Cardiac myosin-specific (MyHC) T cells drive the disease pathogenesis of immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis). To determine whether MyHC T cells are tissue-resident memory T (TRM) cells, we characterized cardiac TRM cells in naive mice and established that they have a distinct phenotypic and transcriptional profile that can be defined by their upregulation of CD69, PD-1, and CXCR6. We then investigated the effects of cardiac injury through a modified experimental autoimmune myocarditis mouse model and an ischemia-reperfusion injury mouse model and determined that cardiac inflammation induces the recruitment of autoreactive MyHC TRM cells, which coexpress PD-1 and CD69. To investigate whether the recruited MyHC TRM cells could increase susceptibility to ICI-myocarditis, we developed a two-hit ICI-myocarditis mouse model where cardiac injury was induced, mice were allowed to recover, and then were treated with anti-PD-1 antibodies. We determined that mice who recover from cardiac injury are more susceptible to ICI-myocarditis development. We found that murine and human TRM cells share a similar location in the heart and aggregate along the perimyocardium. We phenotyped cells obtained from pericardial fluid from patients diagnosed with dilated cardiomyopathy and ischemic cardiomyopathy and established that pericardial T cells are predominantly CD69+ TRM cells that up-regulate PD-1. Finally, we determined that human pericardial macrophages produce IL-15, which supports and maintains pericardial TRM cells.

• Keywords
• ICI-myocarditis, PD-1, cardiac immunology, tissue-resident memory T cells,
• MeSH
• Programmed Cell Death 1 Receptor metabolism   MeSH
• Antigens, CD MeSH
• Antigens, Differentiation, T-Lymphocyte metabolism   immunology   MeSH
• Immune Checkpoint Inhibitors * pharmacology   MeSH
• Lectins, C-Type metabolism   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Myocardium immunology   pathology   metabolism   MeSH
• Myocarditis * immunology   pathology   metabolism   MeSH
• Myosins metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Memory T Cells * immunology   metabolism   MeSH
• Cardiac Myosins immunology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Programmed Cell Death 1 Receptor MeSH
• Antigens, CD MeSH
• CD69 antigen MeSH Browser
• Antigens, Differentiation, T-Lymphocyte MeSH
• Immune Checkpoint Inhibitors * MeSH
• Lectins, C-Type MeSH
• Myosins MeSH
• Pdcd1 protein, mouse MeSH Browser
• Cardiac Myosins MeSH

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

• Keywords
• autoimmunity, connective tissue diseases, extracorporeal membrane oxygenation, immunoglobulin G4-related disease, immunosuppression therapy, lupus erythematosus, systemic, myocarditis, polymyositis,
• MeSH
• Autoimmune Diseases diagnosis   therapy   immunology   complications   MeSH
• Biopsy MeSH
• Adult MeSH
• Immunoglobulin G4-Related Disease diagnosis   therapy   complications   MeSH
• Shock, Cardiogenic therapy   etiology   diagnosis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * methods   MeSH
• Myocardium pathology   immunology   MeSH
• Myocarditis * therapy   diagnosis   physiopathology   immunology   MeSH
• Lupus Erythematosus, Systemic complications   diagnosis   therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• MeSH
• Biopsy methods   MeSH
• Adult MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Immunosuppression Therapy methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Myocardium pathology   immunology   MeSH
• Myocarditis * immunology   diagnosis   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Letter MeSH
• Editorial MeSH
• Names of Substances
• Immunosuppressive Agents MeSH

