Early identification of severe immune checkpoint inhibitor associated myocarditis: From an electrocardiographic perspective

Abstract Objectives Immune checkpoint inhibitor (ICI)‐associated myocarditis, particularly severe ICI‐associated myocarditis, has a high mortality rate. However, the predictive value of electrocardiogram (ECG) remains unclear. The present study aimed to evaluate the predictive value of clinical and electrocardiographic parameters for severe myocarditis. Methods Clinical and electrocardiographic data of 73 cancer patients with ICI‐associated myocarditis were retrospectively collected. The severity of ICI‐associated myocarditis was graded using the NCCN guidelines for managing immunotherapy‐related toxicities. Myocarditis grades 1–2 and grades 3–4 were classified as mild and severe myocarditis, respectively. Logistic regression analysis was performed to analyze the predictive value of each parameter in predicting severe myocarditis. Results Among the 73 patients with myocarditis, 20 (27.4%) patients had severe myocarditis. Compared with mild myocarditis group, sinus tachycardia (p = 0.001), QRS duration ≥110 ms (p = 0.001), prolonged QTc interval (p < 0.001), and bundle branch block (p = 0.007) at the time of myocarditis were more common in the severe myocarditis group. Logistic regression analysis revealed that sinus tachycardia (p = 0.028) and QTc interval prolongation (p = 0.007) were predictors of severe myocarditis. Whereas the predictive value of other electrocardiographic parameters was weak. Concurrent targeted therapy didn't increase the risk of severe myocarditis. A high NT‐proBNP level was associated with severe myocarditis. Conclusions ECG at the onset of myocarditis manifested as sinus tachycardia and prolonged QTc interval predicted a high risk of severe myocarditis. Early detection of ECG abnormalities may faciliate early detection of severe ICI‐associated myocarditis.


| INTRODUCTION
In recent years, immune checkpoint inhibitors (ICIs) as novel anticancer drugs have shown remarkable anti-tumor efficacy and revolutionized tumor therapy. 1 However, despite their better therapeutic effects, ICIs therapy could also lead to a series of immune-related adverse events (irAE), particularly some lethal adverse effects such as myocarditis. 2ICI-associated myocarditis can be classified into different grades according to the National Comprehensive Cancer Network (NCCN) guidelines for managing immunotherapy-related toxicities.Patients with grade 3-4 myocarditis are at a high risk of occurrence of a major adverse cardiovascular event (MACE), 3 which may negatively affect their prognosis.Mild myocarditis in the early stage of ICI treatment could rapidly develop into severe myocarditis, with a fatality rate up to 30%-50%. 4 However, ICIassociated myocarditis is usually asymptomatic and rare, and the incidence of this complication ranges from 0.09% to 1.1%. 2,5Therefore, it is necessary for early diagnosis ICIs-associated myocarditis and detection severe myocarditis to proceed immunotherapy process.
6][7][8] However, most of these studies focused on comparing patients with and without ICIassociated myocarditis.Only a few studies have reported differences in clinical characteristics between patients with mild and severe myocarditis. 9,10Electrocardiogram (ECG) is a simple, economical, and noninvasive test and can be chosen as the first-line tool for detecting cardiovascular abnormalities in ICI users, particularly those with cardiac arrhythmias.2][13][14] However, very few investigations have reported differences in electrocardiographic manifestations between patients with mild and severe ICI-associated myocarditis. 9,15Therefore, to recognize severe myocarditis at an early stage and improve patent prognosis, there is an urgent requirement to determine the electrocardiographic characteristics of severe ICI-associated myocarditis compared with mild ICI-associated myocarditis.
Hence, in the present study, to better investigate the differences in the electrocardiographic characteristics of patients with mild and severe ICI-associated myocarditis, we classified grades 1-2 and grades 3-4 ICIassociated myocarditis, defined according to the NCCN guidelines for managing immunotherapy-related toxicities as mild and severe myocarditis, respectively.We comprehensively compared the ECGs at the onset of myocarditis between patients with mild and severe myocarditis to determine the electrocardiographic characteristics that could predict severe myocarditis.We also analyzed the predictive significance of clinical characteristics and blood laboratory test results for patients with severe myocarditis.Our findings on differences in ECG changes between mild and severe myocarditis may facilitate early screening of severe myocarditis and enable the development of better monitoring strategies for ICI associated myocarditis.

