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Background Corticosteroid therapy for the treatment of clinically manifest cardiac sarcoidosis is generally recommended. Our group previously systematically reviewed the data in 2013; since then, there has been increasing quality and quantity of data and also interest in nonsteroid agents. Methods and Results Studies were identified from MEDLINE, EMBASE, Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, and the National Institutes of Health ClinicalTrials.gov database. The quality of included articles was rated using Scottish Intercollegiate Guidelines Network 50. Outcomes examined were atrioventricular conduction, left ventricular function, ventricular arrhythmias, and mortality. A total of 3527 references were retrieved, and 34 publications met the inclusion criteria. There were no randomized trials, and only 2 studies were rated good quality. In the 34 reports (total of 1297 patients), 1125 patients received corticosteroids, 235 received additional or other immunosuppressant therapy, and 97 patients received no therapy. There were 178 patients treated for atrioventricular conduction disease, with 76/178 (42.7%) improving. In contrast, 21 patients were not treated with corticosteroids and/or immunosuppressant therapy, and none of them improved. Therapy was associated with the prevention of deterioration in left ventricular function. A total of 8 publications reported on ventricular arrhythmia burden, and 19 reported on mortality; the data quality was too limited to draw conclusions for the latter 2 outcomes. Conclusions The best quality data relate to atrioventricular nodal conduction and left ventricular function recovery. In both situations, therapy with corticosteroids and/or immunosuppressant therapy were sometimes associated with positive outcomes. The data quality is too limited to draw conclusions for ventricular arrhythmias and mortality.

Aims: Myocardial infarction (MI) remains a major cause of heart failure. 5-Methoxytryptophan (5-MTP), a 5-methoxyindole metabolite of L-tryptophan, exerts anti-inflammatory and antifibrotic effects, but MI impairs the biosynthesis of cardiac 5-MTP. Therefore, we evaluated the effect of exogenous 5-MTP administration on rescuing post-MI cardiac injury., Methods and Results: After a detailed pharmacokinetic analysis of 5-MTP, Sprague Dawley rats that had undergone left anterior descending coronary artery ligation received intraperitoneal administration of either 17 mg/kg 5-MTP or saline at 0.5 and 24 h after MI. Cardiac systolic function, infarction size, and fibrosis were evaluated using echocardiography, triphenyltetrazolium chloride staining, and Masson trichrome staining, respectively. Myocardial apoptosis was analyzed by staining for caspase-3 and cardiac troponin I. 5-MTP treatment decreased the infarct area and myocardial apoptosis; attenuated systolic dysfunction and left ventricular dilatation; and reduced cardiomyocyte hypertrophy, myocardial fibrosis, and infarct expansion. Crucially, 5-MTP alleviated oxidative stress by preserving mitochondrial antioxidant enzymes and downregulating reactive oxygen species-generating NADPH oxidase isoforms and endothelin-1. Consequently, 5-MTP-treated MI rat hearts exhibited lower levels of chemokines and cytokines, namely interleukin (IL)-1β, IL-18, IL-6, C-C motif chemokine ligand (CCL)-2, and CCL5, accompanied by reduced infiltration of CD11b + cells and CD4 + T cells. Notably, 5-MTP protected against H 2 O 2 -induced damage in HL-1 cardiomyocytes and human umbilical vein endothelial cells in vitro., Conclusion: 5-MTP prevented post-MI cardiac injury by promoting mitochondrial stabilization and controlling redox imbalance. This cytoprotective effect ameliorated macrophage and T-cell infiltration, thus reducing the infarct size, attenuating fibrosis, and restoring myocardial function., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In this case report, a 16-days-old boy presented with reduced feeding, vomiting, respiratory distress and pallor. He developed cardiogenic shock with cardiac arrest and was resuscitated. Echocardiography showed reduced left ventricular systolic function and he was diagnosed with enterovirus myocarditis since enterovirus RNA was found in the blood by polymerase chain reaction. After one month of hospitalization, the patient was discharged without any apparent sequelae. The condition is rare but associated with a high mortality. Early diagnosis and initiation of treatment is essential for survival.

