
namely “elevated hsTnI” (n=126) and “normal hsTnI” (n=249). A comprehensive, comparative
description of baseline characteristics and in-hospital outcomes for patients having an elevated hsTnI
versus normal hsTnI test is presented in Table 1. A rise in troponin was associated with higher age and
comorbid conditions such as pre-existing hypertension, diabetes, dyslipidemia, chronic heart failure,
and chronic kidney disease. In-hospital treatment (antiviral, antibiotics, and anticoagulation) did not
dier between groups (Table 1).
J. Clin. Med. 2020,9, 4078 4 of 9
J. Clin. Med. 2020, 9, x 4 of 9
Figure 1. Study flowchart showing patient selection. COVID-19: Human Coronavirus Disease 2019; Feb:
February; h: hours; hs: high-sensitivity; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Table 1. Baseline characteristics and in-hospital outcomes.
Overall Cohort
N (%)/M(IQR)
N (%)/M(IQR)
Normal hsTnI
N (%)/M(IQR)
p-Value
SMD
N
375
126
249
Age (years)
66 (55.574)
71.5 (64.279)
63 (5171)
<0.001
0.627
Age 65 years old
210 (56)
94 (74.6)
116 (46.6)
<0.001
0.598
Male
252 (67.2)
82 (65.1)
170 (68.3)
0.61
0.076
BMI (kg/m2) (N = 337)
28 (2532)
29 (2634)
28 (2531)
0.04
0.035
eGFR (mL/min/1.73 m2) on admission
81 (5096)
55.5 (2884)
86 (70100)
<0.001
0.816
Cardiovascular risk factors
Hypertension (N = 374)
221 (58.9)
96 (76.2)
125 (50.2)
<0.001
0.575
Diabetes (N = 374)
126 (33.6)
59 (46.8)
67 (26.9)
<0.001
0.430
Dyslipidemia (N = 374)
144 (38.4)
66 (52.4)
78 (31.3)
<0.001
0.446
Smoking (history or current) (N = 330)
80 (21.3)
30 (23.8)
50 (20.1)
0.36
0.121
Obesity (N = 347)
134 (35.7)
51 (40.5)
83 (33.3)
0.20
0.122
Medical history
Heart disease (N = 374)
65 (17.3)
31 (24.6)
34 (13.7)
0.007
0.305
Ischemic heart disease
48 (12.8)
21 (16.7)
27 (10.8)
0.15
0.173
Chronic heart failure
20 (5.3)
12 (9.5)
8 (3.2)
0.009
0.263
HFrEF
13 (3.5)
7 (5.5)
6 (2.4)
0.20
0.478
Chronic kidney disease (N = 374)
65 (17.3)
32 (25.4)
33 (13.2)
0.003
0.316
Chronic respiratory disease (N = 374)
45 (12)
16 (12.7)
29 (11.6)
0.73
0.305
Active cancer
18 (4.8)
9 (7.1)
9 (3.6)
0.20
0.157
Cognitive impairment (N = 374)
15 (4)
7 (5.5)
8 (3.2)
0.19
0.117
VTE (N = 374)
22 (5.9)
11 (8.7)
11 (4.4)
0.07
0.177
Admission treatment
Antithrombotic treatment
121 (32.3)
55 (43.7)
66 (26.5)
<0.001
0.387
Antiplatelet
89 (23.7)
37 (29.4)
52 (20.9)
0.007
0.212
Anticoagulation
41 (10.9)
23 (18.3)
18 (7.2)
<0.001
0.351
Antihypertensive drugs
RASi
150 (40)
63 (50)
87 (34.9)
0.006
0.308
Diuretics
83 (22.1)
41 (32.5)
42 (16.9)
<0.001
0.387
Beta-blockers
103 (27.5)
47 (37.3)
56 (22.5)
<0.001
0.354
Admission Low-dose chest CT *
320 (85.3)
102 (81)
218 (87.6)
1
0.009
Figure 1.
Study flowchart showing patient selection. COVID-19: Human Coronavirus Disease 2019; Feb:
February; h: hours; hs: high-sensitivity; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Table 1. Baseline characteristics and in-hospital outcomes.
