From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis

Myers, J.; Sandel, C.; Alvarez, K.; Garman, L.; wiley, G.; Montgomery, C.; Gaffney, P.; Stavrakis, S.; Fairweather, D.; Bruno, K.; Zhao, Y. D.; Cooper, L. T.; Cunningham, M. W.

doi:10.1101/2024.06.19.599804

bioRxiv · 10.1101/2024.06.19.599804

From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis

Myers, J.·Sandel, C.·Alvarez, K.·Garman, L.·wiley, G.·Montgomery, C.·Gaffney, P.·Stavrakis, S.·Fairweather, D.·Bruno, K.·Zhao, Y. D.·Cooper, L. T.·Cunningham, M. W.

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Abstract

BackgroundMyocarditis leads to dilated cardiomyopathy (DCM) with one-third failing to recover normal ejection fraction (EF50%), and there is a critical need for prognostic biomarkers to assess risk of nonrecovery. Cardiac myosin (CM) autoantibodies (AAbs) cross-reactive with the {beta}-adrenergic receptor ({beta}AR) are associated with myocarditis/DCM, but their potential for prognosis and functional relevance is not fully understood. MethodsCM AAbs and myocarditis-derived human monoclonal antibodies (mAbs) were investigated to define pathogenic mechanisms and CM epitopes of nonrecovery. Myocarditis patients who do not recover ejection fraction (EF<50%) by one year were studied in a longitudinal (n=41) cohort. Sera IgG and human mAbs were investigated for autoreactivity with CM and CM peptides by ELISA, protein kinase A (PKA) activation, and transcriptomic analysis in H9c2 heart cell line. ResultsCM AAbs were significantly elevated in nonrecovered compared to recovered patients and correlated with reduced EF (<50%). CM epitopes specific to nonrecovery were identified. Transcriptomic analysis revealed serum IgG and mAb 2C.4 induced fibrosis/apoptosis pathways in vitro similar to isoproterenol treated cells. Sera IgG and 2C.4 activated PKA in an IgG and {beta}AR-dependent manner. Endomyocardial biopsies from myocarditis/DCM revealed IgG+ trichrome+ tissues. ConclusionsCM AAbs were significantly elevated in nonrecovered patients, suggesting novel prognostic relevance. CM AAbs correlated with lower EF, and Ab-induced fibrosis/apoptosis pathways suggested a role for CM AAbs in patients who do not recover and develop irreversible heart failure. Homology between CM and {beta}ARs supports mechanisms related to cross-reactivity of CM AAbs with the {beta}AR, a potential AAb target in nonrecovery.

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Myers, J., Sandel, C., Alvarez, K., Garman, L., wiley, G., Montgomery, C., Gaffney, P., Stavrakis, S., Fairweather, D., Bruno, K., Zhao, Y. D., Cooper, L. T., Cunningham, M. W.. 2024-06-23. From Cardiac Myosin to the Beta Receptor: Autoantibodies Promote a Fibrotic Transcriptome and Reduced Ventricular Recovery in Human Myocarditis. https://doi.org/10.1101/2024.06.19.599804

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