Keywords
COVID-19 - cardiovascular manifestation - troponin
Introduction
Since December 2019, a large global outbreak of the novel coronavirus disease 2019
(COVID-19) is caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).[1] The pandemic has been spreading in Switzerland since February 2020.[2] COVID-19 most commonly manifests with respiratory illness[3] but cardiovascular involvement has been confirmed. This is due to both the high
prevalence of cardiovascular disease in COVID-19 patients and the development of de
novo cardiac complications.[4]
Several reports have demonstrated the presence of elevated troponin levels in patients
with COVID-19, secondary to acute cardiac lesions including acute myocardial infarction
(MI), myocardial injury, acute heart failure, and arrhythmias.[5] According to the recommendations of the American College of Cardiology (ACC), clinicians
should measure troponin only in cases of specific clinical suspicion, as the existence
of few prospective data in COVID-19 patients with troponins makes their interpretation
complicated.[6] In response to this review, Chapman and colleagues argued in Circulation that high-sensitivity
cardiac troponin is associated with more severe disease and could be an indicator
for poorer prognosis in COVID-19 patients.[7]
We sought to describe a population with elevated levels of cardiac troponin T (hs-cTnT),
report the cardiological investigations performed during patient's hospitalization
and analyze their cardiac diagnosis.
Methods
Study Population and Data Collection
We retrospectively included in this analysis all patients admitted to Fribourg Hospital
with hs-cTnT > 50 ng/L between February 15, 2020, and May 8, 2020. The inclusion period
was chosen based on the peak pandemic according to in-hospital quality monitoring
data. The hs-cTnT levels and other specific biomarkers were performed according to
clinical practice. Indication of further cardiac investigations was performed according
to the clinicians. A clinical follow-up was completed for all included patients during
the hospital stay. The data collection, analysis, and reporting have been approved
by the Institutional Board of the Hospital of Fribourg.
Clinical Endpoints
The primary diagnosis for troponin elevation was recorded. Laboratory, echocardiographic,
electrocardiographic (ECG), and coronary angiographic data were analyzed for signs
of myocardial ischemia, infarction, or other cardiomyopathies. Death from any cause
and cardiac death were defined using the ARC definition.[8]
Statistical Method
Categorical variables are reported as count and percentages; continuous variables
are reported as mean ± standard deviation (SD) or median [interquartile range (IQR):
25–75%]. Normality was assessed by visual inspection of histograms and the computation
of Q-Q plots. Continuous variables are analyzed using the Student t-test or the Wilcoxon rank-sum test according to their distribution. Categorical variables
were compared using Chi-square or Fisher's exact test as appropriate. We performed
a propensity-matched analysis to adjust for baseline imbalances on the outcomes. In
the matching procedure, we used the caliper-matching approach that randomly selected
a COVID-19 patient with a non-COVID-19 patient from the pool of patients within a
caliper of ± 0.015 on the propensity score. Statistical analyses were performed with
Stata version 14.0 (StataCorp LP, College Station, Texas, United States).
Results
Clinical Characteristics
During the inclusion period, 215 patients with elevated troponin T (hs-cTnT) level
were enrolled. The median age of the patients was 75 [65–83] years and and 30% were
women. The median length of stay was 6 [3–11] days. The rates of prior hypertension,
smoking, diabetes and dyslipidemia were 67, 20, 22, and 49% respectively. [Table 1] shows the baseline characteristics of all patients.
