Viral Myocarditis as a Factor Leading to the Development of Heart Failure Symptoms, Including the Role of Parvovirus B19 Infection-Systematic Review.

Myocarditis (MC) is defined as an immunological inflammatory reaction with various etiologies, clinical presentations and prognoses within the myocardium. Currently, parvovirus B19 (PVB19) has become the main factor leading to this disease, replacing the previously dominant viruses A and B. In the case of chronic heart failure with subsequent dilated cardiomyopathy, approximately 67% have a viral etiology, and most of them are the result of PVB19 infection. However, the analysis showed a correlation between PVB19 infection and the risk of developing inflammatory dilated cardiomyopathy (DCMi). PVB19 is detected in 23% of patients with DCMi. Chronic infection may also contribute to progressive left ventricular failure in patients with a history of MC. The above effect suggests the active replication of PVB19 only in heart biopsies with inflammation due to MC or DCMi. Moreover, the supply of IFN-ß to suppress the active transcription of PVB19 accompanied by DCMi over a period of 6 months results in the normalization of NT-proBNP and an improvement in LVEF along with NYHA performance. The small number of reports on this topic and inaccuracies resulting from constantly conducted research and ongoing changes make it impossible to clearly answer the question of whether PVB19 is a factor inducing de novo MC and DCM or only accompanies the above conditions. However, large clinical cohort studies lead to the perception of PVB19 as a viral etiological agent capable of causing de novo MC together with DCMi.

Long-term cardiovascular inflammation and fibrosis in a murine model of vasculitis induced by Lactobacillus casei cell wall extract.

Background: Kawasaki disease (KD), an acute febrile illness and systemic vasculitis, is the leading cause of acquired heart disease in children in industrialized countries. KD leads to the development of coronary artery aneurysms (CAA) in affected children, which may persist for months and even years after the acute phase of the disease. There is an unmet need to characterize the immune and pathological mechanisms of the long-term complications of KD. Methods: We examined cardiovascular complications in the Lactobacillus casei cell wall extract (LCWE) mouse model of KD-like vasculitis over 4 months. The long-term immune, pathological, and functional changes occurring in cardiovascular lesions were characterized by histological examination, flow cytometric analysis, immunofluorescent staining of cardiovascular tissues, and transthoracic echocardiogram. Results: CAA and abdominal aorta dilations were detected up to 16 weeks following LCWE injection and initiation of acute vasculitis. We observed alterations in the composition of circulating immune cell profiles, such as increased monocyte frequencies in the acute phase of the disease and higher counts of neutrophils. We determined a positive correlation between circulating neutrophil and inflammatory monocyte counts and the severity of cardiovascular lesions early after LCWE injection. LCWE-induced KD-like vasculitis was associated with myocarditis and myocardial dysfunction, characterized by diminished ejection fraction and left ventricular remodeling, which worsened over time. We observed extensive fibrosis within the inflamed cardiac tissue early in the disease and myocardial fibrosis in later stages. Conclusion: Our findings indicate that increased circulating neutrophil counts in the acute phase are a reliable predictor of cardiovascular inflammation severity in LCWE-injected mice. Furthermore, long-term cardiac complications stemming from inflammatory cell infiltrations in the aortic root and coronary arteries, myocardial dysfunction, and myocardial fibrosis persist over long periods and are still detected up to 16 weeks after LCWE injection.

Cryptic late-onset myocarditis after coronavirus vaccination.

As we enter a new era of mRNA-based therapeutics, evidence on genetic or environmental factors that might predispose to unknown off-target side effects, gains in importance. Among these factors, exercise appears likely to have influenced otherwise cryptic cases of early-onset postvaccination myocarditis. And the existence of a distinct late-onset myocarditis is now being recognized. Here, three case-history reports suggest crypticity (the author's own case), unless provoked by a preexisting cardiac morbidity (one case), or by immune checkpoint blockade to enhance anticancer autoimmunity (several cases). These reports are supported by noninvasive fluorodeoxyglucose-based cardiac scan comparisons of multiple vaccinated and unvaccinated subjects. In pre-pandemic decades, applications for funds by the leading innovator in mRNA-based therapeutics seldom gained peer-review approval. Thus, at the start of the pandemic, the meager data on such side effects could justify only emergency approval. We must do better.

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.

Early identification of severe immune checkpoint inhibitor associated myocarditis: From an electrocardiographic perspective.

