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Cancer Discovery Mar 2021Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including...
Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of in the context of complete genetic absence of leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that and functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies...
Topics: Animals; Biomarkers, Tumor; Cardiotoxicity; Disease Management; Disease Models, Animal; Disease Susceptibility; Electrocardiography; Humans; Immune Checkpoint Inhibitors; Mice; Molecular Targeted Therapy; Myocarditis; Neoplasms
PubMed: 33257470
DOI: 10.1158/2159-8290.CD-20-0856 -
Heart Rhythm Sep 2020Human coronavirus-associated myocarditis is known, and a number of coronavirus disease 19 (COVID-19)-related myocarditis cases have been reported. The pathophysiology of... (Review)
Review
Human coronavirus-associated myocarditis is known, and a number of coronavirus disease 19 (COVID-19)-related myocarditis cases have been reported. The pathophysiology of COVID-19-related myocarditis is thought to be a combination of direct viral injury and cardiac damage due to the host's immune response. COVID-19 myocarditis diagnosis should be guided by insights from previous coronavirus and other myocarditis experience. The clinical findings include changes in electrocardiogram and cardiac biomarkers, and impaired cardiac function. When cardiac magnetic resonance imaging is not feasible, cardiac computed tomographic angiography with delayed myocardial imaging may serve to exclude significant coronary artery disease and identify myocardial inflammatory patterns. Because many COVID-19 patients have cardiovascular comorbidities, myocardial infarction should be considered. If the diagnosis remains uncertain, an endomyocardial biopsy may help identify active cardiac infection through viral genome amplification and possibly refine the treatment risks of systemic immunosuppression. Arrhythmias are not uncommon in COVID-19 patients, but the pathophysiology is still speculative. Nevertheless, clinicians should be vigilant to provide prompt monitoring and treatment. The long-term impact of COVID-19 myocarditis, including the majority of mild cases, remains unknown.
Topics: Arrhythmias, Cardiac; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Myocarditis; Pandemics; Pneumonia, Viral; SARS-CoV-2
PubMed: 32387246
DOI: 10.1016/j.hrthm.2020.05.001 -
Signal Transduction and Targeted Therapy Dec 2020Fulminant myocarditis (FM) is characterized by a rapid progressive decline in cardiac function and a high mortality rate. Since the first report of FM patients in the... (Review)
Review
Fulminant myocarditis (FM) is characterized by a rapid progressive decline in cardiac function and a high mortality rate. Since the first report of FM patients in the 1980s, several clinical trials and research studies have been published increasing our knowledge regarding FM. Currently, the diagnosis of FM depends on various techniques including electrocardiography, echocardiography, endomyocardial biopsy, and cardiac magnetic resonance. The development of mechanical circulation support (MCS) devices and progress in our understanding of the pathophysiological mechanisms underlying FM, treatment regimens have evolved from simple symptomatic treatment to a life support-based comprehensive treatment approach. The core mechanism underlying the development of FM is the occurrence of an inflammatory cytokine storm. This review provides a comprehensive account of the current understanding of FM pathophysiology and knowledge regarding its etiology, pathophysiology, treatments, and outcomes.
Topics: Biopsy; Cytokine Release Syndrome; Echocardiography; Electrocardiography; Heart-Assist Devices; Humans; Myocarditis
PubMed: 33303763
DOI: 10.1038/s41392-020-00360-y -
Circulation Journal : Official Journal... Apr 2023
Topics: Humans; Myocarditis
PubMed: 36908170
DOI: 10.1253/circj.CJ-22-0696 -
Journal of the American College of... May 2022
2022 ACC Expert Consensus Decision Pathway on Cardiovascular Sequelae of COVID-19 in Adults: Myocarditis and Other Myocardial Involvement, Post-Acute Sequelae of SARS-CoV-2 Infection, and Return to Play: A Report of the American College of Cardiology Solution Set Oversight Committee.
Topics: COVID-19; Cardiology; Consensus; Humans; Myocarditis; Return to Sport; SARS-CoV-2; United States; Post-Acute COVID-19 Syndrome
PubMed: 35307156
DOI: 10.1016/j.jacc.2022.02.003 -
Cell Reports Nov 2022Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect....
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.
