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Background: Prolonged exposure to interleukin-17A (IL-17A) can induce autoimmune myocarditis, and MLN4924, an inhibitor of NEDD8 activating enzyme (NAE), has been reported to effectively suppress various inflammatory reactions. However, the effects of MLN4924 in IL-17A-mediated inflammation associated with autoimmune myocarditis remain uncertain., Methods: An experimental autoimmune myocarditis (EAM) model was established and treated with MLN4924. The inflammation degree of heart tissues was assessed histopathologically. The expression levels of inflammatory cytokines and chemokines were measured using ELISA and RT-qPCR, respectively. Additionally, the interaction of biomacromolecules was detected through co-immunoprecipitation (Co-IP) and RNA immunoprecipitation (RIP)., Results: MLN4924 could attenuate IL-17A-induced inflammation. In the in vivo studies, MLN4924 treatment improved inflammatory responses, diminished immune cell infiltration and tissue fibrosis, and reduced the secretion of various inflammatory cytokines in serum, including IL-1β, IL-6, TNF-α, and MCP-1. In vitro experiments further corroborated these findings, showing that MLN4924 treatment reduced the secretion and transcription of pro-inflammatory factors, particularly MCP-1. Mechanistically, we confirmed that MLN4924 promoted Act1 ubiquitination degradation and disrupted Act1's interaction with IL-17R, thereby impeding the formation of the IL-17R/Act1/TRAF6 complex and subsequent activation of TAK1, c-Jun, and p65. Moreover, MLN4924 interfered with Act1's binding to mRNA, resulting in mRNA instability., Conclusions: In conclusion, MLN4924 effectively alleviated inflammatory symptoms in EAM by disrupting the interaction between IL and 17R and Act1, thereby reducing Act1-mediated mRNA stability and resulting in decreased expression of pro-inflammatory factors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of T. cruzi infection were investigated. Twenty-four hours ​after the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. T. cruzi inoculation induced systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac infection (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H 2 O 2 , and O 2 - ), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Salmonella infections have been associated with cardiovascular complications, including myocarditis and myopericarditis. This presentation of Salmonella myopericarditis highlights key clinical features to aid in diagnosis and the importance of prompt treatment with antibiotics, colchicine and non-steroidal anti-inflammatory drugs (NSAIDs)., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

This case report describes a 40-year-old male patient with severe cardiac failure due to eosinophilic granulomatosis with polyangiitis (EGPA) and myocarditis. The fast diagnostic approach with cardiac MRI (CMR) and immunosuppressive treatment with glucocorticoid and cyclophosphamide near-normalized the patient's cardiac function. Myocarditis due to EGPA is rare, however life-threatening, so a systematic approach and early CMR should be considered in patients with known asthma presenting with eosinophilia and cardiac involvement., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

The aim of this study was to evaluate the clinical course and outcomes of post-COVID myocarditis in patients with cardiomyopathies (CMP). This case series includes 10 patients with different CMPs who had COVID-19 (seven men; 48.4 ± 11.4 yr.): left ventricular non-compaction (n = 2), arrhythmogenic right ventricular CMP in combination with a heterozygous form of hemochromatosis (n = 1, HFE ), restrictive CMP (n = 1, MyBPC3 ), laminopathy (n = 1, LMNA ), dilated cardiomyopathy (n = 1, MYH7 + MyBPC3 ), Danon's disease (n = 1, LAMP2 ) and AL cardiac amyloidosis (n = 3). Myocardial morphological examination with immunohistochemical staining and PCR for SARS-CoV-2 and cardiotropic viruses was performed in six patients, while cardiac MRI and anti-cardiac antibody titres were evaluated in all patients. Post-COVID lymphocytic myocarditis was confirmed morphologically in six patients (with LVNC, RCM, ARCV, Danon's disease, and AL amyloidosis). Spike and nucleocapsid coronavirus proteins were detected in cell infiltrates, endothelium and cardiomyocytes in all biopsies; SARS-CoV-2 RNA was found in five out of six. In four patients, the diagnosis of myocarditis was based on MRI, high titres of anti-cardiac antibodies and clinical data. The mean time from COVID-19 to the diagnosis of myocarditis was 7 (5; 10.5) months. Myocarditis manifested with the onset/increase of arrhythmias and heart failure. Immunosuppressive therapy with corticosteroids was administered to six patients and led to an increase in ejection fraction and improvement of heart failure symptoms in five of them. CMPs are a favourable background for the development of post-COVID myocarditis. The onset or deterioration of heart failure and/or arrhythmias in patients with CMPs after COVID-19 requires the exclusion of myocarditis and, if present, the administration of immunosuppressive therapy.

Acute myocarditis, also known as myocardial inflammation, is a self-limited condition caused by systemic infection with cardiotropic pathogens, primarily viruses, bacteria, or fungi. Despite significant research, inflammatory cardiomyopathy exacerbated by heart failure, arrhythmia, or left ventricular dysfunction and it has a dismal prognosis. In this study, we aimed to evaluate the therapeutic effect of yohimbine against lipopolysaccharide (LPS) induced myocarditis in rat model. The anti-inflammatory activity of yohimbine was assessed in in-vitro using RAW 264.7 and H9C2 cells. Myocarditis was induced in rats by injecting LPS (10 mg/kg), following the rats were treated with dexamethasone (2 mg/kg) or yohimbine (2.5, 5, and 10 mg/kg) for 12 h and their therapeutic activity was examined using various techniques. Yohimbine treatment significantly attenuated the LPS-mediated inflammatory markers expression in the in-vitro model. In-vivo studies proved that yohimbine treatment significantly reduced the LPS-induced increase of cardiac-specific markers, inflammatory cell counts, and pro-inflammatory markers expression compared to LPS-control samples. LPS administration considerably affected the ECG, RR, PR, QRS, QT, ST intervals, and hemodynamic parameters, and caused abnormal pathological parameters, in contrast, yohimbine treatment substantially improved the cardiac parameters, mitigated the apoptosis in myocardial cells and ameliorated the histopathological abnormalities that resulted in an improved survival rate. LPS-induced elevation of cardiac troponin-I, myeloperoxidase, CD-68, and neutrophil elastase levels were significantly attenuated upon yohimbine treatment. Further investigation showed that yohimbine exerts an anti-inflammatory effect partly by modulating the MAPK pathway. This study emphasizes yohimbine's therapeutic benefit against LPS-induced myocarditis and associated inflammatory markers response by regulating the MAPK pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Myocarditis is an inflammatory disease of the cardiac muscle and one of the primary causes of dilated cardiomyopathy. Group B coxsackievirus (CVB) is one of the leading causative pathogens of viral myocarditis, which primarily affects children and young adults. Due to the lack of vaccines, the development of antiviral medicines is crucial to controlling CVB infection and the progression of myocarditis. In this study, we investigated the antiviral effect of baicalein, a flavonoid extracted from Scutellaria baicaleinsis. Our results demonstrated that baicalein treatment significantly reduced cytopathic effect and increased cell viability in CVB3-infected cells. In addition, significant reductions in viral protein 3D, viral RNA, and viral particles were observed in CVB3-infected cells treated with baicalein. We found that baicalein exerted its inhibitory effect in the early stages of CVB3 infection. Baicalein also suppressed viral replication in the myocardium and effectively alleviated myocarditis induced by CVB3 infection. Our study revealed that baicalein exerts its antiviral effect by inhibiting the activity of caspase-1 and viral protease 2A. Taken together, our findings demonstrate that baicalein has antiviral activity against CVB3 infection and may serve as a potential therapeutic option for the myocarditis caused by enterovirus infection., Competing Interests: Conflict of interest The authors declare that there is no conflict of interests in this work., (Copyright © 2024 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

