Treatment Of Myocarditis Research Articles

Abstract 4134426: Targeting the TRIM29-PERK signaling axis for treating viral myocarditis

Introduction: Viral myocarditis is an inflammatory disease of the myocardium that significantly contributes to sudden death in children and young adults. The COVID-19 pandemic underscores the critical need to understand the pathogenesis and develop effective treatment strategies for viral myocarditis. Methods: To investigate the role of the novel E3 ligase TRIM29 in viral myocarditis, we used wild-type and TRIM29 knockout mice infected with coxsackievirus B3 (CVB3) and encephalomyocarditis virus (EMCV), to induce the myocarditis. Additionally, wild-type mice infected with CVB3 were treated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) inhibitor GSK2656157 or a DMSO control to evaluate potential therapeutic interventions. Mice survival and heart function were monitored using transthoracic echocardiography, and hearts were harvested for histological and immunohistochemical analysis. Techniques including real-time PCR, western blotting, co-immunoprecipitation, enzyme-linked immunoassay, flow cytometry, over-expression, and knockdown were employed to elucidate the pathogenic mechanisms by which TRIM29 regulates the endoplasmic reticulum stress response after viral infection. Results: We found that TRIM29 was highly induced by cardiotropic viruses, including CVB3 and EMCV, and promoted PERK-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses, which restricted viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by enhancing cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive cells in vivo . Mechanistically, TRIM29 interacted with PERK to catalyze the SUMOylation of PERK, maintaining its stability and thereby promoting PERK-mediated signaling pathways. Furthermore, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK interaction, which improved cardiac function, enhanced cardiac antiviral responses, and reduced inflammation and immunosuppressive cells in vivo . Conclusions: Our findings provide the first evidence that the TRIM29-PERK signaling axis can be targeted for the treatment of viral myocarditis. This suggests that targeting the TRIM29-PERK axis could effectively mitigate viral myocarditis and associated cardiovascular diseases.

Abstract 4119426: Enhancing early detection of ICI myocarditis cases during hospitalization: A role for large language models

Background: Immune-checkpoint inhibitor (ICI)-induced myocarditis is the most fatal immune-related adverse event (irAE). Early recognition and treatment of ICI myocarditis is associated with improved outcomes. However, current approaches to the diagnosis of ICI myocarditis have limitations. Open-source large language models (LLMs) are an accessible and scalable method of answering queries from human-generated text, and therefore may assist in the real-time early detection of ICI myocarditis among at-risk patients. Research Question: Can a free, open-source LLM detect cases of ICI myocarditis early in admission? Aims: We investigated the ability of a LLM pipeline to screen for ICI myocarditis within one day of admission using hospital medical records. Methods: Hospital admissions of patients on ICI therapy from November 4th, 2021, to September 5th, 2023 were retrospectively reviewed by a multidisciplinary immunotoxicity team using established, published definitions for the presence of ICI myocarditis. Progress notes written the day before, day of, and day after admission were fed into an open-source LLM pipeline built using Mistral 7B OpenOrca with retrieval augmentation generation (RAG). Performance of the LLM was measured via sensitivity and specificity in comparison to the gold standard of manual adjudication. Results: Of the 1874 hospital admissions of patients on ICI therapy, there were 22 (1.2%) cases of myocarditis. The average time to initiation of treatment was 2.45 days. Using notes written within one day after admission, the LLM detected ICI myocarditis with 95.5±8.7% sensitivity and 95.4±1.0% specificity, spending 2.13 seconds per chart. Conclusion: LLMs serve as a useful tool to screen for ICI myocarditis, detecting 95.5% of cases within one day of admission with 95.4% specificity. Future studies will investigate if integrating this tool into the real-time management of irAEs could lead to earlier diagnosis, faster initiation of treatment, and improved patient outcomes.

