Prognostic value of right ventricular late gadolinium enhancement in patients with acute myocarditis: Insight from a cohort study in Asia

To the Editor: Acute myocarditis is an inflammatory myocardial disease with diverse presentations and outcomes. However, the prognostic indicators for myocarditis remain limited. According to the updated 2025 European Society of Cardiology (ESC) guidelines on myocarditis and pericarditis, cardiac magnetic resonance (CMR) is a noninvasive imaging modality for the definitive diagnosis of myocarditis.[1] Moreover, the CMR has significant prognostic value for myocarditis. Previous studies have identified several independent predictors of adverse cardiovascular events, including the presence of late gadolinium enhancement (LGE), septal or midwall LGE, reduced left ventricular ejection fraction (LVEF), and impaired left ventricular global longitudinal strain.[2] These parameters reflect the extent of myocardial inflammation, fibrosis, and functional impairment. A recent study suggested that right ventricular (RV) involvement and systolic dysfunction are significant predictors of adverse outcomes.[3] However, the role of right ventricular LGE in prognostic stratification remains unclear. Furthermore, data from Asian cohorts with myocarditis are limited. Thus, we conducted this single-center retrospective cohort study to explore the association between RV LGE and the prognosis of acute myocarditis. The study complied with China’s regulations and the ethical guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Fuwai Hospital (No. 2023-1935). We received written informed consent from all participants before the start of this study. Between June 2010 and December 2021, patients whose complete medical and CMR information was consistent with that of acute myocarditis were enrolled from Fuwai Hospital [Figure 1A]. The inclusion criteria were as follows: (1) clinical diagnosis of acute myocarditis according to the 2013 ESC criteria;[4] (2) symptom onset ≤1 month; (3) symptom onset on a CMR scan ≤30 days; and (4) CMR presentations meeting two of the updated Lake Louise criteria.[5] The exclusion criteria were as follows: (1) evidence of coronary artery stenosis ≥50% confirmed by previous medical history, computed tomography of the coronary artery or coronary angiography; (2) evidence of hypertensive heart disease, valvular heart disease, dilated cardiomyopathy, congenital heart disease, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, or sarcoidosis; (3) severe renal insufficiency (estimated glomerular filtration rate [eGFR] <30 mL·min–1·1.73 m–2); and (4) incomplete medical records or CMR scans.Figure 1: Association between RV LGE and poor prognosis in acute myocarditis. (A) The flowchart of the enrollment of 193 adult patients diagnosed with acute myocarditis. (B) MACEs-free survival curves of patients with acute myocarditis grouped by RV LGE presence. Patients with RV LGE were at higher risk of long-term MACEs. MACEs included deaths, heart transplantations, re-hospitalization for heart failure, sustained ventricular arrhythmias (>30 s), and recurrent myocarditis. (C) Multivariate Cox analysis performed to determine the factors associated with MACEs. * P <0.05. ARVC: Arrhythmogenic right ventricular cardiomyopathy; CAD: Coronary artery disease; CI: Confidence interval; CMR: Cardiac magnetic resonance; CRP: C-reactive protein; HR: Hazard ratio; LGE: Late gadolinium enhancement; LVEF: Left ventricular ejection fraction; MACEs: Major adverse cardiovascular events; RV: Right ventricular.Medical information, laboratory data, electrocardiographs, CMR features, and treatments of patients were analyzed. During hospitalization, all patients were managed according to the recommended treatment for myocarditis. The quantitative analysis of LGE on CMR is a well-established technique in Fuwai Hospital. The operational protocol and reproducibility assessment were identical to those reported in a previous paper.[6] The analysis was conducted by a radiologist with 7 years of experience using a blinded method, and the results were reviewed by a second radiologist with 10 years of experience, with a kappa value exceeding 0.85. All participants were followed up every 6 months by telephone interview, outpatient visits, and review of electronic medical records. The primary endpoint was a composite of major adverse cardiovascular events (MACEs), including all-cause death, heart transplantation, heart failure requiring hospitalization, sustained ventricular arrhythmia (>30 s), and recurrence of myocarditis. Continuous variables are presented as mean ± standard deviation for normally distributed data or median values with interquartile ranges (Q1–Q3) for non-normally distributed data. Differences in baseline characteristics were evaluated by analysis of variance, the Mann–Whitney U test, the Pearson χ2 test, or Fisher’s exact test. Cox regression was performed to determine the factors associated with MACEs. Kaplan–Meier analysis was used to compare the survival of the divided RV LGE-present and RV LGE-absent groups. A two-sided P value <0.05 was considered statistically significant. Analyses were performed with SPSS 26.0 (IBM, Armonk, NY, USA). The Kaplan–Meier curves were generated with GraphPad Prism 5.0 (GraphPad, La Jolla, CA, USA). A total of 193 patients were enrolled and divided into the RV LGE-present group (n = 19) and the RV LGE-absent group (n = 174). Among the 193 patients, 162 had no evidence of coronary atherosclerotic disease according to invasive coronary angiography (n = 52, 26.9%) or coronary computed tomographic angiography (n = 110, 57.0%), and the other 31 (16.1%) had a low possibility of coronary artery disease (CAD) according to clinical assessment. The baseline characteristics of the two groups are shown in Supplementary Table 1, https://links.lww.com/CM9/C882. The mean age of the patients was 30.6 ± 13.0 years, and almost two-thirds were