Myocarditis may be caused by a viral infection of the heart which may lead to a more chronic heart disease often referred to as dilated cardiomyopathy (DCM). Myocarditis may lead to heart failure or a weakened heart muscle requiring a heart transplant for survival. We have discovered a new myocarditis phenotype which correlates with disease progression, non-recovery, and heart failure in human myocarditis and we have linked it to innate and adaptive immune responses against cardiac myosin. Human cardiac myosin (HCM) we found to be a novel damage associated molecular pattern or DAMP which interacts with TLR2 and stimulates human CD14+ monocytes.
The specific aims proposed will be a significant step forward in understanding human myocarditis and may identify genes and pathways involved in disease progression. We expect to identify predictors of myocarditis progression to heart failure and non-recovery and to identify potential therapeutic interventions which can be instituted before inflammation leads to disease progression. While most studies of myocarditis/DCM are in animal models, our project proposes innovative translational research in a longitudinal study of a human myocarditis cohort to:
Aim 1) Determine blood and heart biopsy immunophenotypes of human myocarditis and identify novel upregulated genes and pathways which associate with heart failure in myocarditis phenotypes by identification of the pro-fibrotic transcriptome of CD4+ T cells in human myocarditis vs normal controls by RNAseq analysis;
Aim 2) Identify T cell epitopes of HCM in human myocarditis using state of the art HLA-epitope discovery combined with traditional T cell epitope mapping of T cell clones using our human cardiac myosin peptide libraries;
Aim 3) Identify the upregulated genes and transcriptome of pro-fibrotic CD14+ monocyte responses against HCM toll like receptor ligands that may lead to identification of pro-fibrotic and novel genes involved in progression of myocarditis. RNAseq analysis of purified cell types such as CD14+ monocytes and CD4+ T cells will provide insight into novel genes and pathways involved in pathogenesis so that future experiments can investigate these new pathways. We expect that our studies using state of the art epitope discovery utilizing mass spec to identify eluted human HLA bound peptides of HCM combined with more traditional epitope mapping using T cell clones and ELISPOT will reveal epitopes and potential targets for immunotherapy. The RNAseq is expected to reveal genes and pathways showing the critical role of monocytes and human cardiac myosin in controlling myocarditis not previously recognized in humans. Most importantly, the phenotypes and upregulated gene pathways will be correlated with outcomes such as heart function and fibrosis in our myocarditis/DCM cohort. The proposed studies in humans will establish myocarditis immunophenotypes (T cell and monocyte) which control outcomes in myocarditis/DCM and correlate individual phenotype with potential therapeutic options to prevent risk of disease progression and heart failure.
Myocarditis and cardiomyopathy are an important cause of heart failure and forty-five percent of all heart transplantions. Our innovative translational study of human myocarditis will uniquely contribute to our understanding of the immunological changes leading to heart failure outcomes in disease. Immunological mechanisms found in the study will be translated into new options for diagnosis and treatment of myocarditis and dilated cardiomyopathy.
|Carapetis, Jonathan R; Beaton, Andrea; Cunningham, Madeleine W et al. (2016) Acute rheumatic fever and rheumatic heart disease. Nat Rev Dis Primers 2:15084|
|Li, Hongliang; Zhang, Ling; Huang, Bing et al. (2015) A peptidomimetic inhibitor suppresses the inducibility of ?1-adrenergic autoantibody-mediated cardiac arrhythmias in the rabbit. J Interv Card Electrophysiol 44:205-12|
|Galloway, Allison; Li, Hongliang; Vanderlinde-Wood, Megan et al. (2015) Activating autoantibodies to the ?1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism. Endocrine 49:457-63|
|Cunningham, Madeleine W (2014) Rheumatic fever revisited. Nat Rev Cardiol 11:123|
|Childs, Helene; Friedrich, Matthias G (2011) Cardiovascular magnetic resonance imaging in myocarditis. Prog Cardiovasc Dis 54:266-75|
|Ellis, Nadia M J; Kurahara, David K; Vohra, Harpreet et al. (2010) Priming the immune system for heart disease: a perspective on group A streptococci. J Infect Dis 202:1059-67|
|Blauwet, Lori A; Cooper, Leslie T (2010) Myocarditis. Prog Cardiovasc Dis 52:274-88|