Purpose: Herbal medicine is one of crucial symbols of Chinese national medicine. Investigation on molecular responses of different herbal strategies against viral myocarditis is immeasurably conducive to targeting drug development in the current international absence of miracle treatment., Methods: Literature retrieval platforms were applied in the collection of existing empirical evidences for viral myocarditis-related single-herbal strategies. SwissTargetPrediction, Metascape, and Discovery Studio coordinating with multidatabases investigated underlying target genes, interactive proteins, and docking molecules in turn., Results: Six single-herbal medicines consisting of Huangqi ( Hedysarum Multijugum Maxim ), Yuganzi ( Phyllanthi Fructus ), Kushen ( Sophorae Flavescentis Radix ), Jianghuang ( Curcumaelongae Rhizoma ), Chaihu ( Radix Bupleuri ), and Jixueteng ( Spatholobus Suberectus Dunn ) meet the requirement. There were 11 overlapped and 73 unique natural components detected in these herbs. SLC6A2, SLC6A4, NOS2, PPARA, PPARG, ACHE, CYP2C19, CYP51A1, and CHRM2 were equally targeted by six herbs and identified as viral myocarditis-associated symbols. MCODE algorithm exposed the hub role of SRC and EGFR in strategies without Jianghuang. Subsequently, we learned intermolecular interactions of herbal components and their targeting heart-tissue-specific CHRM2, FABP3, TNNC1, TNNI3, TNNT2, and SCN5A and cardiac-myocytes-specific IL6, MMP1, and PLAT coupled with viral myocarditis. Ten interactive characteristics such as π -alkyl and van der Waals were modeled in which ARG111, LYS253, ILE114, and VAL11 on cardiac troponin (TNNC1-TNNI3-TNNT2) and ARG208, ASN106, and ALA258 on MMP1 fulfilled potential communicating anchor with ellagic acid, 5 α , 9 α -dihydroxymatrine, and leachianone g via hydrogen bond and hydrophobic interaction, respectively., Conclusions: The comprehensive outcomes uncover differences and linkages between six herbs against viral myocarditis through component and target analysis, fostering development of drugs., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Yu Cao et al.)

Background: Half of U.S. adults have received at least one dose of the COVID-19 vaccines produced by either Pfizer, Moderna, or Johnson and Johnson, which represents a major milestone in the ongoing pandemic. Given the emergency use authorizations for these vaccines, their side effects and safety were assessed over a compressed time period. Hence, ongoing monitoring for vaccine-related adverse events is imperative for a full understanding and delineation of their safety profile., Case Presentation: An 22-year-old Caucasian male presented to our hospital center complaining of pleuritic chest pain. Six months prior he had a mild case of COVID-19, but was otherwise healthy. He had received his first dose of the Moderna vaccine three days prior to developing symptoms. Laboratory analysis revealed a markedly elevated troponin and multiple imaging modalities during his hospitalization found evidence of wall motion abnormalities consistent with a diagnosis of perimyocarditis. He was started on aspirin and colchicine with marked improvement of his symptoms prior to discharge., Conclusions: We present a case of perimyocarditis that was temporally related to COVID-19 mRNA vaccination in an young male with prior COVID-19 infection but otherwise healthy. Our case report highlights an albeit rare but important adverse event for clinicians to be aware of. It also suggests a possible mechanism for the development of myocardial injury in our patient., (© 2021. The Author(s).)

