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IntroductionAcute myocarditis (AM) involves a complex inflammatory response. In certain patients, excessive inflammation leads to myocardial fibrosis and scar formation, however the full pathophysiology driving scar formation in AM remains unknown. Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, used to identify myocardial scar, is associated with worse prognosis in AM. This study aimed to identify inflammatory phenotypes in AM associated with formation and persistence of myocardial fibrosis and inflammation, quantified using LGE, and identify potential novel biomarkers of prognosis.MethodsThis retrospective cohort study included all patients presenting to King’s College Hospital NHS Trust with a CMR-confirmed diagnosis of AM. Baseline variables were collected, and included cytokines. CMR was used to quantify LGE mass at baseline and follow-up. The primary outcomes of this study were baseline LGE mass and change in LGE mass over follow-up.Results56 patients with CMR-confirmed AM were included, 68% were male, with a median age of 35 (IQR=26-46). Linear regression analyses showed that IL-10 and TNF-α were significantly correlated with LGE mass at baseline (p=0.025 and p=0.047, respectively). NLR and TNF-α performed invasive angiography first. were significantly correlated with change in LGE mass over follow-up (p=0.032 andp=0.047, respectively).ConclusionsInflammatory markers were predictive of scar formation and evolution on CMR. They may have a role in risk stratification in AM and identifying patients with a worse prognosis. Further studies with larger patient numbers are required to elucidate the mechanisms of cytokine involvement in scar formation and associations with outcome, and identify potential therapeutic targets.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.In this Review, Tschöpe and colleagues summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with special focus on virus-induced and virus-associated myocarditis. The authors also identify knowledge gaps, appraise available experimental models and propose future directions for the field.

Toxic myocarditis (TM) is rare, and no systematic evidence is available regarding its treatment or prognosis. Hydrocarbons even more rarely cause TM, and they are associated with severe extracardiac toxicity. Moreover, a pathogenic interaction between viral and toxic agents in TM has not been studied. We present the first case of biopsy-proven parvovirus B19 (B19V) viral fulminant myocarditis diagnosed after hydrocarbon exposure, along with a systematic literature review of hydrocarbon-TM cases. A systematic literature review was conducted by searching hydrocarbon-TM cases. Clinical and prognostic data were recorded. After screening of 937 records, 7 were included. All cases were male, with a median age of 24 years (IQR 23–25). Chest pain and dyspnea were the main symptoms, but arrhythmic presentation was also reported; endomyocardial biopsy (EMB) was performed in only one case. Overall, treatment was based on supportive measures, such as antiarrhythmic and/or vasoactive therapy. Our example (male, 47 years old) is the first reported fulminant biopsy-proven case diagnosed after a massive exposure to hydrocarbons, in which EMB molecular analysis unexpectedly revealed B19V with a high viral load. Hemodynamic and arrhythmic instability required percutaneous stellate ganglion blockade and temporary wearable defibrillator use. Left ventricular function spontaneously normalized at 3 months. In conclusion, we report the first fulminant B19V myocarditis case temporally associated with aromatic hydrocarbon exposure due to a coexistence of viral and toxic causes. Our case and the systematic review show that promptly performing EMB can provide a definitive diagnosis and guide treatment, especially in severe cases in which infectious agents may contribute to myocardial damage.

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy 1 . The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1 –/– Ctla4 +/– mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration 2 . Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1 –/– Ctla4 +/– mice, we identify clonal effector CD8 + T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1 –/– Ctla4 +/– mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8 + T cells. The cardiac-specific protein α-myosin, which is absent from the thymus 3 , 4 , was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8 + T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity. Cytotoxic CD8 + T cells specific for α-myosin are identified as pivotal players in myocarditis associated with immune checkpoint inhibitor anticancer therapies.

Severe influenza infection represents a leading cause of global morbidity and mortality. Although influenza is primarily considered a viral infection that results in pathology limited to the respiratory system, clinical reports suggest that influenza infection is frequently associated with a number of clinical syndromes that involve organ systems outside the respiratory tract. A comprehensive MEDLINE literature review of articles pertaining to extra‐pulmonary complications of influenza infection, using organ‐specific search terms, yielded 218 articles including case reports, epidemiologic investigations, and autopsy studies that were reviewed to determine the clinical involvement of other organs. The most frequently described clinical entities were viral myocarditis and viral encephalitis. Recognition of these extra‐pulmonary complications is critical to determining the true burden of influenza infection and initiating organ‐specific supportive care.