OBJECTIVES: Immune checkpoint inhibitor (ICI)-associated myocarditis, particularly severe ICI-associated myocarditis, has a high mortality rate. However, the predictive value of electrocardiogram (ECG) remains unclear. The present study aimed to evaluate the predictive value of clinical and electrocardiographic parameters for severe myocarditis. METHODS: Clinical and electrocardiographic data of 73 cancer patients with ICI-associated myocarditis were retrospectively collected. The severity of ICI-associated myocarditis was graded using the NCCN guidelines for managing immunotherapy-related toxicities. Myocarditis grades 1-2 and grades 3-4 were classified as mild and severe myocarditis, respectively. Logistic regression analysis was performed to analyze the predictive value of each parameter in predicting severe myocarditis. RESULTS: Among the 73 patients with myocarditis, 20 (27.4%) patients had severe myocarditis. Compared with mild myocarditis group, sinus tachycardia (p = 0.001), QRS duration ≥110 ms (p = 0.001), prolonged QTc interval (p < 0.001), and bundle branch block (p = 0.007) at the time of myocarditis were more common in the severe myocarditis group. Logistic regression analysis revealed that sinus tachycardia (p = 0.028) and QTc interval prolongation (p = 0.007) were predictors of severe myocarditis. Whereas the predictive value of other electrocardiographic parameters was weak. Concurrent targeted therapy didn't increase the risk of severe myocarditis. A high NT-proBNP level was associated with severe myocarditis. CONCLUSIONS: ECG at the onset of myocarditis manifested as sinus tachycardia and prolonged QTc interval predicted a high risk of severe myocarditis. Early detection of ECG abnormalities may faciliate early detection of severe ICI-associated myocarditis.

Cohort study of cardiovascular safety of different COVID-19 vaccination doses among 46 million adults in England.

The first dose of COVID-19 vaccines led to an overall reduction in cardiovascular events, and in rare cases, cardiovascular complications. There is less information about the effect of second and booster doses on cardiovascular diseases. Using longitudinal health records from 45.7 million adults in England between December 2020 and January 2022, our study compared the incidence of thrombotic and cardiovascular complications up to 26 weeks after first, second and booster doses of brands and combinations of COVID-19 vaccines used during the UK vaccination program with the incidence before or without the corresponding vaccination. The incidence of common arterial thrombotic events (mainly acute myocardial infarction and ischaemic stroke) was generally lower after each vaccine dose, brand and combination. Similarly, the incidence of common venous thrombotic events, (mainly pulmonary embolism and lower limb deep venous thrombosis) was lower after vaccination. There was a higher incidence of previously reported rare harms after vaccination: vaccine-induced thrombotic thrombocytopenia after first ChAdOx1 vaccination, and myocarditis and pericarditis after first, second and transiently after booster mRNA vaccination (BNT-162b2 and mRNA-1273). These findings support the wide uptake of future COVID-19 vaccination programs.

High-Fat Diet Augments Myocardial Inflammation and Cardiac Dysfunction in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is a familial heart disease characterized by cardiac dysfunction, arrhythmias, and myocardial inflammation. Exercise and stress can influence the disease's progression. Thus, an investigation of whether a high-fat diet (HFD) contributes to ACM pathogenesis is warranted. In a robust ACM mouse model, 8-week-old Desmoglein-2 mutant (Dsg2mut/mut) mice were fed either an HFD or rodent chow for 8 weeks. Chow-fed wildtype (WT) mice served as controls. Echo- and electrocardiography images pre- and post-dietary intervention were obtained, and the lipid burden, inflammatory markers, and myocardial fibrosis were assessed at the study endpoint. HFD-fed Dsg2mut/mut mice showed numerous P-wave perturbations, reduced R-amplitude, left ventricle (LV) remodeling, and reduced ejection fraction (%LVEF). Notable elevations in plasma high-density lipoprotein (HDL) were observed, which correlated with the %LVEF. The myocardial inflammatory adipokines, adiponectin (AdipoQ) and fibroblast growth factor-1, were substantially elevated in HFD-fed Dsg2mut/mut mice, albeit no compounding effect was observed in cardiac fibrosis. The HFD not only potentiated cardiac dysfunction but additionally promoted adverse cardiac remodeling. Further investigation is warranted, particularly given elevated AdipoQ levels and the positive correlation of HDL with the %LVEF, which may suggest a protective effect. Altogether, the HFD worsened some, but not all, disease phenotypes in Dsg2mut/mut mice. Notwithstanding, diet may be a modifiable environmental factor in ACM disease progression.