Table 1
Baseline characteristics
|
All patients
|
Propensity score–matched patients
|
|
All patients (n = 215)
|
COVID-19 (n = 21)
|
Non-COVID-19 (n = 194)
|
p-Value
|
COVID-19 (n = 21)
|
Non-COVID-19 (n = 21)
|
p-Value
|
|
Characteristics
|
|
Male (%)
|
150 (70)
|
16 (76)
|
134 (69)
|
0.62
|
16 (76)
|
12(57)
|
0.33
|
|
Median age (y)
|
75 [65–83]
|
77 [73–86]
|
75 [65–83]
|
0.04
|
77 [73–86]
|
81 [73–86]
|
0.95
|
|
Length of stay (d)
|
6 [3–11]
|
8 [3–21]
|
6 [2–11]
|
0.20
|
8 [3–21]
|
7 [3–10]
|
0.55
|
|
Hypertension
|
143 (67)
|
12 (57)
|
131 (68)
|
0.34
|
12 (57)
|
14 (66)
|
0.75
|
|
Smoking
|
42 (20)
|
2 (10)
|
40 (21)
|
0.38
|
2 (10)
|
3 (14)
|
1.00
|
|
Diabetes
|
48 (22)
|
7 (33)
|
41 (21)
|
0.27
|
7 (33)
|
3 (14)
|
0.28
|
|
Dyslipidemia
|
105 (49)
|
6 (29)
|
99 (51)
|
0.07
|
6 (29)
|
4 (19)
|
0.72
|
|
Family history
|
21 (10)
|
0 (0)
|
21 (11)
|
0.24
|
0 (0)
|
2 (10)
|
0.49
|
|
Previous MI
|
35 (16)
|
2 (10)
|
33 (17)
|
0.54
|
2 (10)
|
5 (24)
|
0.41
|
|
Laboratory values
|
|
Troponins
|
133 [77–320]
|
94 [69–194]
|
137 [77–369]
|
0.14
|
94 [69–194]
|
133 [69–252]
|
0.36
|
|
CRP
|
27 [35–107]
|
145 [69–238]
|
20 [5–70]
|
< 0.01
|
145 [69–238]
|
20 [6–148]
|
0.04
|
|
Creatinine
|
107 [83–144]
|
120 [87–209]
|
105 [82–142]
|
0.15
|
120 [87–209]
|
108 [85–146]
|
0.37
|
|
D-Dimer
|
1,293 [618–3,255]
|
4,581 [1,355–21,637]
|
752 [505–1,830]
|
< 0.01
|
4,581 [1,355–21,637]
|
711 [421–976]
|
< 0.01
|
|
NT-pro-BNP
|
3,653 [991–110,053]
|
3,752 [1,726–5,396]
|
3,650 [991–10,053]
|
0.98
|
3,752 [1,726–5,396]
|
7,196 [732–11,983]
|
0.84
|
Abbreviations: COVID-19, novel coronavirus disease 2019; CRP, C-reactive protein;
MI, myocardial infarction; NT-pro-BNP, probrain natriuretic peptide.
Note: Continuous variables are expressed as mean ± standard deviation, median [interquartile
range] or n (%).
Clinical Investigations
Patients presented a median troponin value of 133 [77–2,487] ng/L. D-dimer level was
available in 43 patients with a median value if 1,293 [618–3,255] ng/mL. The biomarker
of inflammation as measured by C-reactive protein (CRP) was recorded in 168 patients
with a median value of 27 [35–107] mg/L. Probrain natriuretic peptide (NT-pro-BNP)
levels were measured in 71 patients with a median of 3,653 [991–110,053] ng/L. Creatinine
median levels were 107 [83–144] µmol/L. Of all patients included, 110 (51%) underwent
echocardiography with a median ejection fraction (EF) of 55% [47–60%] and 112 (52%)
underwent coronary angiography. Only 1% of patients with troponins underwent other
cardiac investigations, such as cardiac magnetic resonance imaging or coronary computed
tomography, during hospitalization. The overall in-hospital death rate was 13% and
cardiac death was 9% ([Table 2]). This trend was confirmed in a propensity score-matched analysis. ([Tables 1] and [2])
Table 2
In-hospital outcomes
|
All patients
|
Propensity score-matched patients
|
|
Investigations
|
All patients (n = 215)
|
COVID-19 (n = 21)
|
Non-COVID-19 (n = 194)
|
p-Value
|
COVID-19 (n = 21)
|
Non COVID-19 (n = 21)
|
p-Value
|
|
Echocardiography
|
110 (51)
|
4 (19)
|
106 (55)
|
<0.01
|
4 (19)
|
11 (53)
|
0.05
|
|
LVEF
|
55 [47–60]
|
50 [45–55]
|
55 [47–60]
|
0.54
|
50 [45–55]
|
60 [55–65]
|
0.13
|
|
Coronary angiography
|
112 (52)
|
1 (5)
|
111 (58)
|
<0.01
|
1 (5)
|
12 (57)
|
< 0.01
|
|
Other investigations (cardiac MRI, coronary CT)
|
3 (1)
|
0 (0)
|
3 (2)
|
1.00
|
0 (0)
|
0 (0)
|
–
|
|
In-hospital outcome
|
|
In-hospital death
|
28 (13)
|
8 (38)
|
20 (10)
|
0.01
|
8 (38)
|
0 (0)
|
< 0.01
|
|
In-hospital cardiac death
|
19 (9)
|
3 (14)
|
16 (8)
|
0.41
|
3 (14)
|
0 (0)
|
0.23
|
Abbreviations: COVID-19, novel coronavirus disease 2019; CT, computed tomography;
LVEF, left ventricular ejection fraction; MRI, magnetic resonance imaging.
