Review

Authors: Javid Moslehi, Andrew H Lichtman, Arlene H Sharpe...

Immune checkpoint inhibitors (ICIs) have transformed the treatment of various cancers, including malignancies once considered untreatable. These agents, however, are associated with inflammation and tissue damage in multiple organs. Myocarditis has emerged as a serious ICI-associated toxicity, because, while seemingly infrequent, it is often fulminant and lethal. The underlying basis of ICI-associated myocarditis is not completely understood. While the importance of T cells is clear, the inciting antigens, why they are recognized, and the mechanisms leading to cardiac cell injury remain poorly characterized. These issues underscore the need for basic and clinical studies to define pathogenesis, identify predictive biomarkers, improve diagnostic strategies, and develop effective treatments. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems.

Topics: Biomarkers; Humans; Immune Checkpoint Inhibitors; Myocarditis

PubMed: 33645548
DOI: 10.1172/JCI145186

Review

Authors: Enrico Ammirati, Maria Frigerio, Eric D Adler...

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Topics: Acute Disease; Cardiology; Chronic Disease; Consensus; Humans; Myocarditis; Predictive Value of Tests; Risk Factors; Terminology as Topic; Treatment Outcome

PubMed: 33176455
DOI: 10.1161/CIRCHEARTFAILURE.120.007405

Review

Authors: Temi Lampejo, Simon M Durkin, Naman Bhatt...

Acute myocarditis is a serious, likely underdiagnosed condition affecting people of all ages and for which the number of UK hospital admissions is rising. A primary diagnosis of myocarditis accounted for 0.04% (36.5 per 100,000) of all hospital admissions in England between 1998 and 2017, although this is likely to be an underestimate of the true burden of myocarditis. The aetiology is broad, including infective and inflammatory conditions as well as exposure to toxic agents. Clinical features are varied and overlap with other acute cardiac conditions making diagnosis a challenge. Cardiovascular magnetic resonance imaging currently serves as the gold standard non-invasive diagnostic modality. If an underlying aetiological process is identified, then therapy may be directed at the cause; however, for most, treatment is supportive and aimed at managing any complications such as heart failure or arrhythmias. There is emerging evidence for immunosuppressive therapy in certain cases. Prognosis is generally good with recovery in most; however, up to 30% with biopsy-proven myocarditis progress to develop a dilated cardiomyopathy and its potential associated complications. All-cause mortality in the UK for patients presenting to hospital with acute myocarditis is approximately 4%.

Topics: Acute Disease; Biopsy; Cardiomyopathy, Dilated; Heart; Humans; Myocarditis; Prognosis

PubMed: 34507935
DOI: 10.7861/clinmed.2021-0121

Review

Authors: Sandeep Sagar, Peter P Liu, Leslie T Cooper...

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.

Topics: Acute Disease; Bacterial Infections; Humans; Myocarditis; Prognosis; Virus Diseases

PubMed: 22185868
DOI: 10.1016/S0140-6736(11)60648-X

Review

Authors: Yuk M Law, Ashwin K Lal, Sharon Chen...

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.

Topics: Animals; Biopsy; Child; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Models, Animal; Disease Susceptibility; Humans; Multimodal Imaging; Myocarditis; Prognosis; Symptom Assessment; Treatment Outcome

PubMed: 34229446
DOI: 10.1161/CIR.0000000000001001

Review

Authors: Leslie T Cooper

Myocarditis may present with a wide range of symptoms, ranging from mild dyspnea or chest pain that resolves without specific therapy to cardiogenic shock and death. Dilated cardiomyopathy with chronic heart failure is the major long-term sequela of myocarditis. Most often, myocarditis results from common viral infections; less commonly, specific forms of myocarditis may result from other pathogens, toxic or hypersensitivity drug reactions, giant-cell myocarditis, or sarcoidosis. The prognosis and treatment of myocarditis vary according to the cause, and clinical and hemodynamic data usually provide guidance to decide when to refer a patient to a specialist for endomyocardial biopsy. The aim of this review is to provide a practical and current approach to the evaluation and treatment of suspected myocarditis.