males. More patients in the RV LGE-present group had a higher New York Heart Association (NYHA) function class (classes I–IV) and a fulminant myocarditis presentation than those in the RV LGE-absent group. No significant differences were observed in inflammatory markers (white blood cell levels or serum C-reactive protein levels), troponin I levels, N-terminal pro-B-type natriuretic peptide levels, or echocardiographic parameters between the two groups. More than half of the patients with RV LGE had an LVEF less than 50%, which was more prevalent than those without RV LGE. Patients in the RV LGE group needed more aldosterone antagonists, corticosteroids, and invasive life support treatments. The median number of days from the onset of symptoms to CMR was 13 (IQR: 8–18) days. In this cohort, patients with RV LGE had a significantly lower LVEF measured by CMR and cardiac output. Patients with RV LGE had a higher LGE percentage, and septal LGE was more prevalent in these patients than in those without RV LGE. Patients with RV LGE tended to have more transmural LGE, and no significant difference was observed in epicardial, midwall, or perfusion patterns of LGE between the two groups [Supplementary Table 2, https://links.lww.com/CM9/C882]. After a follow-up of 3.6 ± 2.5 years, composite endpoint events occurred in 25 patients (13.0%), including 2 deaths (1.0%), 1 heart transplantation (0.5%), 10 heart failure rehospitalizations (5.2%), 2 cases of sustained ventricular arrhythmia (1.0%), and 10 cases of recurrent myocarditis (5.2%). The cumulative MACE rates were 34.5% and 16.3% in patients with and without RV LGE, respectively (P <0.001) [Figure 1B]. A multivariate Cox model revealed that RV LGE was significantly associated with MACE (hazard ratio [HR] 3.273, 95% confidence interval [CI] 1.188–9.015, P = 0.022) [Figure 1C]. In addition, the LVEF on CMR was another strong independent factor associated with MACE (HR 0.952, 95% CI 0.925–0.979, P = 0.001). The results of multivariate Cox analysis for the subgroup of patients with an LVEF <50% (n = 52) and those with an LVEF ≥50% (n = 141) are shown in Supplementary Tables 3 and 4, https://links.lww.com/CM9/C882. Among the patients with acute myocarditis, RV LGE was present in 9.8% (n = 19) of patients. Patients with RV LGE had significantly lower cardiac function and higher LGE percentage [Supplementary Table 2, https://links.lww.com/CM9/C882], and more MACE after adjustments for confounding factors. Although previous studies reported that midwall and anteroseptal/septal LGE was associated with MACE in myocarditis,[2] the present study revealed that RV LGE was a stronger predictor of MACE. These findings suggest that RV LGE could provide useful information for risk stratification of acute myocarditis. The relationship between RV LGE and the prognosis of acute myocarditis remains controversial. Aquaro et al[3] reported that RV LGE was related with adverse cardiac events. However, Bernhard et al[7] revealed that the RV ejection fraction, rather than RV LGE, was independently related to MACE in suspected myocarditis. In the present study, Cox analysis revealed that compared with the extent, or pattern of LGE, RV LGE demonstrated superior prognostic value for myocarditis. Several possible mechanisms may explain the predictive value of RV LGE. First, RV LGE indicates a more extensive burden of inflammation or fibrosis involving both ventricles, which lead to lower cardiac output. Second, the presence of RV LGE leads to right ventricular dysfunction and reduces blood flow into the pulmonary circulation. This directly results in decreased left ventricular stroke volume and systemic cardiac output. Furthermore, acute RV dilation due to overload displaces the interventricular septum leftward, compressing the left ventricular cavity. This also injures left ventricular function. Last, previous studies have also established LGE as an independent predictor of ventricular arrhythmias. Identifying RV LGE as an independent predictor of MACE in myocarditis might influence clinical management. First, RV LGE could facilitate the risk stratification of acute myocarditis. Second, patients with RV LGE, especially those with heart failure, should be managed by guideline-directed medical therapy. Third, enhanced arrhythmia risk assessment might be considered in patients with RV LGE since ventricular tachycardia is related to mortality in myocarditis,[8] and it may be reasonable to discuss implantable cardioverter-defibrillators for primary prevention in high-risk patients. This study has several limitations. First, the small number of outcome events increases the risk of model overfitting and might introduce statistical uncertainty. Second, the analysis was confined to in-hospital management and changes in therapy may be confounding factors. Third, RV function parameters and novel CMR markers were not available for the analysis. Finally, the primary endpoint of the study is a composite of different clinical implications, and the underlying pathophysiological mechanisms of these events likely differ. Future studies with larger sample sizes should analyze these endpoints separately. In conclusion, we revealed that RV LGE is an independent predictor of MACE in patients with acute myocarditis. RV LGE on CMR may be valuable for the risk stratification of acute myocarditis. Acknowledgments We thank the support of Yang Sun (Department of Pathology, Fuwai Hospital, National Center for Cardiovascular Disease of China, Beijing, China) with myocardial pathological evaluation. We also thank the help from Sidong Li (Medical Research and Biometrics Center, Fuwai Hospital, National Center for Cardiovascular Disease, Beijing, China) with the statistical analyses. Funding This work was supported by National Natural Science Foundation of China (No. 82302170) and National Key R&D Program of China (Nos. 2021YFF0501400 and 2021YFF0501404). Conflicts of interest None.