Baicalein alleviates cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

BACKGROUND: The experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4+T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched. PURPOSE: This study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4+T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice. STUDY DESIGN AND METHODS: Flow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway. RESULTS: These results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4+T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis. CONCLUSION: This study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Lupeol alleviates autoimmune myocarditis by suppressing macrophage pyroptosis and polarization via PPARα/LACC1/NF-κB signaling pathway.

BACKGROUND: Autoimmune myocarditis, with increasing incidence and limited therapeutic strategies, is in urgent need to explore its underlying mechanisms and effective drugs. Pyroptosis is a programmed cell death that may contribute to the pathogenesis of myocarditis. Nonetheless, no direct evidence validated the role of pyroptosis in autoimmune myocarditis. Lupeol (Lup), a pentacyclic triterpene, possesses various biological activities such as antidiabetic properties. However, the effects of Lup on autoimmune myocarditis and pyroptosis remain unelucidated. PURPOSE: This study aimed to reveal the role of pyroptosis in autoimmune myocarditis and explore the protective effects of Lup, and its engaged mechanisms. METHODS: The experimental autoimmune myocarditis (EAM) mouse model was established by immunization with a fragment of cardiac myosin in Balb/c mice. Lup and MCC950 were administered after EAM induction. The protective effects were assessed by inflammation score, cardiac injury, chronic fibrosis, and cardiac function. Mechanistically, the effects of Lup on the M1 polarization and pyroptosis of macrophages were evaluated. Transcriptome sequencing and molecular docking were subsequently employed, and the underlying mechanisms of Lup were further explored in vitro with small interfering RNA and adenovirus. RESULTS: Administration of Lup and MCC950 alleviated EAM progression. Western blotting and immunofluorescence staining identified macrophages as the primary cells undergoing pyroptosis. Lup inhibited the expression of pyroptosis-associated proteins in macrophages during EAM in a dose-dependent manner. Furthermore, Lup suppressed pyroptosis in both bone marrow-derived macrophages (BMDMs) and THP-1-derived macrophages in vitro. In addition, Lup inhibited the M1 polarization of macrophages both in vivo and in vitro. Mechanistically, the protective effects of Lup were demonstrated via the suppression of the nuclear factor-κΒ (NF-κB) signaling pathway. Transcriptome sequencing and molecular docking revealed the potential involvement of peroxisome proliferator-associated receptor α (PPARα). Subsequently, we demonstrated that Lup activated PPARα to reduce the expression level of LACC1, thereby inhibiting the NF-κB pathway and pyroptosis. CONCLUSION: Our findings indicated the crucial role of macrophage pyroptosis in the pathogenesis of EAM. Lup ameliorated EAM by inhibiting the M1 polarization and pyroptosis of macrophages through the PPARα/LACC1/NF-κB signaling pathway. Thus, our results provided a novel therapeutic target and agent for myocarditis.

Diagnostic challenges and forensic implications in a case of infantile fatal myocarditis.

We present the case of a 23-month-old child who died less than 24 h after the onset of cardiac symptoms, despite being admitted to the hospital 72 h earlier. Autopsy revealed no significant macroscopic changes, and histologic examination revealed focal lymphocytic myocarditis with myocyte disruption, diffuse alveolar damage in the exudative phase, and generalized lymphocytic immune activation in other organs. Ante-mortem and post-mortem microbiological exams did not clearly prove a causative role of infectious agents. The peculiarity of this case was characterized by the contrast between the severe clinical features and the mild cardiac histological findings. This discrepancy, coupled with the suspicion of a viral causative role based on both ante-mortem and post-mortem microbiological examinations, presented significant challenges in reaching an etiological diagnosis. This case also confirms that the diagnosis of myocarditis in children cannot be made solely on the basis of histological cut-offs or microbiological results. Using abductive reasoning, various diagnostic hypotheses were formulated and evaluated to arrive at the final diagnosis of fatal myocarditis of viral or post-viral origin. Data from post-mortem examination are often the only source of information that is available to the experts, especially in cases of sudden infant death syndrome. In such cases, the forensic pathologists should accurately evaluate findings that may appear to indicate a different etiology, and, in the absence of clinical or radiological data, interpret post-mortem data in a logically correct manner. The autopsy is the first essential step to evaluate the cause of death and must be integrated with the results of ante- and post-mortem diagnostic tests in a holistic approach, which is crucial to allow forensic pathologists to provide an appropriate and relevant opinion.