Clinical Diagnosis
COVID-19 Subgroup
Clinical diagnosis for troponin elevation was variable. COVID-19 was diagnosed in
21 patients (10%). Cardiovascular manifestations in 21 patients with COVID-19 infection
were analyzed: 14 patients presented with myocardial injury related to COVID-19, 1
patient presented with ST-segment elevation myocardial infarction (STEMI), 1 patient
with stress cardiomyopathy, 2 patients with pulmonary embolism (PE), 2 patients with
type-2 MI, and 1 patient with congestive heart failure (CHF; [Fig. 1]).
Fig. 1 Cardiovascular manifestations of COVID-19 infection during the pandemic peak. CHF,
cardiac heart failure; COVID-19, novel coronavirus disease 2019; MI, myocardial infarction;
NSTEMI, non-ST-elevation MI; STEMI, ST-elevation MI.
Non-COVID-19 Subgroup
The World Health Organization (WHO) type-1 MI was the most common diagnosis present
in 40% of non-COVID-19 patients including 15% with STEMI and 23% with NSTEMI. The
incidence of WHO type-2 MI was 21%. We assessed all clinical diagnoses in [Fig. 2] and [Table 3].
Table 3
Clinical diagnosis in non-COVID-19 patients with elevated troponin levels during the
pandemic peak
|
Clinical diagnose
|
n = 194
|
|
Type-1 MI
|
77 (40)
|
|
NSTEMI
|
48 (23)
|
|
STEMI
|
29 (15)
|
|
Type-2 MI
|
41 (21)
|
|
Myocardial injury in renal failure
|
27 (14)
|
|
Congestive heart failure
|
17 (9)
|
|
Myocardial injury postangioplasty
|
10 (5)
|
|
Myocardial injury in sepsis/infection (non-COVID-19)
|
7 (4)
|
|
Myocardial injury in PE
|
5 (3)
|
|
Takotsubo
|
3 (2)
|
|
Peri-/myocarditis
|
3 (2)
|
|
Other
|
4 (2)
|
Abbreviations: COVID-19, novel coronavirus disease 2019; MI, myocardial infarction;
NSTEMI, non-ST elevation MI; PE, pulmonary embolism; STEMI, ST elevation MI.
Note: Continuous variables are expressed as mean ± standard deviation, median [interquartile
range] or n (%).
Fig. 2 Clinical evidence of acute myocardial ischemia and myocardial injury during the COVID-19
pandemic. COVID, coronavirus disease; MI, myocardial infarction; STEMI, ST-elevation
MI.
COVID-19 versus Non-COVID-19 Patients before Propensity Score Matching
In the COVID-19 subgroup, patients were older than non-COVID-19 patients (77 vs. 75
years, p = 0.04; [Table 1]). The median CRP amounts (145 vs. 20 mg/L, p < 0.001), as well as the D-dimers (4,581 vs. 752 ng/mL, p < 0.01), were higher in the COVID-19 group. Troponins were not significantly different
in both groups (94 vs. 137 ng/L, p = 0.14). Only four patients underwent echocardiography and one patient underwent
coronary angiography in the COVID-19 group, equivalent to a significantly lower median
number of examinations than in the non-COVID-19 group (19 vs. 55%, p ≤ 0.01 and 5 vs. 58%, p ≤ 0.01, respectively). Overall, mortality in the COVID-19 group was very high, as
38% of patients died during hospitalization including 14% for cardiac death.
COVID-19 versus Non-COVID-19 Patients after Propensity Score Matching
After propensity score–matching analysis, 42 patients were identified, and baseline
characteristics of the patients were well balanced between groups ([Table 1]). Troponin levels remained equivalent between the two groups (94 vs. 133, p = 0.36). The results confirm a lower number of echocardiographic examinations (19
vs. 53%, p = 0.05) and coronary angiographies (5 vs. 57%, p ≤ 0.01) between the matched patients ([Table 2]).
Discussion
The main findings of this report are as follows: (1) among patients with elevated
troponins during the pandemic peak, 10% were diagnosed with COVID-19; (2) cardiovascular
manifestations in patients with COVID-19 infection was varied, ranging from myocardial
injury, STEMI, type-2 MI, and stress-induced cardiomyopathy; and (3) in-hospital mortality
and cardiac mortality of COVID-19 patients with troponins were high.
Cardiovascular Manifestations of COVID-19 Infection
This analysis reports a wide and varied panel of cardiac manifestations of COVID-19.
Diagnosis of cardiovascular COVID-19 manifestations was performed on a combination
of clinical symptoms, specific biomarkers, evidence of new electrocardiographic or
echocardiographic abnormalities, or other imaging. Recognition of possible mechanism
of cardiovascular manifestations in COVID-19 patients including myocardial injury,
plaque rupture or thrombosis (WHO type-1 MI), supply–demand mismatch (WHO type-2 MI),
myocarditis, and stress-induced cardiomyopathy is essential for the management and
follow-up of these patients.