| Patients
This retrospective study included patients who received ICI treatment and were diagnosed to have ICI-associated myocarditis at Tianjin Medical University Cancer Institute & Hospital from January 2020 to June 2023.The study was approved by the Ethics Committee of Tianjin Medical University Cancer Institute & Hospital.Written informed consent was waived because of the retrospective nature of the study.
The inclusion criteria were as follows: (1) pathological confirmation of malignancy; (2) received PD-1 or PD-L1 inhibitors treatment; (3) complete clinical and electrocardiographic data at the onset of myocarditis; and (4) diagnosis of ICI-associated myocarditis according to the guidelines of the European Society of Cardiology, 16 and the grading for ICI-associated myocarditis was defined based on the NCCN Guidelines for managing of immunotherapy-related toxicities 3 as follows: Grade 1, asymptomatic, abnormal cardiac biomarkers (creatine kinase and troponin), abnormal ECG or physical findings (e.g., rub) consistent with pericarditis; Grade 2, mild symptoms or symptoms with moderate activity or exertion, abnormal screening tests: cardiac biomarkers (creatine kinase and troponin) and ECG; Grade 3, symptoms at rest or with minimal activity or exertion or new onset of symptoms; cardiac biomarkers (creatine kinase and troponin) > upper limit of the normal range; Grade 4, moderate to severe decompensation (worsening signs and symptoms), hemodynamic instability (hypotension/cardiomyopathy), cardiac biomarkers (creatine kinase and troponin levels) >3× upper limit of the normal range, life-threatening; urgent intervention indicated.In the current study, to better investigate the association between electrocardiac parameters and the severity of ICI-associated myocarditis, ICI-associated myocarditis grades 1-2 were classified as mild myocarditis, whereas grades 3-4 were severe myocarditis.The grading for ICI-associated myocarditis of each patients was defined by two clinicians, and a third clinician resolved any disagreements.
Exclusion criteria were as follows: (1) patients not receiving anti-PD1/PD-L1 immunotherapy; (2) patients with missing electrocardiographic data and laboratory test results; and (3) patients in whom the diagnosis of ICIassociated myocarditis could not be definitely established; and (4) patients had history of myocarditis or who presenting clinical myocarditis before ICI treatment.

| Clinical data collection
The following baseline characteristics were obtained retrospectively from the hospital's electronic medical record system: age, sex, smoking history, cardiovascular risk diseases, cancer type, tumor stage, occurrence of major adverse cardiac events (MACE), and immunotherapyrelated data (including types of ICIs, treatment cycles, treatment efficacy, and concurrent therapies).The results of the following blood laboratory tests were collected at the onset of myocarditis: serum creatine kinase (CK), creatine kinase MB (CK-MB), cardiac troponin I (cTnI), Nterminal pro-B-type natriuretic peptide (NT-proBNP), and peripheral blood cells.Individuals were staged according to the 7th edition of the American Joint Committee on Cancer staging system.Neoadjuvant immunochemotherapy (NICT) responses were evaluated according to the Response Evaluation Criteria of Solid Tumors version 1.1(RECIST). 17The disease control rate (DCR) was evaluated, including complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD).MACE included cardiovascular death, 18 cardiogenic shock, 19 cardiac arrest, 20 and hemodynamically significant complete heart block. 21

| ECG data collection and evaluation
All ECGs were recorded with standard 12-lead placement at a standardization of 10 mm/mV and a paper speed of 25 mm/s.Baseline and at the onset of myocarditis ECGs data were collected for all patients.The primary variables included sinus arrhythmia (including normal sinus arrhythmia, sinus tachycardia, and sinus bradycardia), PR interval, QRS duration, QTc interval, atrial premature beat (APB), ventricular premature beat (VPB), ST-T segment abnormalities, bundle branch block, and pathological Q wave.
Heart rate was defined as tachycardia or bradycardia according to the average rate of QRS complexes of >100/min or < 60/min, respectively.PR interval represents the time delay between atrial depolarization and ventricular depolarization; PR interval of >200 ms was considered prolonged.QRS duration was obtained from the first deflection of the QRS complex to the end of the QRS complex on the isoelectric line.QRS duration of >110 ms was considered prolonged. 22Bundle branch block, which included left/right bundle branch block, represents a disorder in the bundle branch conduction pathway, resulting in slow conduction. 22QT interval was calculated from the first deflection of the QRS complex to the end of the T wave on the isoelectric line.The QTc interval was calculated from the Bazett formula as follows: QTC=QT/√RR; (RR; heart rate).According to the standard criteria, a QTc interval of >450 ms in men and >460 ms in women was considered prolonged. 23ST-T segment abnormalities included ST segment elevation (limb lead elevation >0.10 mV, thoracic lead >0.2 mV), ST segment depression (ST segment depression >0.05 mV for at least two leads), low T wave (limb lead <0.1 mV or chest lead <0.2 mV), bidirectional T wave (positive T wave followed by negative T wave), and inverted T wave (power wave inversion depth ≥0.1 mV). 24Two cardiologists independently reviewed each ECG, and a third cardiologist resolved any disagreements.