Overall Cohort
N (%)/M(IQR)
Elevated hsTnI
N (%)/M(IQR)
Normal hsTnI
N (%)/M(IQR) p-Value SMD
n375 126 249
Age (years) 66 (55.5–74) 71.5 (64.2–79) 63 (51–71) <0.001 0.627
Age 65 years old 210 (56) 94 (74.6) 116 (46.6) <0.001 0.598
Male 252 (67.2) 82 (65.1) 170 (68.3) 0.61 0.076
BMI (kg/m2)(n=337) 28 (25–32) 29 (26–34) 28 (25–31) 0.04 0.035
eGFR (mL/min/1.73 m2) on admission 81 (50–96) 55.5 (28–84) 86 (70–100) <0.001 0.816
Cardiovascular risk factors
Hypertension (n=374) 221 (58.9) 96 (76.2) 125 (50.2) <0.001 0.575
Diabetes (n=374) 126 (33.6) 59 (46.8) 67 (26.9) <0.001 0.430
Dyslipidemia (n=374) 144 (38.4) 66 (52.4) 78 (31.3) <0.001 0.446
Smoking (history or current) (n=330)
80 (21.3) 30 (23.8) 50 (20.1) 0.36 0.121
Obesity (n=347) 134 (35.7) 51 (40.5) 83 (33.3) 0.20 0.122
Medical history
Heart disease (n=374) 65 (17.3) 31 (24.6) 34 (13.7) 0.007 0.305
Ischemic heart disease 48 (12.8) 21 (16.7) 27 (10.8) 0.15 0.173
Chronic heart failure 20 (5.3) 12 (9.5) 8 (3.2) 0.009 0.263
HFrEF 13 (3.5) 7 (5.5) 6 (2.4) 0.20 0.478
Chronic kidney disease (n=374) 65 (17.3) 32 (25.4) 33 (13.2) 0.003 0.316
Chronic respiratory disease (n=374) 45 (12) 16 (12.7) 29 (11.6) 0.73 0.305
Active cancer 18 (4.8) 9 (7.1) 9 (3.6) 0.20 0.157
Cognitive impairment (n=374) 15 (4) 7 (5.5) 8 (3.2) 0.19 0.117
VTE (n=374) 22 (5.9) 11 (8.7) 11 (4.4) 0.07 0.177
Admission treatment
Antithrombotic treatment 121 (32.3) 55 (43.7) 66 (26.5) <0.001 0.387
Antiplatelet 89 (23.7) 37 (29.4) 52 (20.9) 0.007 0.212
Anticoagulation 41 (10.9) 23 (18.3) 18 (7.2) <0.001 0.351
Antihypertensive drugs
RASi 150 (40) 63 (50) 87 (34.9) 0.006 0.308
Diuretics 83 (22.1) 41 (32.5) 42 (16.9) <0.001 0.387
Beta-blockers 103 (27.5) 47 (37.3) 56 (22.5) <0.001 0.354
J. Clin. Med. 2020,9, 4078 5 of 9
Table 1. Cont.