Macrophage-T cell hybrid membrane-camouflaged biomimetic nanoparticles ameliorate autoimmune myocarditis via suppressing macrophage pyroptosis by target gene silencing

Abstract Background Current management of myocarditis mainly relies on conventional approaches and immunosuppressive therapies. However, these strategies often yield limited efficacy. Our previous research revealed the pivotal role of macrophage pyroptosis in myocarditis pathogenesis. Therefore, targeted intervention to inhibit macrophage pyroptosis may provide new insights into myocarditis treatment. Purpose We previously identified interferon regulatory factor 1 (IRF1) as the key modulator of macrophage pyroptosis in myocarditis. In this study, we synthesized a nano-delivery platform consisting of a macrophage-T cell hybrid membrane-coated zeolitic imidazolate framework-8 (ZIF-8) encapsulating IRF1-small interfering RNA (siRNA@ZIF@HM). We aimed to evaluate its targeting capability and therapeutic efficacy for macrophage pyroptosis in myocarditis. Methods The fabrication of siRNA@ZIF@HM was validated using transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cytotoxicity, endolysosome escape, IRF1 silencing, and anti-pyroptotic effect were assessed using mouse bone marrow-derived macrophages and the mouse macrophage cell line J774A.1 and RAW264.7. An experimental autoimmune myocarditis (EAM) mouse model was induced in Balb/c mice for in vivo investigations. Pharmacokinetics and targeting capability were determined with ex vivo fluorescence imaging and immunofluorescence staining. Subsequently, mice were randomly allocated into control, EAM + siRNA, EAM + siRNA@ZIF, and EAM + siRNA@ZIF@HM groups to assess the therapeutic efficacy. Additionally, the biodistribution and biosafety of siRNA@ZIF@HM were also evaluated. Results TEM, DLS, and element mapping confirmed the successful fabrication of siRNA@ZIF@HM, with a diameter of approximately 130 nm. The nanoparticle exhibited pH responsiveness and membrane markers of macrophage and T lymphocytes (Figure 1). It demonstrated high targeting specificity for pro-inflammatory macrophages and myocarditis. Immunofluorescence microscopy revealed successful endolysosome escape of IRF1-siRNA in macrophages. Consequently, the nanoparticle significantly silenced IRF1 protein expression and suppressed macrophage pyroptosis both in vivo and in vitro, resulting in the amelioration of autoimmune myocarditis (Figure 2). Furthermore, the nanoparticle showed good biocompatibility with no significant changes observed in other organs. Conclusions The pH-responsive, macrophage-T cell hybrid membrane-coated biomimetic nanoparticle demonstrates promising capability for targeted siRNA delivery to myocardial inflammation sites, particularly pro-inflammatory macrophages. Additionally, targeting IRF1-mediated macrophage pyroptosis represents a potential therapeutic strategy for myocarditis treatment.Figure 1Figure 2

Rationale and study design of the international randomized control trial MYocarditis THerapy with Steroids: the MYTHS trial

Abstract Background Immunosuppression is generally suggested in patients with specific subtypes of acute myocarditis, such as eosinophilic myocarditis or giant cell myocarditis or associated with systemic autoimmune disorders. In contrast, no specific treatment for most acute myocarditis complicated by acute heart failure (HF) or cardiogenic shock is recommended beyond the management of acute HF and supportive therapy. Nevertheless, large registries commonly reported using corticosteroids in severe forms without data supporting this strategy. Purpose To assess the safety and efficacy of high-dose pulse intravenous (IV) corticosteroid therapy to treat patients with complicated/fulminant acute myocarditis based on clinical suspicion. Methods An international pragmatic investigator-initiated single-blinded randomized controlled trial that screens patients between 18 and 70 years admitted to the hospital for suspected acute myocarditis (cardiac symptoms onset within three weeks) complicated by acute HF/cardiogenic shock and left ventricular (LV) ejection fraction<41% without significant LV dilation is ongoing. Patients are randomized in a 1:1 ratio to pulsed IV methylprednisolone (1 g) in saline solution (250 mL) daily for three days or placebo (saline without methylprednisolone) on top of standard therapy and maximal supportive care. A final diagnosis of myocarditis is confirmed by histology or cardiac magnetic resonance imaging. A population of 288 patients has been planned to assess a reduction in the probability of reaching the primary endpoint from 25% in the placebo arm to 12% in the methylprednisolone arm with a power of 0.80 (Figure). The main analysis will be conducted on an intention-to-treat basis. Results The primary efficacy endpoint of the trial is defined as the time from randomization to the first event occurring within 6 months, including all-cause death, heart transplantation, or long-term LV assist device implant, or need for an upgrading of the temporary mechanical circulatory support (t-MCS), or ventricular tachycardia (VT)/fibrillation (VF) treated with direct current (DC) shock, or first rehospitalization due to HF or VT/VF, or advanced atrioventricular block. The safety endpoints include a composite of potential complications that can occur, including serious infections, acute gastrointestinal bleeding, and other complications that can be related to corticosteroid therapy or prolonged stay on t-MCS. There are 32 active centers, and 48 patients have been randomized since December 2021. The trial is expected to be completed by the end of 2028. Conclusion The results of the MYTHS trial can define the role of IV methylprednisolone in the initial treatment of patients with complicated forms of acute myocarditis that currently have an unacceptably high mortality rate.