Unveiling Cellular Identities and Gene Expression Pathways in Overlapping Myocarditis and Myositis.

Immune checkpoint therapies can drive antitumor responses and benefit patients but can also induce life-threatening immune-related adverse events such as myocarditis and myositis. These immune-related adverse events are rare but carry substantial morbidity and mortality. In this issue, Siddiqui and colleagues use single-cell RNA and T-cell receptor sequencing to identify novel cellular subsets and propose various mechanisms that could contribute to the pathogenesis of immune checkpoint inhibitor-associated myocarditis and myositis. These new insights should help move the field toward the development of improved treatment and prevention options, ultimately improving patient outcomes. See related article by Siddiqui et al., p. 964 (1).

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.

Incidence and management of the main serious adverse events reported after COVID-19 vaccination.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2n first appeared in Wuhan, China in 2019. Soon after, it was declared a pandemic by the World Health Organization. The health crisis imposed by a new virus and its rapid spread worldwide prompted the fast development of vaccines. For the first time in human history, two vaccines based on recombinant genetic material technology were approved for human use. These mRNA vaccines were applied in massive immunization programs around the world, followed by other vaccines based on more traditional approaches. Even though all vaccines were tested in clinical trials prior to their general administration, serious adverse events, usually of very low incidence, were mostly identified after application of millions of doses. Establishing a direct correlation (the cause-effect paradigm) between vaccination and the appearance of adverse effects has proven challenging. This review focuses on the main adverse effects observed after vaccination, including anaphylaxis, myocarditis, vaccine-induced thrombotic thrombocytopenia, Guillain-Barré syndrome, and transverse myelitis reported in the context of COVID-19 vaccination. We highlight the symptoms, laboratory tests required for an adequate diagnosis, and briefly outline the recommended treatments for these adverse effects. The aim of this work is to increase awareness among healthcare personnel about the serious adverse events that may arise post-vaccination. Regardless of the ongoing discussion about the safety of COVID-19 vaccination, these adverse effects must be identified promptly and treated effectively to reduce the risk of complications.

Pathogenic mechanisms of cardiovascular damage in COVID-19.

BACKGROUND: COVID-19 is a new infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2). Since the outbreak in December 2019, it has caused an unprecedented world pandemic, leading to a global human health crisis. Although SARS CoV-2 mainly affects the lungs, causing interstitial pneumonia and severe acute respiratory distress syndrome, a number of patients often have extensive clinical manifestations, such as gastrointestinal symptoms, cardiovascular damage and renal dysfunction. PURPOSE: This review article discusses the pathogenic mechanisms of cardiovascular damage in COVID-19 patients and provides some useful suggestions for future clinical diagnosis, treatment and prevention. METHODS: An English-language literature search was conducted in PubMed and Web of Science databases up to 12th April, 2024 for the terms "COVID-19", "SARS CoV-2", "cardiovascular damage", "myocardial injury", "myocarditis", "hypertension", "arrhythmia", "heart failure" and "coronary heart disease", especially update articles in 2023 and 2024. Salient medical literatures regarding the cardiovascular damage of COVID-19 were selected, extracted and synthesized. RESULTS: The most common cardiovascular damage was myocarditis and pericarditis, hypertension, arrhythmia, myocardial injury and heart failure, coronary heart disease, stress cardiomyopathy, ischemic stroke, blood coagulation abnormalities, and dyslipidemia. Two important pathogenic mechanisms of the cardiovascular damage may be direct viral cytotoxicity as well as indirect hyperimmune responses of the body to SARS CoV-2 infection. CONCLUSIONS: Cardiovascular damage in COVID-19 patients is common and portends a worse prognosis. Although the underlying pathophysiological mechanisms of cardiovascular damage related to COVID-19 are not completely clear, two important pathogenic mechanisms of cardiovascular damage may be the direct damage of the SARSCoV-2 infection and the indirect hyperimmune responses.

TGF-ß Signalling Regulates Cytokine Production in Inflammatory Cardiac Macrophages during Experimental Autoimmune Myocarditis.