Among many of the autoimmune diseases observed in patients with myasthenia gravis (MG), myocarditis is one of the most critical. The goal of this review is to systematically describe and investigate the characteristics of MG complicated with myocarditis. We identified 183 records in PubMed (MEDLINE), Web of Science, and EMBASE from 1948 to September 10, 2020. Studies were included if they presented clinical data on MG complicated with myocarditis. Of the 35 patients from 28 studies in this review, 57.14% (20/35) were males, with a mean age of 59.11 ± 15.87. Dyspnea was the most common cardiac symptom accounting for over 60% in the study. Among the 35 patients, 13 cases of myocarditis occurred concomitantly with MG and the longest interval between MG and myocarditis was 7 years. Forty percent of patients developed myocarditis caused by immune checkpoint inhibitors (ICI). Among the patients with myocarditis, over half of the patients were diagnosed by myocardial biopsy. After active immune regulation and symptomatic treatment, only 15 of 35 patients with MG complicated with myocarditis improved, 18 patients died during hospitalization, one patient died due to tumor progression and 1patient died 5 years later. The prognosis of patients with MG complicated with myocarditis is poor, and myocardial enzymes and other indexes need to be monitored for patients taking ICI drugs. Patients with dyspnea who are still not ideally treated by mechanical ventilation should be vigilant against the occurrence of MG complicated with myocarditis., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Cardiovascular adverse events induced by immune checkpoint inhibitors (ICIs) have gained significant interest over the past decade due to their impact on short- and long-term outcomes. They were initially thought to be rare, but the increasing use of ICIs in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in their incidence. Different guidelines have proposed screening measures for ICI-induced myocarditis by incorporating troponin measurements at baseline and during the first few weeks of treatment. However, no specific guidelines have been developed yet regarding the interpretation of an asymptomatic rise in troponins. This state-of-the art review aims to provide an overview of the clinical relevance of elevated troponins during checkpoint inhibition and recommendations on how to manage elevated troponin levels during ICI therapy., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Virus myocarditis (VMC) is a common cardiovascular disease and a major cause of sudden death in young adults. However, there is still a lack of effective treatments. Our previous studies found that calpain activation was involved in VMC pathogenesis. This study aims to explore the underlying mechanisms further. Neonatal rat cardiomyocytes (NRCMs) and transgenic mice overexpressing calpastatin (Tg-CAST), the endogenous calpain inhibitor, were used to establish VMC model. Hematoxylin and eosin and Masson staining revealed inflammatory cell infiltration and fibrosis. An ELISA array detected myocardial injury. Cardiac function was measured using echocardiography. CVB3 replication was assessed by capsid protein VP1. Apoptosis was measured by TUNEL staining, flow cytometry, and western blot. The endoplasmic reticulum (ER) stress-related proteins were detected by western blot. Our data showed that CVB3 infection resulted in cardiac injury, as evidenced by increased inflammatory responses and fibrosis, which induced myocardial apoptosis. Inhibiting calpain, both by PD150606 and calpastatin overexpression, could attenuate these effects. Furthermore, ER stress was activated during CVB3 infection. However, calpain inhibition could downregulate some ER stress-associated protein levels such as GRP78, pancreatic ER kinase-like ER kinase (PERK), and inositol-requiring enzyme-1α (IRE-1α), and ER stress-related apoptotic factors, during CVB3 infection. In conclusion, calpain inhibition attenuated CVB3-induced myocarditis by suppressing ER stress, thereby inhibiting cardiomyocyte apoptosis.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a potentially life-threatening adverse drug reaction with a mortality rate of 10%. Interstitial nephritis, pneumonitis, myocarditis, meningitis, thyroiditis and pancreatitis are major causes of morbidity and mortality in this syndrome. Cessation of offending medication is paramount. There is paucity in high quality prospective studies guiding the treatment of DRESS, and there are no published therapeutic clinical trials in the treatment of corticosteroid refractory hypersensitivity myocarditis. The authors present a unique case of ciprofloxacin-induced DRESS with concurrent thyroiditis and refractory eosinophilic myocarditis that required mepolizumab and multiple immunosuppressants for successful treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A 58-year-old man presented to the emergency department with recent-onset palpitations and progressive exertional dyspnoea. ECG demonstrated new-onset atrial fibrillation. Transthoracic echocardiogram showed global impairment in left ventricular systolic function with left ventricular ejection fraction of 20%. Cardiac MRI (CMRI) demonstrated generalised severe myocarditis. A SARS-CoV-2 PCR was positive for SARS-CoV-2 RNA. As such, we diagnosed our patient with COVID-19-associated myocarditis based on CMRI appearances and positive SARS-CoV-2 swab. This case highlights that COVID-19-associated myocarditis can present as new atrial fibrillation and heart failure without the classic COVID-19-associated symptoms., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy begins to be widely used due to the increasing exploration and gratifying effects in multiple cancers. Chordoma, as a rare bone malignant tumor, often recurs and metastasizes after undergoing surgery and radiotherapy. Therefore, immunotherapy can be explored as an emerging, potentially effective treatment to improve the survival rate and clinical benefit of patients. However, a variety of immune-related adverse events (irAEs) cannot be avoided completely. And the immunotherapy-induced myocarditis, as a rare but fatal irAE, has been increasingly reported. Understanding the mechanism involved in irAEs can inform best practices for side effects management. Here, we firstly reported a case of immune myocarditis and subsequent myasthenia gravis (MG) following anti-PD-1 treatment for chordoma., 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 © 2021 Liang, Yang, Lin, Li, Zhao, Zhao and Dong.)