Acute myocardial injury, defined by an increase in troponins associated or not with
electrocardiographic modifications and/or cardiovascular imaging,[9]
[10]
[11] was the most commonly described cardiovascular complication in COVID-19 in our center
during the pandemic peak which is consistent with recent literature. Potential mechanisms
of SARS-CoV-2-mediated myocardial injury are direct myocardial injury of the myocardium
or secondary to mechanisms related to an acute systemic inflammatory response (cytokine
storm). The overall incidence of acute cardiac injury in COVID-19 patients is variable
but estimated between 8 and 12% and is considered an important prognostic marker.[3]
[12]
Biomarkers
Troponin values were not different between groups. Although troponins are associated
with poorer outcomes in patients with COVID-19 according to recent literature,[11] it is interesting to note that the degree of elevation did not differ from a group
of patients with non-COVID-related cardiac involvement. Since the pattern of troponin
elevation is an essential diagnostic factor, this similarity between troponin values
is an additional clinical challenge. Shi et al described a case series of 82 patients
with cardiac injury and a median troponin troponin value of 190 ng/L.[10] This higher value of troponin is likely explained by more sever COVID-19 disease
in the epicenter of the pandemic with less clinical management experience in the early
stages of COVID-19. Finally, recent studies used the 99th percentile as a cut-off
point, while our report uses a much higher rule-out threshold (hs-cTnT > 50 ng/L)
to avoid uncertain diagnosis for patients in the gray zone.
Management Implications
Of the 21 COVID-19 patients with troponins, 4 patients (19%) had echocardiography,
and 1 patient had a coronary angiography (5%). The reason for the low number of cardiac
examinations in COVID-19 patients with troponins is the initially uncertain interpretation
of these biomarkers in the COVID-19 context.
Besides, the presence of strict measures to isolate patients and protect health care
workers[13] during the peak of the pandemic also contributed to the decrease in the number of
tests. Indeed, prolonged and close contact during diagnostic tests (e.g., transthoracic
echocardiography, transesophageal echocardiography, and coronary angiography) with
these patients was limited. This was necessary to minimize routine diagnostic procedures
in a setting where health care resources are already stretched and would also expose
health care personnel to an increased risk of exposure to infection.
Targeted Cardiac Evaluation
To optimize the patient's management, targeted cardiac evaluation was indicated in
selected patients with COVID-19 where the evaluation guided the treatment and prognosis.
This approach to cardiac assessment may differ from the standard approach, as it is
based on weighing the likelihood of the evaluation-guiding decision-making with nosocomial
infection control considerations, in a setting with limited availability of medical
resources. The level of precautions taken against COVID-19 were differentiated according
to the level of risk based on patient presentation and the type of procedures.
The imaging technique was reevaluated on a patient-by-patient basis, both in terms
of diagnostic yield and environmental infectious risk. Routine cardiac imaging in
patients with suspected or confirmed COVID-19 was reduced to a strict minimum. The
management of patients in our center was largely guided by the ESC recommendations
for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic.[14] Furthermore, emphasis was placed on a proper triage to favor a correct patient assignment
based on the infective status and rapid intervention for patients requiring urgent
cardiac intervention with adoption of required protective measures.
Potential Long-Term Consequences
Considering this, careful follow-up of those recovering from the current COVID-19
would be important to understand the long-term impact of this illness and also to
protect these patients from future cardiovascular disease.
Limitations
There are a number of limitations in the present report. Because of the reduced number
of invasive and noninvasive imaging during the COVID-19 pandemic, patients were assessed
on clinical evidence, and some mechanisms of cardiac injury may have been misdiagnosed.
Moreover, this report is limited to intrahospital outcomes and long-term follow-up
has not been performed. The presence of COVID-19 infection and cardiac involvement
does not necessarily evoke a direct causal relationship. Further, laboratory values
(such as troponin levels, CRP, creatinine, D-dimer, and NT-pro-BNP) were performed
according to clinical practice and were not available for all patients which limits
generalization of the laboratory results. Finally, outcome analyses in our study should
be interpreted with caution due to the small number of patients. Data from larger
population and multicenter data are needed to further confirm the implications of
cardiac manifestations in COVID-19.
Conclusion
This report displays a large panel of possible cardiovascular manifestations of COVID-19.
The presumed pathophysiological processes provide a better understanding of these
cases but many may have multifactorial etiologies. However, clinical diagnosis was
challenged by a reduction of cardiological investigations during the pandemic.