Efficacy and safety of Shenmai injection in the treatment of viral myocarditis: a systematic review and meta-analysis.

To evaluate the efficacy and safety of Shenmai injection for the treatment of viral myocarditis (VMS) through systematic evaluation and meta-analysis. Seven databases were searched to identify randomized controlled trials that examined the use of Shenmai injection for the treatment of VMS. The databases were searched from inception to 20 January 2024. The quality of the included studies was evaluated via the Cochrane risk of bias tool (RoB 2) version 2. Data analysis was performed using Review Manager 5.4 and Stata 16. In total, 18 randomized controlled trials were included. The trials were conducted in 2006-2024 and included 1,661 patients with VMS. The results reveal that Shenmai injection combined with conventional treatment was superior to conventional treatment alone in terms of the following outcomes: total effective rate [RR = 1.22, 95% CI (1.16, 1.28)], CKMB [SMD = -3.33, 95% CI (-4.85, -1.81)], electrocardiogram (ECG) efficacy [RR = 1.30, 95% CI (1.20, 1.40)], AST [SMD = -0.70, 95% CI (-1.28, -0.11)], LDH [SMD = -1.17, 95% CI (-1.37, -0.97], p < 0.00001], CK [SMD = -1.74, 95% CI (-2.34, -1.13)], TNF-α [SMD = -1.35, 95% CI (-1.85, -0.84)], and IL-6 [SMD = -1.40, 95% CI (-1.76, -1.05)]. There were no significant differences in the incidence of adverse reactions [RR = 1.56, 95% CI (0.73, 3.33), p = 0.25] or cTnI levels [SMD = -3.35, 95% CI (-6.81, 0.11)] between the groups. Shenmai injection with conventional treatment can reduce the degree of myocardial injury in patients with VMS, weaken the inflammatory response and improve the clinical efficacy of the conventional treatment. This approach was found to be safe. However, additional high-quality studies are necessary to confirm the reliability of this treatment method. https://www.crd.york.ac.uk/PROSPERO/logout.php, identifier PROSPERO (CRD42024518665).

Assessing the causal effect of inflammation-related genes on myocarditis: A Mendelian randomization study.

Prior evidence has shown a significant link between inflammation and the development of myocarditis. This study aimed to investigate the causal relationship between inflammation-related genes (IRGs) and myocarditis. In this study, the causal relationship between 167 IRGs and myocarditis were investigated using datasets from the Gene Set Enrichment Analysis and Integrative Epidemiology Unit open genome-wide association study (IEU OpenGWAS) databases. The GWAS data (finn-b-I9 MYOCARD) contained single nucleotide polymorphisms (SNPs) data from 117755 myocarditis samples (16379455 SNPs, 829 cases vs. 116926 controls). Five algorithms [MR-Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode regression] were employed for the MR analysis, with IVW as the primary method, and sensitivity analysis was conducted. Subcellular localization and protein-protein interaction (PPI) network analyses were performed for selected biomarkers. Results were verified in ebi-a-GCST90018882 (24180570 SNPs, 633 cases vs. 427278 controls) and finn-b-I9 MYOCARD EXNONE (16380466 SNPs, 829 cases vs. 217963 controls) to enhance reliability. IRF7 and ADORA2B were shown to be two exposure factors after screening. Univariable MR (UVMR) analysis revealed that IRF7 was a risk factor for myocarditis [IVW: odd ratio (OR)=1.041, 95% confidence interval (CI)=1.018-1.955, P=0.039], while ADORA2B was a protective factors for myocarditis (IVW: OR=0.799, 95% CI=0.640-0.997, P=0.047). Sensitivity analysis confirmed the robustness of these findings. Multivariable MR (MVMR) analysis further demonstrated a direct causal role of ADORA2B in preventing myocarditis. Subcellular localization analysis indicated predominant cytoplasmic expression and limited mitochondrial expression for both genes. The results of PPI analysis showed that 20 genes were predicted to be associated with IRF7 function, such as response to type I interferon, pattern recognition receptor signalling pathway, and toll-like receptor signalling pathway. The results in finn-b-I9 MYOCARD EXNONE were consistent with MR analysis. The findings indicated there was a causal connection between IRGs (IRF7 and ADORA2B) and myocarditis, which offered a crucial point of reference and guidance for future studies and myocarditis treatment.

