This single-center, retrospective, observational study was performed at Fuwai Hospital (National Center of Cardiovascular Diseases, Beijing, China). From August 1, 2006, to March 31, 2020, a total of 269 patients who were clinically diagnosed with acute myocarditis were screened. The clinical diagnosis of acute myocarditis was in accordance with Caforio et al. [13], and patients meeting two or more of the following five criteria were included: (1) clinical presentations (within 3 months): chest pain, dyspnea, heart failure, syncope, palpitation, unexplained cardiogenic shock, or aborted sudden cardiac death; (2) newly abnormal electrocardiography (ECG) or Holter features; (3) elevated myocardial injury biomarkers, namely, troponin I (TnI); (4) dysfunction and structural abnormalities on echocardiographic imaging; and (5) cardiac magnetic resonance (CMR) findings meeting two or more of the Lake Louise criteria [14], namely, edema, hyperemia, and/or late gadolinium enhancement. If endomyocardial biopsy (EMB) or pathology of the heart available after heart transplantation met the revised Dallas criteria [15], the diagnosis of myocarditis was definite. Patients meeting the following criteria were excluded: (1) evidence of coronary artery stenosis $\ge$50%; (2) other preexisting cardiovascular disease including valvular heart disease, hypertensive heart disease, congenital heart disease or cardiomyopathy; (3) admission hemoglobin (Hb) 100 g/L; (4) admission blood glucose 3.9 mmol/L; (5) treatment with corticosteroids before admission; (6) history of ischemic or hemorrhagic stroke, renal or liver dysfunction, thyroid diseases, or malignant tumor; (7) history of erythropoietin application or blood transfusion within 30 days; and (8) missing glucose at admission, glycated hemoglobin (HbA1c), or other important laboratory test information. Ultimately, 185 patients were enrolled. Supplementary Fig. 1 illustrates the process of enrollment.

The electronic medical records of the patients were reviewed by trained attendings. Clinical information, including demographics, medical history, coexisting diseases, physical examination, laboratory test findings, treatment regimen, and in-hospital adverse outcomes, was collected. Diabetes mellitus was diagnosed if the patient had a previous diagnosis of diabetes, used oral hypoglycemic agents or insulin, or had a measured value of HbA1c exceeding 6.5%. The estimated average glycemic level was calculated with the following formula: estimated average glucose (mmol/L) = [(1.59 $\times$ HbA1c %) – 2.59], derived from Nathan et al. [16]. The SHR was defined as glucose at admission divided by estimated average glucose. Participants were divided into two groups according to the optimal cutoff value of the SHR evaluated by receiver operating characteristic (ROC) analysis: the low SHR group (SHR $\le$1.12, n = 111) and the high SHR group (SHR $>$1.12, n = 74).

During hospitalization, all patients were treated based on the recommended strategy for myocarditis [13]. Stable patients with left ventricular dysfunction received the recommended heart failure treatment. Patients with severe heart failure or cardiogenic shock were treated with inotropes and mechanical circulatory support (MCS). MCS included intra-aortic balloon pump (IABP), venous-arterial extracorporeal membrane oxygenation (va-ECMO), or a combination of IABP and va-ECMO.

Glucose at admission was measured on the day the patient was hospitalized, and HbA1c levels were assayed between 1 and 3 days after admission. The blood samples were collected into tubes coated with EDTA-anticoagulant and centrifuged. Serum glucose was measured in the core laboratory of Fuwai Hospital using a LABOSPECT 008 system (Hitachi, Tokyo, Japan), and the HbA1c value was measured with high-performance liquid chromatography (Tosoh G8 HPLC Analyzer, Tosoh Bioscience, Tokyo, Japan).

After discharge, the patients were followed up by telephone interview, outpatient visits, or correspondence. All events were checked and confirmed by an independent group of trained clinical physicians. We defined the primary endpoint as in-hospital major adverse cardiovascular events (MACE), including (1) death; (2) heart transplantation; (3) a need for MCS to maintain hemodynamic stability; and (4) transfer to the intensive care unit (ICU) due to a worsening condition. The secondary endpoint was defined as long-term MACE, including (1) all-cause death; (2) heart transplantation; (3) recorded sustained ventricular arrhythmia ($>$30 s); (4) heart failure requiring hospitalization; and (5) myocarditis relapse.