Topics: Animals; Mice; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cardiac Myosins; Immune Checkpoint Inhibitors; Myocarditis; T-Lymphocytes; Autoimmunity
PubMed: 36351411
DOI: 10.1016/j.celrep.2022.111611 -
Journal of the American Heart... Jan 2020
Review
Topics: Animals; Antineoplastic Agents, Immunological; Biopsy; Cardiac Imaging Techniques; Cardiotoxicity; Electrocardiography; Heart; Heart Disease Risk Factors; Humans; Molecular Targeted Therapy; Myocarditis; Myocardium; Neoplasms; Prognosis; Risk Assessment
PubMed: 31960755
DOI: 10.1161/JAHA.119.013757 -
Annals of Noninvasive Electrocardiology... May 2020Acute myocarditis represents a challenging diagnosis as there is no pathognomonic clinical presentation. In patients with myocarditis, electrocardiogram (ECG) can... (Review)
Review
BACKGROUND
Acute myocarditis represents a challenging diagnosis as there is no pathognomonic clinical presentation. In patients with myocarditis, electrocardiogram (ECG) can display a variety of non-specific abnormalities. Nevertheless, ECG is widely used as an initial screening tool for myocarditis.
METHODS
We researched all possible ECG alterations during acute myocarditis evaluating prevalence, physiopathology, correlation with clinical presentation patterns, role in differential diagnosis, and prognostic yield.
RESULTS
The most common ECG abnormality in myocarditis is sinus tachycardia associated with nonspecific ST/T-wave changes. The presence of PR segment depression both in precordial and limb leads, a PR segment depression in leads with ST segment elevation, a PR segment elevation in aVR lead or a ST elevation with pericarditis pattern favor generally diagnosis of perimyocarditis rather than myocardial infarction. In patients with acute myocarditis, features associated with a poorer prognosis are: pathological Q wave, wide QRS complex, QRS/T angle ≥ 100°, prolonged QT interval, high-degree atrioventricular block and malignant ventricular tachyarrhythmia. On the contrary, ST elevation with a typical early repolarization pattern is associated with a better prognosis.
CONCLUSIONS
ECG alterations in acute myocarditis could be very useful in clinical practice for a patient-tailored approach in order to decide appropriate therapy, length of hospitalization, and frequency of followup.
Topics: Acute Disease; Electrocardiography; Humans; Myocarditis; Prognosis
PubMed: 31778001
DOI: 10.1111/anec.12726 -
Medicina Clinica Nov 2022SARS-CoV-2 is currently causing a persistent COVID-19 pandemic, which poses a risk of causing long-term cardiovascular sequels in the population. The viral mechanism of... (Review)
Review
SARS-CoV-2 is currently causing a persistent COVID-19 pandemic, which poses a risk of causing long-term cardiovascular sequels in the population. The viral mechanism of cell infection through the angiotensin 2 converter enzyme receptor and the limited antiviral innate immune response are the suspected causes for a more frequent cardiovascular damage in SARS-CoV-2 infection. Knowledge of the appearance during acute infection of other cardiac conditions beyond the classical myocarditis and pericarditis, the long-term cardiac manifestations (persistent COVID-19), and the increased incidence of myocarditis and pericarditis after vaccination is of special interest in order to offer our patients best practices based on current scientific evidence.
Topics: Humans; SARS-CoV-2; Pandemics; COVID-19; Angiotensin-Converting Enzyme 2; Myocarditis; Pericarditis
PubMed: 35945062
DOI: 10.1016/j.medcli.2022.07.002 -
International Journal of Cardiology Mar 2024Gene therapy is a technique to correct genetic abnormalities, through introduction of a functional gene or through direct genome editing. Adeno-associated virus... (Review)
Review
Gene therapy is a technique to correct genetic abnormalities, through introduction of a functional gene or through direct genome editing. Adeno-associated virus (AAV)-mediated gene replacement shows promise for targeted therapies in treatment of inherited cardiomyopathies and is the most used approach in clinical trials. However, immune responses from the host to the virus and gene product pose delivery and safety challenges. This review explores the immunological reactions to AAV-based gene therapy, their potential toxic effects, with a focus on myocarditis, and future directions for gene therapy.
Topics: Humans; Myocarditis; Genetic Therapy; Genetic Vectors; Dependovirus
PubMed: 38030043
DOI: 10.1016/j.ijcard.2023.131617