Myocarditis refers to the clinical and histological characteristics of a diverse range of inflammatory cellular pathophysiological conditions which result in cardiac dysfunction. Myocarditis is a major cause of mortality in individuals less than 40 years of age and accounts for approximately 20% of cardiovascular disease (CVD) events. Myocarditis contributes to dilated cardiomyopathy in 30% of patients and can progress to cardiac arrest, which has a poor prognosis of <40% survival over 10 years. Myocarditis has also been documented after infection with SARS-CoV-2. The most commonly used lipid-lowering therapies, HMG-CoA reductase inhibitors (statins), decrease CVD-related morbidity and mortality. In addition to their lipid-lowering effects, increasing evidence supports the existence of several additional beneficial, 'pleiotropic' effects of statins. Recently, several studies have indicated that statins may attenuate myocarditis. Statins modify the lipid oxidation, inflammation, immunomodulation, and endothelial activity of the pathophysiology and have been recommended as adjuvant treatment. In this review, we focus on the mechanisms of action of statins and their effects on myocarditis, SARS-CoV-2 and CVD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2, is currently in a pandemic outbreak and has become a global health issue. In addition to the primarily involvement of the respiratory system, myocarditis is considered an important and fatal lesion in patients with COVID-19. However, effective therapeutic methods are currently lacking. The cholinergic anti-inflammatory pathway (CAP) has been demonstrated to suppress pro-inflammatory cytokine production and control inflammation in sepsis and other medical conditions. Therefore, the CAP may be a potential and effective therapeutic method for COVID-19-related myocarditis. This article reviews the relationship between COVID-19-related myocarditis and the CAP and discusses the CAP as a potential therapeutic modality in the treatment of COVID-19-related myocarditis., Competing Interests: Competing interests The authors have no financial conflicts of interest., (Copyright © 2020 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Infection of mice with Coxsackievirus B3 (CVB3) triggers inflammation of the heart and this mouse model is commonly used to investigate underlying mechanisms and therapeutic aspects for viral myocarditis. Virus-triggered cytotoxicity and the activity of infiltrating immune cells contribute to cardiac tissue injury. In addition to cardiac manifestation, CVB3 causes cell death and inflammation in the pancreas. The resulting pancreatitis represents a severe burden and under such experimental conditions, analgesics may be supportive to improve the animals' well-being. Notably, several known mechanisms exist by which analgesics can interfere with the immune system and thereby compromise the feasibility of the model. We set up a study aiming to improve animal welfare while ensuring model integrity and investigated how tramadol, an opioid, affects virus-induced pathogenicity and immune response in the heart. Tramadol was administered seven days prior to a CVB3 infection in C57BL/6 mice and treatment was continued until the day of analysis. Tramadol had no effect on the virus titer or viral pathogenicity in the heart tissue and the inflammatory response, a hallmark of myocardial injury, was maintained. Our results show that tramadol exerts no disruptive effects on the CVB3 myocarditis mouse model and, therefore, the demonstrated protocol should be considered as a general analgesic strategy for CVB3 infection.

Trichinellosis is a parasitic infection that is associated with the consumption of raw meat. The specific genotype Trichinella nativa has been found in raw bear meat. The most common genotype that has been linked with myocarditis is T spiralis. We present a case of T nativa myocarditis secondary to consumption of raw bear meat. The clinical manifestations as well as therapy of this specific genotype is outlined., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Berberine (BBR), an isoquinoline alkaloid isolated from Rhizoma coptidis, is reported to possess antiviral activity. Our previous study has shown that BBR alleviates coxsackievirus B3 (CVB3) replication in HeLa cells. However, the anti-CVB3 activity of BBR is still unclear in vivo. In this study, we explored the effect of BBR on CVB3-induced viral myocarditis in mice. These results demonstrated the beneficial effect of BBR on alleviating CVB3-induced myocarditis in vivo, which sheds new light on the utility of BBR as a therapeutic strategy against CVB3-induced viral myocarditis., (© 2020 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Competing Interests: The authors declare no conflict of interest.

