The absolute and relative change of high-sensitivity cardiac troponin I are associated with in-hospital outcome of patients with fulminant myocarditis

we sought to describe the tendency and extent of high-sensitivity cardiac troponin I (hs-cTnI) changes in patients with fulminant myocarditis (FM) after admission, and to explore the relationship between in-hospital outcome of FM and the value of absolute and relative change of hs-cTnI within 24 h and 48 h after admission. a total of 83 of 69 and The absolute and relative of within and as Receiver operating characteristic (ROC) curves and Cox analysis were performed to determine the relationship between in-hospital outcome of and hs-cTnI change.


Introduction
Myocarditis is an in ammatory disease of the myocardium which has a broad spectrum of clinical presentations, ranging from mild symptoms to life-threatening arrhythmias and/or severe heart failure (HF) 1 . Fulminant myocarditis (FM) is a rare but the most severe type of myocarditis and is characterized by sudden occurrence, rapid progress, and hemodynamic dysfunction 2 . Though endomyocardial biopsy (EMB) is the golden standard of myocarditis diagnosis, it is pragmatic to determine the treatment for the patients suspected of myocarditis by clinical diagnosis referred to clinical state as well as laboratory and imaging tests 2,3 . To be exactly, FM can be clinically de ned as patients presenting with a distinct onset of symptoms in the prior 2 weeks, severe symptoms of HF, and hypotension or overt cardiogenic shock needing inotropes, vasopressor, and/or mechanical circulation support 3 . As the technology advanced, gadolinium contrast-enhanced cardiac magnetic resonance (CMR) can afford tissue-level pathologies consistent with myocarditis, including myocardial edema and brosis (e.g., T2-and T1-weighted sequences and late gadolinium enhancement [LGE]) which has high diagnostic accuracy 4,5 .
Myocarditis is an in ammatory cardiac disorder induced predominantly by viruses 6 . The mechanisms of myocardial injury were recognized as the direct injury and the indirect immunogenic injury 7 . The former indicates the intracellular viral replication in the myocardium and other tissues, resulting in degeneration, necrosis, and dysfunction 8 . The latter is triggered by cytotoxic and antigen-antibody reaction which are caused by virus infection 9 . An elevated serum cardiac troponin (cTn) is almost always observed in patients with FM as myocardial injury, especially the assay of high-sensitivity troponin I (hs-cTnI) detection was more sensitive in re ecting the potential injury of myocardium. The same as hs-cTnI elevated, research in patients with myocardial infraction (MI) about the diagnostic and prognostic value of serial changes of hs-cTnI had been widely performed [10][11][12][13][14][15] . It is undetermined that the FM patients' hs-cTnI kinetic in the early phase after admission and the relationship between the serial change of hs-cTnI and patients' outcome.
Therefore, this retrospective research aimed to describe the serial changes of hs-cTnI, and to determine the prognostic value of the absolute (Δ) and relative(Δ%) changes in hs-cTnI within 24 h and 48 h after admission for FM patients' outcome in hospital.

Study population and diagnosis of fulminant myocarditis
All patients were in-hospital patients in TongJi hospital, a tertiary teaching medical center in Wuhan, China. From January 1, 2010 to December 31, 2019. A total of 105 FM cases were retrospectively included in the study, of whom 22 cases were excluded (Fig. 1). The exclusive criteria include: 1) age less than 16 years old, 2) diagnosis of other severe disease, such as malignant tumor. 3) dead within 24 h after admission to hospital, 4) lack of serial hs-cTnI record within 48 h. At last, the nal analysis consist of 83 FM patients.
FM is usually de ned as myocardial in ammatory disease with a rapid outbreak complicated with severe hemodynamic dysfunction. FM is more likely to be a clinical diagnosis rather than a histological or pathological diagnosis. Therefore, FM was diagnosed in our center, predominantly as Chinese expert consensus statement recommended 2 , by following signs: sudden attack, obvious premonitory symptoms of viral infection (especially severe fatigue and poor appetite), and rapid emerging severe hemodynamic dysfunction, serious myocardial injuries, and diffuse ventricular wall motion decrease. Since 2018, CMR was widely used in our center to ascertain the diagnosis of FM, 25 cases of 36 FM patients in that period performed CMR examination. EMB had been performed in 3 patients with unexplained heart failure as the guideline recommended 16 . Coronary angiography had been operated in 36 cases to distinguish from myocardial infraction for clinical signs as chest pain and elevated ST wave in electrocardiogram and elevated hs-cTnI 17 . All patients' ultimate diagnosis was ascertained by at least two cardiologists before admitted to the study.

Statistical analysis
The data are presented as proportions, mean ± SD, and median with interquartile range if variable was nonnormal distribution. Comparisons were made with the t test for normally distributed continuous variables, Mann-Whitney U test for nonnormally distributed continuous variables, χ2 test for categorical variables. Receiver operating characteristic (ROC) curves were constructed to assess the relationship between in-hospital outcome of FM and the value of absolute (Δ) and relative (Δ%) changes of hs-cTnI within 24 hour and 48 hours after admission. Optimal cutoff values were derived from ROC curves as described by Youden, and sensitivity, speci city, were calculated. Cox regression analysis was performed to determine the prognostic value of optimal cutoff of absolute (Δ) and relative (Δ%) changes of hs-cTnI within 24 hour and 48 hours. All hypothesis testing was 2 tailed, and a P value of 0.05 was considered statistically signi cant. All statistical analyses were performed with SPSS 22.0 (SPSS Inc., Chicago, IL) for Windows (Microsoft Corp, Redmond, WA).