[Effect and mechanism of 1, 25(OH)2D3 on myocardial inflammation induced by Coxsackie virus B3 in mice].

Objective: To explore the effect and mechanism of 1, 25(OH)2D3 on myocardial inflammation induced by Coxsackie virus B3 (CVB3) in mice. Methods: Wild type (WT) and 1α-hydroxylase knockout [1(OH)ase-/-] male mice were divided into four groups: WT group, WT+CVB3 group, 1(OH)ase-/-+CVB3 group and 1(OH)ase-/-+CVB3+VD3 group, with 8 mice in each group. The indicators for evaluating myocardial cell injury were examined by different methods. The mRNA levels of pro-inflammatory cytokines [interlenkin (IL)-1ß, IL-6, interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α)] were determined by quantitative real-time PCR. Hematoxylin-eosin (HE) staining was used to observe the myocardial histopathological changes. The apoptosis of myocardial cells was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and flow cytometry. Fluo-4/AM fluorescence probe was used to detect intracellular calcium ion content. Meanwhile, the expression levels of Ca2+/Calmodulin-dependent protein kinase Ⅱ (CaMKⅡ) protein as well as endoplasmic reticulum stress-related proteins like glucose-related protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the myocardial tissues were detected by Western blot. Results: Compared with WT group, the mRNA levels of pro-inflammatory factors increased in the cardiomyocytes of mice in WT+CVB3 group, including IL-1ß (14.88±3.32 vs 1.03±0.02, P=0.009), IL-6 (7.00±1.09 vs 1.81±0.18, P=0.005), IFN-γ (4.70±1.11 vs 1.34±0.34, P=0.006) and TNF-α (17.20±3.22 vs 1.02±0.12, P<0.001). Similarly, the infiltration of inflammatory cells, and the apoptosis rate of cardiomyocytes elevated (16.66%±1.09% vs 7.85%±1.12%, P=0.012). The level of calcium ions in myocardial cytoplasm was significantly higher in WT+CVB3 group than that in the WT group (2.98±1.05 vs 0.96±0.10, P=0.006). Likewise, the expression levels of pCaMKⅡ(1.97±0.34 vs 1.00±0, P<0.001), GRP78 (1.78±0.19 vs 1.00±0, P=0.005) and CHOP (1.62±0.09 vs 1.00±0, P=0.002) in WT+CVB3 group up-regulated. The above myocardial cell injury markers were more significant in the 1(OH)ase-/-+CVB3 group. In the 1(OH)ase-/-+CVB3+VD3 group, 1, 25(OH)2D3 supplementation significantly improved myocardial cell injury indicators. Meanwhile, the specific inhibitors of CaMKⅡ can also reduce the myocardial injury and apoptosis rate of CVB3-infected mice. Conclusion: 1, 25(OH)2D3 deficiency can aggravate myocardial inflammation through over activation of CaMKⅡ.

Chinese Herbal Medicine for the Treatment of Adult Viral Myocarditis: An Overview of Systematic Reviews and Meta-analyses of Randomized Controlled Trials.

