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Background: To investigate the clinical features of nivolumab-induced myasthenia gravis (MG) and provide evidence for the rational use of nivolumab in the clinic., Methods: We collected case reports and case series of nivolumab-induced MG for retrospective analysis by searching Chinese and English databases from 2014 to October 31, 2022., Results: Of the 67 patients included, the median age was 72.5 years (range 34-86), including 44 males (65.7%). MG occurred in the median 2nd treatment cycle (range, 1st-6th) after nivolumab treatment, being mild in 12 patients (17.9%) and moderate to severe in 44 patients (65.7%). Ptosis (n = 48,71.6%), diplopia (n = 34,50.7%), dyspnea (n = 30, 44.8%), limb muscle weakness (n = 30, 44.8%) and dysphagia (n = 27, 40.3%) were the most common symptoms. Fifty-six patients (83.6%) were classified as having generalized myasthenia gravis (GMG), the remaining 11 patients (16.4%) isolated ocular myasthenia gravis (OMG). Twenty-one patients (31.3%) had MG combined with myositis, 10 patients (14.9%) had myocarditis, and 9 patients (13.4%) had both myositis and myocarditis. Forty patients (59.7%) were positive for anti-acetylcholine receptor antibodies. The serum creatine kinase level was significantly increased in 37 patients (55.2%), with a median value of 4000 IU/L (219,14229). After discontinuation of nivolumab and immunosuppressive therapy, 46 patients (68.7%) finally recovered or improved their MG symptoms, while 15 patients (22.4%) did not recover. Eleven patients (16.4%) died of MG complications., Conclusion: MG is a serious and rare adverse reaction to nivolumab. Nivolumab-induced MG should be timely and correctly identified, and immunotherapy should be given., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In drug-induced lupus (DIL), symptoms similar to those of systemic lupus erythematosus (SLE) usually resolve after discontinuation of the offending drug. A 41-year-old-woman with a history of ulcerative colitis presented with polyarthritis and myositis and was positive for anti-double stranded (ds) DNA IgG antibody. After discontinuation of mesalazine, the symptoms resolved, and the antibody titer decreased. The patient was diagnosed with DIL. Six months later, lupus myocarditis developed. After treatment with glucocorticoids, cyclophosphamide, intravenous immunoglobulin, and an intra-aortic balloon pump, she showed dramatic improvement. Patients with DIL and an immunological predisposition, such as anti-dsDNA antibodies, may have SLE and should be carefully monitored.

Psychoactive substances are a diverse group of chemical substances that are ever-evolving structurally. Novel psychoactive substances are being reported in and are becoming increasingly popular in East and Southeast Asia, with synthetic cathinones becoming the drugs of choice. The use of synthetic cathinones has increased significantly over the years. However, the easy accessibility of these substances and their potentially damaging health effects have raised many concerns. Herein, we present the case of a patient who ingested mixed synthetic cathinones and eventually developed acute myocarditis and subsequent psychotic symptoms. The delayed presentation of psychosis coupled with initial cardiovascular symptoms was a unique phenomenon, making differential diagnosis challenging. The association between the use of synthetic cathinones and psychosis and myocarditis should be explored in view of the lack of relevant clinical data and potentially dire outcomes., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 American Society of Addiction Medicine.)

