Exercise Training Reduces Inflammation and Fibrosis and Preserves Myocardial Function and Perfusion in a Model of Chronic Chagas Cardiomyopathy. / Treinamento Físico Reduz a Inflamação e a Fibrose e Preserva a Função e a Perfusão Miocárdica em um Modelo de Cardiomiopatia Chagásica Crônica.

BACKGROUND: Chronic Chagas cardiomyopathy (CCC) is caused by an inflammatory process induced by Trypanosoma cruzi, which leads to myocarditis with reactive and reparative fibrosis. CCC progresses with myocardial perfusion abnormalities and histopathological events that affect cardiorespiratory fitness (CRF). OBJECTIVES: We evaluated the effects of aerobic physical training (APT) on myocardial perfusion and on morphological and functional impairments related with inflammation and fibrosis in Syrian hamsters with CCC. As a secondary objective, we analyzed the cross-sectional areas of the skeletal muscle. METHODS: Hamsters with CCC and their respective controls were divided into four groups: CCC sedentary, CCC-APT, sedentary control and APT control. Seven months after infection, the animals underwent echocardiography, myocardial perfusion scintigraphy and cardiopulmonary exercise testing. Moderate-intensity APT was performed for fifty minutes, five times a week, for eight weeks. Subsequently, the animals were reassessed. Histopathological analysis was conducted after the above-mentioned procedures. The level of significance was set at 5% in all analyses (p<0.05). RESULTS: CCC sedentary animals presented worse myocardial perfusion defects (MPD) over time, reduced left ventricle ejection fraction (LVEF) and showed more inflammation and fibrosis when compared to other groups (mixed ANOVA analysis). Conversely, APT was able to mitigate the progression of MPD, ameliorate inflammation and fibrosis and improve CRF efficiency in CCC-APT animals. CONCLUSIONS: Our study demonstrated that APT ameliorated cardiac dysfunction, MPD, and reduced inflammation and fibrosis in CCC hamster models. Additionally, CCC-SED animals presented skeletal muscle atrophy while CCC-APT animals showed preserved skeletal muscle CSA. Understanding APT's effects on CCC's pathophysiological dimensions is crucial for future research and therapeutic interventions.

FUNDAMENTO: A Cardiomiopatia Chagásica Crônica (CCC) é causada por um processo inflamatório induzido pelo Trypanosoma cruzi, que leva à miocardite com fibrose reativa e reparativa. A CCC progride com alterações de perfusão miocárdica e eventos histopatológicos que afetam a Aptidão Cardiorrespiratória (ACR). OBJETIVOS: Avaliamos os efeitos do Treinamento Físico Aeróbico (TFA) na perfusão miocárdica e nos comprometimentos morfológicos e funcionais relacionados à inflamação e fibrose em hamsters sírios com CCC. Como objetivo secundário, analisamos as áreas de secção transversa do músculo esquelético. MÉTODOS: Hamsters com CCC e seus respectivos controles foram divididos em quatro grupos: CCC sedentário, CCC-TFA, controle sedentário e controle TFA. Sete meses após a infecção, os animais foram submetidos à ecocardiografia, à cintilografia de perfusão miocárdica e ao teste de esforço cardiopulmonar. TFA de intensidade moderada foi realizado durante cinquenta minutos, cinco vezes por semana, por oito semanas. Posteriormente, os animais foram reavaliados. A análise histopatológica foi realizada após os procedimentos acima mencionados. O nível de significância foi estabelecido em 5% em todas as análises (p<0,05). RESULTADOS: Animais com CCC sedentários apresentaram piores Defeitos de Perfusão Miocárdica (DPM) ao longo do tempo, Fração de Ejeção do Ventrículo Esquerdo (FEVE) reduzida, e apresentaram mais inflamação e fibrose quando comparados aos demais grupos (análise ANOVA mista). Por outro lado, o TFA foi capaz de mitigar a progressão do DPM, atenuar a inflamação e a fibrose e melhorar a eficiência da ACR em animais CCC-TFA. CONCLUSÃO: Nosso estudo demonstrou que o TFA melhorou a disfunção cardíaca, DPM e reduziu a inflamação e a fibrose em modelos de hamster com CCC. Além disso, os animais CCC-SED apresentaram atrofia do músculo esquelético, enquanto os animais CCC-TFA apresentaram a AST do músculo esquelético preservada. Compreender os efeitos da TFA nas dimensões fisiopatológicas da CCC é crucial para futuras pesquisas e intervenções terapêuticas.