PURPOSE: Viral myocarditis (VMC) is a life-threatening disease that can affect all ages and genders, with middle-aged adults being particularly susceptible. Numerous systematic reviews have been conducted to investigate the efficacy and safety of Chinese herbal medicine (CHM) in treating adult viral myocarditis (AVM). The objective of this study was to conduct a comprehensive overview of systematic reviews and meta-analyses of randomized controlled trials (RCTs) regarding the efficacy and safety of CHM for AVM. METHODS: A comprehensive systematic search was conducted across 8 electronic databases from their inception to June 23, 2022, augmented by manual searches of the gray literature. Systematic reviews were independently selected and data extracted in accordance with predetermined criteria by 2 reviewers. Included systematic reviews were assessed for methodologic and reporting quality using Assessing the Methodological Quality of Systematic Reviews 2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The quality of evidence relating to outcome measures was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation tool. Recalculation of effect sizes and subsequent determination of 95% CIs were conducted with either a fixed-effects or random-effects model. FINDINGS: The current overview of systematic reviews included a total of 6 systematic reviews, which reported on 67 RCTs with a participant pool of 5611 individuals. The findings of our study indicate that the combination of CHM and Western medications had positive effects on the effective rate, cure rate, ECG recovery, atrial premature contraction/premature ventricular contraction, left ventricular ejection fraction, myocardial enzymes, and improvement of clinical symptoms for AVM. The adverse drug reactions in the combination therapy group were generally less than or lighter than that in the Western medication group (relative risk = 0.79; 95% CI, 0.44-1.40; P > 0.05, I2 = 0). IMPLICATIONS: Our research results provide evidence that combining CHM with Western medicine could offer potential benefits for patients with AVM. However, the number of studies included in our review is limited and the methodologic quality of these studies is modest. Therefore, there are potential uncertainties regarding the conclusion that CHM with Western medication may benefit patients with AVM. We call for more large-scale, high-quality studies with standardized designs to further verify and support our findings. This would promote a better understanding of the efficacy and safety profile of CHM and provide reliable reference evidence for clinical practice and policy making. Moreover, future research should explore optimal drug combinations, examine therapeutic doses and durations of CHM combination therapy, and evaluate its long-term efficacy and safety.

La cardio-oncología como una visión multidisciplinaria en el enfoque y tratamiento de la patología oncológica contemporánea / Cardio-oncology as a multidisciplinary vision in approaching and treating contemporary oncological pathology

Introducción: Las enfermedades cardiovasculares son la principal causa de muerte en el mundo, y las enfermedades oncológicas están aumentando en prevalencia. Los medicamentos oncológicos pueden tener efectos secundarios cardiovasculares, y la cardiooncología es una subespecialidad de la cardiología que se ocupa de la prevención y el tratamiento de las complicaciones cardiovasculares relacionadas con el cáncer. Puntos importantes del editorial: Las antraciclinas son un grupo de medicamentos oncológicos que pueden causar cardiotoxicidad, lo que puede causar una variedad de síntomas, incluyendo fatiga, disnea, edema y dolor en torácico. En casos graves, la cardiotoxicidad puede provocar insuficiencia cardíaca. Otros medicamentos oncológicos que pueden causar cardiotoxicidad incluyen los anticuerpos anti-HER2, el fluorouracilo y la gemcitabina. Los inhibidores de la tirosinkinasa y los inhibidores del factor de crecimiento derivado del endotelio también pueden causar problemas cardiovasculares, como hipertensión, formación de coágulos sanguíneos y arritmia. Los pacientes con cáncer también tienen un mayor riesgo de desarrollar complicaciones tromboembólicas venosas en miembros inferiores. Conclusión: El diagnóstico temprano y el tratamiento de las complicaciones cardiovasculares relacionadas con el cáncer son esenciales para mejorar la supervivencia de los pacientes con cáncer. La cardiooncología es una especialidad emergente y multidisciplinaria que requiere la participación de oncólogos, hematólogos, radiooncólogos y cardiólogos. El equipo de cardiooncología trabaja en conjunto para evaluar el riesgo cardiovascular de los pacientes con cáncer, prevenir las complicaciones cardiovasculares y tratar las complicaciones cardiovasculares que ocurren.