Assessing the Anti-Inflammatory and Antioxidant Activity of Mangiferin in Murine Model for Myocarditis: Perspectives and Challenges.

Myocarditis is a major cause of heart failure and death, particularly in young individuals. Current treatments are mainly symptomatic, but emerging therapies focus on targeting inflammation and fibrosis pathways. Natural bioactive compounds like flavonoids and phenolic acids show promising anti-inflammatory and antioxidant properties. Corticosteroids are frequently employed in the treatment of autoimmune myocarditis and appear to lower mortality rates compared to conventional therapies for heart failure. This study aims to explore the effects of Mangiferin on pro-inflammatory cytokine levels, nitro-oxidative stress markers, histopathological alterations, and cardiac function in experimental myosin-induced autoimmune myocarditis. The effects were compared to Prednisone, used as a reference anti-inflammatory compound, and Trolox, used as a reference antioxidant. The study involved 30 male Wistar-Bratislava rats, which were randomly divided into five groups: a negative control group (C-), a positive control group with induced myocarditis using a porcine myosin solution (C+), three groups with induced myocarditis receiving Mangiferin (M), Prednisone (P), or Trolox (T) as treatment. Cardiac function was evaluated using echocardiography. Biochemical measurements of nitro-oxidative stress and inflammatory markers were conducted. Finally, histopathological changes were assessed. At echocardiography, the evaluation of the untreated myocarditis group showed a trend toward decreased left ventricular ejection fraction (LVEF) but was not statistically significant, while all treated groups showed some improvement in LVEF and left ventricular fraction shortening (LVFS). Significant changes were seen in the Mangiferin group, with lower end-diastolic left ventricular posterior wall (LVPWd) by day 21 compared to the Trolox group (p < 0.001). In the first week of the experiment, levels of interleukins (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α were significantly higher in the myosin group compared to the negative control group (p < 0.001, p < 0.001, p < 0.01), indicating the progression of inflammation in this group. Treatment with Mangiferin, Prednisone, and Trolox caused a significant reduction in IL-1β compared to the positive control group (p < 0.001). Notably, Mangiferin resulted in a superior reduction in IL-1β compared to Prednisone (p < 0.05) and Trolox (p < 0.05). Furthermore, Mangiferin treatment led to a statistically significant increase in total oxidative capacity (TAC) (p < 0.001) and a significant reduction in nitric oxide (NOx) levels (p < 0.001) compared to the negative control group. Furthermore, when compared to the Prednisone-treated group, Mangiferin significantly reduced NOx levels (p < 0.001) and increased TAC levels (p < 0.001). Mangiferin treatment significantly lowered creatine kinase (CK) and aspartate aminotransferase (AST) levels on day 7 (p < 0.001 and p < 0.01, respectively) and reduced CK levels on day 21 (p < 0.01) compared to the untreated group. In the nontreated group, the histological findings at the end of the experiment were consistent with myocarditis. In the group treated with Mangiferin, only one case exhibited mild inflammatory infiltrates, represented by mononucleated leukocytes admixed with few neutrophils, with the severity graded as mild. Statistically significant correlations between the grades (0 vs. 1-2) and the study groups have been highlighted (p < 0.005). This study demonstrated Mangiferin's cardioprotective effects in autoimmune myocarditis, showing reduced oxidative stress and inflammation. Mangiferin appears promising as a treatment for acute myocarditis, but further research is needed to compare its efficacy with other treatments like Trolox and Prednisone.