Fulminant Myocarditis in Patients With Autoimmune Disease That Requires Extracorporeal Membrane Oxygenation Support.

Myocarditis is a potentially life-threatening inflammatory disease of the myocardium, often resulting from infectious and immune-mediated responses. Clinical presentation in severe cases often results in a devastating illness requiring extracorporeal membrane oxygenation support as a result of cardiogenic shock. Although endomyocardial biopsy is still considered the gold standard for diagnosis, it often reveals nonspecific lymphocytic infiltration. Because the precise cause is usually unknown, the initial treatment typically involves immunosuppression and frequent assessment of myocardial contractility. This report presents 3 rare cases of autoimmune diseases (polymyositis, immunoglobulin G4-related disease, and systemic lupus erythematosus) that require extracorporeal membrane oxygenation support as a result of fulminant myocarditis, including their follow-up periods.

Viral myocarditis: From molecular mechanisms to therapeutic prospects.

Myocarditis is characterized as local or diffuse inflammatory lesions in the myocardium, primarily caused by viruses and other infections. It is a common cause of sudden cardiac death and dilated cardiomyopathy. In recent years, the global prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the widespread vaccination have coincided with a notable increase in the number of reported cases of myocarditis. In light of the potential threat that myocarditis poses to global public health, numerous studies have sought to elucidate the pathogenesis of this condition. However, despite these efforts, effective treatment strategies remain elusive. To collate the current research advances in myocarditis, and thereby provide possible directions for further research, this review summarizes the mechanisms involved in viral invasion of the organism and primarily focuses on how viruses trigger excessive inflammatory responses and in result in different types of cell death. Furthermore, this article outlines existing therapeutic approaches and potential therapeutic targets for the acute phase of myocarditis. In particular, immunomodulatory treatments are emphasized and suggested as the most extensively studied and clinically promising therapeutic options.

Coronavirus disease 2019-related myocarditis genes contribute to ECMO prognosis.

BACKGROUND: Acute myocardial injury, cytokine storms, hypoxemia and pathogen-mediated damage were the major causes responsible for mortality induced by coronavirus disease 2019 (COVID-19)-related myocarditis. These need ECMO treatment. We investigated differentially expressed genes (DEGs) in patients with COVID-19-related myocarditis and ECMO prognosis. METHODS: GSE150392 and GSE93101 were analyzed to identify DEGs. A Venn diagram was used to obtain the same transcripts between myocarditis-related and ECMO-related DEGs. Enrichment pathway analysis was performed and hub genes were identified. Pivotal miRNAs, transcription factors, and chemicals with the screened gene interactions were identified. The GSE167028 dataset and single-cell sequencing data were used to validate the screened genes. RESULTS: Using a Venn diagram, 229 overlapping DEGs were identified between myocarditis-related and ECMO-related DEGs, which were mainly involved in T cell activation, contractile actin filament bundle, actomyosin, cyclic nucleotide phosphodiesterase activity, and cytokine-cytokine receptor interaction. 15 hub genes and 15 neighboring DEGs were screened, which were mainly involved in the positive regulation of T cell activation, integrin complex, integrin binding, the PI3K-Akt signaling pathway, and the TNF signaling pathway. Data in GSE167028 and single-cell sequencing data were used to validate the screened genes, and this demonstrated that the screened genes CCL2, APOE, ITGB8, LAMC2, COL6A3 and TNC were mainly expressed in fibroblast cells; IL6, ITGA1, PTK2, ITGB5, IL15, LAMA4, CAV1, SNCA, BDNF, ACTA2, CD70, MYL9, DPP4, ENO2 and VEGFC were expressed in cardiomyocytes; IL6, PTK2, ITGB5, IL15, APOE, JUN, SNCA, CD83, DPP4 and ENO2 were expressed in macrophages; and IL6, ITGA1, PTK2, ITGB5, IL15, VCAM1, LAMA4, CAV1, ACTA2, MYL9, CD83, DPP4, ENO2, VEGFC and IL32 were expressed in vascular endothelial cells. CONCLUSION: The screened hub genes, IL6, ITGA1, PTK2, ITGB3, ITGB5, CCL2, IL15, VCAM1, GZMB, APOE, ITGB8, LAMA4, LAMC2, COL6A3 and TNFRSF9, were validated using GEO dataset and single-cell sequencing data, which may be therapeutic targets patients with myocarditis to prevent MI progression and adverse cardiovascular events.