Introduction: Cardiovascular diseases are the main cause of death in the world, and oncological diseases are increasing in prevalence. Cancer drugs can have cardiovascular side effects, and cardio-oncology is a subspecialty of cardiology concerned with preventing and treating cardiovascular complications related to cancer. Important points from the editorial: Anthracyclines are a group of cancer drugs that can cause cardiotoxicity, which can cause various symptoms, including fatigue, dyspnea, edema, and chest pain. In severe cases, cardiotoxicity can lead to heart failure. Other cancer drugs that can cause cardiotoxicity include anti-HER2 antibodies, fluorouracil, and gemcitabine. Tyrosine kinase and endothelium-derived growth factor inhibitors can also cause cardiovascular problems, such as high blood pressure, blood clot formation, and arrhythmia. Cancer patients are also at increased risk of developing lower limb venous thromboembolic complications. Conclusion: Early diagnosis and treatment of cancer-related cardiovascular complications are essential to improve the survival of cancer patients. Cardio-oncology is an emerging, multidisciplinary specialty that requires the participation of oncologists, hematologists, radiation oncologists, and cardiologists. The cardio-oncology team works together to assess cardiovascular risk in cancer patients, prevent cardiovascular complications, and treat cardiovascular complications that do occur.

Reversible Myocarditis Following Black Widow Spider (Latrodectus spp.) Bite in Egypt: A case report.

Black widow spiders (BWSs) are poisonous spiders of the Arthropoda phylum that live in the Mediterranean region. The effects of BWS bites ranges from local damage to systemic manifestations including paresthesia, stiffness, abdominal cramps, nausea, vomiting, headache, anxiety, hypertension and tachycardia. However, cardiac involvement following a BWS bite is uncommon. We report a 35-year-old male patient who presented to a tertiary hospital in Menoufia, Egypt, in 2019 and developed acute pulmonary oedema with electrocardiogram (ECG) changes that showed ST elevation in leads I and aVL with reciprocal ST segment depression in infero-lateral leads with elevated cardiac biomarkers. Echocardiography showed regional wall motion abnormalities with an impaired ejection fraction of 42%. The condition was reversible after one week of supportive treatment and the patient was discharged from the hospital with normal electrocardiogram, ejection fraction and negative cardiac markers. A routine cardiac evaluation, serial ECG, serial cardiac markers and echocardiography should be considered for any patient exposed to a BWS bite for detection of any potentially fatal cardiac abnormalities.

Integrating network pharmacology and experimental validation to decipher the mechanism of action of Jingfang Granule in the treatment of viral myocarditis.

This study investigated the mechanisms of Jingfang Granule (JFG) in viral myocarditis (VMC) treatment via network pharmacology-based approach combined with molecular docking and validated the results through in vitro and in vivo experiments. The chemical composition of JFG and its therapeutic targets was queried in Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The targets related to VMC were retrieved from the disease database, and the overlapping targets were screened. Based on the STRING database, a protein-protein interaction network was constructed. Cytoscape software was used to construct the "component-target-disease" interaction network for visualization. GO and KEGG pathway enrichment analyses were performed using Metascape data. Molecular docking was performed using PyMoL2.3.0 and AutoDock Vina software programs. The target genes were further verified in vitro and in vivo. JFG contains 88 active components. The main biological targets of JFG in VMC include quercetin, luteolin, and kaempferol. The molecular docking results showed that the three key targets showed strong binding properties with both the height components of the molecular docking interaction energies. The results of experimental verification results showed that JFG may be used to treat VMC mainly by down-regulating inflammatory factors TNF-α and NF-κB and inhibiting myocardial apoptosis. The results support the network pharmacological data. JFG reduces myocardial inflammation and myocardial cell apoptosis in VMC and protects myocardial tissue.

Case Report: Soldier With Latrodectism After Black Widow Spider Bite During a Field Training Exercise.

Latrodectism from black widow spider (BWS) bites is rare in the United States. Latrodectism is a severe systemic manifestation of the envenomation that includes severe abdominal pain mimicking acute surgical abdomen and, in rare cases, could lead to acute myocarditis and rhabdomyolysis. The BWS typically inhabits dark, low-lying areas such as woodpiles, tree stumps, outdoor storage, outdoor furniture, outdoor toilets, and rock piles and is most active during warm weather months. Military service members often participate in field training exercises during warm weather in wooded areas littered with woodpiles and tree stumps; therefore, they are at an increased risk for bites by arachnids. We report the case of a 26-year-old active duty male soldier evacuated from field training with latrodectism and possible envenomation-induced myocarditis after a suspected BWS bite.

Assessment of Cardiac Sarcoidosis: FDG PET and BMIPP SPECT.

PURPOSE OF REVIEW: Cardiac sarcoidosis (CS) is an inflammatory disease of unknown etiology that can lead to life-threatening arrhythmias, heart failure, and death. Advanced cardiac imaging modalities have improved the clinician's ability to detect this disease. The purpose of this review is to discuss the recent evidence of cardiac metabolic imaging as assessed by [18F]FDG PET and [123I]BMIPP SPECT in the evaluation of CS patients. RECENT FINDINGS: [18F]FDG PET is the gold standard to identify myocardial inflammation. [123I]BMIPP SPECT can uncover early myocardial damage as well as advanced stages of CS when fibrosis prevails. In presence of inflammation, myocardial [18F]FDG uptake is increased, but in contrast, BMIPP myocardial uptake is reduced or even suppressed. Thus, a complementary role of cardiac metabolic imaging by [18F]FDG PET and BMIPP SPECT has been proposed to detect the whole spectrum of CS. [18F]FDG PET is considered an important tool to improve the diagnosis and optimize the management of CS. The role of [123I]BMIPP SPECT in diagnosing CS is still under investigation. Further studies are needed to evaluate the clinical utility of combined cardiac metabolic imaging in the diagnosis, prognosis, and for selecting treatments in CS patients.

Effect of Astragalus injection on inflammatory mediators in patients with viral myocarditis: A systematic review and meta-analysis.

BACKGROUND: To explore the therapeutic effect and mechanism of Astragalus injection on viral myocarditis, we conducted a systematic review and meta-analysis to identify the influence of Astragalus injection on inflammatory mediators and overall efficiency in patients undergoing viral myocarditis. METHODS: EMBASE, Cochrane Library, PubMed, Chinese Biomedical Literature, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched to screen randomized controlled trials (RCTs) published before July 3, 2022. The quality of participating studies was assessed by the Cochrane Collaboration Risk of Bias tool. The calculation of qualitative data used a risk ratio (RR) with a 95% confidence interval (95% CI), and quantitative data had standardized mean differences (SMDs) with a 95% CI. The heterogeneity among trials was quantified with Cochran's Q test and the I2 statistic. Confounding factors were estimated by sensitivity analysis, meta-regression, and subgroup analysis. The publication bias of participating articles was evaluated by funnel plot and Egger's test. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was recommended for assessing the strength of evidence. RESULTS: Nineteen available studies were included in our present meta-analysis, all of which were conducted in China. The outcomes expose that Astragalus injection dramatically decreased the levels of pro-inflammatory TNF-α (SMD=-2.271, 95% CI=-2.802 to -1.739, p<0.001, I2=90.6%), IL-6 (SMD=-1.501, 95% CI=-1.872 to -1.130, p<0.001, I2=83.2%), IL-17 (SMD=-3.194, 95% CI=-4.569 to -1.818, p<0.001, I2=88.9%), 1L-8 (SMD=-6.133, 95% CI=-9.938 to -2.328, p = 0.002, I2=97%), 1L-1 (SMD=-1.814, 95% CI=-2.557 to -1.070, p<0.001, I2=92.1%), CRP (SMD=-2.020, 95% CI=-3.107 to -0.932, p<0.001, I2=92.7%), and IFN-γ (SMD=-1.512, 95% CI=-2.771 to -0.253, p = 0.019, I2=92%) and increased the total effective rate of treatment (RR=1.225, 95% CI=1.17 to 1.29, p<0.001, I2=0.0%) in patients with viral myocarditis. CONCLUSION: Astragalus injection can play a therapeutic role in patients with viral myocarditis through immunomodulatory effects. Outcomes were treated with caution due to significant heterogeneity among studies. Large-scale RCTs should be performed to support these conclusions.

Risk of myocarditis and pericarditis following BNT162b2 and mRNA-1273 COVID-19 vaccination.

BACKGROUND: Evidence indicates that mRNA COVID-19 vaccination is associated with risk of myocarditis and possibly pericarditis, especially in young males. It is not clear if risk differs between mRNA-1273 versus BNT162b2. We assessed if risk differs using comprehensive health records on a diverse population. METHODS: Members 18-39 years of age at eight integrated healthcare-delivery systems were monitored using data updated weekly and supplemented with medical record review of myocarditis and pericarditis cases. Incidence of myocarditis and pericarditis events that occurred among vaccine recipients 0 to 7 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by conditional Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. Head-to-head comparison directly assessed risk following mRNA-1273 versus BNT162b2 during 0-7 days post-vaccination. RESULTS: From December 14, 2020 - January 15, 2022 there were 41 cases after 2,891,498 doses of BNT162b2 and 38 cases after 1,803,267 doses of mRNA-1273. Cases had similar demographic and clinical characteristics. Most were hospitalized for ≤1 day; none required intensive care. During days 0-7 after dose 2 of BNT162b2, the incidence was 14.3 (CI: 6.5-34.9) times higher than the comparison interval, amounting to 22.4 excess cases per million doses; after mRNA-1273 the incidence was 18.8 (CI: 6.7-64.9) times higher than the comparison interval, amounting to 31.2 excess cases per million doses. In head-to-head comparisons 0-7 days after either dose, risk was moderately higher after mRNA-1273 than after BNT162b2 (RR: 1.61, CI 1.02-2.54). CONCLUSIONS: Both vaccines were associated with increased risk of myocarditis and pericarditis in 18-39-year-olds. Risk estimates were modestly higher after mRNA-1273 than after BNT162b2.

Successful use of stellate ganglion phototherapy in refractory ventricular tachycardia in a patient with cardiac sarcoidosis.

Ventricular arrhythmias are a life-threatening factor in cardiac sarcoidosis (CS), posing a significant therapeutic challenge. Stellate ganglion phototherapy (SGP), a non-invasive procedure for modification of the sympathetic nervous system, is an effective treatment for refractory ventricular tachycardia (RVT). However, there are limited data on the efficacy of SGP for RVT in patients with CS. In our case report, we found that SGP was effective for treating RVT in a patient with CS.We present the case of a man in his 60s with multiple cardioversions of implantable cardioverter defibrillator for ventricular tachycardia. The patient was administered prednisolone for the management of CS, which subsequently led to an increase in anti-tachycardia pacing for ventricular tachycardias. We introduced SGP to suppress RVT and anti-tachycardia pacing decreased from 371 to 25 events. Thus, SGP could be a feasible option for the management of RVT in patients with CS.

Computational identification of Shenshao Ningxin Yin as an effective treatment for novel coronavirus infection (COVID-19) with myocarditis.

BACKGROUND: The newly identified betacoronavirus SARS-CoV-2 is the causative pathogen of the 2019 coronavirus disease (COVID-19), which has killed more than 4.5 million people. SARS-CoV-2 causes severe respiratory distress syndrome by targeting the lungs and also induces myocardial damage. Shenshao Ningxin Yin (SNY) has been used for more than 700 years to treat influenza. Previous randomized controlled trials (RCTs) have demonstrated that SNY can improve the clinical symptoms of viral myocarditis, reverse arrhythmia, and reduce the level of myocardial damage markers. METHODS: This work uses a rational computational strategy to identify existing drug molecules that target host pathways for the treatment of COVID-19 with myocarditis. Disease and drug targets were input into the STRING database to construct proteinɃprotein interaction networks. The Metascape database was used for GO and KEGG enrichment analysis. RESULTS: SNY signaling modulated the pathways of coronavirus disease, including COVID-19, Ras signaling, viral myocarditis, and TNF signaling pathways. Tumor necrosis factor (TNF), cellular tumor antigen p53 (TP53), mitogen-activated protein kinase 1 (MAPK1), and the signal transducer and activator of transcription 3 (STAT3) were the pivotal targets of SNY. The components of SNY bound well with the pivotal targets, indicating there were potential biological activities. CONCLUSION: Our findings reveal the pharmacological role and molecular mechanism of SNY for the treatment of COVID-19 with myocarditis. We also, for the first time, demonstrate that SNY displays multi-component, multi-target, and multi-pathway characteristics with a complex mechanism of action.

Paving the Way Towards Precision Vaccinology: The Paradigm of Myocarditis After Coronavirus Disease 2019 (COVID-19) Vaccination.