Background: Nivolumab has been used for the treatment of various types of cancers and has achieved improvements in overall survival. However, nivolumab can cause a variety of adverse events (AEs). Among these, cardiac-specific AEs have received little attention in clinical trials, despite their life-threatening potential., Objective: The present study aimed to determine the risk of nivolumab-induced cardiac AEs, time to onset, incidence rates, and post hoc outcomes using the Japanese Adverse Drug Event Report database., Methods: We analyzed data for the period between April 2004 and March 2021. Data on cardiac AEs were extracted and relative risk of AEs was estimated using the reporting odds ratio (ROR)., Results: We analyzed 1,772,494 reports and identified 18,721 reports of AEs caused by nivolumab. Of these, 409 reports involved cardiac AEs. Signals were detected for four cardiac AEs: myocarditis; pericardial effusion; pericarditis; and immune-mediated myocarditis. Among these, myocarditis was the most frequently reported (35.0%) and included fatal cases. A histogram of times to onset showed nivolumab-associated AEs occurring 41-127 days after starting administration, with outlier cases of myocarditis or pericardial effusion occurring after more than one year, both with catastrophic consequences., Conclusion: This study focused on cardiac AEs caused by nivolumab as post-marketing AEs. Myocarditis and pericardial effusion have been associated with some fatal cases after administration of nivolumab. Patients should be monitored for signs of onset for these AEs, not only at the start of administration, but also over an extended period after nivolumab administration., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Vaccines have had a tremendous impact on reducing the burden of infectious diseases; however, they have the potential to cause adverse events following immunization (AEFIs). Prelicensure clinical trials are limited in their ability to detect rare AEFIs that may occur in less than one per thousand individuals. While postmarketing surveillance systems have shown COVID-19 mRNA vaccines to be safe, they led to the identification of rare cases of myocarditis and pericarditis after COVID-19 vaccination that were not initially detected in clinical trials. In this narrative review, we highlight concepts of vaccine pharmacovigilance during mass vaccination campaigns and compare the approaches used in the context of myocarditis and pericarditis following COVID-19 vaccination to historical examples. We describe mechanisms of passive and active surveillance, their strengths and limitations, and how they interacted to identify and characterize the safety signal of myocarditis and pericarditis after COVID-19 mRNA vaccination. Articles were synthesized from a PubMed search using relevant keywords for articles published on vaccine surveillance systems and myocarditis and pericarditis after COVID-19 vaccination, as well as the authors' collections of relevant publications and grey literature reports. The global experience around the identification and monitoring of myocarditis and pericarditis after COVID-19 mRNA vaccination has provided important lessons for vaccine safety surveillance and highlighted its importance in maintaining public trust in mass vaccination programmes in a pandemic context., (© 2022 British Pharmacological Society.)

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity., (© 2022. The Author(s).)

COVID vaccine-associated myocarditis was first identified in March 2021. There have been numerous case reports that detail the clinical course of paediatric patients older than age 12 with COVID vaccine-associated myocarditis. There are still very few reports of children between the ages of 5 and 11 with COVID vaccine-associated myocarditis. We present an 8 year- old with COVID vaccine-associated myocarditis after his second vaccination against SARS-CoV-2.