Phenothiazines inhibit antioxidant enzymes in trypanosomatids. However, potential interferences with host cell antioxidant defenses are central concerns in using these drugs to treat Trypanosoma cruzi-induced infectious myocarditis. Thus, the interaction of thioridazine (TDZ) with T. cruzi and cardiomyocytes antioxidant enzymes, and its impact on cardiomyocytes and cardiac infection was investigated in vitro and in vivo. Cardiomyocytes and trypomastigotes in culture, and mice treated with TDZ and benznidazole (Bz, reference antiparasitic drug) were submitted to microstructural, biochemical and molecular analyses. TDZ was more cytotoxic and less selective against T. cruzi than Bz in vitro. TDZ-pretreated cardiomyocytes developed increased infection rate, reactive oxygen species (ROS) production, lipid and protein oxidation; similar catalase (CAT) and superoxide dismutase (SOD) activity, and reduced glutathione's (peroxidase - GPx, S-transferase - GST, and reductase - GR) activity than infected untreated cells. TDZ attenuated trypanothione reductase activity in T. cruzi, and protein antioxidant capacity in cardiomyocytes, making these cells more susceptible to H 2 O 2 -based oxidative challenge. In vivo, TDZ potentiated heart parasitism, total ROS production, myocarditis, lipid and protein oxidation; as well as reduced GPx, GR, and GST activities compared to untreated mice. Benznidazole decreased heart parasitism, total ROS production, heart inflammation, lipid and protein oxidation in T. cruzi-infected mice. Our findings indicate that TDZ simultaneously interact with enzymatic antioxidant targets in cardiomyocytes and T. cruzi, potentiating the infection by inducing antioxidant fragility and increasing cardiomyocytes and heart susceptibility to parasitism, inflammation and oxidative damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to assess the effectiveness and safety of levosimendan as an alternative treatment for pediatric patients with decompensated heart failure unresponsive to conventional inotropes and to emphasize its role in enhancing cardiovascular stability., Methods: A total of 15 pediatric patients with decompensated heart failure, stemming from acute fulminant myocarditis (53.3%) and post-congenital heart disease surgery complications (46.7%), received levosimendan. The evaluation focused on adverse effects, respiratory support requirements, and concurrent inotropic medication use during levosimendan treatment. Key cardiovascular parameters were assessed at 0, 6, 12, and 24 h post-levosimendan infusion., Results: Levosimendan administration significantly improved key cardiovascular metrics. Left ventricular ejection fraction increased notably from 45±14.8% to 58±15.6% at 24 h (p<0.001). Systolic and diastolic blood pressures rose significantly, with systolic increasing from 79 (68-90) to 98 (89-109) mmHg and diastolic from 47 (40-57) to 66 (54-76) mmHg by 24 h (p<0.001). Heart rate decreased from 162 (111-175) to 132 (99-148) bpm (p=0.02), and lactate levels significantly decreased from 4.15 (2.3-6.5) to 1.85 (0.8-2.6) mmol/L within 6 h (p<0.001)., Conclusion: Levosimendan demonstrates its significance in managing pediatric heart failure, indicating its safety and potential to enhance cardiac outcomes by reducing reliance on traditional inotropes.

Thymic epithelial tumors are rare malignancies with an incidence of 1.7 cases per million people per year. They pose significant management challenges due to their association with autoimmune disorders. In this case report, we present the 21-year history of a patient diagnosed with advanced B2/B3 thymoma and Good's syndrome. The patient achieved a complete and durable response after receiving only two cycles of the immune checkpoint inhibitor Nivolumab. However, this positive outcome was accompanied by the development of severe immune-related myocarditis complicated by reactivation of cytomegalovirus. Moreover, the patient developed a highly uncommon subdiaphragmatic pararectal dissemination of the thymic tumor, which is a condition rarely described in the literature. Despite the success in achieving complete and durable response with immune checkpoint inhibitors, the emergence of immune-related adverse events highlights the potential challenges associated with these treatments, emphasizing the need for careful monitoring and a comprehensive understanding of the intricate interplay between cancer, immune system dysregulations and immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Luciano, Pietroluongo, Ottaviano, Grieco, Peddio, De Placido, Servetto, Mascolo, Varricchio, Bianco, Palmieri and Giuliano.)