Background: Immune checkpoint inhibitors are effective therapies for a wide range of malignancies. Their increased use has led to a wide range of immune-related adverse effects including skin, gastrointestinal, pulmonary, endocrine, cardiac, and neurologic complications., Case Presentation: We present the case of a 72-year-old Caucasian man with non-small cell lung cancer who was admitted for dyspnea after two cycles of durvalumab. He was found to have significantly elevated levels of serum creatinine kinase and troponin with a negative cardiac catheterization. During his hospitalization, he developed progressive dyspnea and new-onset axial weakness, ultimately leading to the diagnosis of durvalumab-induced myocarditis, myasthenia gravis, and myositis., Conclusion: This is, to our knowledge, the first reported case of anti-programmed cell death ligand 1-induced combination of myocarditis, myasthenia gravis, and myositis. While the use of immunologic agents has resulted in overall improved cancer outcomes, their increased use has led to a vast spectrum of immune-related adverse effects. We review the diagnostic workup and management of patients with these immune-related adverse effects, underscoring the importance of early identification given the potential for rapid deterioration.

Background: The functional characteristics of NLRP3 in the pathogenesis of coxsackievirus B3- (CVB3-) induced viral myocarditis (VMC) have not been fully elucidated, and the targeted therapeutic effect of NLRP3 or its related pathway in VMC has not been reported., Method: In this work, the change patterns of NLRP3- and Th17-related factors were detected during the pathological process of CVB3-induced VMC in Balb/c mice. The correlation between NLRP3 and Th17 cells during the VMC process was analyzed by Spearman test. The coculture system of spleen CD4 + T and bone marrow CD11c + DC cells was set to explore the orchestration of NLRP3 and Th17 in the pathological development of VMC in vitro. Anti-IL-1 β antibody or NLRP3 -/- Balb/c were used to block the NLRP3 pathway indirectly and directly to analyze the NLRP3-targeting therapeutic value., Results: The change patterns of NLRP3- and Th17-related molecules in the whole pathological process of mouse CVB3-induced VMC were described. Through Spearman correlation analysis, it was confirmed that there was a close correlation between NLRP3 and Th17 cells in the whole pathological process of VMC. And the interaction mode between NLRP3 and Th17 was preliminarily explored in the cell experiment in vitro. Under the intervention of an anti-IL-1 β antibody or NLRP3 knockout, the survival rate of the intervention group was significantly improved, the degree of myocardial inflammation and fibrosis was significantly alleviated, and the content of myocardial IL-17 and spleen Th17 was also significantly decreased., Conclusion: Our findings demonstrated a key role of the NLRP3 inflammasome and its close relationship with Th17 in the pathological progression of CVB3-induced VMC and suggested a possible positive feedback-like mutual regulation mechanism between the NLRP3 inflammasome and Th17 in vitro and in the early stage of CVB3 infection. Taking NLRP3 as a new starting point, it provides a new target and idea for the prevention and treatment of CVB3-induced VMC., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Jifei Chen et al.)