Background and Objective: Recently, studies have pointed to a link between coronavirus disease 2019 vaccinations and myocarditis. Myocarditis following an influenza vaccine has been sporadically reported. However, it is not known whether this adverse event occurs among elderly individuals who have received influenza vaccines. We used a population-based database and a self-controlled case-series design to estimate the incidence of myocarditis following an influenza vaccination., Methods: Data were extracted from Taiwan's National Health Insurance Research Database. The study population consisted of elderly people aged ≥ 65 years who had de novo myocarditis, which required hospitalization, within 6 months after receiving an influenza vaccination between 2003 and 2017. The first 1-7, 1-14, and 1-42 days after vaccination were defined as risk intervals, and the other periods were defined as control intervals. Poisson regression was used to calculate the incidence rate ratio for myocarditis between the risk and control periods., Results: Within 180 days following a vaccination, 191 people were hospitalized for myocarditis among 19,678,904 people. In comparison with control intervals, the incidence rate ratios of an admission for myocarditis for days 1-7, 1-14, and 1-42 were 0.80 (95% confidence interval 0.36-1.81), 0.72 (95% confidence interval 0.39-1.32), and 0.73 (95% confidence interval 0.50-1.05), respectively. Subgroup analyses by sex, age, Charlson Comorbidity Index scores, and comorbidities did not yield significant differences in the incidence rate ratio., Conclusions: Regardless of the post-vaccination time and underlying baseline characteristics, the incidence risk of myocarditis is not significantly increased in the elderly following an influenza vaccination., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the management of multiple tumors, due to improved efficacy, quality of life, and safety. While most immune-related adverse events (irAEs) are mild and easily managed, in rare cases such events may be life-threatening, especially those affecting the neuromuscular and cardiac system. The management of neuromuscular/cardiac irAEs is not clear due to the lack of consistent data. Therefore, we carried out a pooled analysis of collected cases from selected Italian centers and individual data from published case reports and case series, in order to improve our understanding of these irAEs., Patients and Methods: We collected retrospective data from patients treated in six Italian centers with ICIs (programmed cell death protein 1 or programmed death-ligand 1 and/or cytotoxic T-lymphocyte antigen 4 inhibitor) for any solid tumor who experienced neuromuscular and/or cardiovascular toxicity. Then, we carried out a search of case reports and series of neuromuscular/cardiac irAEs from ICIs with any solid tumor., Results: This analysis includes cases from Italian institutions (n = 18) and the case reports identified in our systematic literature search (n = 120), for a total of 138 patients. Among these patients, 50 (36.2%) had complete resolution of their neuromuscular/cardiac irAEs, in 21 (15.2%) cases there was a clinical improvement with mild sequelae, and 53 (38.4%) patients died as a result of the irAEs. Factors significantly associated with worse outcomes were early irAE onset, within the first two cycles of ICI (Fisher P < 0.0001), clinical manifestation of both myositis and myocarditis when compared with patients who developed only myositis or myocarditis (chi-square P = 0.0045), and the development of arrhythmia (Fisher P = 0.0070)., Conclusions: To the best of our knowledge, this is the largest collection of individual cases of immune-related myocarditis/myositis. Early irAE onset, concurrent development of myositis and myocarditis, as well as occurrence of arrhythmias are associated with worse outcomes and should encourage an aggressive immunomodulatory treatment., Competing Interests: Disclosure FS received honoraria for presentations or lectures from Sanofi Genzyme, Roche, BMS, Novartis, Merck, Sunpharma, MSD, Pierre Fabre, advisory boards for Novartis, Philogen, Sunpharma, MSD. GB received contracts from AstraZeneca, GSK, honoraria from Roche and Pierre Fabre, advisory boards for Pierre Fabre and Roche. FDR received honoraria from MSD, Sunpharma, Pierre Fabre, Novartis, BMS. RM received honoraria for presentations or lectures from BMS, Novartis, Ipsen, Pierre Fabre, MSD, Roche, Sanofi, AAA, advisory boards for Novartis, BMS, Ipsen, Pierre Fabre, MSD. ML received honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Knight, Takeda, advisory boards for Roche, Lilly, Novartis, AstraZeneca, MSD, Exact Sciences, Seagen, Gilead, Pfizer, and received honoraria from AstraZeneca, BMS, Boehringer-Ingelheim, MSD, Roche. All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Acute myocarditis (especially) and pericarditis have been consistently associated with the administration of vaccines against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), generating anxiety in the general population, uncertainty in the scientific community and obstacles to ambitious mass vaccination programs, especially in foreign countries. Like some of its European counterparts, the Portuguese Society of Cardiology (SPC), through its Studies Committee, decided to take a position on some of the most pressing questions related to this issue: (i) How certain are we of this epidemiological association? (ii) What is the probability of its occurrence? (iii) What are the pathophysiological bases of these inflammatory syndromes? (iv) Should their diagnosis, treatment and prognosis follow the same steps as for typical idiopathic or post-viral acute myopericarditis cases? (v) Is the risk of post-vaccine myocarditis great enough to overshadow the occurrence of serious COVID-19 disease in unvaccinated individuals? In addition, the SPC will issue clinical recommendations and offer its outlook on the various paths this emerging disease may take in the future., (Copyright © 2023 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.

Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events including myocarditis, whilst improving cancer-related outcomes. There is thus a clinical need to identify electrocardiographic manifestations of ICI-related myocarditis to guide clinical management. PubMed was searched for clinical studies and case reports describing electrocardiographic changes in patients with ICI-related myocarditis. A total of 6 clinical studies and 79 case reports were included. This revealed a range of presentations for patients on ICIs, including supraventricular arrhythmias, ventricular arrhythmias and heart block, and new changes of ST-T segment unrelated to coronary artery disease, ST-segment elevation or depression and T-wave abnormalities. Several patients showed low voltages in multiple leads and new onset Q-wave development. Patients with ICI-related myocarditis may develop new arrhythmia and ST-T changes, and infrequently low voltages in multiple leads., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitor (ICI)-mediated myocarditis is a rare but devastating side effect of cancer immunotherapy with up to 40% mortality and long-term cardiac issues such as arrhythmias and heart failure in affected patients. 1 Recently, Axelrod et al. 2 suggested an auto-antigen-driven mechanism as the immunological basis for this disease., Competing Interests: Declaration of interests H.Z. and S.M.W. are holders of a patent application related to targeting signaling pathway active in ICI myocarditis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) improve clinical outcomes in various cancers, but sometimes induce autoimmune adverse effects, including myocarditis, which is the most serious complication. There are many reports on ICI-induced myocarditis; however, only a few prospective surveillance reports exist. Therefore, we developed a prospective screening protocol and performed monitoring clinically suspected myocarditis in every patient treated with ICIs., Methods: We prospectively enrolled 126 consecutive patients treated with ICIs in this cohort. Outcomes of patients were determined and analyzed between April 2017 and May 2020. We evaluated vital signs, biomarkers, electrocardiograms, chest radiographs, and echocardiographs before and at 7 ± 3, 14 ± 3, 21 ± 3, and 60 ± 7 days after ICI initiation., Results: Eighteen (14.3 %) presented troponin I elevation and 13 of them presented signs of clinically suspected myocarditis (10.3 %). Among the 13 patients, ICI was discontinued in four cases (3.2 %) without fatal events. Myocarditis appeared at an early stage of ICI treatment, regardless of severity (median, 44 days)., Conclusions: We observed the frequency of patients with myocarditis or myocardial damage through a prospective screening program in the real world. Although the frequency was higher than expected, most cases were mild and ICI treatment could be continued under careful observation., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Clozapine, a superior treatment for treatment-resistant schizophrenia can cause potentially life-threatening myocarditis and dilated cardiomyopathy. While the occurrence of this condition is well known, its molecular mechanisms are unclear and may be multifactorial. Putative mechanisms warrant an in-depth review not only from the perspective of toxicity but also for understanding the molecular mechanisms of the adverse cardiac effects of clozapine and the development of novel therapeutic approaches. Clozapine-induced cardiac toxicity encompasses a diverse set of pathways, including (i) immune modulation and proinflammatory processes encompassing an IgEmediated (type I hypersensitivity) response and perhaps a cytokine release syndrome (ii) catecholaminergic activation (iii) induction of free radicals and oxidative stress (iv) activation of cardiomyocyte cell death pathways, including apoptosis, ischemia through impairment in coronary blood flow via changes in endothelial production of NO and vasoconstriction induced by norepinephrine as well as other factors released from cardiac mast cells. (v) In addition, an extensive examination of the effects of clozapine on non-cardiac cellular proteins demonstrates that clozapine can impair enzymes involved in cellular metabolism, such as pyruvate kinase, mitochondrial malate dehydrogenase, and other proteins, including α-enolase, triosephosphate isomerase and cofilin, which might explain clozapine-induced reductions in myocardial energy generation for cell viability as well as contractile function. Pharmacologic antagonism of these cellular protein effects may lead to the development of strategies to antagonize the cardiac damage induced by clozapine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Past research shows that media coverage of medicine side effects can produce a nocebo response. New Zealand news media discussed myocarditis following the Pfizer COVID-19 vaccine. This study examined whether side effects mentioned in the media increased compared to control symptoms not mentioned., Methods: The study analysed 64,086 vaccine adverse reaction reports, retrieved from the medicine safety authority. Generalised linear regressions compared the side effect rate during three discrete periods of media reporting (August 2021, December 2021, April 2022) with the pre-media baseline rate. The outcomes were weekly reports of chest discomfort, monthly reports of chest, heart and breathing symptoms, and myocarditis, pericarditis, and anxiety. Control symptoms were fever, numbness, and musculoskeletal pain. Logistic regressions investigated factors associated with side effect reporting., Results: The reporting rate of chest discomfort was 190% greater in the five weeks after the first media item (p < .001). The monthly reporting rates of the symptoms mentioned in the media were significantly greater after the news coverage (ps ≤ 0.001). There was no effect of media on the control side effect fever (p = .06). There was an effect of media on myocarditis, pericarditis and anxiety (ps < 0.001). Anxiety, male gender, and younger age were significantly associated with side effects., Conclusion: The results indicate that a media-induced nocebo response occurred. This is most likely due to increased expectations and awareness of COVID-19 vaccine side effects, elevated symptom experience from anxiety, and consequently greater reporting of the symptoms in line with the media coverage., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Immunological checkpoint inhibitors have been revolutionary in the treatment of cancer. A rare but serious adverse effect is the development of heart muscle inflammation (myocarditis). The prevalence of this type of myocarditis is increasing as more cancer patients receive treatment with immune checkpoint inhibitors. Knowledge of immune checkpoint inhibitor-induced myocarditis is important to enable early diagnosis and initiation of treatment. In this article we provide a clinical review of this.