BACKGROUND AND AIMS: While endomyocardial biopsy (EMB) is recommended in adult patients with fulminant myocarditis, the clinical impact of its timing is still unclear. METHODS: Data were collected from 419 adult patients with clinically suspected fulminant myocarditis admitted to intensive care units across 36 tertiary centres in 15 countries worldwide. The diagnosis of myocarditis was histologically proven in 210 (50%) patients, either by EMB (n = 183, 44%) or by autopsy/explanted heart examination (n = 27, 6%), and clinically suspected cardiac magnetic resonance imaging confirmed in 96 (23%) patients. The primary outcome of survival free of heart transplantation (HTx) or left ventricular assist device (LVAD) at 1 year was specifically compared between patients with early EMB (within 2 days after intensive care unit admission, n = 103) and delayed EMB (n = 80). A propensity score-weighted analysis was done to control for confounders. RESULTS: Median age on admission was 40 (29-52) years, and 322 (77%) patients received temporary mechanical circulatory support. A total of 273 (65%) patients survived without HTx/LVAD. The primary outcome was significantly different between patients with early and delayed EMB (70% vs. 49%, P = .004). After propensity score weighting, the early EMB group still significantly differed from the delayed EMB group in terms of survival free of HTx/LVAD (63% vs. 40%, P = .021). Moreover, early EMB was independently associated with a lower rate of death or HTx/LVAD at 1 year (odds ratio of 0.44; 95% confidence interval: 0.22-0.86; P = .016). CONCLUSIONS: Endomyocardial biopsy should be broadly and promptly used in patients admitted to the intensive care unit for clinically suspected fulminant myocarditis.

• Keywords
• ECMO, Endomyocardial biopsy, Fulminant myocarditis, Mechanical circulatory support, Outcome,
• MeSH
• Biopsy methods   MeSH
• Adult MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Myocardium pathology   MeSH
• Myocarditis * complications   MeSH
• Retrospective Studies MeSH
• Cardiac Catheterization MeSH
• Heart Transplantation * MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Thymic carcinoma (TC) is a rare subtype of thymic epithelial malignancy. Surgical resection is a mainstay in the treatment of TC, while radiotherapy and chemotherapy are modalities used in adjuvant or palliative setting. Immune checkpoint inhibitors (ICI) including anti-PD-1 (programmed cell death 1) antibodies represent an emerging treatment modality in TC; however, their administration could be associated with life-threatening toxicity. CASE: We present a case of a 59-year-old female with grade III TC, who had received neoadjuvant chemotherapy followed by surgery and subsequent adjuvant radio-immunotherapy with an ICI, nivolumab. We provide our experience with the toxicity of an administered treatment. RESULTS: Fourteen days after the first dose of nivolumab and on 21st day after starting of radiotherapy (total dose of 40 Gy), the patient developed fulminant myocarditis with subsequent heart failure. Despite immunosuppressive therapy with high-dose glucocorticoids and mycophenolate mofetil and intensive support, the patient died within 6 days after the onset of first symptoms. CONCLUSION: Physicians should be aware of these extremely rare, but potentially fatal complications of immunotherapy.

• Keywords
• cardiotoxicity, checkpoint inhibitors, immune checkpoint inhibitors, immunotherapy, immunother­apy, nivolumab, thymic carcinoma,
• MeSH
• Immunotherapy MeSH
• Immune Checkpoint Inhibitors MeSH
• Middle Aged MeSH
• Humans MeSH
• Myocarditis * chemically induced   MeSH
• Nivolumab adverse effects   MeSH
• Antineoplastic Agents, Immunological * adverse effects   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Immune Checkpoint Inhibitors MeSH
• Nivolumab MeSH
• Antineoplastic Agents, Immunological * MeSH