Continuous variables are described as the mean $\pm$ standard deviation (SD) or median (interquartile range) according to the results of normality tests. Categorical variables are presented as quantities and percentages. Differences between the groups were compared by Student’s t test or the Mann–Whitney U test for continuous variables and the Pearson $\chi$${}^2$ test or Fisher’s exact test for categorical variables. Univariate and multivariate logistic regression and Cox proportional hazards analyses were performed to identify risk factors predicting in-hospital and long-term MACE, respectively. The confounding factors selected in the multivariate Cox analysis model included age, sex, the variables that were significantly associated with prognosis in univariate analysis, and factors that had ever been reported to be associated with MACE or might affect glucose status (coexisting diabetes mellitus, QRS duration $>$120 ms, creatinine, left ventricular ejection fraction (LVEF), etc.). In addition, Kaplan–Meier (K-M) survival analyses and the log-rank test were used to compare the event-free survival between the two groups. The ability of the SHR to predict MACE was assessed by receiver operating characteristic (ROC) analysis and was quantified by the area under the ROC curve (AUC), in which a value of 1.0 indicates perfect ability and a value of 0.5 indicates no ability. Analyses were performed with SPSS statistics (version 26.0, IBM Corp., Chicago, IL, USA). The K-M and ROC curves were drawn with GraphPad Prism (version 5.0, Dotmatics, Boston, MA, USA). All analyses were two tailed, and p values 0.05 were considered indicative of statistical significance.

The baseline characteristics of the study population are reported in Table 1. A total of 185 patients with available SHR data were included in the analysis. The population was divided into two groups according to SHR (Table 1). The average age of the patients was 30.68 $\pm$ 12.73 years, and 132 (71.4%) patients were men. Patients in the high SHR group (SHR $>$1.12) were older than those in the low SHR group (SHR $\le$1.12). There was no significant difference in the percentage of males, body mass index (BMI), clinical symptoms, or the prevalence of comorbidities between the two groups. Patients with higher SHR had significantly lower systolic blood pressure and higher heart rate. On ECG, patients with higher SHR had higher incidence rates of sinus tachycardia, complete atrioventricular block, and bundle-branch block, although the incidence rates of supraventricular tachycardia and sustained ventricular tachycardia were not significantly different. In addition, we found that subjects in the higher SHR group had more obvious abnormalities in laboratory test results, including higher white blood cell count, lower hemoglobin, worse liver function, and higher levels of troponin I, C-reactive protein (CRP), and admission glucose. Patients with higher SHR also had a thicker intraventricular septum and lower LVEF, and patients with LVEF 50% accounted for 41.9% of the study population. The medication regimen was not significantly different in the use of $\beta$-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs), or aldosterone antagonists between the two groups. Subjects with higher SHR were more likely to require inotropic drugs and invasive life support devices (IABP, ECMO, ventilator, continuous venovenous hemofiltration (CVVH), and temporary pacing) to maintain hemodynamic stability.

A total of 28 (15.1%) patients underwent EMB. Among them, immunopathology findings showed lymphocyte myocarditis in 13 patients (46.4%), giant cell myocarditis in 3 patients (10.7%), and eosinophilic myocarditis in 2 patients (7.1%).

To assess the predictive value of the SHR in the outcomes of patients with acute myocarditis, ROC curves for the SHR were generated. In predicting in-hospital MACEs, including death, heart transplantation, MCS, and transfer to the ICU, the sensitivity and specificity of the SHR were 64.58% and 72.26%, respectively (AUC = 0.710, optimal cutoff value: 1.12) (Fig. 1A). In predicting long-term MACEs, the sensitivity and specificity of the SHR were 25.00% and 84.21%, respectively (AUC = 0.509, optimal cutoff value: 1.39) (Fig. 1B).

Fig. 1.