Rationale: The therapeutic value of immune checkpoint inhibitors (ICIs) in a variety of tumors has been found and recognized, and although ICIs have improved the prognosis of many patients with advanced tumors, these drugs sometimes cause immune-related adverse events (irAEs)., Patient Concerns: We report a 67-year-old woman with advanced rectal endocrine tumor. Ten days after receiving two cycles of treatment with camrelizumab combined with http://www.baidu.com/link?url=shAWG4LYTwwBcZAEb6pLb6DkDndJR2tUgOfFiWAkOf0hS-&#95;sj2jjSLBwYaxSiHY3r6yPj31Lp2DCP-7q3w7ho5HIV46V4fbIShFyUY7Cbka sorafenib, the patient suddenly suffered from chest tightness, shortness of breath and progressive aggravation of limb weakness, the high-sensitivity cardiac troponin T (hs-cTnT) was elevated to 3015pg/mL and N-terminal pro-B-type natriuretic peptide (NT-proBNP) up to 5671pg/mL, and creatine kinase (CK) was 1419U/L., Diagnosis and Interventions: The patient was diagnosed as immune checkpoint inhibitor-induced myocarditis with myasthenia gravis overlap syndrome. The patient was transferred to the intensive care unit (ICU) in time and given oxygen inhalation, glucocorticoids, immunoglobulin and anticholinesterase drugs, and other related treatments., Outcomes: After 2 weeks, the symptoms of myasthenia gravis (MG) were relieved, and the level of myocardial injury markers decreased significantly, but it was still at a high level. The patient's family refused further treatment, and the patient died soon after., Lessons: In this paper, Through the report and follow-up analysis of this case, this paper recognizes that the early correct understanding and evaluation of this fulminant and fatal irAEs and the reasonable treatment of patients are very important for the prognosis of patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pembrolizumab, a humanised monoclonal antibody and immune checkpoint inhibitor (ICI) that blocks programmed death receptor 1 and its ligands, is an effective immunotherapy for malignancies such as melanoma, lung, head and neck, cancers, and Hodgkin's lymphoma. It has an overall response rate between 73% and 83%, with complete response rate of 27%-30%. It is well tolerated with minor side effects in 70% of cases characterised by fatigue, rash, pruritus and diarrhoea. In rare cases, more serious and life-threatening complications can occur at a rate of 0.3%-1.3%. We report a case of a woman in her 70s with non-small-cell lung cancer treated with ICI. She presented to the emergency department with left-sided ptosis and muscle weakness 3 weeks of her first dose of pembrolizumab infusion as a treatment plan of her cancer. She was diagnosed with myasthenia gravis, myocarditis and myositis as ICI-induced immune-related adverse effects resistant to medical intervention. We wish to raise awareness of the triad of life-threatening complication of ICI therapy that accounts for 30%-50% of fatal complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitor (ICI)-induced cardiotoxicity is a rare immune-related adverse event (irAE) characterized by a high mortality rate. From a pathological point of view, this condition can result from a series of causes, including binding of ICIs to target molecules on nonlymphocytic cells, cross-reaction of T lymphocytes against tumor antigens with off-target tissues, generation of autoantibodies and production of proinflammatory cytokines. The diagnosis of ICI-induced cardiotoxicity can be challenging, and cardiac magnetic resonance (CMR) represents the diagnostic tool of choice in clinically stable patients with suspected myocarditis. CMR is gaining a central role in diagnosis and monitoring of cardiovascular damage in cancer patients, and it is entering international cardiology and oncology guidelines. In this narrative review, we summarized the clinical aspects of ICI-associated myocarditis, highlighting its radiological aspects and proposing a novel algorithm for the use of CMR., (© 2022 UICC.)