Topics: Acute Disease; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Diagnosis, Differential; Echocardiography; Electrocardiography; Humans; Magnetic Resonance Imaging; Myocarditis; Myocardium; Prognosis

PubMed: 19357408
DOI: 10.1056/NEJMra0800028

Review

Authors: Diego Araiza-Garaygordobil, Carlos Eduardo García-Martínez, Lucrecia María Burgos...

Dengue is a neglected viral arthropod-borne tropical disease transmitted by the bite of infected spp. mosquitoes. It is responsible for a significant global burden of disease and corresponding socio-economic implications. There are four different virus serotypes, all of which are found predominantly in countries with tropical climates. Patients with dengue may present with cardiovascular (CV) manifestations, contributing to associated death and disability. A systematic review was conducted to identify CV manifestations of dengue, wherein 30 relevant studies were identified in the MEDLINE and PubMed databases. CV complications of dengue include rhythm abnormalities, hypotension, myocarditis, pericarditis and deterioration in myocardial function. Prompt recognition and treatment of CV complications of dengue are essential to reduce morbidity and mortality in these patients, who are at risk of progressing to cardiogenic shock and heart failure.

Topics: Animals; Dengue; Heart; Humans; Myocarditis; Neglected Diseases

PubMed: 34292294
DOI: 10.5830/CVJA-2021-033

Review

Authors: Robyn E Bryde, Leslie T Cooper, DeLisa Fairweather...

Myocarditis is an inflammatory disease of the myocardium secondary to infectious and noninfectious insults. The most feared consequence of myocarditis is sudden cardiac death owing to electrical instability and arrhythmia. Typical presenting symptoms include chest pain, dyspnea, palpitations and/or heart failure. Diagnosis is usually made with history, electrocardiogram, biomarkers, echocardiogram, and cardiac MRI (CMR). Application of the Lake Louise criteria to CMR results can help identify cases of myocarditis. Treatment is usually supportive with medical therapy, and patients are recommended to abstain from exercise for 3 to 6 months. Exercise restrictions may be lifted after normalization on follow-up testing.

Topics: Humans; Myocarditis; Return to Sport; Myocardium; Magnetic Resonance Imaging; Electrocardiography

PubMed: 36368807
DOI: 10.1016/j.ccl.2022.08.009

Review

Authors: Carsten Tschöpe, Leslie T Cooper, Guillermo Torre-Amione...

Myocarditis is generally a mild and self-limited consequence of systemic infection of cardiotropic viruses. However, patients can develop a temporary or permanent impairment of cardiac function including acute cardiomyopathy with hemodynamic compromise or severe arrhythmias. In this setting, specific causes of inflammation are associated with variable risks of death and transplantation. Recent translational studies suggest that treatments tailored to specific causes of myocarditis may impact clinical outcomes when added to guideline-directed medical care. This review summarizes recent advances in translational research that influence the utility of endomyocardial biopsy for the management of inflammatory cardiomyopathies. Emerging therapies for myocarditis based on these mechanistic hypotheses are entering clinical trials and may add to the benefits of established heart failure treatment.

Topics: Animals; Cardiomyopathies; Disease Progression; Heart Failure; Humans; Myocarditis; Recovery of Function; Risk Factors; Treatment Outcome

PubMed: 31120823
DOI: 10.1161/CIRCRESAHA.118.313578

Authors: Syed S Mahmood, Michael G Fradley, Justine V Cohen...

BACKGROUND

Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.

OBJECTIVES

The authors sought to understand the presentation and clinical course of ICI-associated myocarditis.

METHODS

After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.

RESULTS

The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.

CONCLUSIONS

Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.

Topics: Aged; Antineoplastic Agents, Immunological; Case-Control Studies; Female; Glucocorticoids; Humans; Male; Methylprednisolone; Middle Aged; Myocarditis; Neoplasms; Registries; Troponin T

PubMed: 29567210
DOI: 10.1016/j.jacc.2018.02.037