Purpose: The emergence of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, but these drugs can also cause severe immune-related adverse effects (irAEs), including myocarditis. Researchers have become interested in exploring ways to mitigate this side effect, and one promising avenue is the use of baricitinib, a Janus kinase inhibitor known to have anti-inflammatory properties. This study aimed to examine the potential mechanism by which baricitinib in ICIs-related myocarditis., Methods: To establish an ICIs-related myocarditis model, BALB/c mice were administered murine cardiac troponin I (cTnI) peptide and anti-mouse programmed death 1 (PD-1) antibodies. Subsequently, baricitinib was administered to the mice via intragastric administration. Echocardiography, HE staining, and Masson staining were performed to evaluate myocardial functions, inflammation, and fibrosis. Immunofluorescence was used to detect macrophages in the cardiac tissue of the mice.In vitro experiments utilized raw264.7 cells to induce macrophage polarization using anti-PD-1 antibodies. Different concentrations of baricitinib were applied to assess cell viability, and the release of pro-inflammatory cytokines was measured. The activation of the JAK1/STAT3 signaling pathway was evaluated through western blot analysis., Results: Baricitinib demonstrated its ability to improve cardiac function and reduce cardiac inflammation, as well as fibrosis induced by ICIs. Mechanistically, baricitinib treatment promoted the polarization of macrophages towards the M2 phenotype. In vitro and in vivo experiments showed that anti-PD-1 promoted the release of inflammatory factors. However, treatment with baricitinib significantly inhibited the phosphorylation of JAK1 and STAT3. Additionally, the use of RO8191 reversed the effects of baricitinib, further confirming our findings., Conclusion: Baricitinib demonstrated its potential as a protective agent against ICIs-related myocarditis by modulating macrophage polarization. These findings provide a solid theoretical foundation for the development of future treatments for ICIs-related myocarditis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Imaging strategies for the specific detection and therapeutic monitoring of myocarditis are still lacking. Stimulator of interferon genes (STING) is a signal transduction molecule involved in an innate immune response. Here, we evaluated the feasibility of the recently developed STING-targeted radiotracer [ 18 F]FBTA for positron emission tomography (PET) imaging to detect myocardial inflammation and monitor treatment in myocarditis mice. [ 18 F]FBTA-PET imaging was performed in myocarditis mice and normal mice to verify the specificity of [ 18 F]FBTA for the diagnosis of myocarditis. We also performed PET imaging in mice with myocarditis treated to verify the ability of [ 18 F]FBTA in therapeutic monitoring. The expression of STING and inflammatory cell types was confirmed by flow cytometry and immunohistochemistry. [ 18 F]FDG-PET imaging of myocarditis was used as a contrast. [ 18 F]FBTA-PET imaging showed that the average radioactive uptake was significantly higher in the hearts of the myocarditis group than in the control group. STING was highly overexpressed in cardiac inflammatory cells, including macrophages, dendritic cells (DCs), and T cells. However, there was no significant difference in cardiac radiotracer uptake of [ 18 F]FDG between the myocarditis group and the control group. Moreover, cardiac uptake of [ 18 F]FBTA was significantly reduced in cyclosporin A-treated myocarditis mice and myocardial STING expression was also significantly reduced after the treatment. Overall, we showed that a STING-targeted PET tracer [ 18 F]FBTA can be used to monitor changes in the inflammatory microenvironment in myocarditis. Besides, [ 18 F]FBTA-PET is also suitable for real-time monitoring of myocarditis treatment, representing a promising diagnostic and therapeutic monitoring approach for myocarditis.

Myocarditis (MC) is a myocardial inflammatory disease that threats human life. Pitavastatin (Pit) is a unique lipophilic statin with potent effects on lowering plasma total cholesterol and triacylglycerols. It has been reported to have pleiotropic effects, such as reducing inflammation and oxidative stress. However, the regulatory mechanism of Pit in MC remains a mystery. Two MC models were established in vitro (lipopolysaccharides-(LPS)-stimulated H9c2 cells) and in vivo (intraperitoneal injection of LPS in mice). The levels of microRNA-106b-5p (miR-106b-5p) and mitogen-activated protein kinase kinase kinase 2 (MAP3K2) were detected. ELISA was used to analyze in vivo cell inflammatory factors and myocardial injury markers, kits were used to detect the expression of antioxidant enzymes, cell counting kit-8 (CCK-8) was used to detect cell proliferation, and flow cytometry was used to detect apoptosis. Hematoxylin and eosin (HE) staining was used to detect the pathological changes of myocardial tissue in mice, and TUNEL staining was used to detect in vivo tissue cell apoptosis. The regulatory mechanism of Pit on miR-106b-5p/MAP3K2 was verified by a series of functional rescue experiments. The results demonstrated that in LPS-induced H9c2 cells, antioxidant enzymes decreased and pro-inflammatory factors and cardiac injury markers increased (p<0.05). However, these phenomenons were attenuated by Pit pretreatment. LPS decreased miR-106b-5p and elevated MAP3K2 in H9c2 cells, while Pit could recover their expression patterns (p<0.05). MAP3K2 was confirmed as a target gene of miR-106b-5p. Upregulating miR-106b-5p or downregulating MAP3K2 could further promote the protective effect of Pit, and vice versa (p<0.05). In addition, in the LPS-induced MC mouse model, histological examination showed that Pit significantly improved the myocardial tissue damage in MC mice, while downregulating miR-106b-5p or upregulating MAP3K2 could suppress the ameliorative effect of Pit (p<0.05). In conclusion, our study demonstrated that Pit ameliorates myocardial injury by suppressing myocardial inflammation and oxidative stress by modulating the miR-106b-5p/MAP3K2 axis.

Background: The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4 + T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C 15 H 10 O 5 , BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched., Purpose: This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4 + T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice., Study Design and Methods: Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway., Results: These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4 + T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis., Conclusion: This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

The purpose of this paper was to unravel the clinical effect analysis of different doses of creatine phosphate sodium (CPS) combined with immunoglobulin in the treatment of pediatric viral myocarditis (VMC). One hundred and twenty children with VMC were recruited and randomized into three groups (40 patients each). Group I received 1.0 g of CPS dissolved in 100 mL of 5% glucose injection intravenously 1 time/day; group II received 1.25 g of CPS dissolved in 125 mL of 5% glucose injection intravenously 1 time/day; group III received 1.5 g of CPS dissolved in 150 mL of 5% glucose injection intravenously 1 time/day; then all three groups were treated with combined use of immunoglobulin (300-400 mg/day) intravenously once a day; and all three groups were treated for 14 days. The clinical efficacy, cardiac function, serum inflammatory factor levels, immune function, and the occurrence of drug toxicity and adverse effects of the children in the three groups were compared after 14 days of treatment. All three groups achieved better therapeutic effects after treatment, in which the effective rate of the Group II and Group III was notably higher versus the Group I. Lower levels of cTnI, CK-MB, LDH, AST, IL-18, IL-6, IFN-γ, and LVEDD and higher CD3 + , CD4 + , and CD4 + /CD8 + , FS, and LVEF values were noted in the Group II and Group III versus the Group I, and the results were more pronounced in the high-dose group. The liver and kidney functions of the children in the three groups before and after treatment did not show any significant changes and the incidence of adverse reactions during the treatment period was low in all three groups. Children with VMC can be treated with high-dose CPS in combination with immunoglobulin, which can improve their cardiac function and immune function and reduce the inflammatory response with good overall therapeutic efficacy and fewer adverse effects., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: 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., Methodology: 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., 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., Conclusions: Trimetazidine combined with CoQ10 is an effective and safe treatment for AVM., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Min Zeng, Zhi Chen, Yan Zhang, Yusheng Pang.)