Myocarditis is characterized by an influx of inflammatory cells, predominantly of myeloid lineage. The progression of myocarditis to a dilated cardiomyopathy is markedly influenced by TGF-ß signalling. Here, we investigate the role of TGF-ß signalling in inflammatory cardiac macrophages in the development of myocarditis and post-inflammatory fibrosis. Experimental autoimmune myocarditis (EAM) was induced in the LysM-Cre × R26-stop-EYFP × Tgfbr2-fl/fl transgenic mice showing impaired TGF-ß signalling in the myeloid lineage and the LysM-Cre × R26-stop-EYFP control mice. In EAM, immunization led to acute myocarditis on day 21, followed by cardiac fibrosis on day 40. Both strains showed a similar severity of myocarditis and the extent of cardiac fibrosis. On day 21 of EAM, an increase in cardiac inflammatory macrophages was observed in both strains. These cells were sorted and analysed for differential gene expression using whole-genome transcriptomics. The analysis revealed activation and regulation of the inflammatory response, particularly the production of both pro-inflammatory and anti-inflammatory cytokines and cytokine receptors as TGF-ß-dependent processes. The analysis of selected cytokines produced by bone marrow-derived macrophages confirmed their suppressed secretion. In conclusion, our findings highlight the regulatory role of TGF-ß signalling in cytokine production within inflammatory cardiac macrophages during myocarditis.

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.

Cardiovascular Safety of COVID-19 Vaccination in Patients With Cancer: A Self-Controlled Case Series Study in Korea.

BACKGROUND: Cancer patients have an increased risk of cardiovascular outcomes and are susceptible to coronavirus disease 2019 (COVID-19) infection. We aimed to assess the cardiovascular safety of COVID-19 vaccination for cancer patients in South Korea. METHODS: We conducted a self-controlled case series study using the K-COV-N cohort (2018-2021). Patients with cancer aged 12 years or older who experienced cardiovascular outcomes were identified. Cardiovascular outcomes were defined as myocardial infarction, stroke, venous thromboembolism (VTE), myocarditis, or pericarditis, and the risk period was 0-28 days after receiving each dose of COVID-19 vaccines. A conditional Poisson regression model was used to calculate the incidence rate ratio (IRR) with 95% confidence interval (CI). RESULTS: Among 318,105 patients with cancer, 4,754 patients with cardiovascular outcomes were included. The overall cardiovascular risk was not increased (adjusted IRR, 0.99 [95% CI, 0.90-1.08]) during the whole risk period. The adjusted IRRs of total cardiovascular outcomes during the whole risk period according to the vaccine type were 1.07 (95% CI, 0.95-1.21) in the mRNA vaccine subgroup, 0.99 (95% CI, 0.83-1.19) in the ChAdOx1 nCoV-19 vaccine subgroup, and 0.86 (95% CI, 0.68-1.10) in the mix-matched vaccination subgroup. However, in the analysis of individual outcome, the adjusted IRR of myocarditis was increased to 11.71 (95% CI, 5.88-23.35) during the whole risk period. In contrast, no increased risk was observed for other outcomes, such as myocardial infarction, stroke, VTE, and pericarditis. CONCLUSION: For cancer patients, COVID-19 vaccination demonstrated an overall safe profile in terms of cardiovascular outcomes. However, caution is required as an increased risk of myocarditis following COVID-19 vaccination was observed in this study.

Genome-wide association study of BNT162b2 vaccine-related myocarditis identifies potential predisposing functional areas in Hong Kong adolescents.

Vaccine-related myocarditis associated with the BNT162b2 vaccine is a rare complication, with a higher risk observed in male adolescents. However, the contribution of genetic factors to this condition remains uncertain. In this study, we conducted a comprehensive genetic association analysis in a cohort of 43 Hong Kong Chinese adolescents who were diagnosed with myocarditis shortly after receiving the BNT162b2 mRNA COVID-19 vaccine. A comparison of whole-genome sequencing data was performed between the confirmed myocarditis cases and a control group of 481 healthy individuals. To narrow down potential genomic regions of interest, we employed a novel clustering approach called ClusterAnalyzer, which prioritised 2,182 genomic regions overlapping with 1,499 genes for further investigation. Our pathway analysis revealed significant enrichment of these genes in functions related to cardiac conduction, ion channel activity, plasma membrane adhesion, and axonogenesis. These findings suggest a potential genetic predisposition in these specific functional areas that may contribute to the observed side effect of the vaccine. Nevertheless, further validation through larger-scale studies is imperative to confirm these findings. Given the increasing prominence of mRNA vaccines as a promising strategy for disease prevention and treatment, understanding the genetic factors associated with vaccine-related myocarditis assumes paramount importance. Our study provides valuable insights that significantly advance our understanding in this regard and serve as a valuable foundation for future research endeavours in this field.

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.