BACKGROUND: Pembrolizumab is a standard-of-care for advanced non-small-cell lung cancer (NSCLC). We assessed pembrolizumab as adjuvant therapy for completely resected stage IB-IIIA NSCLC. METHODS: In this randomised, triple-blind, phase 3 trial (PEARLS/KEYNOTE-091), patients were recruited from 196 medical centres in 29 countries. Eligible patients were aged 18 years or older, with completely resected, pathologically confirmed stage IB (tumours of ≥4 cm in diameter), II, or IIIA NSCLC per the American Joint Committee on Cancer staging system (7th edition) of any histology or PD-L1 expression level, and an Eastern Cooperative Oncology Group performance status of 0 or 1; adjuvant chemotherapy was to be considered for stage IB disease and was strongly recommended for stage II and IIIA disease, according to national and local guidelines. Using a central interactive voice-response system, eligible participants were randomly assigned (1:1), using a minimisation technique and stratified by disease stage, previous adjuvant chemotherapy, PD-L1 expression, and geographical region, to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks for up to 18 cycles. Participants, investigators, and analysts were masked to treatment assignment. Dual primary endpoints were disease-free survival in the overall population and in the population with PD-L1 tumour proportion score (TPS) of 50% or greater. Efficacy was assessed in the intention-to-treat (ITT) population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants randomly assigned to treatment who received at least one dose of study treatment. Here we report results of the second interim analysis, prespecified to occur when approximately 118 disease-free survival events had occurred in the PD-L1 TPS of 50% or greater population. This study is registered with ClinicalTrials.gov, NCT02504372, and is active but not recruiting. FINDINGS: Between Jan 20, 2016, and May 6, 2020, 1177 (60%) of 1955 screened participants were randomly assigned to pembrolizumab (n=590, including n=168 with PD-L1 TPS of ≥50%) or placebo (n=587; including n=165 with PD-L1 TPS of ≥50%) and included in the ITT population. Median follow-up as of data cutoff (Sept 20, 2021) for this interim analysis was 35·6 months (IQR 27·1-45·5). In the overall population, median disease-free survival was 53·6 months (95% CI 39·2 to not reached) in the pembrolizumab group versus 42·0 months (31·3 to not reached) in the placebo group (HR 0·76 [95% CI 0·63-0·91], p=0·0014). In the PD-L1 TPS of 50% or greater population, median disease-free survival was not reached in either the pembrolizumab group (95% CI 44·3 to not reached) or the placebo group (95% CI 35·8 to not reached; HR 0·82 [95% CI 0·57-1·18]; p=0·14). Grade 3 or worse adverse events occurred in 198 (34%) of 580 participants who received pembrolizumab and 150 (26%) of 581 participants who received placebo. Grade 3 or worse events that occurred in at least ten participants in either treatment group were hypertension (35 [6%]) and pneumonia (12 [2%]) with pembrolizumab and hypertension (32 [6%]) with placebo. Serious adverse events occurred in 142 (24%) participants in the pembrolizumab group and 90 (15%) in the placebo group; serious adverse events that occurred in more than 1% of participants were pneumonia (13 [2%]), pneumonitis (12 [2%]), and diarrhoea (seven [1%]) with pembrolizumab and pneumonia (nine [2%]) with placebo. Treatment-related adverse events led to death in four (1%) participants treated with pembrolizumab (one due to both cardiogenic shock and myocarditis, one due to both septic shock and myocarditis, one due to pneumonia, and one due to sudden death) and in no participants treated with placebo. INTERPRETATION: Pembrolizumab significantly improved disease-free survival compared with placebo and was not associated with new safety signals in completely resected, PD-L1-unselected, stage IB-IIIA NSCLC. Pembrolizumab is potentially a new treatment option for stage IB-IIIA NSCLC after complete resection and, when recommended, adjuvant chemotherapy, regardless of PD-L1 expression. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

• MeSH
• B7-H1 Antigen metabolism   MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Hypertension * drug therapy   MeSH
• Humans MeSH
• Myocarditis * MeSH
• Lung Neoplasms * drug therapy   metabolism   surgery   MeSH
• Carcinoma, Non-Small-Cell Lung * drug therapy   surgery   MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• B7-H1 Antigen MeSH
• Antibodies, Monoclonal, Humanized MeSH
• pembrolizumab MeSH Browser

Although the involvement of the heart muscle in the coronavirus disease 2019 (COVID-19) is relatively common (5-10%), myocarditis is a complication with a much lower incidence, depending, however, on the diagnostic methods used. The pathophysiological mechanisms have been described, but there are significant gaps in current knowledge. Myocarditis in connection with vaccination against the disease COVID-19 is a separate nosological unit. Even here, the pathophysiological processes are not explored in detail. The incidence of this complication is estimated in the low tens per million vaccinated.