Purpose of Review: To review myocarditis and pericarditis developing after COVID-19 vaccinations and identify the management strategies., Recent Findings: COVID-19 mRNA vaccines are safe and effective. Systemic side effects of the vaccines are usually mild and transient. The incidence of acute myocarditis/pericarditis following COVID-19 vaccination is extremely low and ranges 2-20 per 100,000. The absolute number of myocarditis events is 1-10 per million after COVID-19 vaccination as compared to 40 per million after a COVID-19 infection. Higher rates are reported for pericarditis and myocarditis in COVID-19 infection as compared to COVID-19 vaccines. COVID-19 vaccine-related inflammatory heart conditions are transient and self-limiting in most cases. Patients present with chest pain, shortness of breath, and fever. Most patients have elevated cardiac enzymes and diffuse ST-segment elevation on electrocardiogram. Presence of myocardial edema on T2 mapping and evidence of late gadolinium enhancement on cardiac magnetic resonance imaging are also helpful additional findings. Patients were treated with non-steroidal anti-inflammatory drugs and colchicine with corticosteroids reserved for refractory cases. At least 3-6 months of exercise abstinence is recommended in athletes diagnosed with vaccine-related myocarditis. COVID-19 vaccination is recommended in all age groups for the overall benefits of preventing hospitalizations and severe COVID-19 infection sequela., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis., ((Neuropsychopharmacol Hung 2022; 24(4): 153–161).)

Background: Myocarditis is a myocardial injury that can easily cause adolescent death. Traditional research models of animal invasion with viral components, lipopolysaccharide (LPS) or porcine myocardial myosin, among others, have the shortcomings of potential biological safety hazards and high animal mortality., Objective: To explore the construction of a novel myocarditis model with cyclosporine A and the potential genes and pathways associated with it., Methods: BALB/c mice were used in this study, and cyclosporin A and LPS were injected into the peritoneal cavity of mice. The successful establishment of the model was assessed by detecting serum myocardial injury markers and inflammatory factors levels, HE, IHC staining, and RT-qPCR methods. Key genes were obtained using the GSE35182 dataset from the GEO database and validated with the RT-qPCR method., Results: We found that a large number of inflammatory cells infiltrated the myocardium of mice in each group of Cyclosporin A constructed model, while the expression of inflammatory factor indicators was increased, and this model has the characteristics of high degree of local inflammation in myocardial tissue, low mortality, and safe and non-toxic treatment. Using GSE35182 data, we selected 18 Hub genes and validated Hub genes in myocardial tissue with RT-qPCR and found that multiple signaling pathways such as Toll-likereceptor signaling pathway(TLRs), Rap1 signal pathway(Rap1), and Chemokine signaling pathway may be involved in the development of myocarditis., Conclusion: Cyclosporin A can construct a new myocarditis model, and TLRs, Chemokines and Rap1 signaling pathways may be the core pathways of myocarditis., (© 2022. The Author(s) under exclusive licence to The Genetics Society of Korea.)