Introduction: Intravenous immunoglobulin (IVIg) is currently used with considerable success for the treatment of many autoimmune diseases, including systemic lupus erythematosus (SLE). Among its various indications, IVIg has also been found to be beneficial in myocarditis, whether or not it is associated with an autoimmune disease. Nevertheless, data regarding IVIg treatment for myocarditis/cardiomyopathy in patients with SLE are sparse. The objective of this case series was to describe our experience with IVIg as a treatment for lupus myocarditis and to review the literature for IVIg for this indication., Patient Concerns: We report 5 female patients with SLE, who presented with signs of acute heart failure including pulmonary congestion and arrhythmias., Diagnosis: Echocardiography demonstrated new reduced left ventricular ejection fraction of 20% to 30%. Two patients underwent coronary artery angiography, which demonstrated normal coronary arteries, supporting the diagnosis of myocarditis or nonischemic cardiomyopathy., Interventions: High-dose IVIg treatment was initiated in all 5 patients., Outcomes: Following the treatment, clinical and echocardiographic improvement in cardiac function occurred within a few days to 1 month. This dramatic improvement persisted for several years., Conclusion: Based on our case series, we believe that IVIg has an important role in the management of lupus acute cardiomyopathy. This safe, well-tolerated optional treatment should be considered, especially in severe cases., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: This study aimed to evaluate the protective effect of quercetin and its in-depth mechanism in TNF-α-stimulated cardiomyocytes. The differential expression of TNF-alpha (TNF-α) and signal transducer and activator of transcription 1 (STAT1) was analyzed based on the GEO database. H9c2 cells were stimulated with TNF-α to simulate myocarditis. Cell counting kit-8 assay and flow cytometry assay were performed to detect the cell viability and apoptosis. ELISA was used to measure the levels of proinflammatory cytokines (IL-6 and IL-17A) and anti-inflammatory cytokine (IL-10). STAT1 expression was downregulated by transfection with si-STAT1, and its expression was detected using quantitative real-time polymerase chain reaction and Western blot. Western blot was also performed to assess the expression of the mitogen-activated protein kinase (MAPK) pathway-related factors. In this article, TNF-α was highly expressed in patients with myocarditis, and TNF-α (20 μg/mL) declined the viability of H9c2 cells. Quercetin pretreatment partially alleviated the decrease of cell viability, the increase of apoptosis, and the release of inflammatory cytokines (IL-10, IL-6, and IL-17A) induced by TNF-α. In addition, TNF-α increased STAT1 expression, but quercetin prevented the TNF-α-increased STAT1 level. Remarkably, knockdown of STAT1 enhanced the protective effect of quercetin on TNF-α-injured H9c2 cells. Moreover, quercetin restrained the TNF-α-induced activation of the MAPK pathway. Also, the inhibitory effect of quercetin on the pathway was aggravated by STAT1 lacking. In summing, quercetin plays a protective role in TNF-α-stimulated H9c2 cell injury, which may be related to the regulation of STAT1 and MAPK pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Experimental autoimmune myocarditis (EAM) is characterized by pronounced macrophage infiltration, cardiac necrosis, and cardiac fibrosis. Our previous studies have demonstrated that suppressed androgen receptor (AR) enables anti-inflammation to promote tissue repair by decreasing M1 macrophages and increasing M2 macrophages in an EAM model. Given that autophagy mediates inflammatory response in macrophages, we investigated whether AR inhibition executes its protective role in inflammation through the autophagy pathway in EAM., Materials and Methods: To determine whether AR inhibition can perform its anti-inflammatory effects by upregulating autophagy, we pre-treated mice with 3-methyl adenine (3-MA), a pharmacological inhibitor of autophagy. Immunofluorescence assay and Western blot were used to detect autophagy levels and autophagy activity in five different groups. Immunofluorescence marked F4/80 and LC3 to illustrate the autophagy level in macrophages. TUNEL assays were used to detect the apoptosis level in heart tissue of five different groups., Results: We demonstrated that AR inhibition resolves injury with sustained inhibition of inflammatory cytokines associated with enhanced autophagy, especially in macrophages. Increased LC3II/I expression corroborated complete autolysosome formation detected by electron microscopy and correlated with degradation of SQSTM1/p62 in the AR inhibition group by Western blot. These effects could be reversed within 3-MA, a pharmacological inhibitor of autophagy. Specifically, pharmacological inhibition of autophagy increased apoptosis and inflammation, which could be attenuated by AR inhibition., Conclusions: AR inhibition alleviates the inflammatory response and tissue apoptosis by enhancing autophagy, especially in macrophages.

The cardiac effects of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include myocarditis, takotsubo cardiomyopathy, pericardial effusion, and cardioembolic events in the general population. The effects of SARS-CoV-2 in heart transplant patients are unclear. We describe a case of myocarditis in the transplanted heart that responded to methylprednisolone., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Interleukin-16 (IL-16) is an important inflammatory regulator and has been shown to have a powerful effect on the regulation of the inflammatory response. Cardiac inflammation has been reported to be closely related to doxorubicin- (DOX-) induced cardiac injury. In this study, the role of IL-16 in DOX-induced cardiac injury and the possible mechanisms were examined., Methods: Cardiac IL-16 levels were first measured in DOX- or saline-treated mice. Additionally, mice were pretreated with the anti-IL-16-neutralizing antibody (nAb) or isotype IgG for 1 day and further administered DOX or saline for 5 days. Then, cardiac injury, cardiac M1 macrophage levels, and cardiomyocyte apoptosis were analyzed. The effects of the anti-IL-16 nAb on macrophage differentiation and cardiomyocyte apoptosis were also investigated in vitro., Results: DOX administration increased IL-16 expression in cardiac macrophages compared with that of saline treatment. The anti-IL-16 nAb significantly decreased serum levels of lactate dehydrogenase (LDH), myocardial-bound creatine kinase (CK-MB), and cardiac troponin T (cTnT) and elevated cardiac function in DOX-induced mice. Treatment with the anti-IL-16 nAb also reduced p65 pathway activation, decreased M1 macrophage-related marker and cytokine expression, and protected against cardiomyocyte apoptosis in DOX-induced mice. In cell studies, the anti-IL-16 nAb also reduced DOX-induced M1 macrophage differentiation and alleviated apoptosis in cardiomyocytes cocultured with macrophages., Conclusions: The anti-IL-16 nAb protects against DOX-induced cardiac injury by reducing cardiac inflammation, and IL-16 may be a promising target to prevent DOX-related cardiac injury., Competing Interests: The authors declare that they have no conflicts of conflicts., (Copyright © 2021 Jianwei Zhang et al.)

