Consequences of unlocking the cardiac myosin molecule in human myocarditis and cardiomyopathies

Abstract

Myocarditis, often initiated by viral infection, may progress to autoimmune inflammatory heart disease, dilated cardiomyopathy and heart failure. Although cardiac myosin is a dominant autoantigen in animal models of myocarditis and is released from the heart during viral myocarditis, the characterization, role and significance of anti-cardiac myosin autoantibodies is poorly defined. In our study, we define the human cardiac myosin epitopes in human myocarditis and cardiomyopathies and establish a mechanism to explain how anti-cardiac myosin autoantibodies may contribute to heart disease. We show that autoantibodies to cardiac myosin in sera from myocarditis and dilated cardiomyopathies in humans targeted primarily epitopes in the S2 hinge region of cardiac myosin. In addition, anti-cardiac myosin antibodies in sera or purified IgG from myocarditis and cardiomyopathy targeted the beta-adrenergic receptor and induced antibody-mediated cAMP-dependent protein kinase A (PKA) cell signaling activity in heart cells. Antibody-mediated PKA activity in sera was abrogated by absorption with anti-human IgG. Antibody-mediated cell signaling of PKA was blocked by antigen-specific inhibition by human cardiac myosin or the beta-adrenergic receptor but not the alpha adrenergic receptor or bovine serum albumin. Propranolol, a beta blocker and inhibitor of the beta-adrenergic receptor pathway also blocked the antibody-mediated signaling of the beta-adrenergic receptor and PKA. The data suggest that IgG antibody against human cardiac myosin reacts with the beta-adrenergic receptor and triggers PKA signaling in heart cells. In summary, we have identified a new class of crossreactive autoantibodies against human cardiac myosin and the beta-adrenergic receptor in the heart. In addition, we have defined disease specific peptide epitopes in the human cardiac myosin rod S2 region in human myocarditis and cardiomyopathy as well as a mechanistic role of autoantibody in the pathogenesis of disease.

• Myocarditis
• cardiomyopathy
• autoimmunity
• myosin
• beta-adrenergic receptor

Acknowledgements

We thank Dr Mark Hemric for preparation of human cardiac myosin, Mona Cantu, R. N., N. P. for recruiting study subjects at the University of Colorado Health Sciences Center, Dr Nadia Mertens-Ellis, Dr Ya Li and Dr Carol Cox for helpful discussions, Dr Ken Jackson and the Molecular Biology Resource Facility at the University of Oklahoma Heatlh Sciences Center for synthesis of the human cardiac myosin peptides. We thank the many human subjects whose participation made our study possible. Our work was supported by grant HL56257 to MWC from the National Heart Lung and Blood Institute (NHLBI), and by the American Diabetes Association. MWC is the recipient of a NHLBI Award HL35282.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.