Case report: Potential role of immunotherapy in thymic malignancies: a unique case of a durable and complete response upon an immune checkpoint inhibitor.

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.

Case report: eosinophilic myocarditis in hypereosinophilic syndrome: a journey to heart transplantation.

Introduction: Hypereosinophilic Syndrome (HES) is a rare disorder characterized by persistent elevation of eosinophils, leading to multi-organ infiltration and damage. Eosinophilic Myocarditis (EM) is one of its severe complications contributing significantly to morbidity and mortality. Herein, we describe the diagnostic and therapeutic challenges of EM, emphasizing the significance of early recognition and multidisciplinary management. Case presentation: A 51-year-old female with a history of EM, heart failure, and peripheral eosinophilia presented with NYHA class 3b symptoms. Laboratory findings revealed elevated peripheral eosinophil count, NT-Pro BNP, and characteristic electrocardiogram abnormalities. Imaging studies confirmed biventricular thrombi and myocardial abnormalities consistent with EM. Treatment involved Solu-Medrol for HES and heparin for ventricular thrombi, leading to initial clinical improvement. However, refractory heart failure necessitated urgent heart transplantation. Discussion: EM, an under-recognized complication of HES, poses diagnostic and management challenges. Management includes standard heart failure treatments, steroids, and emerging therapies like Mepolizumab. Early diagnosis and aggressive management are pivotal for improving outcomes in this rare and potentially fatal condition. Conclusion: Advancements in the detection of complications, surgical management, and therapeutic options have improved outcomes in HES. Ongoing research is essential to further understand and address the diagnostic and therapeutic challenges of HES and EM.

Autoimmune Myocarditis, Old Dogs and New Tricks.

Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.

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

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

Rationale and design of the French cohort of acute myocarditis diagnosed by cardiac magnetic resonance imaging (MyocarditIRM).

BACKGROUND: Acute myocarditis usually presents as chest pain with rising troponin and normal coronary arteries. Despite frequent favourable evolution at the acute phase, it is associated with heart failure and ventricular rhythm disorders, and is considered the leading cause of sudden cardiac death in young, apparently healthy, adults. There are no specific recommendations for acute myocarditis diagnosis and management, only expert consensus, given the lack of large databases. AIM: The main objective is to describe the contemporary presentation of acute myocarditis, its management and in-hospital outcomes. Secondary objectives are to investigate survival and event-free survival for up to 10years of follow-up, the determinants of prognosis, the modalities of treatment and follow-up and the gaps between expert consensus and real-life management. METHODS: MyocarditIRM is a prospective multicentre cohort that enrolled 803 consecutive patients with acute myocarditis in 49 participating centres in France between 01 May 2016 and 28 February 2019. The diagnosis of acute myocarditis was acknowledged by cardiac magnetic resonance, using the Lake Louise Criteria. Exclusion criteria were age<18years, lack of health coverage, contraindication to cardiac magnetic resonance and refusal to participate. Detailed information was collected prospectively, starting at admission. Cardiac magnetic resonance imaging (diagnosis and follow-up) is analysed centrally by the certified core laboratory IHU ICAN. Ten years of follow-up for each patient is ensured by linking with the French National Health Database, and includes information on death, hospital admissions, major clinical events and drug consumption. CONCLUSION: This prospective cohort with long-term follow-up represents the largest database on acute myocarditis worldwide, and will improve knowledge about its presentation, management and outcomes.