Overall Cohort
N (%)/M(IQR)
Elevated hsTnI
N (%)/M(IQR)
Normal hsTnI
N (%)/M(IQR) p-Value SMD
Admission Low-dose chest CT * 320 (85.3) 102 (81) 218 (87.6) 1 0.009
abnormal 314 (98.1) 100 (98) 245 (98.4) 1
COVID-19 infection severity indicators
Oxygen therapy flow rate of >5 L/min
231 (67.9) 82 (77.4) 149 (63.7) 0.01 0.304
ICU admission 215 (57.6) 85 (67.5) 130 (52.6) 0.008 0.307
Intubation 205 (54.8) 84 (66.7) 121 (48.8) 0.001 0.353
HFNO therapy/NIV 10 (2.7) 1 (0.8) 9 (3.6) 0.17
CT scan extension >25% (n=320) 179 (47.7) 69 (54.8) 110 (44.2) 0.052 0.655
CRP 100 mg/L (n=371) 270 (72) 106 (84.1) 164 (65.9) <0.001 0.458
D-dimer count 3000 µg/L (n=292) 170 (45.3) 77 (61.1) 93 (37.3) <0.001 0.546
Lymphopenia <1000/µL (n=371) 284 (75.7) 104 (82.5) 180 (72.2) 0.026 0.276
In-hospital treatment
Prophylactic/therapeutic
anticoagulation 329 (88.2) 108 (86.4) 221 (89.1) 0.55
Antibiotics 331 (88.3) 109 (86.5) 222 (89.2) 0.49
Antiviral $199 (53.1) 60 (47.6) 139 (55.8) 1
In-hospital outcomes
Death 90 (24) 60 (47.6) 30 (12) <0.001 0.844
Severe sepsis or septic shock 98 (27.2) 47 (37.9) 51 (21.6) <0.001 0.389
Acute renal impairment 136 (36.3) 77 (61.1) 59 (23.7) <0.001 0.851
VTE 57 (15.2) 25 (19.8) 32 (12.9) 0.10 0.190
Stroke/TIA 16 (4.3) 10 (7.9) 6 (2.4) 0.026 0.289
Hospital length of stay (days) 15 (8–29) 16.5 (8–35) 15 (8–27) 0.26 0.277
BMI: body mass index; CRP: C-reactive protein; CT: computer tomography; eGFR: estimated glomerular filtration
rate; HFrEF: heart failure with reduced ejection fraction; hs-cTnI: high-sensitivity cardiac troponin I; HFNO:
high-flow nasal oxygen; ICU: intensive care unit; IQR: interquartile range; M: median; N: number; NHF: nasal high
flow; NIV: noninvasive ventilation; PCR: polymerase chain reaction; RASi: renin–angiotensin system inhibitor;
SMD: standardized mean dierence; VTE: venous thromboembolism; TIA: transient ischemic attack. * number
(frequencies) of low-dose CT scans performed in each group.
$
remdesivir, lopinavir/ritonavir, oseltamivir,
interferon, hydroxychloroquine
3.2. Troponin Elevation and in Hospital Outcomes
A rise in troponin was associated with unfavorable outcomes such as severe sepsis, acute renal
impairment, stroke, and death (Table 1, Figure 2).
J. Clin. Med. 2020, 9, x 5 of 9
abnormal
314 (98.1)
100 (98)
245 (98.4)
1
COVID-19 infection severity indicators
Oxygen therapy flow rate of >5 L/min
231 (67.9)
82 (77.4)
149 (63.7)
0.01
0.304
ICU admission
215 (57.6)
85 (67.5)
130 (52.6)
0.008
0.307
Intubation
205 (54.8)
84 (66.7)
121 (48.8)
0.001
0.353
HFNO therapy/NIV
10 (2.7)
1 (0.8)
9 (3.6)
0.17
CT scan extension > 25% (N = 320)
179 (47.7)
69 (54.8)
110 (44.2)
0.052
0.655
CRP ≥ 100 mg/L (N = 371)
270 (72)
106 (84.1)
164 (65.9)
<0.001
0.458
D-dimer count ≥ 3000 µg/L (N = 292)
170 (45.3)
77 (61.1)
93 (37.3)
<0.001
0.546
Lymphopenia < 1000/µ L (N = 371)
284 (75.7)
104 (82.5)
180 (72.2)
0.026
0.276
In-hospital treatment
Prophylactic/therapeutic anticoagulation
329 (88.2)
108 (86.4)
221 (89.1)
0.55
Antibiotics
331 (88.3)
109 (86.5)
222 (89.2)
0.49
Antiviral $
199 (53.1)
60 (47.6)
139 (55.8)
1
In-hospital outcomes
Death
90 (24)
60 (47.6)
30 (12)
<0.001
0.844
Severe sepsis or septic shock
98 (27.2)
47 (37.9)
51 (21.6)
<0.001
0.389
Acute renal impairment
136 (36.3)
77 (61.1)
59 (23.7)
<0.001
0.851
VTE
57 (15.2)
25 (19.8)
32 (12.9)
0.10
0.190
Stroke/TIA
16 (4.3)
10 (7.9)
6 (2.4)
0.026
0.289
Hospital length of stay (days)
15 (829)
16.5 (835)
15 (827)
0.26
0.277
BMI: body mass index; CRP: C-reactive protein; CT: computer tomography; eGFR: estimated glomerular
filtration rate; HFrEF: heart failure with reduced ejection fraction; hs-cTnI: high-sensitivity cardiac troponin I;
HFNO: high-flow nasal oxygen; ICU: intensive care unit; IQR: interquartile range; M: median; N: number; NHF:
nasal high flow; NIV: noninvasive ventilation; PCR: polymerase chain reaction; RASi: reninangiotensin system
inhibitor; SMD: standardized mean difference; VTE: venous thromboembolism; TIA: transient ischemic attack.*
number (frequencies) of low-dose CT scans performed in each group. $ remdesivir, lopinavir/ritonavir,
oseltamivir, interferon, hydroxychloroquine
3.2. Troponin Elevation and in Hospital Outcomes
A rise in troponin was associated with unfavorable outcomes such as severe sepsis, acute renal
impairment, stroke, and death (Table 1, Figure 2).