A 37-year-old immunocompromised woman was admitted with palpitations, fevers and myalgias. An echocardiogram demonstrated a mass in the right atrial walls and interatrial septum. Endovascular biopsy of the myocardium revealed neutrophilic necrotising myocarditis isolated to the right atrium. Multiple blood, urine and stool cultures were negative but a high anti-streptolysin O antibody titre was detected. The combination of these findings led to the working diagnosis of necrotising myocarditis. Without a positive culture, it was not possible to definitively state the cause of this condition. She was treated with intravenous antibiotics and continued to improve physically and biochemically on discharge., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A previously healthy 16-year-old adolescent was admitted to our hospital with fever, sore throat, diarrhoea, strawberry tongue, rashes on lower extremities, and pain in the neck, abdomen and joints. He was initially diagnosed with IgA vasculitis triggered by acute pharyngitis. Despite antibiotic treatment, he gradually developed multiorgan failure and cardiac shock. Cardiac catheterisation did not show any signs of coronary artery disease. Subsequently, he developed serious rhabdomyolysis and peripheral extremity necrosis, suggesting peripheral arteritis. Although blood culture results were negative, he received endotoxin adsorption therapy, but it was ineffective. Hence, we suspected Kawasaki disease (KD). We administered high-dose intravenous immunoglobulin therapy (2 g/kg), which was effective. He gradually recovered without major complications and was given ambulatory discharge 43 days after admission. Early diagnosis and administration of intensive care in adolescents with KD with acute myocarditis are critical but challenging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

The monocyte β 2 -integrin Mac-1 is crucial for leukocyte-endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the α M I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry. Homology modelling and docking studies defined distinct interaction sites which were verified by mutagenesis. Intravital microscopy showed reduced leukocyte-endothelium adhesion in mice treated with this DARPin. Using mouse models of sepsis, myocarditis and ischaemia/reperfusion injury, we demonstrate therapeutic anti-inflammatory effects. Finally, the activated Mac-1-specific DARPin is established as a tool to detect monocyte activation in patients receiving extra-corporeal membrane oxygenation, as well as suffering from sepsis and ST-elevation myocardial infarction. The activated Mac-1-specific DARPin F7 binds preferentially to activated monocytes, detects inflammation in critically ill patients, and inhibits monocyte and neutrophil function as an efficient new anti-inflammatory agent.

Wei and colleagues showcase a genetic mouse model of immune-mediated myocarditis that shares homology with immune checkpoint inhibitor (CPI)-induced myocarditis in patients with cancer. They demonstrate that abatacept (CTLA4-Ig) limits cardiac toxicity in the mouse model and, thus, may ameliorate the CPI-induced myocarditis in patients with cancer while potentially maintaining antitumor activity. See related article by Wei et al., p. 614 ., (©2021 American Association for Cancer Research.)