Cardiac magnetic resonance imaging (MRI) for detecting acute myocardial injury of fulminant myocarditis survivors after extracorporeal membrane oxygenation (ECMO) treatment in adults.

AIMS: To detect the acute myocardial injury in fulminant myocarditis (FM) survivors after extracorporeal membrane oxygenation (ECMO) and to demonstrate its significant differences from non-FM patients by cardiac magnetic resonance (CMR). MATERIALS AND METHODS: This retrospective study enrolled 59 patients with acute myocarditis (AM), including 35 non-FM patients, 24 FM patients, and 54 controls. The peak value of cardiac troponin T (cTnT) was recorded. Tissue parameters, including native T1, extracellular volume (ECV), late gadolinium-enhancement (LGE)%, and T2 by CMR were assessed. RESULTS: The mean age was 35 ± 14 years, and 45.8% of the population were males in the AM group. Patients had higher levels of peak cTnT, peak NT-proBNP and peak C-reactive protein in the FM group (all p<0.05). Comparing with non-FM, the values of T1-based imaging parameters were significantly higher in the FM group (all p<0.05). In contrast, no difference was observed among the two groups in terms of T2 value (p=0.707). The septal area was more frequently involved in FM survivors after ECMO treatment, both in T1 and T2-based images. In addition, the cubic relationship was the relative best fit of LGE% against logcTnT and indicated that cTnT value exceeding 300ng/L exhibited a rapid upward trend of LGE%. CONCLUSION: Comparing to non-FM, higher myocardial necrosis and fibrosis but similar edema determined by T1 and T2 based imaging was found in FM survivors after ECMO treatment. Furthermore, the inter-ventricular septal area was more frequently involved by acute myocardial injury in FM survivors after ECMO treatment. In addition, LGE% showed an overall increasing trend with cTnT values elevating with rapidly increasing with cTnT exceeding 300 ng/L.

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

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

Clinical analysis of temporary pacemaker implantation in 6 children with fulminant myocarditis.

BACKGROUND: There is little literature on the use of temporary pacemakers in children with fulminant myocarditis. Therefore, we summarized the use of temporary cardiac pacemakers in children with fulminant myocarditis in our hospital. METHODS: The clinical data of children with fulminant myocarditis treated with temporary pacemakers in Wuhan Children's Hospital from January 2017 to May 2022 were retrospectively analyzed. RESULTS: A total of 6 children were enrolled in the study, including 4 boys and 2 girls, with a median age of 50 months and a median weight of 15 kg. The average time from admission to pacemaker placement was 2.75 ± 0.4 h. The electrocardiogram showed that all 6 children had third-degree atrioventricular block (III°AVB). The initial pacing voltage, the sensory sensitivity of the ventricle and the pacing frequency were set to 5-10 mV, 5 V and 100-120 bpm respectively. The sinus rhythm was recovered in 5 patients within 61 h (17-134) h, and the median time of using temporary pacemaker was 132 h (63-445) h. One of the children had persistent III°AVB after the temporary pacemaker. With parental consent, the child was fitted with a permanent pacemaker on the 12th day of his illness. CONCLUSIONS: When fulminant myocarditis leads to severe bradycardia or atrioventricular block in children, temporary pacemakers have the characteristics of high safety to improve the heart function.

RNA m5C methylation modification: a potential therapeutic target for SARS-CoV-2-associated myocarditis.