| Statistical analysis
Continuous variables were expressed as mean ± SD or median, and categorical variables were expressed as percentages.Chi-square test and Fisher's exact test were used to compare categorical variables, while Mann-Whitney U test was used to compare continuous variables between patients with mild and severe myocarditis.Logistic regression analysis was performed to assess the value of each parameter in predicting severe myocarditis.SPSS Statistics version 17.0 (SPSS, Inc., Chicago, IL) was used utilized for all statistical analyses.p-values were corrected for multiple comparisons and a twosided p-value of <0.05 was used to indicate statistical significance.
Our results showed that ICI-associated myocarditis occurred in the early treatment stage.The median number of days and immunotherapy cycles from the start of ICI treatment to myocarditis onset were 25.0 (20.0-37.5)days and 2 (1.0-5.0)cycles.The incidence of pneumonitis, liver injury, myositis, and pituitary/adrenal axis dysfunction was 9.6%, 24.7%, 15.1%, and 15.1%, respectively.Overall, the initial presenting symptom of ICI-associated myocarditis was shortness of breath or chest distress in 17/73 (23.3%) patients, while 33/73 (45.2%) patients were asymptomatic.Among those, a total of 11/73 (15.1%) patients were diagnosed with myocarditis with myositis/myasthenia overlap syndrome, and 10/11 (90.9%) of patients were in the severe myocarditis group.Almost all patients in the severe myocarditis group showed initial presenting symptoms, and the most common symptom was precordial discomfort or chest tightness.Furthermore, nearly 60% of patients in the mild myocarditis group were asymptomatic.All patients in the severe myocarditis group received glucocorticoid

| Association of electrocardiographic and clinical characteristics with the severity of ICI-associated myocarditis
The clinical characteristics were compared between the mild and severe myocarditis groups to identify indicators for severe myocarditis (Table 3).We found that patients' characteristics, including gender, age, smoking and drinking history, diabetes, hypertension, heart disease, and prior cardiovascular medications were not associated with myocarditis severity.Additionally, immunotherapyrelated parameters, including therapeutic cycles, ICI drugs, concurrent chemotherapy, and radiotherapy history, were also not significantly associated with myocarditis severity (all p-values >0.05).However, only concurrent targeted therapy was inversely associated with severe myocarditis (p = 0.047).
We further analyzed differences in serum cardiac biomarkers at the onset of ICI-associated myocarditis between the two groups.The median values of cTnI, NT-proBNP, CK, and CK-MB were higher in the severe myocarditis group than in the mild myocarditis group (median values:  2, the pre-ICI baseline sinus arrythmia, APB, VPB, ST-T segment abnormalities, QRS duration, QTc interval, PR interval, bundle branch block and pathological Q wave were similar between mild and severe myocarditis groups (all p-values >0.05).A similar testing strategy was adopted for analyzing the association of electrocardiographic parameters at the onset of ICI-associated myocarditis with severe myocarditis.The following on-ICI electrocardiographic abnormalities were more commonly observed in the severe myocarditis group than in the mild myocarditis group: sinus tachycardia (p = 0.001), QRS duration ≥110 ms (p = 0.001), prolonged QTc interval (p < 0.001), and bundle branch block (p = 0.007).Whereas, no differences were observed in the incidence of APB, VPB, ST-T segment abnormalities, PR interval prolongation, and pathological Q wave (all p-values >0.05).
To investigate the effects of the above-mentioned four electrocardiographic abnormalities at the onset of  T A B L E 3 Differences in clinical features between patients with mild and severe ICI-associated myocarditis.ICI-associated myocarditis to predict the severe of ICIassociated myocarditis, we further analyzed the differences of electrocardiographic parameters between baseline and at the onset of ICI-associated myocarditis.With this approach, the percentage of sinus arrhythmia (p = 0.008), QRS duration (p = 0.011), the QTc interval (p = 0.008) and bundle branch block (p < 0.001) at the onset of myocarditis were increased when compared to baseline electrocardiographic parameters (Table S1).We further explored if above ECG abnormalities at the onset of ICI-associated myocarditis were associated with MACE.In all nine ICIassociated myocarditis patients with MACE, 5/9 (55.6%) patients harbored with sinus tachycardia, 3/9 (33.3%) patients harbored with prolonged QRS duration, 5/9 (55.6%) patients harbored with prolonged QTc interval, and none of the patients harbored with bundle branch block.We found that only sinus tachycardia (p = 0.031) at the onset of ICI-associated myocarditis was associated with MACE, which prolonged QRS duration (p = 0.484), prolonged QTc interval (p = 0.202), and bundle branch block (p = 1.000) did not show a clear relationship with MACE (Table S2).