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.

BackgroundRheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.MethodsFirst, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.ResultsThe overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.ConclusionThese statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Key Points Myocarditis is a frequent cause of dilated cardiomyopathy with heterogeneous clinical presentations and a wide range of clinical outcomes After infection by a cardiotropic virus, a maladaptive post-viral response ensues, which can cause myocardial cell dysfunction and compromised contractility Advances in our diagnostic capabilities using cardiac MRI as well as molecular detection of viruses by endomyocardial biopsy have improved our understanding and ability to characterize the disease Although comprehensive clinical recommendations specific to the treatment of myocarditis do not exist, modulation of the immune system is a promising therapeutic strategy as suggested by several randomized trials This Review explores the pathophysiology and natural history of viral myocarditis—a common cause of dilated cardiomyopathy and sudden cardiac death. Despite established standards, heterogeneity exists in the evaluation, diagnosis, and treatment of patients with myocarditis, and these aspects are also covered in detail by Pollack and colleagues. Investigational treatment options are highlighted. Myocarditis—a frequent cause of dilated cardiomyopathy and sudden cardiac death—typically results from cardiotropic viral infection followed by active inflammatory destruction of the myocardium. Characterization of this disease has been hampered by its heterogeneous clinical presentations and diverse aetiologies. Advances in cardiac MRI and molecular detection of viruses by endomyocardial biopsy have improved our ability to diagnose and understand the pathophysiological mechanisms of this elusive disease. However, therapeutic options are currently limited for both the acute and chronic phases of myocarditis. Several randomized, controlled trials have demonstrated potential benefit with immunosuppressive and immunomodulatory therapies, but further investigations are warranted. In this Review, we explore the pathophysiology, natural history, and modes of diagnosis of myocarditis, as well as evidence-based treatment strategies. As novel imaging techniques and human in vitro models of the disease emerge, the landscape of therapies for myocarditis is poised to improve.

Human umbilical cord mesenchymal stem cell‐derived exosomes (hucMSC‐exosomes) have been implicated as a novel therapeutic approach for tissue injury repair and regeneration, but the effects of hucMSC‐exosomes on coxsackievirus B3 (CVB3)‐induced myocarditis remain unknown. The object of the present study is to investigate whether hucMSC‐exosomes have therapeutic effects on CVB3‐induced myocarditis (VMC). HucMSC‐exosomes were identified using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and Western blot. The purified hucMSC‐exosomes tagged with PKH26 were tail intravenously injected into VMC model mice in vivo and used to administrate CVB3‐infected human cardiomyocytes (HCMs) in vitro, respectively. The effects of hucMSC‐exosomes on myocardial pathology injury, proinflammatory cytokines and cardiac function were evaluated through haematoxylin and eosin (H&E) staining, quantitative polymerase chain reaction (qPCR) and Doppler echocardiography. The anti‐apoptosis role and potential mechanism of hucMSC‐exosomes were explored using TUNEL staining, flow cytometry, immunohistochemistry, Ad‐mRFP‐GFP‐LC3 transduction and Western blot. In vivo results showed that hucMSC‐exosomes (50 μg iv) significantly alleviated myocardium injury, shrank the production of proinflammatory cytokines and improved cardiac function. Moreover, in vitro data showed that hucMSC‐exosomes (50 μg/mL) inhibited the apoptosis of CVB3‐infected HCM through increasing pAMPK/AMPK ratio and up‐regulating autophagy proteins LC3II/I, BECLIN‐1 and anti‐apoptosis protein BCL‐2 as well as decreasing pmTOR/mTOR ratio, promoting the degradation of autophagy flux protein P62 and down‐regulating apoptosis protein BAX. In conclusion, hucMSC‐exosomes could alleviate CVB3‐induced myocarditis via activating AMPK/mTOR‐mediated autophagy flux pathway to attenuate cardiomyocyte apoptosis, which will be benefit for MSC‐exosome therapy of myocarditis in the future.