Визначення предикторів стійких порушень серцевого ритму у військовослужбовців із тяжким перебігом міокардиту

The aim – to study heart rhythm and conduction disturbances in different localization and distribution of myocardial lesions in combatants with severe myocarditis based on the results of a 6-month follow-up.Materials and methods. 46 male military personnel with a severe course of acute myocarditis (AM) with a reduced ejection fraction (EF) of the left ventricle (LV) (≤ 40 %) with an average age of (35,1±2,4) years were examined. Examinations were carried out in the 1st month after the onset of symptoms of myocarditis and after 6 months of observation. The diagnosis of myocarditis and the severe course of the disease were established on the basis of the Recommendations for the diagnosis and treatment of myocarditis of the All-Ukrainian Association of Cardiologists of Ukraine. All patients underwent for 24-hour ECG monitoring with analysis of the frequency and spectrum of rhythm and conduction disturbances and cardiac magnetic resonance (CMR) imaging with contrast analysis of the topography of the lesion and counting the number of LV segments affected by inflammatory changes and LV segments with the presence of late gadolinium enhancement (LGE).Results and discussion. When comparing the results of heart MRI with the data of daily ECG monitoring, a clear association of the presence of frequent ventricular extrasystoles (VE) and paroxysms of non-sustained ventricular tachycardia (NSVT) with the localization of LGE in the interventricular septum (IS) was established – among patients with LGE lesions at the onset of AM more than in a third (37.0 %) had frequent VE, and NSVT paroxysms, which increase the risk of developing life-threatening ventricular arrhythmias, were detected in 25,9 % of cases. After 6 months of observation in the presence of LGE in the IS, the frequency of detection of frequent VE and NSVT paroxysms was also significantly higher compared to other localization of the lesion and amounted to 20,0 and 13,3 %, respectively. With the help of correlation analysis, an associative relationship was revealed between the presence of LGE in the IS and the presence of frequent VE and NSVT paroxysms in the debut of myocarditis – r=0.73 (р&lt;0.01) and r=0.66 (р&lt;0,01) respectively, and also after 6 months of observation – r=0.65 (р&lt;0.01) and r=0.59 (р&lt;0.05), respectively. According to the results of the multivariate regression analysis, predictors of frequent VE persistence after 6 months were: LVEF ≤30 %; LV end-diastolic volume index ≥105 ml/m2; presence of inflammatory changes in ≥5.0 LV segments; presence of LGE in ≥4.0 LV segments and its presence in the IS, determined in the 1st month from the onset of the disease. The predictors NSVT paroxysms persistence after 6 months were the same factors with the exception of LV EF, and, according to the value of the β coefficient (β=1.302; p&lt;0.001), the most significant contribution was the presence of LGE in the IS.Conclusions. In combatants with severe myocarditis, the presence of late gadolinium enhancement in the interventricular septum is an additional risk factor for the persistence of frequent ventricular extrasystoles and paroxysms of non-sustained ventricular tachycardia during 6 months, while the presence of late gadolinium enhancement in the posterior and lateral walls of the left ventricle has no reliable relationship with the presence of rhythm and conduction disorders. On the basis of multivariate regression analysis, predictors of frequent ventricular extrasystoles and paroxysms of non-sustained ventricular tachycardia persistence were established in combatants with myocarditis.

Brief Version of Chinese Society of Cardiology Guidelines on the Diagnosis and Treatment of Adult Fulminant Myocarditis

Review Brief Version of Chinese Society of Cardiology Guidelines on the Diagnosis and Treatment of Adult Fulminant Myocarditis Hongyang Shu, Chen Chen, Luyun Wang, Jiangang Jiang and Daowen Wang * Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China * Correspondence: dwwang@tjh.tjmu.edu.cn Received: 3 April 2024; Revised: 6 June 2024; Accepted: 25 June 2024; Published: 20 August 2024 Abstract: Fulminant myocarditis is an acute and severe diffuse inflammatory disease of the heart with a high mortality rate. Its pathogenesis is driven by overactivation of the innate immunity and inflammatory storms. Based on China’s practical experience, the clinical guidelines for the management of the disease recommend adoption of a “life support-based comprehensive treatment regimen” which comprises mechanical circulatory support and immunomodulatory therapy at optimized doses of glucocorticoids and immunoglobin rather than immunosuppression to improve survival rates and long-term prognosis. The application experience of this treatment regimen in China provides evidence upon which the guidelines are formulated. This regimen emphasizes the importance of early identification, diagnosis, prediction, and treatment in patients with fulminant myocarditis. This is a brief introduction of the guidelines.