| DISCUSSION
Although ICI-associated myocarditis is a severe irAE, patients with this complication usually do not exhibit specific clinical manifestations.Furthermore, severe ICIassociated myocarditis often shows a violent course and may be at a high risk of occurrence of MACE, such as acute heart failure and cardiogenic shock. 21Therefore, it is essential to promptly identify cases of severe ICIassociated myocarditis and implement effective therapies.Thus far, some serum or echocardiographic markers have been reported to predict severe ICI-associated myocarditis. 9,10However, few studies were focused on comparing patients with mild and severe myocarditis and most studies explored the predictive value of fewer electrocardiographic parameters.
ECG, a simple and noninvasive test, could enable early detection of ICI-associated myocarditis before the occurrence of clinical manifestations and changes in serum cardiac markers or left ventricular ejection fraction.However, to date, few studies have reported differences in electrocardiographic characteristics between patients with mild and severe myocarditis and have evaluated the predictive ability of electrocardiographic

T A B L E 4
Logistic regression analysis to determine the predictive value of clinical and electrocardiographic characteristics for ICI-associated myocarditis severity.
parameters for stratifying the severity of ICI-associated myocarditis.In this paper, we present novel findings describing the predictive value of comprehensive electrocardiographic parameters on predicting the severity of ICI-associated myocarditis and identified the relevant predictors of severe myocarditis.The comparison of the clinical and electrocardiographic characteristics of patients with severe and mild ICI-associated myocarditis yielded several important results.First, severe ICI-associated myocarditis occurred in the early stages of treatment and was accompanied by initial presenting symptoms, the most common of which were precordial discomfort or chest tightness.Second, almost all patients in the severe myocarditis group had elevated levels of cardiac biomarkers, and a high NT-proBNP level was one of the predictors of severe myocarditis.Third, the severe myocarditis group showed a high incidence of MACE.Fourth and most critically, almost all patients in the severe myocarditis group showed abnormalities in their ECG results at the onset of myocarditis.Sinus arrhythmia (especially sinus tachycardia) and QTc interval prolongation at the onset of ICI-myocarditis but not baseline ECG parameters were the predictors of severe myocarditis in this group.Tang et al. 9 retrospectively analyzed the clinical characteristics of patients with ICI-associated myocarditis and reported several predictors of severe ICIassociated myocarditis.However, they did not found that ECG abnormalities were associated with the severity of ICI-associated myocarditis.In contrast, our results demonstrated that ECG abnormalities (mainly sinus tachycardia and QTc interval prolongation) were associated with myocarditis severity.This inconsistency could be explained by the differences in the criteria used for grading myocarditis severity and the fewer ECG parameters included in the previous study.Our study findings also did not completely agree with the results of Zlotoff et al., 13 who reported that the QRS duration, but not QTc interval, was increased at myocarditis onset as compared to the pre-myocarditis baseline value.However, in a preliminary analysis, we found an initial increase in the QRS duration of patients in the severe myocarditis group as compared to that in the mild myocarditis group patients; this difference disappeared once sinus tachycardia and QTc interval prolongation were included in the logistic regression analysis.A noteworthy finding is our study population was different from the cohort in the study of Zlotoff et al. 13 These authors focused on comparing the clinical characteristics of patients with and without ICI-associated myocarditis, while our study mainly analyzed the differences in ECG abnormalities between mild and severe myocarditis.Moreover, our study showed findings similar to those of the study of Liu et al., in which they reported ECG manifestations of sinus tachycardia, ST-T segment changes, and prolonged QTc interval in patients with severe ICI-associated myocarditis. 15The specific electrocardiographic mechanisms of severe ICI-associated myocarditis are poorly understood.Histologically, patients with ICI-associated myocarditis show dense acute lymphocytic infiltration in the myocardium. 25Previous studies have shown an increase in effector cytotoxic CD8+ cells in mice models of PD-1 blockade. 26These expanded CD8+ cells, along with the upregulated levels of the chemokines CCL5/ CCL4/CCL4L2, may affect both the myocardium and the electrical conduction system. 27Therefore, the increase in sinus heart rate and prolongation in QT interval in patients with severe ICI-associated myocarditis may be mediated by lymphocyte infiltration, which may affect both the sinus node and the conduction system.