Background: Clozapine is the only medication with Food and Drug Administration approval for treatment-resistant schizophrenia. However, it is underutilized in the United States because of several life-threatening adverse effects, including clozapine-associated myocarditis (CAM), and a limited understanding of how to manage these complications. To date, recommendations for rechallenging patients with CAM that incorporate the cardiac literature or cardioprotective medications have not been developed., Findings: In this article, we outline a protocol developed with cardiologists and guided by the cardiac literature that provides direction on how to monitor for the initial development of CAM and how to rechallenge patients with CAM. Furthermore, we present 2 successful cases of clozapine rechallenge that were managed using this protocol., Conclusions: In both cases, the patients showed marked improvement in their psychiatric symptoms and functioning, demonstrating the importance of considering rechallenge in patients after CAM., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We present, to our knowledge, the first case of immunosuppressive therapy (IST) application in a 12-year-old child with arrhythmogenic inflammatory cardiomyopathy resulting from the overlap between autoimmune myocarditis and primary arrhythmogenic cardiomyopathy. Indication to off-lable IST was compelling, because of recurrent drug-refractory ventricular arrhythmias (VAs). We show that IST was feasible, safe, and effective on multiple clinical endpoints, including symptoms, VA recurrences, and T-troponin release. Remarkably, all diagnostic and therapeutic strategies were worked out by a dedicated multidisciplinary team, including specialized pediatric immunologists., (© 2020 Wiley Periodicals LLC.)

We herein report the case of a 75-year-old man with asymptomatic immune checkpoint inhibitor (ICI)-associated myocarditis diagnosed on the basis of elevated levels of creatine kinase (CK), CK-myocardial band and troponin I (TNI). He was suspected of being complicated with myasthenia gravis (MG). High-dose prednisolone (PSL) is associated with a risk of MG exacerbation; therefore, PSL therapy was gradually increased from 5 mg/day to 20 mg/day, which resulted in the normalization of the TNI level, and no PSL-related side effects occurred. MG easily complicates myocarditis as an immune-related adverse event; thus, the treatment plan should be carefully considered.

A preclinical model of troponin I-induced myocarditis (AM) revealed a prominent role of the immunoproteasome (ip), the main immune cell-resident proteasome isoform, in heart-directed autoimmunity. Viral infection of the heart is a known trigger of cardiac autoimmunity, with the ip enhancing systemic inflammatory responses after infection with a cardiotropic coxsackievirusB3 (CV). Here, we used ip-deficient A/J-LMP7 -/- mice to investigate the role of ip-mediated effects on adaptive immunity in CV-triggered myocarditis and found no alteration of the inflammatory heart tissue damage or cardiac function in comparison to wild-type controls. Aiming to define the impact of the systemic inflammatory storm under the control of ip proteolysis during CV infection, we targeted the ip in A/J mice with the inhibitor ONX 0914 after the first cycle of infection, when systemic inflammation has set in, well before cardiac inflammation. During established acute myocarditis, the ONX 0914 treatment group had the same reduction in cardiac output as the controls, with inflammatory responses in heart tissue being unaffected by the compound. Based on these findings and with regard to the known anti-inflammatory role of ONX 0914 in CV infection, we conclude that the efficacy of ip inhibitors for CV-triggered myocarditis in A/J mice relies on their immunomodulatory effects on the systemic inflammatory reaction.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also referred to as COVID-19, was declared a pandemic by the World Health Organization in March 2020. The manifestations of COVID-19 are widely variable and range from asymptomatic infection to multi-organ failure and death. Like other viral illnesses, acute myocarditis has been reported to be associated with COVID-19 infection. However, guidelines for the diagnosis of COVID-19 myocarditis have not been established., Methods: Using a combination of search terms in the PubMed/Medline, Ovid Medline and the Cochrane Library databases and manual searches on Google Scholar and the bibliographies of articles identified, we reviewed all cases reported in the English language citing myocarditis associated with COVID-19 infection., Results: Fourteen records comprising a total of fourteen cases that report myocarditis/myopericarditis secondary to COVID-19 infection were identified. There was a male predominance (58%), with the median age of the cases described being 50.4 years. The majority of patients did not have a previously identified comorbid condition (50%), but of those with a past medical history, hypertension was most prevalent (33%). Electrocardiogram findings were variable, and troponin was elevated in 91% of cases. Echocardiography was performed in 83% of cases reduced function was identified in 60%. Endotracheal intubation was performed in the majority of cases. Glucocorticoids were most commonly used in treatment of myocarditis (58%). Majority of patients survived to discharge (81%) and 85% of those that received steroids survived to discharge., Conclusion: Guidelines for diagnosis and management of COVID-19 myocarditis have not been established and our knowledge on management is rapidly changing. The use of glucocorticoids and other agents including IL-6 inhibitors, IVIG and colchicine in COVID-19 myocarditis is debatable. In our review, there appears to be favorable outcomes related to myocarditis treated with steroid therapy. However, until larger scale studies are conducted, treatment approaches have to be made on an individualized case-by-case basis., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)