The Corona Virus Disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has quickly spread worldwide and resulted in significant morbidity and mortality. Although most infections are mild, some patients can also develop severe and fatal myocarditis. In eukaryotic RNAs, 5-methylcytosine (m5C) is a common kind of post-transcriptional modification, which is involved in regulating various biological processes (such as RNA export, translation, and stability maintenance). With the rapid development of m5C modification detection technology, studies related to viral m5C modification are ever-increasing. These studies have revealed that m5C modification plays an important role in various stages of viral replication, including transcription and translation. According to recent studies, m5C methylation modification can regulate SARS-CoV-2 infection by modulating innate immune signaling pathways. However, the specific role of m5C modification in SARS-CoV-2-induced myocarditis remains unclear. Therefore, this review aims to provide insights into the molecular mechanisms of m5C methylation in SARS-CoV-2 infection. Moreover, the regulatory role of NSUN2 in viral infection and host innate immune response was also highlighted. This review may provide new directions for developing therapeutic strategies for SARS-CoV-2-associated myocarditis.

A review regarding the article 'The potential relationship between cardiovascular diseases and monkeypox'.

Cardiovascular involvement in the context of viral infections is a well-documented phenomenon, for their potential to induce myocarditis, pericarditis, and other cardiac complications. While monkeypox is predominantly known for its predilection for the skin and mucous membranes, manifesting as characteristic skin lesions, emerging research suggests that the monkeypox virus can also infiltrate endothelial cells, thereby disseminating systemically and potentially impacting various organ systems, including the cardiovascular system. This has led to the identification of several inflammatory conditions, such as myocarditis and pericarditis, which can complicate the clinical course of monkeypox virus infection. Notably, an increase in cardiac biomarkers, often associated with symptoms of chest pain, has been observed in case reports detailing monkeypox-induced myocarditis. From a clinical cardiology perspective, it is imperative to deepen our understanding of monkeypox to better recognize and manage its cardiovascular implications. Conditions like myocarditis, viral pericarditis, heart failure, and arrhythmias have been known to arise, significantly impacting patients' health and quality of life. A thorough comprehension of the intricate pathophysiological mechanisms underlying these cardiovascular manifestations is crucial for enhancing diagnostic accuracy and refining management strategies. The social implications of cardiovascular complications from viral infections are multifaceted, extending beyond direct health concerns to include psychological distress, social stigma, and broader public health considerations. The clinical management of these complications is challenging and necessitates a multidisciplinary approach, often requiring specialized care. The resultant strain on healthcare resources underscores the importance of preparedness and strategic resource allocation to effectively address these complex health issues.

Cardiovascular toxicity of immune therapies for cancer.

In addition to conventional chemoradiation and targeted cancer therapy, the use of immune based therapies, specifically immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T cell therapy (CAR-T), has increased exponentially across a wide spectrum of cancers. This has been paralleled by recognition of off-target immune related adverse events that can affect almost any organ system including the cardiovascular system. The use of ICIs has been associated with myocarditis, a less common but highly fatal adverse effect, pericarditis and pericardial effusions, vasculitis, thromboembolism, and potentially accelerated atherosclerosis. CAR-T resulting in a systemic cytokine release syndrome has been associated with myriad cardiovascular consequences including arrhythmias, myocardial infarction, and heart failure. This review summarizes the current state of knowledge regarding adverse cardiovascular effects associated with ICIs and CAR-T.

[Venoarterial extracorporeal membrane oxygenation: from evidence to clinical practice]. / Il supporto della circolazione extracorporea nelle emergenze cardiologiche: evidenze scientifiche e pratica clinica.

Mortality for cardiogenic shock is still high despite optimal pharmacological therapy. Therefore, active mechanical circulatory support devices are increasingly used; venoarterial extracorporeal membrane oxygenation (VA-ECMO) enables full circulatory and respiratory support. However, recent data show that in patients with infarct-related shock unselected early use of VA-ECMO does not improve survival and is associated with major bleeding and peripheral ischemic complications. Nowadays, waiting for the results of definitive randomized controlled trials, the main indication for ECMO utilization is in selected patients with cardiac arrest, in those with shock for advanced heart failure refractory to conventional therapy, in those with fulminant myocarditis, in patients candidate for heart transplant or ventricular assistance, especially in presence of respiratory insufficiency and severe biventricular dysfunction. An important recommendation is its utilization in specialized, high-volume centers in the setting of hub and spoke hospitals.