• Keywords
• COVID-19, myocarditis, vaccination,
• MeSH
• COVID-19 * prevention & control   MeSH
• Incidence MeSH
• Humans MeSH
• Myocarditis * complications   diagnosis   MeSH
• Vaccination adverse effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

INTRODUCTION: The indications for specific treatment in the cases of inflammatory cardiomyopathy are based on limited data from several small clinical trials. AIM: A comparison of the effect of two dose regimens of combined immunosuppressive therapy by adding them to conventional heart failure therapy and comparing them with conventional heart failure therapy alone in patients with inflammatory cardiomyopathy. METHODS AND STUDY POPULATION: We enrolled 20 patients; mean age 46.10±7.33 years, duration of symptoms <6 months, LVEF ≤40 %, NYHA class II-IV, with biopsy‑proven myocarditis. Patients were randomly separated into groups treated with immunosuppressive therapy in addition to conventional heart failure therapy or to a group treated with conventional heart failure therapy alone. Clinical and echocardiographic parameters were evaluated. RESULTS: The baseline values of LVEF in the group of immunosuppressive therapy (LVEF 22.3±4.7 %) were similar to those in the group treated with conventional heart failure therapy (LVEF 21.7±4.7 %; p=0.757). After twelve months there was no statistically significant difference in LVEF between the two studied groups (LVEF 33.7±9.5 % for the immunosuppressive therapy group and 41.3±13.0 % for the conventional therapy group; p=0.175). CONCLUSION: In our study population, we proved no positive effect of combined immunosuppressive therapy on the left ventricular function over 12 months. The main limitation of the study is the small number of enrolled patients (Tab. 4, Fig. 1, Ref. 35).

• Keywords
• endomyocardial biopsy immunosuppressive therapy., inflammatory cardiomyopathy, myocarditis,
• MeSH
• Adult MeSH
• Ventricular Function, Left MeSH
• Immunosuppression Therapy MeSH
• Middle Aged MeSH
• Humans MeSH
• Myocarditis * drug therapy   MeSH
• Heart Failure * MeSH
• Stroke Volume MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Sarcoidosis is a systemic granulomatous disease of unknown cause. Its clinical presentations are heterogeneous and virtually any organ system can be affected, most commonly lungs. The manifestations of cardiac sarcoidosis (CS) are heterogenous depending on the extent and location of the disease and range from asymptomatic forms to life-threatening arrhythmias as well as to progressive heart failure. Cardiac involvement is associated with a worse prognosis. The diagnosis of CS is often challenging and requires a multimodality approach based on current international recommendations. Pharmacological treatment of CS is based on administration of anti-inflammatory therapy (mainly corticosteroids), which is often combined with heart failure medication and/or antiarrhythmics. Nonpharmacological therapeutic approaches in CS cover pacemaker or defibrillator implantation, catheter ablations and heart transplantation. This review aims to summarize the current understanding of CS including its epidemiology, etiopathogenesis, clinical presentations, diagnostic approaches, and therapeutic possibilities.

• Keywords
• FDG-PET/CT, conduction disorders, granulomas, heart failure, ventricular arrhythmias,
• MeSH
• Cardiomyopathies * diagnosis   therapy   MeSH
• Pacemaker, Artificial * MeSH
• Humans MeSH
• Myocarditis * MeSH
• Sarcoidosis * diagnosis   epidemiology   therapy   MeSH
• Arrhythmias, Cardiac diagnosis   therapy   MeSH
• Heart Failure * diagnosis   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Giant cell myocarditis (GCM) is a rare inflammatory disease of the heart that often affects younger patients. The clinical course is typically rapid with fulminant congestive heart failure. Prognosis is poor; the proper diagnosis is often rendered at the autopsy. Herein, we present a prototypical case of this rare type of myocarditis, affecting a 44-year-old previously healthy woman who was referred to the intensive care department due to an acute onset cardiac arrest followed by resuscitation. The heart ultrasound and imaging examinations revealed a severe dysfunction and dilatation of both ventricles, without any significant finding in the coronary arteries. Twelve days after the initial presentation, the patient died due to congestive heart failure refractory to intensive therapy. The post-mortem histology of the heart revealed multiple small necrotic foci in the myocardium in both ventricles, with dense inflammatory infiltration with abundant multinucleated giant histiocytes, in line with a diagnosis of GCM. The natural history, pathophysiology, and histological differential diagnosis is discussed, together with review of the relevant literature including uncommon and emerging units.

• Keywords
• Autopsy, congestive heart failure, giant cell myocarditis, research,
• MeSH
• Adult MeSH
• Echocardiography MeSH
• Humans MeSH
• Myocardium MeSH
• Myocarditis * diagnosis   MeSH
• Giant Cells MeSH
• Autopsy MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH