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INTRODUCTION: Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. METHODS: Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-μg doses were randomized to receive BNT162b2 30 μg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 μg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 μg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. RESULTS: Percentages of 12- to 30-year-olds (n = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 (n = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. CONCLUSIONS: Among 5- to

BACKGROUND: Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1) or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), have revolutionized cancer management but are associated with devastating immune-related adverse events including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI myocarditis is often fulminant and is pathologically characterized by myocardial infiltration of T lymphocytes and macrophages. Although much has been learned about the role of T-cells in ICI myocarditis, little is understood about the identity, transcriptional diversity, and functions of infiltrating macrophages. METHODS: We used an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, flow cytometry, in situ RNA hybridization, molecular imaging, and antibody neutralization studies. RESULTS: We observed marked increases in CCR2 (C-C chemokine receptor type 2)+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation highly expressing Cxcl9 (chemokine [C-X-C motif] ligand 9), Cxcl10 (chemokine [C-X-C motif] ligand 10), Gbp2b (interferon-induced guanylate-binding protein 2b), and Fcgr4 (Fc receptor, IgG, low affinity IV) that originated from CCR2+ monocytes. It is important that a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) was expanded in patients with ICI myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ (interferon gamma) and CXCR3 (CXC chemokine receptor 3) signaling pathways. Depleting CD8+ T-cells or macrophages and blockade of IFN-γ signaling blunted the expansion of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis, suggesting that this interaction was necessary for disease pathogenesis. CONCLUSIONS: These data demonstrate that ICI myocarditis is associated with the expansion of a specific population of IFN-γ-induced inflammatory macrophages and suggest the possibility that IFN-γ blockade may be considered as a treatment option for this devastating condition.

Therapeutic antibodies designed to target three immune checkpoint proteins have been applied in the treatment of various malignancies, including small and non-small cell lung cancers, melanoma, renal cell carcinoma, and others. These treatments combat cancers by reactivating cytotoxic T cells. Nevertheless, this mode of action was found to be associated with a broad range of immune-related adverse events (irAEs), including pneumonitis, sarcoidosis, myocarditis, nephritis, colitis, and hepatitis. Depending on their severity, these irAEs often necessitate the suspension or discontinuation of treatment and, in rare instances, may lead to fatalities. We analyzed over nineteen million reports and identified over eighty thousand adverse event reports from patients treated with immune checkpoint inhibitors submitted to the Food and Drug Administration's Adverse Event Reporting System MedWatch. Reports concerning pembrolizumab, nivolumab, cemiplimab, avelumab, durvalumab, atezolizumab, and ipilimumab revealed a statistically significant association between the irAEs and concurrent infectious diseases for five out of seven treatments. Furthermore, the association trend was preserved across all three types of checkpoint inhibitors and each of the five individual therapeutic agent cohorts, while the remaining two showed the same trend, but an increased confidence interval, due to an insufficient number of records.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) can lead to cardiovascular complications. We aimed to understand the trends in admission for COVID-19 and the incidence of various cardiovascular events. MATERIAL AND METHODS: The 2020 and 2021 National Inpatient Sample (NIS) was studied for cases of COVID-19 between April 2020 and December 2021 in the United States. Linear-by-linear association helped us understand the trends of various events. RESULTS: The number of cases of COVID-19 was highest in January 2021 (261,469 patients). The incidence of acute pulmonary embolism rose from 2.08% in April 2020 to 4.82% in November 2021, while deep vein thrombosis cases rose from 1.74% in April 2020 to 2.63% in December 2021. The incidence of cardiac arrest varied, with a maximum of 3.00% in August 2021. Similarly, acute ischemic stroke cases experienced their highest incidence in January 2021 (0.91%). The incidence of myocarditis was highest in April and May 2020 (0.42% each). Peak takotsubo cases were seen between October and December 2021. The highest overall all-cause mortality among COVID-19 cases was seen in April 2020 (16.74%). CONCLUSIONS: Throughout the 21 months of our analysis, various trends in COVID-19 cases and incidence of cardiac events were noticed. This could relate to the different variants of COVID-19, their direct and indirect impact on coagulation pathways and the myocardial tissues, and the protective roles of the vaccines.

Introduction: In children with myocarditis or dilated cardiomyopathy (DCM) on extracorporeal membrane oxygenation (ECMO) for cardiogenic shock, it is often necessary to decompress the left heart to minimize distension and promote myocardial recovery. We compare outcomes in those who underwent balloon atrial septostomy (BAS) versus direct left atrial (LA) drainage for left heart decompression in this population. Methods: Retrospective study of the Extracorporeal Life Support Organization (ELSO) multicenter registry of patients ≤ 18 years with myocarditis or DCM on ECMO who underwent LA decompression. Descriptive and univariate statistics assessed association of patient factors with decompression type. Multivariable logistic regression sought independent associations with outcomes. Results: 369 pediatric ECMO runs were identified. 52% myocarditis, 48% DCM, overall survival 74%. 65% underwent BAS and 35% LA drainage. Patient demographics including age, weight, gender, race/ethnicity, diagnosis, pre-ECMO pH, mean airway pressure, and arrest status were similar. 89% in the BAS group were peripherally cannulated onto ECMO, versus 3% in the LA drainage group (p <.001). On multivariable analysis, LA drainage (OR 3.96; 95% CI, 1.47-10.711; p =.007), renal complication (OR 2.37; 95% CI, 1.41-4.01; p =.001), cardiac complication (OR 3.14; 95% CI, 1.70-5.82; p <.001), and non-white race/ethnicity (OR 1.75; 95% CI, 1.04-2.94; p =.035) were associated with greater odds of mortality. There was a trend toward more episodes of pulmonary hemorrhage in BAS (n = 17) versus LA drainage group (n = 3), p =.08. Comparing only those with central cannulation, LA drainage group was more likely to be discontinued from ECMO due to recovery (72%) versus the BAS group (48%), p =.032. Conclusions: In children with myocarditis or DCM, there was a three times greater likelihood for mortality with LA drainage versus BAS for LA decompression. When adjusted for central cannulation groups only, there was better recovery in the LA drainage group and no difference in mortality. Further prospective evaluation is warranted. [ABSTRACT FROM AUTHOR]

This study investigated sex differences in acute myocarditis patients during index hospitalization. We included 365 patients with acute myocarditis, hospitalized with continuous monitoring at the intensive care unit from 2000-2023 into the Basel Myocarditis Cohort study. We compared sex differences in clinical presentation, the presenting electrocardiogram, prior medical history, inflammatory and cardiac biomarkers, cardiac imaging, arrhythmia occurrence, and short- to midterm outcomes. Mean age was 41.3 years, and 26.3% were female. Compared with men, women were older (median 49.7 vs 38.3 years, P <.001) at the time of diagnosis and presented more frequently with dyspnea (41 vs 26%, P =.013) and a higher Killip class (P =.011). In the presenting electrocardiogram, men had a higher occurrence of diffuse ST-elevation (38 vs 9%, P <.001) and PQ-depression (31 vs 20%, P =.042), compared with women. Women had higher N-terminal pro B-type natriuretic peptide levels (1180 vs 387 ng/L, P =.015), lower cardiac troponin T levels (389 vs 726 ng/L, P =.006), and fewer segments with nonischemic late gadolinium enhancement on cardiac magnetic resonance imaging (1 vs 3, P =.005), but similar left ventricular ejection fraction (55 vs 55%, P =.629), compared with men. Overall, hospital stay was longer in women compared with men (7 vs 5 days, P =.018), with a similar length of intensive care unit stay (2.6 vs 2.7 days, P =.922). Women more often developed severe arrhythmia (8.3 vs 2.2%, P =.015) and heart failure during the hospitalization (31.3 vs 16.4%, P =.003). Compared with men, women with acute myocarditis were older at the time of diagnosis, presented more often with heart failure, and had an increased frequency of severe arrhythmia. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are specific monoclonal antibodies directed against inhibitory targets of the immune system, mainly represented by programmed death-1 (PD1) ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4), thus enabling an amplified T-cell–mediated immune response against cancer cells. These drugs have significantly improved prognosis in patients with advanced metastatic cancer (e.g., melanoma, non-small cell lung cancer, renal cell carcinoma). However, uncontrolled activation of anti-tumor T-cells could trigger an excessive immune response, possibly responsible for multi-organ damage, including, among others, lymphocytic myocarditis. The incidence of ICIs-induced myocarditis is underestimated and the patients affected are poorly characterized. The diagnosis and management of this condition are mainly based on expert opinion and case reports. EKG and ultrasound are tests that can help identify patients at risk of myocarditis during treatment by red flags, such as QRS complex enlargement and narrowing of global longitudinal strain (GLS). Therapy of ICI-related myocarditis is based on immunosuppressors, monoclonal antibodies and fusion proteins. A future strategy could involve the use of microRNAs. This review considers the current state of the art of immune-related adverse cardiovascular events, focusing on histological and clinical features, diagnosis and management, including current treatments and future pharmacological targets. [ABSTRACT FROM AUTHOR]

Viral myocarditis (MC) is caused by Coxsackie virus B3 (CVB3)-induced cardiomyocyte apoptosis and inflammation, and changes in miRNA and lncRNA are linked to cardiac remodeling. The long non-coding RNA XIST (XIST) has been identified as a regulator in various pathological processes in heart diseases, but its role in CVB3-induced MC is not well understood. This research aimed to evaluate the impact that XIST has on CVB3-induced MC as well as the mechanism behind this effect. XIST expression in CVB3-exposed H9c2 cells (H9c2 cells) was evaluated by qRT-PCR. In CVB3-exposed H9c2 cells, reactive oxygen species production, inflammatory mediators, and apoptosis were experimentally observed. An investigation into and confirmation of the existence of an interaction involving XIST, miR-140-3p, and RIPK1 were carried out. The findings showed that CVB3 induced upregulation of XIST in H9c2 cells. However, XIST knockdown reduced oxidative stress, inflammation, and apoptosis of CVB3-exposed H9c2 cells. XIST was specifically bound to miR-140-3p, and there was mutual negative regulation between the two. Moreover, XIST downregulated RIPK1, which was mediated by miR-140-3p. The study suggests that downregulating XIST can alleviate inflammatory injury in CVB3-exposed H9c2 cells through the miR-140-3p/RIPK1 axis. These findings provide novel insights into the underlying mechanisms of MC. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), including anti-programmed cell death protein 1 and its ligand (PD-1/PD-L1) as well as anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), have been widely used for treating solid tumors. Myocarditis is a potentially lethal immune-related adverse events (irAEs) caused by ICIs therapy. The treatment of steroid-refractory myocarditis is challenging. We reported two non-small-cell lung cancer patients with steroid-refractory myocarditis induced by ICI. The symptoms were not resolved after pulse corticosteroid therapy and subsequent treatment including intravenous immunoglobulin and mycophenolate mofetil. Considering the level of serum interleukin (IL)-6 decreased by > 50% and level of serum tumor necrosis factor-α (TNF-α) increased during the course of the disease, infliximab was used. Myocarditis gradually alleviated after infliximab treatment. The cases revealed that specific cytokine inhibitors have promising roles in the treatment of steroid-refractory myocarditis. Infliximab could be considered for patients with low level of IL-6 and elevated level of TNF-α. [ABSTRACT FROM AUTHOR]

Cardiac toxicity is an adverse event of several classes of anti-cancer drugs. Herein, we present the case of a 52-year-old woman with metastatic renal cell carcinoma (RCC), previously treated with debulking surgery, pembrolizumab (immune checkpoint inhibitor) in combination with axitinib (tyrosine kinase inhibitor (TKI)), followed by lenvatinib (TKI) and belzutifan (HIF-2α inhibitor), who developed myocarditis proven by cardiac magnetic resonance and endomyocardial biopsy. The case was notable for reporting a not-yet described adverse event during treatment with belzutifan plus lenvatinib, the etiology of which was of unobvious determination given the pre-exposure to pembrolizumab, a known cause of drug-related myocarditis. We surmise that myocarditis was a delayed adverse event related to pembrolizumab (8 months after treatment interruption), although we emphasize that only attentive monitoring of cardiac adverse events of patients exposed to belzutifan and lenvatinib in the context of large clinical trials may rule out any causal implication of these drugs. [ABSTRACT FROM AUTHOR]

Myocarditis, marked by heart muscle inflammation, poses significant clinical challenges. This study, guided by PRISMA guidelines, explores the expanding role of artificial intelligence (AI) in myocarditis, aiming to consolidate current knowledge and guide future research. Following PRISMA guidelines, a systematic review was conducted across PubMed, Cochrane Reviews, Scopus, Embase, and Web of Science databases. MeSH terms including artificial intelligence, deep learning, machine learning, myocarditis, and inflammatory cardiomyopathy were used. Inclusion criteria involved original articles utilizing AI for myocarditis, while exclusion criteria eliminated reviews, editorials, and non-AI-focused studies. The search yielded 616 articles, with 42 meeting inclusion criteria after screening. The identified articles, spanning diagnostic, survival prediction, and molecular analysis aspects, were analyzed in each subsection. Diagnostic studies showcased the versatility of AI algorithms, achieving high accuracies in myocarditis detection. Survival prediction models exhibited robust discriminatory power, particularly in emergency settings and pediatric populations. Molecular analyses demonstrated AI's potential in deciphering complex immune interactions. This systematic review provides a comprehensive overview of AI applications in myocarditis, highlighting transformative potential in diagnostics, survival prediction, and molecular understanding. Collaborative efforts are crucial for overcoming limitations and realizing AI's full potential in improving myocarditis care. [ABSTRACT FROM AUTHOR]

Immunotherapy is increasingly used in advanced non-small-cell lung cancer (NSCLC), offering a significant anti-tumor response, as well as causing rising immune-related adverse effects. The incidence of immune checkpoint inhibitorinduced myocarditis-myositis-myasthenia gravis is increasing and particularly concerning due to its high mortality rate. Prompt recognition, diagnosis, and management are crucial. A 40-year-old patient, diagnosed with stage IV nononcogene addicted lung adenocarcinoma, with nivolumab-ipilimumab-chemotherapy as first-line treatment, developed a rare myocarditis-myositis-myasthenia gravis overlap syndrome. Following the treatment, the patient presented with flu-like symptoms and chest pain and subsequently transferred to the cardiac intensive care unit. The physical examination revealed a visual acuity deficit, diplopia, ophthalmoparesis, ptosis, mydriasis, dysphagia, dyspnea, headache, nausea, dry mouth, asthenia, myalgia, and muscle weakness. Imaging and laboratory tests confirmed the triad, showing an elevation of hs-cTnI and CK and positive results for anti-SAE1 and anti-PL-7 Abs. ECG revealed ST segment elevation and RBBB. The echo showed hyperechogenicity of the inferolateral wall, pericardial detachment, and thickening. The cardiac MRI demonstrated hypokinesia, edema, subepicardial LGE, and pericardial effusion. Muscle biopsy revealed muscle fiber necrosis and regeneration with B and T lymphocytic endomysial inflammatory infiltrate and expression of MHC-I. Treatment with oral prednisone, pyridostigmine, and IV Igs was started due to poor clinical response followed by methylprednisolone. Despite stopping immunotherapy, the patient continued to benefit from it, as highlighted on subsequent reevaluation CT scans by partial disease response, and as the patient was in complete remission, we decided to resume chemotherapy by omitting immunotherapy. At the radiological control following the four cycles of double CHT and during CHT maintenance, there was a further reduction of the disease. This report aims to raise awareness among physicians about these serious side effects. A multidisciplinary approach led to clinical improvement and early intervention, optimizing patient outcomes. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications Fulminant myocarditis (FM) is a myocardial inflammatory disease that can result from either viral diseases or autoimmune diseases. In this study, we have determined the treatment effects of immunomodulatory drugs on FM.FM was induced in A/JGpt mice by intraperitoneal administration of coxsackievirus B3, after which immunoglobins were administered daily by intraperitoneal injection. On the seventh day, the cardiac structure and function were determined using echocardiography and cardiac catheterisation. Single‐cell RNA sequencing (scRNA‐seq) was performed to evaluate CD45+ cells in the heart.Immunoglobin, a typical immunomodulatory drug, dramatically reduced mortality and significantly improved cardiac function in mice with FM. ScRNA‐seq revealed that immunoglobin treatment effectively modulated cardiac immune homeostasis, particularly by attenuating overactivated innate immune responses. At the cellular level, immunoglobin predominantly targeted Plac8+ monocytes and S100a8+ neutrophils, suppressing their proinflammatory activities, and enhancing antigen processing and presentation capabilities, thereby amplifying the efficiency and potency of the immune response against the virus. Immunoglobin benefits are mediated by the modulation of multiple signalling pathways, including relevant receptors on immune cells, direction of inflammatory cell chemotaxis, antigen presentation and anti‐viral effects. Subsequently, Bst2-ILT7 ligand‐receptor‐mediated cellular interactions manipulated by immunoglobin were further confirmed in vivo.Immunoglobin treatment significantly attenuated FM‐induced cardiac inflammation and improved cardiac function by inhibiting overactivated innate immune responses. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion To estimate the global burden of myocarditis in the general population from 1990 to 2021.Data on myocarditis were retrieved from the Global Burden of Disease Study 2021. Incidence, deaths, and disability‐adjusted life years (DALYs), along with their age‐standardized rates (ASRs) per 100 000 population, were used to measure the burden of myocarditis. Global, regional, and national analyses were performed for the period between 1990 and 2021. Further sub‐analyses were conducted based on age group, sex, and sociodemographic index (SDI). In 2021, there were 1.3 million (95% uncertainty interval [UI]: 1.1 to 1.6) incident cases, 31.7 thousand (95% UI: 25.5 to 37.1) deaths, and 96.3 thousand (95% UI: 79.6 to 114.8) DALY cases globally. The ASRs of incidence, death, and DALYs significantly decreased from 1990 to 2021, with percentage changes of −3.9% (95% UI: −4.7% to −2.9%), −28.2% (95% UI: −42.2% to −12.5%), and −37.8% (95% UI: −50.5% to −24.3%), respectively. The global burden of myocarditis was higher in males, children, and the elderly. Additionally, the burden of myocarditis varied widely across different SDI regions, with high SDI regions having the highest ASR of incidence, and high‐middle SDI regions having the highest ASRs of deaths and DALYs.Although the ASRs of incidence, deaths, and DALYs significantly decreased from 1990 to 2021, the global number of incidences, deaths, and DALYs increased substantially. Certain populations, including males, children, the elderly, and regions with advanced sociodemographic levels, experienced a heavier burden of myocarditis. [ABSTRACT FROM AUTHOR]

Introcudtion Myocarditis is one of the leading causes of sudden cardiac deaths among athletes. One of the factors increasing the risk of this disease is engaging in sports training during an infection. Many athletes, regardless of their level of advancement, are not aware of the risks associated with training during an infection, and those who are aware often ignore them and continue training. Purpose Assessment of behaviors and awareness among runners in Poland regarding the risk of developing myocarditis as a result of training during respiratory tract infections. Material and method In December 2023, a voluntary and anonymous online survey was conducted among a group of 399 adult runners from Poland. The survey included 13 questions, consisting of 11 singlechoice questions and 2 multiple-choice questions. Results The percentage of individuals who do not associate training during an infection with an increased risk of myocarditis amounts to as much as 44.4% (n=177), while a staggering 86.7% (n=346) of respondents declare that they undertake training during respiratory infections. Conslusion After analyzing the survey, it's evident that while the Polish running community recognizes the risks of training during infections, many still exercise despite symptoms. Although most understand that intense training and early return to sports can harm health, awareness of myocarditis risks from exertion during infection is lacking. Despite protocols for post-illness return to sports, there's a need for campaigns to educate the running community on infectionrelated training risks. [ABSTRACT FROM AUTHOR]

Although COVID-19 is a disease consisting of mostly upper and lower respiratory symptoms, a subset of patients develop cardiac sequelae including myocarditis and pericarditis. For these patients, a standardized set of diagnostic imaging techniques and treatments has not been established. While there have been numerous case reports on this topic, there are few reviews that evaluate the effectiveness of different treatment modalities with a significant number of cases. We reviewed 146 cases of patients (ages ranging from 2 months old to mid 80 s) obtained from searches on PubMed, Google Scholar, and several case report journals. ECG abnormalities, elevated inflammatory markers, and reduced left ventricular ejection fraction were most associated with COVID-19 myocarditis. While classic symptoms of COVID-19 include upper respiratory symptoms, a subset of patients diagnosed with COVID-19 displayed no signs of respiratory disease at all. In 22% of cases, cardiac sequelae was not present until after the patient recovered from COVID-19. Steroids were given in 57.5% of cases. Cardiac MRI was used in 40.4% of cases for diagnosis of myocarditis. Of all the patients who were treated with ECMO, 82.1% of these patients were able to fully recover. The use of cardiac MRI and transthoracic echocardiogram for diagnosis of COVID-19 myocarditis should be heavily considered in any patient with COVID-19 infection. ECMO, IVIG, steroids, and anticoagulants should also be heavily considered. A randomized controlled trial should be conducted to better associate treatments with outcomes. [ABSTRACT FROM AUTHOR]