Figure 2. Crude survival rates according to high-sensitivity troponin levels. CI: confidence interval;
HR: hazard ratio; hsTnI: high-sensitivity troponin I.
Figure 2.
Crude survival rates according to high-sensitivity troponin levels. CI: confidence interval;
HR: hazard ratio; hsTnI: high-sensitivity troponin I.
J. Clin. Med. 2020,9, 4078 6 of 9
3.3. Mortality Predictors
In the multivariate logistic regression analysis between survivors and nonsurvivors, including
variables statistically significant in univariate analysis and deemed clinically pertinent, mortality was
independently associated with an age of at least 65 years old (OR 3.17, 95% CI 1.45–7.18), C-reactive
protein (CRP) elevation of at least 100 mg/L (OR 3.62, 95% CI 1.12–13.98), and hsTnI elevation (OR 3.12,
95% CI 1.49–6.65) (Table 2).
Table 2. Univariate and multivariate analysis of baseline risk factors for death.
Risk Factor Unadjusted OR (95% CI) p-Value Adjusted OR (95% CI) p-Value
Age 65 years old 5.55 (3.12–10.47) <0.001 3.17 (1.45–7.18) 0.004
High blood pressure 2.08 (1.25–3.55) 0.005 0.78 (0.28–2.10) 0.63
Diabetes mellitus 1.66 (1.01–2.71) 0.04 0.95 (0.40–2.15) 0.90
Dyslipidemia 1.60 (0.98–2.59) 0.054 0.54 (0.22–1.25) 0.16
Tobacco consumption 2.33 (1.33–4.04) 0.002 1.99 (0.89–4.49) 0.09
Active Cancer 5.52 (2.10–15.47) <0.001 2.80 (0.67–11.65) 0.15
Chronic kidney disease 3.07 (1.74–5.41) <0.001 2.30 (0.84–6.41) 0.10
Ischemic heart disease 2.39 (1.25–4.50) 0.007 1.02 (0.30–3.36) 0.96
Chronic heart failure 5.39 (2.15–14.22) <0.001 0.93 (0.17–4.86) 0.94
Previous antithrombotic drug 2.52 (1.54–4.13) <0.001 1.72 (0.70–4.26) 0.23
Previous RASi 1.61 (1.00–2.60) 0.049 1.40 (0.55–3.61) 0.47
Lymphopenia 2.35 (1.25–4.77) 0.011 3.05 (0.90–14.35) 0.10
CRP 100 mg/L (max) 3.26 (1.71–6.76) <0.001 3.62 (1.12–13.98) 0.042
D-dimer count (max) 3000 µg/L 2.52 (1.42–4.62) 0.002 1.55 (0.70–3.55) 0.28
hsTroponin elevation 6.63 (3.98–11.25) <0.001 3.12 (1.49–6.65) 0.003
CI: confidence interval; CRP: C-reactive protein; hs: high-sensitivity; max: maximum; OR: odds ratio; RASi:
renin–angiotensin system inhibitor.