Receiver operating characteristic (ROC) curve of the ability of SHR to predict in-hospital MACE (A) and long-term MACE (B) in patients with acute myocarditis. In predicting in-hospital MACE including death, heart transplantation, mechanic circulatory support, and need to transfer to ICU, the area under the curve (AUC) for SHR was 0.710, with sensitivity of 64.58% and specificity of 72.26%. In predicting long-term MACE including deaths, heart transplantations, sustained ventricular tachycardias ($>$30 s), rehospitalization for heart failure, and myocarditis relapse, the AUC for SHR was 0.509, with sensitivity of 25.00% and specificity of 84.21%. MACE, major adverse cardiac events; SHR, stress hyperglycemia ratio.

A total of 165 patients had complete follow-up information, and there was no significant difference in baseline characteristics between the patients with follow-up (n = 165) and those lost to follow-up (n = 20), except that the corrected QT (QTc, QT means the Interval from the beginning of the Q wave to the end of the T wave on the electrocardiogram) intervals of those lost to follow-up were longer (Supplementary Table 1). In-hospital MACE occurred in 48 patients (25.9%) and included 9 deaths (5.5%), 2 heart transplantations (1.1%), 5 MCS (2.7%), and 32 transfers to the ICU (17.3%). After a median follow-up of 3.9 years (interquartile range 2.3 years, 6.6 years), long-term MACE had occurred in 32 patients (19.4%) and included 10 deaths (6.1%), 3 heart transplantations (1.8%), 3 sustained ventricular arrhythmias (1.8%), 7 heart failure hospitalizations (4.2%), and 9 recurrences of myocarditis (5.5%).

K-M survival analysis showed that there was no significant difference in the incidence of long-term MACE between the two groups divided around the SHR cutoff of 1.39 (Fig. 2; log-rank p = 0.319), although patients with SHR $>$1.39 had a tendency to suffer from more long-term MACEs within the first two years.

Fig. 2.

Long-term MACE-free survival of patients with acute myocarditis, with SHR $\mathrm{>}$1.39 and $\mathrm{\le }$1.39. There was no significant difference in the two survival curves. Long-term MACE included deaths, heart transplantations, rehospitalization for heart failure, and sustained ventricular arrhythmias ($>$30 s), and myocarditis relapse. MACE, major adverse cardiac events; SHR, stress hyperglycemia ratio.

To determine whether the SHR was an independent predictor of short-term and long-term adverse outcomes, logistic and Cox regression analyses were performed (Table 2 and Supplementary Table 2). For the primary endpoint (in-hospital MACE), multivariate logistic analysis showed that SHR $>$1.12 (hazard ratio [HR]: 3.946, 95% confidence interval [CI]: 1.098–14.182; p = 0.035), baseline LVEF (HR: 0.887, 95% CI: 0.844–0.932; p 0.001), C-reactive protein level (HR: 1.021, 95% CI: 1.009–1.032; p 0.001), and alanine transaminase $>$120 IU/L (HR: 5.566, 95% CI: 1.347–22.997; p = 0.018) were independent predictors. For the secondary endpoint (long-term MACE), multivariate Cox analysis demonstrated that BMI (HR: 0.824, 95% CI: 0.744–0.912; p 0.001), diabetes mellitus (HR: 6.727, 95% CI: 1.231–36.756; p = 0.028), creatinine level (HR: 1.007, 95% CI: 1.002–1.012; p = 0.007), troponin I level (HR: 1.019, 95% CI: 1.001–1.037; p = 0.035), and right ventricular diameter (HR: 1.185, 95% CI: 1.054–1.332; p = 0.004) were independent predictors. According to the above results, the SHR level was an independent predictive factor for in-hospital MACE but not for long-term prognosis in patients with acute myocarditis.

Sensitivity analysis was carried out to test the association between the SHR and adverse outcomes in patients without diabetes mellitus. The five patients diagnosed with diabetes mellitus were excluded, and both logistic and Cox regression analyses were performed (Supplementary Tables 3,4). The results suggested that the SHR remained an independent predictor of in-hospital adverse outcomes in patients with acute myocarditis, even for nondiabetic patients.