Background: Myocarditis is an important clinical issue which lacks specific treatment by now. Ivermectin (IVM) is an inhibitor of importin α/β-mediated nuclear translocation. This study aimed to explore the therapeutic effects of IVM on acute myocarditis., Methods: Mouse models of coxsackie B3 virus (CVB3) infection-induced myocarditis and experimental autoimmune myocarditis (EAM) were established to evaluate the effects of IVM. Cardiac functions were evaluated by echocardiography and Millar catheter. Cardiac inflammatory infiltration was assessed by histological staining. Cytometric bead array and quantitative real-time PCR were used to detect the levels of pro-inflammatory cytokines. The macrophages and their M1/M2 polarization were analyzed via flow cytometry. Protein expression and binding were detected by co-immunoprecipitation, Western blotting and histological staining. The underlying mechanism was verified in vitro using CVB3-infected RAW264.7 macrophages. Cyclic polypeptide (cTN50) was synthesized to selectively inhibit the nuclear translocation of NF-κB/p65, and CVB3-infected RAW264.7 cells were treated with cTN50., Results: Increased expression of importin β was observed in both models. IVM treatment improved cardiac functions and reduced the cardiac inflammation associated with CVB3-myocarditis and EAM. Furthermore, the pro-inflammatory cytokine (IL-1β/IL-6/TNF-α) levels were downregulated via the inhibition of the nuclear translocation of NF-κB/p65 in macrophages. IVM and cTN50 treatment also inhibited the nuclear translocation of NF-κB/p65 and downregulated the expression of pro-inflammatory cytokines in RAW264.7 macrophages., Conclusions: Ivermectin inhibits the nuclear translocation of NF-κB/p65 and the expression of major pro-inflammatory cytokines in myocarditis. The therapeutic effects of IVM on viral and non-viral myocarditis models suggest its potential application in the treatment of acute myocarditis., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Viral myocarditis (VMC) is one of the most common acquired heart diseases in children and teenagers. However, its pathogenesis is still unclear, and effective treatments are lacking. This study aimed to investigate the regulatory pathway by which exosomes alleviate ferroptosis in cardiomyocytes (CMCs) induced by coxsackievirus B3 (CVB3). CVB3 was utilized for inducing the VMC mouse model and cellular model. Cardiac echocardiography, left ventricular ejection fraction (LVEF), and left ventricular fractional shortening (LVFS) were implemented to assess the cardiac function. In CVB3-induced VMC mice, cardiac insufficiency was observed, as well as the altered levels of ferroptosis-related indicators (glutathione peroxidase 4 (GPX4), glutathione (GSH), and malondialdehyde (MDA)). However, exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-exo) could restore the changes caused by CVB3 stimulation. Let-7a-5p was enriched in hucMSCs-exo, and the inhibitory effect of hucMSCs-exo let-7a-5p mimic on CVB3-induced ferroptosis was higher than that of hucMSCs-exo mimic NC (NC: negative control). Mothers against decapentaplegic homolog 2 (SMAD2) increased in the VMC group, while the expression of zinc-finger protein 36 (ZFP36) decreased. Let-7a-5p was confirmed to interact with SMAD2 messenger RNA (mRNA), and the SMAD2 protein interacted directly with the ZFP36 protein. Silencing SMAD2 and overexpressing ZFP36 inhibited the expression of ferroptosis-related indicators. Meanwhile, the levels of GPX4, solute carrier family 7, member 11 (SLC7A11), and GSH were lower in the SMAD2 overexpression plasmid (oe- SMAD2 )+ let-7a-5p mimic group than in the oe-NC+ let-7a-5p mimic group, while those of MDA, reactive oxygen species (ROS), and Fe 2+ increased. In conclusion, these data showed that ferroptosis could be regulated by mediating SMAD2 expression. Exo- let-7a-5p derived from hucMSCs could mediate SMAD2 to promote the expression of ZFP36, which further inhibited the ferroptosis of CMCs to alleviate CVB3-induced VMC.

Chagas disease, caused by Trypanosoma cruzi , stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b + LY6C high ). Furthermore, both CD11b + Ly6C low F4/80 high macrophages (MΦ) and recently differentiated CD11b + Ly6C high F4/80 high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206 high ) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.

Obesity, which is driven by inflammation and oxidative stress, is a risk factor for cardiovascular disease. Semaglutide, a glucagon-like peptide-1 receptor agonist, is an antidiabetic drug with major effects on weight loss. In this study, single-cell transcriptomics was used to examine non-cardiomyocytes to uncover the mechanism of obesity-induced myocardial damage and the cardioprotective impact of semaglutide. We constructed obese mouse models and measured Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Reactive Oxygen Species (ROS), and Malonic dialdehyde (MDA) levels in serum and heart tissue to determine the levels of inflammation and oxidative stress in obesity and the effect of semaglutide on these levels. Then, utilizing single-cell transcriptomes to screen for key cell populations and differentially expressed genes (DEGs), we assessed the effects of obesity and semaglutide on non-cardiac cells. Finally, a DEG localization analysis was performed to explore DEGs as well as cell types associated with inflammation and oxidative stress. Semaglutide reduced increased TNF-α, IL-6, ROS, and MDA levels in serum and cardiac tissues in obese mouse. Several genes are closely associated with inflammation and oxidative stress. Chemokine (C-X-C motif) ligand 2 (Cxcl2), S100 calcium binding protein A8 (S100a8), and S100 calcium binding protein A9 (S100a9), which were elevated in obesity but decreased following semaglutide treatment, were also expressed particularly in neutrophils. Finally, by decreasing neutrophil Cxcl2, S100a8, and S100a9 expressions, semaglutide may help to reduce cardiac inflammation and oxidative stress. Semaglutide significantly reduced body weight in obese mice as well as exerted anti-inflammatory and antioxidant effects possibly by inhibiting the expression of S100a8, S100a9, and Cxcl2 in neutrophils. These discoveries are expected to reveal new molecular mechanisms underlying obesity-related heart damage and semaglutide's cardioprotective properties., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Standardized immunosuppressive therapy (IS) had been previously investigated in biopsy-proven (BP) lymphocytic myocarditis with heart failure (HF). This study evaluated efficacy and safety of tailored IS in BP immune-mediated myocarditis, irrespective of histology and clinical presentation., Methods and Results: Consecutive BP myocarditis patients treated with long-term tailored IS on top of optimal medical therapy (OMT), were compared with OMT non-IS controls using propensity-score weighting. The primary outcome was a composite of death or heart transplant, the secondary outcome was a composite of biventricular function, New York Heart Association (NYHA) class variation, and relapse. IS was managed by a multidisciplinary Cardioimmunology Team, involved a safety checklist and active patients' education. Ninety-one IS patients were compared with 267 non-IS patients. IS patients more frequently had systemic immune-mediated diseases (35% vs. 9.7%), lower baseline echocardiographic left ventricular ejection fraction (35% vs. 43%), lower right ventricular fractional area change (34% vs. 41%) and higher frequency of active lymphocytic, eosinophilic and giant cell myocarditis (71% vs. 58%, 12% vs. 1.1%, and 6.6% vs. 1.5%, respectively). At 5-year follow up, no difference was observed in the primary outcome (survival rate 93% in IS vs. 87% in non-IS), but IS patients had a higher relapse rate. Thus, IS patients, with a lower biventricular function and a higher risk profile at baseline, presented similar biventricular function and NYHA class to non-IS patients at follow-up. Minor adverse drug reactions occurred in 13% of patients, all resolved with therapy switch., Conclusions: Prolonged tailored IS is effective and safe in BP immune-mediated myocarditis irrespective of histology and clinical presentation., (© 2024 European Society of Cardiology.)