After performing a sensitivity analysis on the entire cohort including patients without hsTnI
measurement, age of at least 65 years old (OR 4.99, 95% CI 2.69–9.25), active cancer (OR 2.52, 95% CI
1.22–5.22), chronic kidney disease (OR 3.26, 95% CI 1.85–5.76), CRP elevation of at least 100 mg/L
(OR 2.34, 95% CI 1.28–4.28), D-dimer elevation over 3000
µ
g/L (OR 1.95, 95% CI 1.04–3.52), and hsTnI
elevation (OR 3.84, 95% CI 1.78–8.28) were significantly associated with death (Supplementary Table S1).
4. Discussion
4.1. Troponin Elevation and in-Hospital Mortality
In our study, a rise in hsTnI was identified in 34% of the cohort. Patients with hsTnI elevation
had a higher prevalence of “cardiovascular burden,” translating into a four-fold increased risk of
death compared to normal hsTnI patients (47% vs. 12%). Furthermore, when performing a sensitivity
analysis for missing values of hsTnI, a rise in troponin remained independently associated with
death. Our findings are consistent with recently published data showing that cardiac biomarkers
such as Tn, B-type natriuretic peptide, or D-dimer are commonly elevated in hospitalized COVID-19
patients [14]. However, a rise in Tn appears more accurate in predicting mortality compared to other
biomarkers [
14
,
17
]. In a meta-analysis of 16 studies, Zou et al. found a pooled overall incidence of
myocardial injury of 24.4% (542/2224) and a markedly increased all-cause mortality associated with
a rise in Tn (72.6% vs. 14.5%) [
12
]. Furthermore, in the largest study published to date on Tn as a
predictor of death including 6247 COVID-19 patients, Majure et al. observed significantly increased
death rates in the case of Tn elevation compared to normal Tn levels (43% vs. 13%) [13].
Troponin assays dier among studies and details concerning cut-os and manufacturers were
not systematically reported in the literature [
18
]. Nonetheless, Tn remains an objective marker easily
obtainable with an obvious prognosis impact. Indeed, Manocha et al. showed in a cohort of 446 patients
that high Tn levels were a potent predictor of 30-day in-hospital mortality with an adjusted OR of
4.38, allowing the authors to develop and validate a mortality score including age, hypoxia, and Tn
elevation beyond the 75th percentile (HA2T2) to predict death [14].
J. Clin. Med. 2020,9, 4078 7 of 9
TheACS-related rise in hsTnI in our study was modest (2.3%) and is consistent with other
retrospective studies reporting similar observations. Thus, Tn appears to have low specificity for ACS
in the COVID-19 context, but myocardial injury could serve as a severity marker rather than being a
cause of death per se [13,14,19].
4.2. Myocardial Injury in COVID-19: Definition and Potential Mechanisms
Although most studies defined myocardial injury on the sole basis of Tn elevation, Giustino et al.
performed an extensive study on echocardiographic abnormalities and found cardiac structural
alterations in two-thirds of patients with enzymatic rise, which was strongly correlated to mortality [
20
].
The recent perception of COVID-19 as a systemic condition acting through multiple deleterious
mechanisms, such as inflammation, endothelial dysfunction, prothrombotic state, and myocardial
injury, could explain the severe course of the disease in some patients. The hypothetical mechanisms of
myocardial injury include tissular hypoxia, cytokine storm, and direct viral myocardial lesions [
1
,
12
,
18
].
4.3. Limitations
Given the retrospective nature of our study, only patients with a hsTnI measurement were included
in the first analysis, which is susceptible to selection bias. However, performing a sensitivity analysis
for missing values allowed us to confirm the initial results, adding robustness to our observation.
Moreover, the use of two troponin measurement assays with dierent URLs did not allow a ROC-curve
cut-ocalculation. Nonetheless, high-sensitivity troponin tests are recognized as being more accurate
than previous measurement techniques and are the recommended assayfor assessing myocardial injury
defined by an increase in hsTnI over the 99th percentile URL. As hsTnI URLs dier between assays,
compiling data using hsTnI as a continuous variable could be biased. For this reason, we consider
that using hsTnI elevation as a categorical variable was a practical alternative, palliating sex- and
site-specific URLs and responding to guidelines’ myocardial injury definition.