characteristics of FM patients
The baseline characteristics of all 83 FM patients are shown in Table 1. The median age was 37 (Q1-Q3: 29-48) years old, 49.4% were women. Premonitory symptoms of viral infection, like fever, was observed in 75.9% of total population while the co-existing conditions including hypertension or diabetes mellitus were observed in less than 10% of patients. The median time from onset to admission was 3 days, which indicated that FM was an acute disease; while this period in survive group was signi cant shorter than in death group (P = 0.028). Chest distress (69.9%) was the most common symptoms of FM patients, and chest pain (22.9%), palpitation (22.9%), dizziness (25.3%), and disturbances of consciousness (21.7%) were also recorded. The incidence of severe arrhythmia, such as ventricular tachycardia or ventricular brillation, was signi cant higher in death group than in survive group (35.7% vs. 10.1%, P = 0.026). Higher level of creatinine rather than alanine transaminase was also observed at admission in death group than survive group (P = 0.016). 42% of survive group received CMR examination, all of the examination were performed in the recent two years, while no patients in death group received such examination as severe hemodynamic dysfunction. Coronary angiography was performed in 28.6% of death group and 46.4% of survive group. Patients in death group with so rapid illness progression as to all of them received vasoactive agent(100%), 50% of whom received intraaortic balloons pump(IABP) and mechanical ventilation therapy. The majority of patients (87%) in survive group were performed IABP to maintain hemodynamic stable. Vasoactive agent was used in 66.7% of survive patients and mechanical ventilation was used in 36.2% of survive patients. About 20% of patients in both group operated extracorporeal membrane oxygenation (ECMO).

baseline and tendency of hs-cTnI
The baseline hs-cTnI was illustrated in Fig. 2A, which revealed no signi cant difference between the death and survive groups(value: survive patients 27.62 ± 2.4 ng/ml and death patients 31.05 ± 7.1 ng/ml, P = 0.81). hs-cTnI tested within 24 h lower than hs-cTnI baseline was de ned as declined tendency, otherwise it was de ned as not declined tendency. Figure 2B showed the signi cant difference of tendency of hs-cTnI change in death and survive FM patients within 24 h after admission, in survive group 78% patients experienced the declined hs-cTnI change, while 36% of death group had the declined tendency of hs-cTnI (P = 0.003).

absolute and relative hs-cTnI changes within 24 h and 48 h
As available hs-cTnI data was concentrate within 24 h and 48 h after admission, the absolute and relative changes of hs-cTnI in these periods were illustrated in Table 2 and Fig. 3. The absolute change of hs-cTnI in survival group within 24 h was mainly at the scale of -10 to 0 ng/ml, accounting for 39.68% of the patients, followed by the scale of -20 to -10 ng/ml which accounted for 19.05% of the patients.   3.5 Value of absolute hs-cTnI change and relative hs-cTnI change in predicting hospital mortality ROC curve was performed to calculate cutoff and to evaluate the value of absolute and relative hs-cTnI change in predicting in-hospital outcome of FM. Results including cutoff, area under curve(AUC),95% con dence interval were displayed as Fig. 4 and  Fig. 4 and Table 3). Cox regression analysis for mortality in FM patients grouped by cutoff of relative and absolute change of hs-cTnI within 24 h and 48 h were shown in Fig. 5 and   All models were adjusted for gender, time from onset to admission, occurrence of ventricular tachycardia or ventricular brillation.

Discussion
The main ndings of this study include three aspects: 1) we rstly described the tendency and extent of In contrary, other studies reported that elevated troponin in the early phase for myocarditis was associated with ECMO or worse prognosis 23,24 . It is still debated that the prognostic value of cardiac troponin baseline in myocarditis.
Though the increased level of hs-cTnI in FM is well-recognized, it is unknown that the tendency and exact extent of hs-cTnI change in reality. This study described the situation of hs-cTnI change, revealing that it is regular for hs-cTnI change in FM. Most survive patients experienced decline of hs-cTnI change within 24 h while few patients in death group had decreased hs-cTnI, signi cantly differently compared to survive group. Within 24 h after admission, 40% of survive patients had absolute change of hs-cTnI dropped by 0-10 ng/ml and 58% of survive patients showed relative change of hs-cTnI dropped by 25%-75%. While patients in death group have absolute change of hs-cTnI increased by 0-10 ng/ml, accounting for 50%. The depiction of hs-cTnI change in FM is of importance for us to know more about fulminant myocarditis and give better treatment for patients.
Besides, the declined tendency of hs-cTnI change within 24 h was found to be associated with in-hospital outcome of FM, after the adjustment of the abnormal of creatinine, IVIG treatment and time from onset to hospital. The declined tendency may reveal that treatment for FM in our center was effective, including anti-viral therapy, immunomodulating therapy, circulation support, and respiratory support, resulting in the relief of in ammation reaction which caused myocardium injury and reduction of incidence of ventricular tachycardia or ventricular brillation. In contrary, the opposite tendency may in ected that in ammation reaction was still severe after treatment, with high incidence of arrhythmia. There are still some limitations in the current study. The retrospective nature of this research may have introduced potential bias. Although we collect all FM patients in our singer center for 10 years, the cases are not enough for further subanalysis. The median time for patients from onset to hospital was three days, thus the peak time of hs-cTnI is undetermined for patients experienced declined tendency of hs-cTnI after admission. The prospective research with more regular and frequent detection of hs-cTnI need to be performed for better understanding of hs-cTnI change in FM. Funding:

Conclusion
None.
Availability of data and materials The information and data of the study population were acquired from Hospital Information System and were recorded manually in EXCEL to form the database. The datasets analyzed during the current study are not publicly available due to the protection of the individual privacy but are available from the corresponding author on reasonable request.
Ethics approval and consent to participate All methods were performed in accordance with the relevant guidelines and regulations. The study has been approved by the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board (TJ-C20160202). Informed consent was obtained from all