Abstract: Myocarditis is an inflammatory disease of the myocardium characterized by a great heterogeneity of presentation and evolution. Treatment of myocarditis is often supportive, and the evidence for immunosuppression is scarce and debated. Conventional treatment is based on clinical presentation, ranging from conservative to advanced mechanical assist devices. In this setting, immunosuppression and immunomodulation therapies are mostly reserved for patients presenting with major clinical syndromes. In this review, we will summarize the current evidence and strategies for conventional and immunosuppressive treatments for patients presenting with acute myocarditis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Studies have shown that Sacubitril/valsartan (Sac/Val) can reduce myocardial inflammation in myocarditis mice, in addition to its the recommended treatment of heart failure. However, the underlying mechanisms of Sac/Val in myocarditis remain unclear. C-type natriuretic peptide (CNP), one of the targeting natriuretic peptides of Sac/Val, was recently reported to exert cardio-protective and anti-inflammatory effects in cardiovascular systems. Here, we focused on circulating levels of CNP in patients with acute myocarditis (AMC) and whether Sac/Val modulates inflammation by targeting CNP in experimental autoimmune myocarditis (EAM) mice as well as LPS-induced RAW 264.7 cells and bone marrow derived macrophages (BMDMs) models. Circulating CNP levels were higher in AMC patients compared to healthy controls, and these levels positively correlated with the elevated inflammatory cytokines IL-6 and monocyte count. In EAM mice, Sac/Val alleviated myocardial inflammation while augmenting circulating CNP levels rather than BNP and ANP, accompanied by reduction in intracardial M1 macrophage infiltration and expression of inflammatory cytokines IL-1β, TNF-α, and IL-6. Furthermore, Sac/Val inhibited CNP degradation and directly blunted M1 macrophage polarization in LPS-induced RAW 264.7 cells and BMDMs. Mechanistically, the effects might be mediated by the NPR-C/cAMP/JNK/c-Jun signaling pathway apart from NPR-B/cGMP/NF-κB pathway. In conclusion, Sac/Val exerts a protective effect in myocarditis by increasing CNP concentration and inhibiting M1 macrophages polarization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Autoimmune myocarditis is the limited or diffuse inflammation of the myocardium due to dysfunctional cellular and humoral immunity mechanisms. We constructed mouse models of experimental autoimmune myocarditis (EAM) using peptide MyHC-α614-629. On the day after secondary immunization, the mice were intraperitoneally injected with Rho kinase (ROCK) inhibitor Y-27632. On day 21, the cardiac tissues were harvested and weighed. The hearts of EAM mice were significantly enlarged and whitened. Furthermore, body weight (BW) slowly increased during the treatment period, the heart weight (HW) and the ratio of HW/eventual BW were increased, and inflammatory infiltration and fibrosis were aggravated in the myocardial tissue. Y-27632 treatment improved the aforementioned phenotypic and pathological features of EAM mice. Mechanistic analysis revealed a significant increase in Notch1, Hes1, Jag2, Dil1, Toll-like receptor (Tlr) 2, and interleukin (IL)-1β expression in the myocardial tissue of EAM mice. Notably, IL-1β expression was correlated with that of Notch1 and Tlr2. Following Y-27632 treatment, the expression of key target genes of the Notch signaling pathway (Notch1, Hes1, Dil1, and Jag2) and Tlr2 were obviously decreased. Y-27632 treatment also decreased the number of monocytes in the spleen of EAM mice. Thus, ROCK inhibitor Y-27632 exerted a protective effect in EAM mice by downregulating IL-1β expression. This study aimed to provide a reference point for the future treatment of myocarditis in clinical settings., (© 2024. The Author(s).)

Coxsackievirus B3 (CVB3) is a positive single-strand RNA genome virus which belongs to the enterovirus genus in the picornavirus family, like poliovirus. It is one of the most prevalent pathogens that cause myocarditis and pancreatitis in humans. However, a suitable therapeutic medication and vaccination have yet to be discovered. Caboxamycin, a benzoxazole antibiotic isolated from the culture broth of the marine strain Streptomyces sp., SC0774, showed an antiviral effect in CVB3-infected HeLa cells and a CVB3-induced myocarditis mouse model. Caboxamycin substantially decreased CVB3 VP1 production and cleavage of translation factor eIF4G1 from CVB3 infection. Virus-positive and -negative strand RNA was dramatically reduced by caboxamycin treatment. In addition, the cleavage of the pro-apoptotic molecules BAD, BAX, and caspase3 was significantly inhibited by caboxamycin treatment. In animal experiments, the survival rate of mice was improved following caboxamycin treatment. Moreover, caboxamycin treatment significantly decreased myocardial damage and inflammatory cell infiltration. Our study showed that caboxamycin dramatically suppressed cardiac inflammation and mouse death. This result suggests that caboxamycin may be suitable as a potential antiviral drug for CVB3.