4.4. Further Implications
Although current ICU approaches have marginally changed between the first and second waves
of the epidemics, potentially aecting the generalizability of our conclusions, there is still no available
prognosis-changing antiviral treatment. Thus, given the considerable size of our population, we deem
that our results could be pertinent for presently hospitalized patients as Tn is one of the earliest markers
of end-organ dysfunction reflecting relative hypoxia [
13
,
21
]. As such, we advocate for Tn assessment
to improve risk stratification and prompt more intensive surveillance with potential therapeutic
consequences on enhancing tissular perfusion.
5. Conclusions
Elevated troponin measurement in COVID-19 hospitalized patients was independently correlated
to in-hospital mortality and could serve as a predictor for short-term survival providing an indication
for intensive clinical vigilance and potentially improving patients’ triage.
Supplementary Materials:
The following are available online at http://www.mdpi.com/2077-0383/9/12/4078/s1;
Table S1: Univariate and multivariate analysis of baseline risk factors for death on sensitivity analysis with
multiple imputation for missing hsTnI measurements (n=772).
Author Contributions:
Conceptualization, E.-M.C., N.D., V.S.-K. and D.S.; methodology, E.-M.C., N.D., A.D.,
W.Y. and D.S.; software, E.-M.C., L.J., H.L. and A.-S.F.; validation, E.-M.C., E.A., P.B., P.O., V.S.-K. and D.S.;
formal analysis, E.-M.C. and F.S.; investigation, E.-M.C., L.J., H.L., J.T., C.M., H.M., P.B., P.O. and E.A.; resources,
A.-S.F., E.-M.C. and D.S.; data curation, E.-M.C., L.J., H.L., J.T., A.D., W.Y. and A.-S.F.; writing—original draft
preparation, E.-M.C. and D.S.; writing—review and editing, E.-M.C., E.A., F.S. and D.S.; visualization, E.-M.C. and
D.S.; supervision, D.S.; project administration, E.-M.C. and D.S. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
J. Clin. Med. 2020,9, 4078 8 of 9
Acknowledgments:
The authors would like to thank Veronique Kemmel for her biochemistry expertise in the
field of high-sensitivity troponin I measurement.
Conflicts of Interest: The authors declare no conflict of interest.
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Background During the current coronavirus disease 2019 (COVID-19) pandemic, a link between acute cardiac injury and COVID-19 infection has been observed. There is currently no consensus on the incidence of cardiac injury, its relationship to prognosis, or its possible cause. This article provides a comprehensive review and meta-analysis of the incidence, comorbidities, outcomes and possible mechanisms of acute cardiac injury in COVID-19 patients. Methods We searched PubMed and Embase for studies that evaluated cardiac injury in hospitalized COVID-19 patients. Demographic information, co-morbidities, and relevant laboratory values were extracted and a meta-analysis was performed. Results Sixteen studies from China, Italy and the US with 2224 patients were included in this meta-analysis. The incidence of cardiac injury was 24.4% (542/2224 patients) in hospitalized COVID-19 patients. The all-cause mortality in patients with cardiac injury was 72.6% (OR=17.32, 95% CI 9.21-32.57) compared to those without cardiac injury (14.5%). In subgroup analyses, factors associated with increased risk of developing cardiac injury were older age and history of hypertension (HTN), and chronic obstructive respiratory disease (COPD). Conclusion Cardiac injury is common in hospitalized COVID-19 patients and is significantly associated with mortality. Patients who were older with HTN and COPD were prone to develop cardiac injury. Early screening, triage and cardiac monitoring are recommended for these patients.
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Background The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among US hospitalized patients with Coronavirus Disease 2019 (COVID-19) are unknown. Objectives To describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19. Methods Patients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27th and April 12th, 2020 with troponin-I (normal value <0.03ng/mL) measured within 24 hours of admission were included (n=2,736). Demographics, medical history, admission labs, and outcomes were captured from the hospitals’ EHR. Results The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. In all, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g. troponin I 0.03-0.09ng/mL, n=455, 16.6%) were significantly associated with death (adjusted HR: 1.75, 95% CI 1.37-2.24; P<0.001) while greater amounts (e.g. troponin I>0.09 ng/dL, n=530, 19.4%) were significantly associated with higher risk (adjusted HR 3.03, 95% CI 2.42-3.80; P<0.001). Conclusions Myocardial injury is prevalent among patients hospitalized with COVID-19 however troponin concentrations were generally present at low levels. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.