Abstract We119: Treatment of Viral Myocarditis by Targeting the TRIM29-PERK Axis-Mediated ER Stress Immune Response

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro . TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo . Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo . Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

Immunomodulating and Immunosuppressive Therapy for Virus-Negative Immune-Mediated Myocarditis.

Myocarditis is an inflammatory disease of the myocardium caused by infectious and noninfectious agents. Clinical manifestations range from mildly symptomatic forms to acute heart failure, cardiogenic shock, life-threatening arrhythmias and sudden death. Myocarditis is still a challenging diagnosis because of its wide variability in clinical presentation and unpredictable course. Moreover, a standardized, specific treatment in not yet available. Immunosuppressive treatment for virus-negative lymphocytic myocarditis is still controversial. Conversely, immunosuppression is well established in sarcoidosis, eosinophilic, giant-cell, drug hypersensitivity, and trauma-related myocarditis as well as lymphocytic myocarditis associated with connective tissue diseases or with the rejection of a transplanted heart. Recently, immunosuppressive therapy has been also recognized as an effective treatment in virus-negative inflammatory cardiomyopathy. The aim of this review is to underline the role of immunomodulating and immunosuppressive therapies in patients with immune-mediated myocarditis and illustrate the different treatment strategies depending on the etiology. An endomyocardial biopsy remains the gold standard for the diagnosis of myocarditis as well as for a tailored treatment.

A guideline that changes the diagnosis and treatment practices of fulminant myocarditis: review of the "Chinese guideline on the diagnosis and treatment of fulminant myocarditis in adults"

A guideline that changes the diagnosis and treatment practices of fulminant myocarditis: review of the "Chinese guideline on the diagnosis and treatment of fulminant myocarditis in adults"

Infliximab for Immune Checkpoint Inhibitor Therapy-Related Toxicities

What Is the Issue? Immune checkpoint inhibitor (ICI) therapy has become a treatment option for various types of advanced cancer, resulting in significant improvement in disease outcomes. However, ICIs can overstimulate the immune system leading to various side effects known as immune-related adverse events (irAEs) that can occur in any organ system. Administration of corticosteroids is the initial mainstay treatment of irAEs. However, there is little evidence of how to treat steroid-resistant irAEs. Treatment of steroid-resistant irAEs includes holding ICI and starting immunosuppressive therapy. Decision-makers are interested in understanding the use of infliximab, a selective immunosuppressive drug, for the treatment of steroid-resistant irAEs affecting various organs. What Did We Do? We identified and summarized the literature regarding the efficacy and safety of infliximab for the treatment of steroid-resistant irAEs. Due to the limitation of evidence, we included studies of any design, including case reports and case series. A research information specialist conducted a literature search of peer-reviewed and grey literature sources published between January 1, 2019 and April 8, 2024. One reviewer screened citations for inclusion based on predefined criteria, critically appraised the included studies, and narratively summarized the findings. What Did We Find? The evidence presented in this report was based on 2 systematic reviews of case reports and case series, 1 retrospective cohort study, and 40 additional publications consisting of 29 case reports and 11 case series. We identified 4 main irAEs, which were colitis, hepatitis, pneumonitis, and myocarditis. Very low-quality evidence, which was mainly derived from case reports and case series, suggests that infliximab may be effective for the treatment of steroid-resistant immune-induced colitis, while there are concerns regarding its use for the treatment of hepatitis due to potential hepatotoxicity and infectious complications. There is mixed evidence regarding the use of infliximab for the treatment of immune-induced pneumonitis and myocarditis. Recent consensus guidelines recommend the use of infliximab as first-line treatment for steroid-resistant immune-induced colitis, while its use for hepatitis is not recommended due to potential hepatotoxicity and infectious complications. The use of infliximab for the treatment of pneumonitis is an option, while its use for myocarditis remains to be determined. The usual dose of infliximab was 5 mg/kg, administered by IV. A higher dose of 10 mg/kg was seen in some cases. The number of infusions, the period between infusions and the length of treatment varied depending on the responsiveness of infliximab and the type and severity of irAEs. Treatment with infliximab as compared with vedolizumab resulted in comparable immune-induced colitis response rates, higher recurrent rate of colitis, and more hospitalizations despite a shorter time to clinical response. What Does This Mean? The very low-quality evidence identified suggests the potential benefits of infliximab in the management of immune-induced colitis due to its efficacy and fast response. When using the clinical evidence and recommendations summarized in this report to inform decisions, decision-makers should consider that the evidence is of very low quality, mainly derived from case reports and case series. Large prospective and comparative studies are needed to verify the findings and to determine the role of infliximab in the treatment of other irAEs.