ICI-associated myocarditis is known to have a higher risk of adverse events as compared to other irAEs. 2 The present study also showed that patients in the severe myocarditis group were more likely to develop MACE.Sinus arrhythmia (especially sinus tachycardia) at the onset of ICI-associated myocarditis was associated with MACE.However, other electrocardiographic parameters and serum cardiac biomarkers were not associated with MACE in this study.These important results need to be interpreted carefully.New sinus tachycardia may early suggest ICI-related electrophysiological and functional myocardial injury cardiotoxicity and a higher risk of developing malignant arrhythmia and MACE.Treatment with high-dose corticosteroids, gamma globulins, and immunosuppressants can improve outcome of severe myocarditis. 28In our study cohort, all patients in the severe myocarditis group received high-dose corticosteroid therapy, and nearly 60% of the patients received corticosteroids in combination with gamma globulins and/ or immunosuppressants.These findings emphasized the importance of early identification and diagnosis of severe myocarditis in patients receiving ICIs.
In our study, VPB/APB, ST-T segment abnormalities, PR interval, and pathological Q wave were not associated with the severity of myocarditis in preliminary analysis.Moreover, in the logistic regression analysis, QRS duration and bundle branch block showed no differences between the mild and severe myocarditis groups.Patients with ICI-associated myocarditis may have new changes in ECG as compared to the baseline findings, manifested as arrhythmias, conduction block, ST-T segment abnormalities, pathological Q waves, and low QRS voltage at multiple leads. 11However, the above-mentioned electrocardiographic characteristics of ICI-associated myocarditis have been rarely reported as predictors of severe myocarditis as compared to the predictors for mild myocarditis.Although ICIassociated myocarditis is highly arrhythmogenic, the specific electrocardiographic manifestations are poorly understood.We also showed that VPB/APB was not related to severe ICI-associated myocarditis.Pathological Q wave is a manifestation of electrically inert myocardium.In ICI-associated myocarditis, immune cell infiltrates lead to cardiomyocyte necrosis and electrical inactivity. 29However, it is difficult to differentiate pathological Q waves of ICI-associated myocarditis from myocardial infarction (MI) and cardiomyopathy.ST-T represents the process of ventricular muscle repolarization.Various factors can lead to changes in ST-T in the ECG, including sinus tachycardia, cardiac conduction disorder, or nonspecific ST changes.Therefore, in view of the different centers show variations in the results of ECG parameters related to ICI-associated myocarditis, further research is required to determine which electrocardiographic parameters are appropriate to stratify the severity of ICI-associated myocarditis.
In recent years, several clinical trials have evaluated the effects of PD-1/PDL1 and/or the combination of chemotherapy, radiotherapy, and targeted therapy from different perspectives. 30Therefore, we examined whether ICI treatment cycles, ICI types, and concurrent systematic therapies (including chemotherapy, radiotherapy, and targeted therapy) were high-risk factors for severe ICI-associated myocarditis.We found that, except for concurrent targeted therapy, ICI treatment cycles, ICI types, concurrent chemotherapy, and radiotherapy history were not related to myocarditis severity.Hence, for patients in the early or late stages of immunotherapy, those receiving different types of ICI, and those undergoing concurrent chemotherapy and radiotherapy, clinicians should equally focus on the occurrence of severe myocarditis.Tang et al. 9 also noted that ICI treatment cycles, ICI types, and concurrent systematic therapies did not increase the risk of severe ICIassociated myocarditis.Additionally, a noteworthy finding of our study was that concurrent targeted therapy did not increase myocarditis severity, but it reduced the risk of severe ICI-associated myocarditis.There is currently no consensus regarding whether the combination of systemic therapy increases the risk of cardiovascular events during ICI treatment.Wu et al. reported that the combination of ICI drugs and vascular endothelial growth factor receptor inhibitors had an increased risk of cardiovascular adverse events. 