Objective: Clinical trials have evaluated the efficacy and safety of colchicine only in simple pericarditis, excluding cases of concomitant myocarditis. The aim of this paper is to evaluate the efficacy and safety of colchicine for the treatment of the first attack of acute pericarditis with concomitant myocardial involvement., Methods: Double-centre retrospective cohort study analysing consecutive patients admitted for first attack of pericarditis with myocarditis and treated with or without colchicine. The primary efficacy end point was the time to the first recurrence. Propensity score matching was used to generate two groups of patients with similar baseline characteristics. Colchicine-associated side effects were analysed as safety end-point., Results: A total of 175 patients (mean age 46.2±20.1 years, 25.1% females, 88.6% with idiopathic/viral aetiology) were included. Seventy-nine (45.1%) patients were treated with colchicine. After a median follow-up of 25.3 (IQR 8.3-45.6) months, 58 (33.1%) patients had recurrences. The propensity score generated two groups of 73 patients with similar baseline characteristics but the use of colchicine. Patients treated with colchicine had a lower incidence of recurrences (respectively, 19.2% vs 43.8%; p=0.001) and a longer event-free survival (p=0.005). In multivariable analysis, women (HR 1.97, 95% CI 1.04 to 3.73; p=0.037) and corticosteroid use (HR 2.27, 95% CI 1.15 to 4.47; p=0.018) were independent risk factors for recurrences. Colchicine-associated side effects were mild and occurred in 3 (1.7%) patients., Conclusion: In patients with first attack of pericarditis associated with myocardial involvement, colchicine was safe and efficacious for the reduction of recurrences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICIs) are reshaping the prognosis of many cancers, but often cause immune-related adverse events (irAEs). Among neurological irAEs, myositis is the most frequently reported. Our aim is to describe clinical and non-clinical characteristics, treatment and outcome of all irMyositis (skeletal limb-girdle and/or ocular myositis) and irMyocarditis cases in our reference center., Methods: We retrospectively enrolled all irMyositis/irMyocarditis patients seen between 2018 and 2022. We reviewed demographics, clinical characteristics, biological, neurophysiological, imaging workup, treatment and outcome., Results: We included 14 consecutive patients. The most frequent treatments were pembrolizumab (35%) or ipilimumab-nivolumab combination (35%). Limb-girdle, ocular (non-fluctuating palpebral ptosis and/or diplopia with or without ophthalmoparesis) and cardiac phenotypes were equally distributed, overlapping in 40% of cases. Ocular involvement was frequently misdiagnosed; review of brain MRIs disclosed initially missed signs of skeletal myositis in one patient and ocular myositis in 3. Seven patients had other co-existing irAEs. When performed, myography showed a myogenic pattern. CK was elevated in 8/15 patients, troponin-T in 12/12 and troponin-I in 7/9 tested patients. ICI were discontinued in all cases, with further immunosuppressive treatment in nine patients. In most cases, neurological and cardiological outcome was good at last follow-up., Conclusion: Myositis is a potentially severe irAE. Despite its heterogeneous presentation, some highly suggestive clinical symptoms, such as ocular involvement, or radiological signs should raise physicians' attention to avoid misdiagnosis. We thus recommend a multidisciplinary assessment (including complete neuromuscular evaluation) even in case of isolated myocarditis. Our series underlines the importance of an early diagnosis, since suspension of ICI and adequate treatment are usually associated with good functional outcome., (© 2023. The Author(s).)

Myocarditis can be caused by viral infection, drug reaction or general inflammatory condition. To provide understanding on inflammatory myocarditis, we describe clinical, genetic, and immunological properties of a young male patient who suffered from recurrent myocarditis episodes since the age of four years. Electrocardiography, troponin I/T, echocardiography, myocardial magnetic resonance imaging and histological findings were consistent with recurrent myocarditis episodes. Homozygous c.245 A > G p.Tyr82Cys pathogenic variant in Hepatitis A Virus Cellular Receptor 2 (HAVCR2) gene encoding T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) receptor was found. Peripheral blood mononuclear cells were collected when the patient was asymptomatic; CD4 + and CD8 + T lymphoblasts, CD56 + natural killer cells and CD14 + monocytes were negative for surface TIM-3 expression. In vitro, TLR4 mediated interleukin-1β (IL-1β) response was high after LPS/ATP stimulation. Clinical symptoms responded to IL-1 receptor antagonist anakinra. TIM-3 p.Tyr82Cys CD4 + and CD8 + T cell proliferation in vitro was unrestrained. Findings on IL-2, interferon gamma, regulatory T cells, signal transducer and activator of transcription (STAT) 1, 3 and 4 phosphorylation, and PD-1 and LAG-3 checkpoint inhibitor receptor analyses were comparable to controls. We conclude that TIM-3 deficiency due to homozygous HAVCR2 c.245 A > G p.Tyr82Cys pathogenic variant in the patient described here is associated with autoinflammatory symptoms limited to early onset recurrent febrile myocarditis. Excessive IL-1β production and defective regulation of T cell proliferation may contribute to this clinical condition responsive to anakinra treatment., (© 2024. The Author(s).)