Systems vaccinology approaches have introduced novel tools for the evaluation of the safety profile of novel vaccine antigens by developing biomarkers of vaccine reactogenicity associated with potential adverse events. The use of such approaches may prove extremely advantageous in the context of a global pandemic where accelerated approval of new vaccine formulations for all ages is essential for the containment of the epidemic. The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had devastating effects on global health, but the emergency authorization of mRNA vaccines significantly reduced SARS-CoV-2-associated morbidity and mortality. Despite their favorable safety profile in adult populations, recent reports have raised concerns about an association of the mRNA-based vaccines with acute myocarditis, predominantly among male adolescents and young adults following the second vaccine dose. Here, we review data on myocarditis epidemiology following SARS-CoV-2 mRNA vaccination and describe potential mechanisms involved that may explain the sex- and age-related differences, focusing on mRNA immune reactivity. The case of vaccine-associated myocarditis highlights the need to incorporate precision vaccinology approaches for the development of safe and effective vaccines for everyone.

Coexistence of Rhabdomyolysis, Myocarditis and Arrhythmia after Spider Bite: A Case Report.

BACKGROUND: Rhabdomyolysis after spider bite has been reported in a small number of patients, and myocarditis in even fewer. However, arrhythmia associated with latrodectism in children has not been described in the literature to date. CASE SUMMARY: A girl presented approximately 4.5 h after being bitten on the left ankle by a black spider. Two unifocal premature ventricular contractions (PVCs) were observed on the electrocardiogram. In laboratory tests, creatine kinase was elevated. On day 2, levels of troponin, pro-brain and natriuretic peptide were elevated. Electrocardiogram revealed inverted and biphasic T waves. Echocardiography revealed mild left ventricular dilation, mitral and aortic valve regurgitation. Holter electrocardiogram showed PVCs. Her laboratory and echocardiography findings completely normalized after discharge, and no arrhythmia was observed on the Holter electrocardiogram during outpatient follow-up. CONCLUSION: Although spider bites are uncommon, they can cause serious systemic effects. These patients should be evaluated for arrhythmia, rhabdomyolysis and myocarditis.

Rarely, spider bites can cause serious systemic effects, severe morbidity and death. In a small number of patients, spider envenomation causes rhabdomyolysis and myocarditis. In the present case, the elevated troponin and pro-brain natriuretic peptide levels and electrocardiogram/echocardiography findings were consistent with myocarditis, and an increase in creatinine kinase level indicated rhabdomyolysis. In addition, the electrocardiogram and Holter electrocardiogram revealed unifocal premature ventricular contraction. To our knowledge, arrhythmia due to Latrodectus spider bite has not been described in children to date. In addition, this case demonstrates the coexistence of two serious systemic effects, rhabdomyolysis and myocarditis, with full recovery after appropriate treatment.

Risk of myopericarditis following COVID-19 mRNA vaccination in a large integrated health system: A comparison of completeness and timeliness of two methods.