31Yet, a meta-analysis by Agostinetto et al. clarified that the use of ICI as a single or combination systemic therapy did not increase the risk of cardiotoxicity. 32Given this inconsistency in views regarding on the risk of cardiovascular events following systemic therapy combined with ICIs and the small sample size of our study, these findings should be interpreted with caution.Hence, larger and prospective studies of ICI-based combinations are required to further confirm these findings.
Cardiac biomarkers, including troponin, CK, CK-MB, and BNP/NT-proBNP, have been reported to indicate acute coronary syndromes and heart failure. 33Among these biomarkers, elevated cTnI and BNP/NT-proBNP levels were shown to be associated with increased mortality of cancer patients and to predict the occurrence of ICI-associated cardiotoxicities, including myocarditis. 34TnI is the primary biomarker for the diagnosis of acute MI.Puzanov I et al. reported that elevated cTnI, CK, and CK-MB were the predictors of myocarditis and mortality.However, BNP did not show a correlation with progression to severe myocarditis. 35Our preliminary analysis revealed that cTnI, CK, CK-MB, and NT-proBNP levels were related to severe ICI-associated myocarditis.However, in the subsequent multivariate analysis, only NT-proBNP was correlated with an increased risk of severe ICI-associated myocarditis.These results are in contrast with current ICI myocarditis diagnostic guidelines. 36Meanwhile, our findings were consistent with those of Xu et al., who reported that advanced nonsmall cell lung cancer patients with severe myocarditis exhibited higher BNP levels than those with mild myocarditis. 37NT-proBNP is synthesized and secreted by cardiomyocytes, which are markers of cardiac wall stress and heart failure criterion. 38Therefore, it was speculated that patients with severe ICI-associated myocarditis had a risk of developing heart failure.Because of the small sample size of study, the different cTnI assays and timing of sample procurement, the predictive value of NT-proBNP not cTnI in severe myocarditis cannot be ruled out.Further investigations are required to confirm the utility of BNP in predicting severe ICI-associated myocarditis.Nonetheless, we still support the idea that early and serial measurements of cTnI, CK, CK-MB, and NT-proBNP could be useful for the early diagnosis of severe ICI-associated myocarditis and improving prognosis through appropriate treatment interventions.
Considering several limitations of the present study, our results should be interpreted with caution.First, this was a retrospective, single-center study with a small sample size; hence, there is an inevitable selection bias associated with our findings.Second, this study enrolled patients with heterogeneous tumor types and different treatment regimens in combination with ICI.Thus, more homogenous conclusions could not be derived from our results.Finally, echocardiography data were missing for some patients during the follow-up period, which likely enriched for patients with ICI-associated myocarditis.Despite these weaknesses, our study is the first to report the comprehensive differences in the electrocardiographic characteristics of patients with mild and severe ICI-associated

| CONCLUSIONS
Severe ICI-associated myocarditis has a high risk of mortality; hence, it is critical to detect this complication early to improve patient prognosis.The present study comprehensively investigated the relevance of ECG abnormalities in predicting the severity of ICI-associated myocarditis.We found that ECG of patients with severe ICI-associated myocarditis manifested as sinus tachycardia and prolonged QTc interval.Concurrent targeted therapy did not increase the risk of severe myocarditis.Furthermore, a correlation was observed between higher serum NT-proBNP levels and the severity of ICI-associated myocarditis.During ICI treatment, regular ECG monitoring is crucial for the early identification of severe ICI-associated myocarditis, as this could enable the prompt implementation of therapeutic interventions for patients with highrisk features.

| 11 of 12 GAO
et al. myocarditis.Large prospective and multicenter studies are required in the future to validate the findings of the present study.
T A B L E 1