Chlamydia psittaci ‒ related community-acquired pneumonia associated to acute myocarditis was diagnosed in a young man with no medical history, and a professional exposition to birds. The diagnosis was confirmed with positive specific polymerase chain reaction in bronchoalveolar lavage. The patient was treated with spiramycin for two weeks with anti-inflammatory treatment for myocarditis for three months. Clinical and biological improvement was rapidly observed followed by normalization of electrocardiogram and chest CT scan. No relapse was reported for over a two-year follow-up., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2024 Sociedade Brasileira de Infectologia. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To investigate the anti-inflammatory actions and molecular mechanisms of the sodium/glucose cotransporter 2 (SGLT-2) inhibitor empagliflozin on autoimmune myocarditis., Methods: The experimental autoimmune myocarditis (EAM) mouse model was constructed using peptides, and the therapeutic effects of empagliflozin on cardiac inflammation and fibrosis were observed using hematoxylin and eosin (HE), Sirius red staining, and Masson's trichome staining. Western blotting was used to identify the actions of empagliflozin on the surface marker expression levels of M2 macrophages and inflammatory factors. In vitro, experiments were completed using lentiviral overexpression of SGLT-2 in macrophages. Macrophage inflammation and anti-inflammatory models were constructed using lipopolysaccharide and interleukin-4, respectively. Enzyme-linked immunosorbent assay, immunofluorescence staining, and reverse-transcription polymerase chain reaction were applied to detect the effects of empagliflozin on the levels of inflammatory factors and macrophage surface markers. Western blotting was used to identify variability in SGLT-2 expression and the role of empagliflozin on the signal transducer and activator of the transcription 3 (STAT3) pathway. The Genomic Spatial Event 142564 dataset was studied in an EAM mouse model. We selected single-cell sequencing results from day 0 and day 21 of modeling to visualize differentially expressed genes. Immune cell infiltration correlation analysis was implemented to explore the expression of inflammatory factors and phenotypic markers., Results: Empagliflozin increased the expression of the M2 macrophage surface marker CD206 and reduced the level of inflammatory factors in the EAM mouse model while reducing the levels of inflammation and fibrosis. In vitro experiments revealed that the phosphorylation of STAT3 pathway was enhanced after macrophages were polarized to M1 phenotype by LPS, the phosphorylation of STAT3 pathway was inhibited after empagliflozin intervention, and the levels of inflammatory factors were decreased., Conclusion: Empagliflozin can reduce the level of inflammation in autoimmune myocarditis through the STAT3 pathway and macrophage phenotype transformation. These results indicate the expression of SGLT-2 can be a target for autoimmune myocarditis therapy., Competing Interests: Declaration of interest The authors announce that they have no known financial competing interests or personal relationships that may have affected the work reported in this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ethnopharmacological Relevance: Jingfang Granules (JFG) originate from the traditional herbal formula Jingfang Baidu powder. It has the effects of inducing sweating and dispelling wind. It is a classic medication used for treating external pathogenic factors and viral diseases. However, the therapeutic mechanism of JFG for viral myocarditis needs further clarification., Aim of the Study: This study aimed to explore the therapeutic efficacy of JFG on coxsackievirus B3-induced viral myocarditis (VMC), along with the elucidation of its underlying mechanisms., Materials and Methods: C57 BL/6JNifdc mice were divided randomly into several groups: control, model, Jingfang Granule groups (0.23, 0.46, and 0.69 g/20g, respectively), and a positive group (oseltamivir, 19.33 mg/kg). Following the establishment of the VMC model, the mice underwent an 8 -week treatment regimen. Pathological alterations in cardiac tissues and inflammatory protein expression were monitored. Differential gene analysis was conducted utilizing transcriptomic techniques. The differential gene mucolipin 1 (Mcoln1) was knocked down by transfection with siRNA in H9C2 cell, and investigative techniques such as immunoblotting, qRT-PCR, immunofluorescence, JC-1 staining, reactive oxygen species (ROS) detection, and mitochondrial stress testing were employed to examine its mechanism of action., Results: JFG significantly mitigates the pathological damage observed in the cardiac tissues of CVB3-induced VMC mice and attenuates the expression of inflammatory genes. Subsequently, differentially expressed genes are identified through transcriptomic analysis and validated via PCR. Among these, the upregulation of Mcoln1 promotes autophagy, facilitating the clearance of damaged mitochondria and excessive ROS. This has been substantiated through in vitro experiments. Excessive ROS precipitates a reduction in mitochondrial membrane potential, instigating cell apoptosis. In accordance with TUNEL staining results, JFG acts to inhibit cell apoptosis. To ascertain whether Mcoln1 is a crucial target for JFG in treating VMC, Mcoln1 was suppressed in H9C2 cells. The suppression of Mcoln1 hinders the elevation in autophagy levels post-JFG treatment, obstructs the enhancement of mitochondrial function, and impedes the clearance of ROS. Furthermore, the inhibitory effect of JFG on cell apoptosis is attenuated., Conclusion: The research findings indicate that JFG has a protective effect on CVB3-induced H9C2 cell injury. JFG may exert its effects in VMC treatment by enhancing autophagy to suppress cell apoptosis through the mitochondrial pathway, thereby counteracting cell damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Treatment with tumor-infiltrating lymphocytes (TILs) is rapidly evolving for patients with solid tumors. Following metastasectomy, TILs (autologous, intratumoral CD4+ and CD8+ T cells with the potential to recognize tumor-associated antigens) are isolated and non-specifically expanded ex vivo in the presence of interleukin-2 (IL-2). Subsequently, the TILs are adoptively transferred to the patients after a preconditioning non-myeloablative, lymphodepleting chemotherapy regimen, followed by administration of high-dose (HD) IL-2. Here, we provide an overview of known cardiac risks associated with TIL treatment and report on seven patients presenting with cardiac symptoms, all with different clinical course and diagnostic findings during treatment with lymphodepleting chemotherapy, TIL, and HD IL-2, and propose a set of clinical recommendations for diagnosis and management of these symptoms., Patients and Methods: This single-center, retrospective study included selected patients who experienced TIL treatment-related cardiac symptoms at the Netherlands Cancer Institute. In addition, 12 patients were included who received TIL in the clinical trial setting without experiencing cardiac symptoms, from whom complete cardiac biomarker follow-up during treatment was available [creatine kinase (CK), CK-myocardial band, troponin T and N-terminal pro-B-type natriuretic peptide]., Results: Within our TIL patient population, seven illustrative cases were chosen from the patients who developed symptoms suspected of severe cardiotoxicity: myocarditis, myocardial infarction, peri-myocarditis, atrial fibrillation, acute dyspnea, and two cases of heart failure. An overview of their clinical course, diagnostics carried out, and management of the symptoms is provided., Conclusions: In the absence of evidence-based guidelines for the treatment of TIL therapy-associated cardiotoxicity, we provided an overview of literature, case descriptions, and recommendations for diagnosis and management to help physicians in daily practice, as the number of patients qualifying for TIL treatment is rapidly increasing., Competing Interests: Disclosure AWS received a speakers fee from Philips. SK participated in an advisory board for Regeneron. JBAGH has provided consultation, attended advisory boards, and/or provided lectures for BMS, CureVac, GSK, Imcyse, Iovance Bio, Instil Bio, Immunocore, Ipsen, Merck Serono, MSD, Molecular Partners, Novartis, Pfizer, Roche/Genentech, Sanofi, Scenic, and Third Rock Ventures; has participated in the SAB of Achilles Tx, BioNTech US, Instil Bio, PokeAcell, T-Knife, Scenic and Neogene Therapeutics, and through this the NKI has received grant support from Amgen, Asher Bio, BioNTech, BMS, MSD, Novartis, Sastra Cell Therapy. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immune regulation therapies are considered promising for treating classically activated macrophage (M1)-driven viral myocarditis (VM). Alternatively, activated macrophage (M2)-derived extracellular vesicles (M2 EVs) have great immunomodulatory potential owing to their ability to reprogram macrophages, but their therapeutic efficacy is hampered by insufficient targeting capacity in vivo. Therefore, we developed cardiac-targeting peptide (CTP) and platelet membrane (PM)-engineered M2 EVs enriched with viral macrophage inflammatory protein-II (vMIP-II), termed CTP/PM-M2 EVs vMIP-II-Lamp2b , to improve the delivery of EVs "cargo" to the heart tissues. In a mouse model of VM, the intravenously injected CTP/PM-M2 EVs vMIP-II-Lamp2b could be carried into the myocardium via CTP, PM, and vMIP-II. In the inflammatory microenvironment, macrophages differentiated from circulating monocytes and macrophages residing in the heart showed enhanced endocytosis rates for CTP/PM-M2 EVs vMIP-II-Lamp2b . Subsequently, CTP/PM-M2 EVs vMIP-II-Lamp2b successfully released functional M2 EVs vMIP-II-Lamp2b into the cytosol, which facilitated the reprogramming of inflammatory M1 macrophages to reparative M2 macrophages. vMIP-II not only helps to increase the targeting ability of M2 EVs but also collaborates with M2 EVs to regulate M1 macrophages in the inflammatory microenvironment and downregulate the levels of multiple chemokine receptors. Finally, the cardiac immune microenvironment was protectively regulated to achieve cardiac repair. Taken together, our findings suggest that CTP-and-PM-engineered M2 EVs vMIP-II-Lamp2b represent an effective means for treating VM and show promise for clinical applications.