Diagnosis and management of cancer therapy-related myocarditis in a young female: A case report and review of literature

BackgroundThe treatment of choice for Extra-osseous Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET), a rare neoplasm, is the VAC/IE regimen. This regimen includes Doxorubicin, Vincristine, Cyclophosphamide, Ifosfamide, and Etoposide, all of which have cardiotoxic effects. Myocarditis, a potentially threatening side effect following cancer therapy, can be accurately managed and diagnosed.Case PresentationIn the current study, we report the case of a 19-year-old female with a mass on the abdominal wall, diagnosed with ES/PNET. She was treated with the VAC/IE regimen. A month after the last session of chemotherapy, she experienced dyspnea. Upon evaluation, a high level of troponin and a low left ventricular ejection fraction (LVEF) were detected via transthoracic echocardiography. She was treated with anti-heart failure drugs, but the response was unsatisfactory. The possibility of Cancer therapy-related myocarditis was suspected, and cardiac magnetic resonance imaging (CMR) confirmed acute myocarditis. This patient exhibited a significant response to intravenous immunoglobulin (IVIG), with her LVEF improving from 30–35% to 50% within three months.ConclusionIn this case, based on negative tests and the absence of viral signs and symptoms, Cancer therapy-related myocarditis is highly suspected as the cause of myocarditis. This case underscores the importance of accurately utilizing CMR as a non-invasive method for diagnosing myocarditis. It effectively highlights the identification of reversible myocarditis with appropriate treatment and the notable response to IVIG, suggesting its potential as a favorable treatment for myocarditis in younger patients.

Extracorporeal membrane oxygenation treatment of fulminant myocarditis: the key role of point-of-care ultrasound in pacemaker lead perforation

Extracorporeal membrane oxygenation treatment of fulminant myocarditis: the key role of point-of-care ultrasound in pacemaker lead perforation

Combination of trimetazidine and coenzyme Q10 for the treatment of acute viral myocarditis: a systematic review and meta-analysis.

Coenzyme Q10 (CoQ10) is considered to be beneficial for patients with acute viral myocarditis (AVM). In addition, trimetazidine may be also beneficial to patients with AVM by promoting cardiac energy metabolism. This systematic review and meta-analysis examined the efficacy and safety of combining trimetazidine and CoQ10 with respect to CoQ10 alone in patients suffering from AVM. PubMed, Embase, the Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched for relevant randomized controlled trials (RCTs). An analysis of random effects was employed to combine the results. Sixteen RCTs that included 1,364 patients with AVM contributed to the meta-analysis. Overall, 687 patients received the combined treatment, while 677 received the CoQ10 alone for a duration of 2-12 weeks (mean: 5.2 weeks). In contrast to monotherapy with CoQ10, combined treatment with trimetazidine and CoQ10 significantly improved overall therapy effectiveness (risk ratio [RR]: 1.19, 95% confidence interval [CI]: 1.13 to 1.24, p < 0.001; I2 = 0%). Differences in study parameters such as the incidence of heart failure upon admission, dosage of CoQ10, or length of treatment did not significantly alter the outcomes (p for all subgroup analyses > 0.05). The combined treatment was associated with improved myocardial enzyme levels and recovery of cardiac systolic function as compared to CoQ10 alone (p all < 0.05). In addition, trimetazidine combined with CoQ10 caused no greater increase in adverse events than CoQ10 alone. Trimetazidine combined with CoQ10 is an effective and safe treatment for AVM.

Susceptibility to innate immune activation in genetically-mediated myocarditis.

Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment for myocarditis is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis with biomarkers and pathological features indistinguishable from other forms of myocarditis. DSP-associated myocarditis can progress to dilated cardiomyopathy with heightened arrhythmia risk. To model the cardiomyocyte aspects of DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients and gene-edited healthy control hiPSC lines. Homozygous and heterozygous DSP disrupted EHTs were generated to contain 90% hiPSC-CMs and 10% healthy control human cardiac fibroblasts. We measured innate immune activation and function at baseline and in response to Toll-like receptor (TLR) stimulation in EHTs. At baseline, DSP-/- EHTs displayed a transcriptomic signature of immune activation which was mirrored by EHT cytokine release. Importantly, DSP-/- EHTs were hypersensitive to TLR stimulation demonstrating greater contractile function impairment compared to isogenic controls. Compared to homozygous DSP-/- EHTs, heterozygous DSP patient-derived EHTs had less functionally impairment but also displayed heightened sensitivity to TLR stimulation. When subjected to strain, heterozygous DSP EHTs developed greater functional deficit indicating reduced contractile reserve compared to healthy control. Colchicine or NFΚB inhibitors improved baseline force production and strain-induced force deficits in DSP EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Genetic reduction of DSP renders cardiomyocytes susceptible to innate immune activation and strain-dependent contractile deficits. EHTs replicate electrical and contractile phenotypes seen in human myocarditis implicating cytokine release as a key part of the myogenic susceptibility to inflammation. This heightened innate immune activation and sensitivity is a target for clinical intervention.

ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection.

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

Elevated IL-6 and Tumor Necrosis Factor-α in Immune Checkpoint Inhibitor Myocarditis.

The impact of peripheral cytokine levels on the prognosis and treatment of immune checkpoint inhibitor (ICI) myocarditis has not been well studied. This study aimed to identify cytokines that can prognosticate and direct the treatment of ICI myocarditis. This was a single-center, retrospective cohort study of patients with ICI myocarditis who had available peripheral cytokine levels between January 2011 and May 2022. Major adverse cardiovascular events (MACEs) were defined as a composite of heart failure with/without cardiogenic shock, arterial thrombosis, life-threatening arrhythmias, pulmonary embolism, and sudden cardiac death. In total, 65 patients with ICI myocarditis had cytokine data available. Patients were mostly males (70%), with a mean age of 67.8 ± 12.7 years. Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were the most common cytokines to be elevated with 48/65 (74%) of patients having a peak IL-6 above normal limits (>5 pg/mL) and 44/65 (68%) of patients with peak TNF-α above normal limits (>22 pg/mL). Patients with elevated peak IL-6 had similar 90-day mortality and MACE outcomes compared to those without (10.4% vs. 11.8%, p = 0.878 and 8.8% vs. 17.7%, p = 0.366, respectively). Similarly, those with elevated peak TNF-α had similar 90-day mortality and MACEs compared to those without (29.6% vs. 14.3%, p = 0.182 and 13.6% vs. 4.8%, p = 0.413, respectively). Kaplan-Meier survival analysis also showed that there was not a significant difference between MACE-free survival when comparing elevated and normal IL-6 and TNF-α levels (p = 0.182 and p = 0.118, respectively). MACEs and overall survival outcomes were similar between those who received infliximab and those who did not among all patients and those with elevated TNF-α (p-value 0.70 and 0.83, respectively). Peripheral blood levels of IL-6 and TNF-α are the most commonly elevated cytokines in patients with ICI myocarditis. However, their role in the prognostication and guidance of immunomodulatory treatment is currently limited.

Diagnosis and treatment of myocarditis and inflammatory cardiomyopathy. Consensus document of the SEC-Working Group on Myocarditis

Myocarditis is defined as myocardial inflammation and its etiology is highly diverse, including infectious agents, drugs, and autoimmune diseases. The clinical presentation also varies widely, extending beyond the classic clinical picture of acute chest pain, and includes cases of cardiomyopathy of unknown cause whose etiology may be inflammatory. Because certain patients may benefit from targeted treatments, the search for the etiology should begin when myocarditis is first suspected. There remain several areas of uncertainty in the diagnosis and treatment of this disease. Consequently, this consensus document aims to provide clear recommendations for its diagnosis and treatment. Hence, a diagnostic algorithm is proposed, specifying when non-invasive diagnosis with cardiac MR is appropriate vs a noninvasive approach with endomyocardial biopsy. In addition, more novel aspects are discussed, such as when to suspect an underlying genetic etiology. The recommendations cover the management of myocarditis and inflammatory cardiomyopathy, both for general complications and specific clinical entities.