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The rapidly evolving pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection worldwide cost many lives. The angiotensin converting enzyme-2 (ACE-2) has been identified as the receptor for the SARS-CoV-2 viral entry. As such, it is now receiving renewed attention as a potential target for anti-viral therapeutics. We review the physiological functions of ACE2 in the cardiovascular system and the lungs, and how the activation of ACE2/MAS/G protein coupled receptor contributes in reducing acute injury and inhibiting fibrogenesis of the lungs and protecting the cardiovascular system. In this perspective, we predominantly focus on the impact of SARS-CoV-2 infection on ACE2 and dysregulation of the protective effect of ACE2/MAS/G protein pathway vs. the deleterious effect of Renin/Angiotensin/Aldosterone. We discuss the potential effect of invasion of SARS-CoV-2 on the function of ACE2 and the loss of the protective effect of the ACE2/MAS pathway in alveolar epithelial cells and how this may amplify systemic deleterious effect of renin-angiotensin aldosterone system (RAS) in the host. Furthermore, we speculate the potential of exploiting the modulation of ACE2/MAS pathway as a natural protection of lung injury by modulation of ACE2/MAS axis or by developing targeted drugs to inhibit proteases required for viral entry.
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Background Myocardial injury is frequent among patients hospitalized with coronavirus disease-2019 (COVID-19) and is associated with a poor prognosis. However, the mechanisms of myocardial injury remain unclear and prior studies have not reported cardiovascular imaging data. Objectives This study sought to characterize the echocardiographic abnormalities associated with myocardial injury and their prognostic impact in patients with COVID-19. Methods We conducted an international, multicenter cohort study including 7 hospitals in New York City and Milan of hospitalized patients with laboratory-confirmed COVID-19 who had undergone transthoracic echocardiographic (TTE) and electrocardiographic evaluation during their index hospitalization. Myocardial injury was defined as any elevation in cardiac troponin at the time of clinical presentation or during the hospitalization. Results A total of 305 patients were included. Mean age was 63 years and 205 patients (67.2%) were male. Overall, myocardial injury was observed in 190 patients (62.3%). Compared with patients without myocardial injury, those with myocardial injury had more electrocardiographic abnormalities, higher inflammatory biomarkers and an increased prevalence of major echocardiographic abnormalities that included left ventricular wall motion abnormalities, global left ventricular dysfunction, left ventricular diastolic dysfunction grade II or III, right ventricular dysfunction and pericardial effusions. Rates of in-hospital mortality were 5.2%, 18.6%, and 31.7% in patients without myocardial injury, with myocardial injury without TTE abnormalities, and with myocardial injury and TTE abnormalities. Following multivariable adjustment, myocardial injury with TTE abnormalities was associated with higher risk of death but not myocardial injury without TTE abnormalities. Conclusions Among patients with COVID-19 who underwent TTE, cardiac structural abnormalities were present in nearly two-thirds of patients with myocardial injury. Myocardial injury was associated with increased in-hospital mortality particularly if echocardiographic abnormalities were present.
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Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged late in 2019 causing COVID-19 (coronavirus disease-2019) may adversely affect the cardiovascular system. Publications from Asia, Europe and North America have identified cardiac troponin as an important prognostic indicator for patients hospitalized with COVID-19. We recognized from publications within the first 6 months of the pandemic that there has been much uncertainty on the reporting, interpretation, and pathophysiology of an increased cardiac troponin concentration in this setting. Content The purpose of this mini-review is: a) to review the pathophysiology of SARS-CoV-2 and the cardiovascular system, b) to overview the strengths and weaknesses of selected studies evaluating cardiac troponin in patients with COVID-19, and c) recommend testing strategies in the acute period, in the convalescence period and in long-term care for patients who have become ill with COVID-19. Summary This review provides important educational information and identifies gaps in understanding the role of cardiac troponin and COVID-19. Future, properly designed studies will hopefully provide the much-needed evidence on the path forward in testing cardiac troponin in patients with COVID-19.