Competing Interests: Conflict of interest: K.K. and A.S. have been granted research funding and honorarium by Biosense Webstar, Inc. M.Y. does not have a real or perceived conflict of interest.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days., Competing Interests: Competing interests: ED: None. TW: None. DK: Received consulting/advisor fees from AstraZeneca, Amgen, Sanofi, Merck Sharp & Drohne, MSD and support for attending meetings and/or travel from Amgen, Roche, Sanofi. AZ: Received consulting/advisor fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Hoffmann–La Roche, NBE Therapeutics, Secarna, ACM Pharma, and Hookipa, and maintains further non-commercial research agreements with Secarna, Roche, Vectorbiopharma, T3 Pharma and Bright Peak Therapeutics. HL: Received travel grants and consultant fees from BMS, Alector, and MSD; received research support from BMS, Novartis, GlycoEra and Palleon Pharmaceuticals. JN: Received consulting/advisor fees from AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Arcus Biosciences, NGM Pharmaceuticals, Bayer, Regeneron, Takeda, Pfizer, Elevation Oncology, AbbVie, Kaleido Biosciences, Daiichi Sankyo. JN: Received research support from AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Arcus Biosciences and Mirati. LC: Research funding from Bristol-Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of Review: In systemic sclerosis (SSc) primary heart involvement (pHI) is frequent, even though often unrecognized due to its occult nature and to the lack of a specific diagnostic algorithm. The purpose of this review is to report the state of the art of the evidence in the current literature, as well as the overall diagnostic modalities and therapeutic strategies for primary heart involvement in SSc., Recent Findings: SSc-pHI is defined by the presence of cardiac abnormalities that are predominantly attributable to SSc rather than other causes and/or complications; it may be sub-clinical and must be confirmed through diagnostic investigations. Novel electrocardiographic analysis and cardiac magnetic resonance (CMR) with mapping techniques have been recently proposed, showing a great utility in the early identification of SSc-pHI and in the noninvasive characterization of myocardial tissue. Immunosuppressive therapy emerged as fundamental to curb myocardial inflammation, and recent preclinical and clinical data support the role of antifibrotic drugs to treat SSc-pHI., Summary: our review will help clinicians to properly integrate the available diagnostic modalities for the assessment of SSc-pHI. The ultimate goal is to propose a feasible diagnostic algorithm for the early identification of patients with SSc-pHI, and a schematic therapeutic approach to manage SSc-pHI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Autoimmune myocarditis, which falls within the broad spectrum of myocarditis, is characterized by an excessive inflammatory response in the heart, and can progress into dilated cardiomyopathy and irreversible heart failure in all possibility. However, effective clinical therapeutics are limited due to its complex inflammatory reactions. Empagliflozin (EMPA) has been previously demonstrated to possess anti-inflammatory properties. This study aimed to determine the improvement effects of EMPA on cardiac dysfunction under the condition of autoimmune myocarditis, and to further investigate the potential mechanisms. In vivo, all male Balb/c mice were randomly divided into four groups: control, experimental autoimmune myocarditis (EAM), EAM+EMPA and EMPA. In vitro, the effects of EMPA on IL-18-stimulated H9C2 cells were explored and the underlying molecular mechanisms were further determined. EMPA treatment significantly inhibited the development of autoimmune myocarditis, and mice treated with EMPA exhibited improved cardiac function compared with that in the EAM group, potentially through modulating pyroptosis of myocardium. Specifically, the NF-κB pathway was activated in the hearts of the EAM mice, which further activated NLRP3 inflammasome-dependent pyroptosis. EMPA treatment significantly inhibited such activation, thus alleviating inflammatory reactions in the context of EAM. Moreover, in vitro, we also observed that EMPA significantly inhibited pyroptosis of IL-18-stimulated H9C2 cells, and reduced nuclear translocation of NF-κB and degradation of activated IκBα. This work provides the first direct evidence that EMPA can inhibit myocardial inflammation and improve cardiac function in EAM mice, partly attributed to the drug-induced suppression of cardiomyocyte pyroptosis via disrupting the NF-κB pathway., Competing Interests: Declaration of Competing Interest The authors declare no competing interest exists., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Enterovirus A71 (EV71), coxsackievirus A16 (CVA16), and coxsackievirus B3 (CVB3) are pathogenic members of the Picornaviridae family that cause a range of diseases, including severe central nervous system complications, myocarditis, and pancreatitis. Despite the considerable public health impact of these viruses, no approved antiviral treatments are currently available. In the present study, we confirmed the potential of saucerneol, a compound derived from Saururus chinensis , as an antiviral agent against EV71, CVA16, and CVB3. In the in vivo model, saucerneol effectively suppressed CVB3 replication in the pancreas and alleviated virus-induced pancreatitis. The antiviral activity of saucerneol is associated with increased mitochondrial ROS (mROS) production. In vitro inhibition of mROS generation diminishes the antiviral efficacy of saucerneol. Moreover, saucerneol treatment enhanced the phosphorylation of STING, TBK-1, and IRF3 in EV71- and CVA16-infected cells, indicating that its antiviral effects were mediated through the STING/TBK-1/IRF3 antiviral pathway, which was activated by increased mROS production. Saucerneol is a promising natural antiviral agent against EV71, CVA16, and CVB3 and has potential against virus-induced pancreatitis and myocarditis. Further studies are required to assess its safety and efficacy, which is essential for the development of effective antiviral strategies against these viruses.

Galectin-1 (Gal-1), a member of a highly conserved family of animal lectins, plays a crucial role in controlling inflammation and neovascularization. However, the potential role of Gal-1 in preventing myocarditis remains uncertain. We aimed to explore the functions and mechanisms of Gal-1 in preventing myocarditis. In vivo, C57/BL6 mice were pre-treated with or without Gal-1 and then exposed to lipopolysaccharide (LPS) to induce myocarditis. Subsequently, cardiac function, histopathology, inflammation, oxidative stress, and apoptosis of myocardial tissues were detected. Following this, qRT-PCR and Western blotting were applied to measure iNOS, COX2, TXNIP, NLRP3 and Caspase-1 p10 expressions. In vitro, H9c2 cells pre-treated with different doses of Gal-1 were stimulated by LPS to induce myocarditis models. CCK8, flow cytometry and reactive oxygen species (ROS) assay were then employed to estimate cell viability, apoptosis and oxidative stress. Furthermore, Nrf2 and HO-1 protein expressions were evaluated by Western blotting in vivo and in vitro. The results showed that in vivo, Gal-1 pre-treatment not only moderately improved cardiac function and cardiomyocyte apoptosis, but also ameliorated myocardial inflammation and oxidative damage in mice with myocarditis. Furthermore, Gal-1 inhibited TXNIP-NLRP3 inflammasome activation. In vitro, Gal-1 pre-treatment prevented LPS-induced apoptosis, cell viability decrease and ROS generation. Notably, Gal-1 elevated HO-1, total Nrf2 and nuclear Nrf2 protein expressions both in vivo and in vitro. In conclusion, pre-treatment with Gal-1 exhibited cardioprotective effects in myocarditis via anti-inflammatory and antioxidant functions, and the mechanism may relate to the Nrf2 pathway, which offered new solid evidence for the use of Gal-1 in preventing myocarditis.