PURPOSE: How completely do hospital discharge diagnoses identify cases of myopericarditis after an mRNA vaccine? METHODS: We assembled a cohort 12-39 year-old patients, insured by Kaiser Permanente Northwest, who received at least one dose of an mRNA vaccine (Pfizer-BioNTech or Moderna) between December 2020 and October 2021. We followed them for up to 30 days after their second dose of an mRNA vaccine to identify encounters for myocarditis, pericarditis or myopericarditis. We compared two identification methods: A method that searched all encounter diagnoses using a brief text description (e.g., ICD-10-CM code I40.9 is defined as 'acute myocarditis, unspecified'). We searched the text description of all inpatient or outpatient encounter diagnoses (in any position) for "myocarditis" or "pericarditis." The other method was developed by the Centers for Disease Control and Prevention's Vaccine Safety Datalink (VSD), which searched for emergency department visits or hospitalizations with a select set of discharge ICD-10-CM diagnosis codes. For both methods, two physicians independently reviewed the identified patient records and classified them as confirmed, probable or not cases using the CDC's case definition. RESULTS: The encounter methodology identified 14 distinct patients who met the confirmed or probable CDC case definition for acute myocarditis or pericarditis with an onset within 21 days of receipt of COVID-19 vaccination. When we extended the search for relevant diagnoses to 30 days since vaccination, we identified two additional patients (for a total of 16 patients) who met the case definition for acute myocarditis or pericarditis, but those patients had been misdiagnosed at the time of their original presentation. Three of these patients had an ICD-10-CM code of I51.4 "Myocarditis, Unspecified;" that code was omitted by the VSD algorithm (in the late fall of 2021). The VSD methodology identified 11 patients who met the CDC case definition for acute myocarditis or pericarditis. Seven (64%) of the 11 patients had initial care for myopericarditis outside of a KPNW facility and their diagnosis could not be ascertained by the VSD methodology until claims were submitted (median delay of 33 days; range of 12-195 days). Among those who received a second dose of vaccine (n = 146 785), we estimated a risk as 95.4 cases of myopericarditis per million second doses administered (95% CI, 52.1-160.0). CONCLUSION: We identified additional valid cases of myopericarditis following an mRNA vaccination that would be missed by the VSD's search algorithm, which depends on select hospital discharge diagnosis codes. The true incidence of myopericarditis is markedly higher than the incidence reported to US advisory committees in the fall of 2021. The VSD should validate its search algorithm to improve its sensitivity for myopericarditis.

[Pharmacoeconomic evaluation of Qidong Yixin Oral Liquid in treatment of viral myocarditis (Qi-Yin deficiency syndrome) with TreeAge Pro].

To evaluate the pharmacoeconomic value of Qidong Yixin Oral Liquid in the treatment of viral myocarditis(Qi-Yin deficiency syndrome) by supplementing Qi, nourishing the heart, calming the mind, and relieving palpitation, the present study performed the Meta-analysis based on the published papers on Qidong Yixin Oral Liquid by AMSTAR and carried out pharmacoeconomic evaluation using TreeAge Pro by the cost-effectiveness analysis. The results showed that the quality of the included papers was good. After four weeks of treatment, Qidong Yixin Oral Liquid combined with the conventional treatment regimen was superior to the conventional treatment in improving creatine kinase isoenzyme, and the difference was statistically significant. Furthermore, the treatment cost was also higher than that of conventional treatment, with an incremental cost-effectiveness ratio of CNY 95.89, accounting for 0.30% of per capita disposable income. The results of sensitivity analysis showed that the research results were robust. Therefore, based on the assumption that the per capita disposable income in 2020 was the threshold of patients' willingness to pay, it is more economical for patients with viral myocarditis to use Qidong Yixin Oral Liquid combined with conventional secondary prevention regimen than conventio-nal secondary prevention regimen alone. The economic evaluation of Qidong Yixin Oral Liquid in the treatment of viral myocarditis will help physicians and patients choose optimal treatment options, improve rational clinical medication, and provide references for the efficient allocation and utilization of medical resources in China.

Protective role of nutraceuticals against myocarditis.

Myocarditis is an inflammatory disease of the myocardium that mostly affects young adults. The disease is commonly caused by viral infection, medications, autoimmune disorders, and inflammatory conditions. Nearly 50% of the cases of myocarditis are due to post-viral immune response in a setting of an identifiable or non-identifiable infection. The clinical manifestation is nonspecific ranging from asymptomatic courses to sudden death in infants and young patients. This review describes the properties of phytochemicals as plant-derived active ingredients which can be used in the prevention and treatment of myocarditis and its associated risk factors. Meanwhile, it has illustrated epidemiological analyses, mechanism of action, and the metabolism of phytochemicals in animal and human clinical trials. We also mentioned the precise mechanism of action by which phytochemicals elicit their anti-viral, anti-inflammatory, antioxidant, and immunomodulatory effects and how they regulate signal transduction pathways. Nevertheless, comprehensive clinical trials are required to study the properties of phytochemicals in vivo, in vitro, and in silico for a proper management of myocarditis. Our findings indicate that phytochemicals function as potent adjunctive therapeutic drugs in myocarditis and its related complications.