Meeting the Challenges of Myocarditis Workshop

DESCRIPTION

The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of 27 international experts in the field on, “Meeting the Challenges of Myocarditis: New Opportunities for Prevention, Detection, and Intervention.” The workshop was conducted virtually on May 3, 4, and 6, 2021 to address the following objectives:

• Foster exchange of novel ideas pertaining to myocarditis
• Identify critical clinical and research gaps, barriers, and opportunities
• Explore approaches and technologies utilized for other cardiac diseases that could be leveraged to inform and advance understanding of myocarditis
• Discuss strategies to encourage and develop training of the next generation of researchers in the field

The workshop included a concurrent poster session for trainees in the field and provided them with an opportunity to engage in a panel discussion with workshop speakers.

The workshop is responsive to NHLBI Strategic Vision Objectives 1-5.

BACKGROUND

Myocarditis is defined as an inflammation of the myocardium based on histological findings. Myocarditis can be triggered by a wide range of pathogens, including viruses, bacteria (e.g., chlamydia, and rickettsia), fungi, and protozoa, as well as non-infectious causes, such as hypersensitivity to drugs, hyper-eosinophilia of different origins, and autoimmune responses. In addition, new causes of myocarditis, such as side effects of cancer therapies, are emerging. Mild myocarditis can involve symptoms such as chest pain or shortness of breath, or even no symptoms. However, significant morbidity and mortality are associated with severe myocarditis, particularly in children and young adults. This heterogeneity of etiologies, presentations, outcomes, and lack of accurate noninvasive prognostic testing makes prevention, detection, and intervention challenging. There is a critical need to understand the molecular, immunological, and pathological mechanisms of myocarditis and lower the overall burden of disease.

DISCUSSIONS

Presentations and discussions focused on five primary areas: clinical presentation; pathogenesis; diagnostic testing; new diagnostic and therapeutic targets; and lessons learned from cardiac immunology for application to myocarditis research.

Overarching Goals: Workshop participants identified two overarching goals for future studies in myocarditis:

• Refine clinically meaningful subtypes of patients with acute myocarditis through integration of state-of-the-art immunological analysis of biospecimens linked to deep phenotyping of diverse clinical cohorts.
• Develop standards for the collection of clinical data, incorporating measures of social determinants of health.

Gaps and Opportunities: Workshop participants identified the following gaps and opportunities to guide future research:

Diagnostic Frontiers

• Define myocarditis by subtype based on a current understanding of immunology, and incorporate distinct patterns of molecular pathogenesis into diagnostic criteria.
• Examine the roles of integrated endomyocardial biopsy, imaging, laboratory, and clinical criteria in revised diagnostic categories to improve the management of myocarditis. Specifically, develop large-scale, clinical and biospecimen-based data sets that include standardized imaging, laboratory, and clinical criteria. Apply artificial intelligence (AI)-based approaches for cluster analysis and phenotype profiling to these data.
• Develop, validate, and standardize imaging protocols, particularly cardiovascular magnetic resonance imaging and nuclear positron emission tomography, to improve the reproducibility, sensitivity, and specificity for myocarditis. Utilize AI techniques to define clinically relevant inflammation and fibrosis (e.g., automated scoring and threshold setting). Develop molecular imaging techniques targeted towards subtype specificity.
• Refine the use of emerging tools such as next-generation sequencing, proteomics, and metagenomics approaches for unbiased pathogen detection, new blood biomarker identification, and longitudinal monitoring across multiple markers.
• Use a standardized clinical and imaging platform in prospective multicenter imaging-based trials that establishes the role of imaging and biopsy to identify new biomarkers for myocarditis diagnosis and prognostication.
• Address how to standardize, collect, and make accessible measures of social determinants of health.
• Foster multicenter genetic studies in myocarditis to identify cardiomyopathy-associated genes for diagnosis and prognosis.
• Identify and mitigate the cardiotoxicity of oncological therapies, such as immune checkpoint inhibitors and other immunotherapies, in combination with radiation or other anti-cancer agents.
• Create diverse, international registries with well-defined standard operating procedures (SOPs) for rare forms of myocarditis such as fulminant, giant cell, and eosinophilic myocarditis and sarcoidosis.

Therapeutic Frontiers

• Leverage basic research in animal models to design clinical studies to translate cytokine and chemokine targets into treatments for myocarditis.
• Develop vaccines and pathway-specific therapeutics targeting cardiotropic viruses and post-viral autoimmune and pro-fibrotic pathways.
• Deep phenotype diverse cohorts with myocarditis to define new immunophenotype-based classifications.
• Identify biomarkers that stratify outcomes to personalize the treatment of myocarditis and improve outcomes.
• Promote public-private partnerships with pharmaceutical companies for pivotal clinical trials.

Translational Frontiers

• Establish SOP-driven collaboration between basic/translational researchers and clinicians to enhance collection of biospecimens.
• Leverage existing databases of endomyocardial biopsies with myocarditis and comparator pathologies to improve our understanding of stromal cell response and immunopathology.
• Develop interventions that prevent or reverse fibrosis following acute myocarditis, including targeting cardiac fibroblasts in clinical trials.
• Distinguish patients more susceptible and resistant to myocarditis and identify associated genetic polymorphisms and mutations. Identify strategies to protect cardiomyocytes from viral-induced injury in cohorts with high-risk genetic predisposition.
• Delineate common pathways that define cardiac inflammation irrespective of initial trigger or cause.
• Apply serum and tissue proteomics to identify autoantigen and autoantibodies in myocarditis, and precisely quantify circulating proteins covering diverse functional pathways.
• Conduct single cell analyses to identify all cells involved in myocarditis for both immunotyping and stromal cell characterization to define new immunophenotype-based subgroups.

Basic Science Frontiers

• Determine sex and age differences in immune responses and their relationship to outcomes of myocarditis.
• Standardize animal models and develop new animal models to examine the broad spectrum of etiologies in myocarditis. Examples are:
  • New viral-induced animal myocarditis models, such as SARS-CoV-2 or influenza-induced myocarditis mouse models.
  • Large animal models with heart sizes similar to human heart size for catheter-based studies.
  • New zebrafish models to study genetics.
  • Animal models of pediatric myocarditis.
• Develop new in vitro models of cardiomyocytes and other stromal cells co-cultured with immune cells, as well as engineered heart tissue models.

PUBLICATION PLANS:

A white paper outlining the gaps and opportunities that were identified at the workshop is in preparation.