The SARS-COV-2 pandemic led to the development of several vaccinations to contain the disease. The Pfizer-BioNTech COVID-19 (BNT162b2) vaccine was recommended on May 2021 for use in children above 12 years and older. The vaccine is safe, well tolerated and highly effective. Initial reports showed no serious adverse events; however, cases of myocarditis in young healthy male adolescents have been reported. We report two cases of myocarditis/perimyocarditis who presented with short history of chest pain following administration of the second dose of the MRN COVID-19 vaccine., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Immune checkpoint inhibitors (ICIs) are currently approved for a variety of cancers and their use is expanding from advanced disease to first-line metastatic and adjuvant therapies. With the wide application of immunotherapy, its adverse reactions are also the object we need to pay attention to. Among its adverse events, immune myocarditis has low morbidity, but a high fatality rate. Simultaneously, the unique biological properties of thymic epithelial tumors (TETs) increase the risk of immune-mediated toxicity., Patient Concerns: Patient 1 underwent chest computed tomography (CT) in April 2019 due to physical examination, which showed pleural metastasis of thymoma. Tissue puncture under CT guidance revealed type B2 thymoma. First-line chemotherapy with docetaxel combined with nedaplatin was administered, and apatinib was administered as a maintenance therapy after chemotherapy. After a regular review, progression of the disease was observed in April 12, 2021.Patient 2 underwent anterior mediastinal tumor resection on August 2, 2019, due to the completion of the CT examination during myasthenia gravis to suggest a thymic tumor. Postoperative pathology revealed type B3 thymoma. The patient underwent local radiotherapy from October 2019 to November 2019. After irregular reexamination, the patient's condition was stable. Disease progression has been observed in June 2021., Diagnosis: Both patients were diagnosed with thymoma., Interventions: Patient 1 was administered one cycle of gemcitabine, carboplatin, and sintilimab after disease progression. Patient 2 was treated with docetaxel and cisplatin for 2 cycles, and tislelizumab was added in the second cycle., Outcomes: Both patient 1 and patient 2 developed immune myocarditis after one cycle of immunotherapy. The difference was that patient 1 died within a few days. After a few days of active treatment for patient 2, the immune myocarditis did not improve significantly, and the patient chose to give up the treatment and go home. The shocking outcome is that the patient remains alive and stable., Lessons: Oncologists should be wary of ICI-related myocarditis owing to its early onset, nonspecific symptoms, and fulminant progression, especially when ICIs are used in combination. The patient's cardiac condition should be assessed before administering ICIs., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

An increasing number of patients with cancer are being treated with immune checkpoint inhibitors. Consequently, the incidence of immune checkpoint inhibitor-related myocarditis has been increasing. Nonetheless, the diagnostic criteria for the immune checkpoint inhibitor-related myocarditis have not been sufficiently established. Therefore, the real-world incidence or prevalence of immune checkpoint inhibitor-related myocardial damage remains unknown. This was a single-center cohort study that included 100 patients admitted for immune checkpoint inhibitor therapy for any type of cancer. The patients underwent monthly measurement of cardiac troponin I and N-terminal pro-brain natriuretic peptide levels with electrocardiography. Additionally, echocardiography was performed every 3 months. Our protocol was continued until 6 months after the initiation of immune checkpoint inhibitors. We defined immune checkpoint inhibitor-related myocardial damage as an increase in cardiac troponin I levels by &gt;0.026 ng/mL and/or a decrease in the left ventricular ejection fraction by &gt;10% to &lt;53% on echocardiography. The mean patient age was 64 years; 71% were men. The most commonly used immune checkpoint inhibitor was nivolumab (47%), followed by pembrolizumab (29%). Overall, 5% of patients received combination therapy. Among 100 patients, 10 (10%) were diagnosed with immune checkpoint inhibitor-related myocardial damage. Among them, five patients underwent endomyocardial biopsy. Of these patients, four were histopathologically observed to have lymphocyte infiltration in their myocardium. In conclusion, serial cardiac troponin I measurement during immune checkpoint inhibitor treatment could help detect early-phase myocardial damage. The prevalence of myocardial damage was much higher than previously expected., Competing Interests: K.N. received honoraria from MSD and Bristol Myers Squibb. R.I. has received honoraria from Bristol Myers Squibb. T.I. received honoraria from Ono Pharmaceutical, Bristol Myers Squibb, AstraZeneca, and Chugai Pharmaceutical. T.I. received honoraria from Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Merck Serono Pharmaceutical, and Novartis Pharma. T.K. received grants or contracts from Ono Pharmaceutical, Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma, Nippon Boehringer Ingelheim, MSD, AstraZeneca, Eli Lilly Japan, Pfizer Japan Inc., Taiho Pharmaceutical, and The Osaka Foundation for the Prevention of Cancer and Life-style related Diseases (Public Interest Incorporated Foundation); consulting fees from Takeda Pharmaceutical and Nitto Denko Corporation; and payment or honoraria for lectures from Ono Pharmaceutical, Taiho Pharmaceutical, Nippon Boehringer Ingelheim, Pfizer Japan, Bristol-Myers Squibb, AstraZeneca, Novartis Pharma, Eli Lilly Japan, and Chugai Pharmaceutical. The remaining authors have nothing to disclose., (Copyright: © 2022 Nishikawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

We report two cases of acute hypotension after intravenous azithromycin administration in children with acute, decompensated heart failure. In each of our reported cases, azithromycin was being used to treat possible Mycoplasma myocarditis. In this report, we aim to describe hypotension as a potentially rare adverse reaction to intravenous azithromycin and encourage judicious use in patients with cardiac dysfunction.

Competing Interests: EA has received a grant from the Italian Ministry of Health (GR-2019–12368506), and is a consultant for Kiniksa and Cytokinetics. LTC has served as a consultant for Moderna, receives grant funding from the National Institutes of Health, consults for Bristol Myers Squibb, Kiniksa, Moderna, and CardiolRX, and is a board member of Stromal Therapeutics.

The indications for immune checkpoint inhibitors (ICIs) are expanding in cancer drug therapy, and while cardiac events associated with ICIs are often fatal, there are few reports regarding cardiac complications associated with long-term ICI therapy. We aimed to study cardiac complications in patients undergoing long-term ICI therapy. From the database of our local cardio-oncology unit, we enrolled patients with cancer undergoing ICI therapy for more than 6 months and for whom cardiologists continuously performed routine follow-ups. We defined the primary endpoint as discontinuation of ICI due to cardiac events. We also analyzed changes in cardiac biomarkers and echocardiographic parameters. We retrospectively analyzed 55 consecutive patients (43 males, mean age: 65 ± 11 years) treated with ICI therapy in our hospital between January 2017 and June 2021. None of the patients discontinued ICI therapy due to cardiac events more than 6 months after treatment was initiated. Among the participants, we observed four patients with elevated serum troponin I levels, seven patients with decreased global longitudinal strain values, and two patients with elevated plasma brain natriuretic peptide levels. No patient required drug intervention for these cardiac events; furthermore, there were no cases of clinically diagnosed myocarditis. In the present study, there were no cardiac events causing ICI discontinuation in patients undergo ICI therapy for more than 6 months., (© 2022. Springer Japan KK, part of Springer Nature.)

Objectives: Immune checkpoint inhibitor (ICI)-associated myocarditis is a potentially fatal complication. Sparse published researches evaluated the prognostic value of cardiovascular magnetic resonance feature tracking (CMR-FT) for ICI-associated myocarditis., Methods: In the single-center retrospective study, 52 patients with ICI-associated myocarditis and CMR were included from August 2018 to July 2021. The ICI-associated myocarditis was diagnosed by using the clinical criteria of the European Society of Cardiology guidelines. Major adverse cardiovascular events (MACE) were comprised of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block., Results: During a median follow-up of 171 days, 14 (27%) patients developed MACE. For patients with MACE, the global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and left ventricular ejection fraction (LVEF) were significantly worse and native T1 values and late gadolinium enhancement (LGE) extent were significantly increased, compared with patients without MACE (p < 0.05). The GLS remained the independent factor associated with a higher risk of MACE (hazard ratio (HR): 2.115; 95% confidence interval (CI): 1.379-3.246; p = 0.001) when adjusting for LVEF, LGE extent, age, sex, body mass index, steroid treatment, and prior cardiotoxic chemotherapy or radiation. After adjustment for LVEF, the GLS remained the independent risk factor associated with a higher rate of MACE among patients with a preserved LVEF (HR: 1.358; 95% CI: 1.007-1.830; p = 0.045)., Conclusions: GLS could provide independent prognostic value over GCS, GRS, traditional CMR features, and clinical features in patients with ICI-associated myocarditis., Key Points: • The global circumferential strain (GCS), global radial strain (GRS), and global longitudinal strain (GLS) by cardiovascular magnetic resonance feature tracking were significantly impaired in patients with an immune checkpoint inhibitor (ICI)-associated myocarditis. • GLS was still significantly impaired in patients with preserved left ventricular ejection fraction. • The worse GLS was an independent risk factor over GCS, GRS, traditional CMR features, and clinical features for predicting major adverse cardiovascular events in patients with ICI-associated myocarditis., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)