MRI Assessment of Cardiomyopathy Induced by \u03b21-Adrenoreceptor Autoantibodies and Protection Through \u03b23-Adrenoreceptor Overexpression

Laetitia Vanhoutte,Bernard Gallez,Chantal Dessy,Ruben Martherus,Caroline Bouzin,Olivier Feron,Jean-Luc Balligand,Stéphane Moniotte,Céline Guilbaud

doi:10.1038/srep43951

Abstract

The cardiopathogenic role of autoantibodies (aabs) directed against β1-adrenoreceptors (β1-AR) is well established. In mouse models, they cause progressive dilated cardiomyopathy (DCM) whose characterization with echocardiography requires prolonged protocols with numerous animals, complicating the evaluation of new treatments. Here, we report on the characterization of β1-aabs-induced DCM in mice using 11.7T MRI. C57BL/6J mice (n = 10 per group) were immunized against the β1-AR and left ventricular (LV) systolic function was assessed at 10, 18 and 27 weeks. Increase in LV mass/tibial length ratio was detected as the first modification at 10 weeks together with dilation of cavities, thereby outperforming echocardiography. Significant impairment in diastolic index was also observed in immunized animals before the onset of systolic dysfunction. Morphometric and histological measurements confirmed these observations. The same protocol performed on β3-AR-overexpressing mice and wild-type littermates (n = 8–12 per group) showed that transgenic animals were protected with reduced LV/TL ratio compared to wild-type animals and maintenance of the diastolic index. This study demonstrates that MRI allows a precocious detection of the subtle myocardial dysfunction induced by β1-aabs and that β3-AR stimulation blunts the development of β1-aabs-induced DCM, thereby paving the way for the use of β3AR-stimulating drugs to treat this autoimmune cardiomyopathy.

Highlights

Dysfunction after the active immunization against this antigen[14,15,16] and assessed the possibility of generating cardiac impairment after transfer of homologous pathogenic antibodies to healthy animals[17]
The major findings of this study are related to the application of ultra-high field MRI (UHF MRI) technology to study the early development of β1aabs-driven autoimmune cardiac dysfunction and to the identification of β3-AR as key actor of a counterbalancing pathway preventing the occurrence of dilated cardiomyopathy (DCM) in this model
In our study with C57BL/6J mice immunized against the β1 -AR, using UHF MRI, we were able to show early aabs-induced cardiomyopathic changes after only 10 weeks

Summary

Introduction

Dysfunction after the active immunization against this antigen (indirect evidence)[14,15,16] and assessed the possibility of generating cardiac impairment after transfer of homologous pathogenic antibodies to healthy animals (direct evidence)[17]. Preliminary results suggest that they act as allosteric agonists[19], enabling dimerization and stabilization of β1 -AR in its active conformation[20], subsequently promoting sustained downstream signaling in a manner distinct from the natural ligand[21,22]. This leads to cardiomyocyte apoptosis[23], enhanced contractility and prolonged action potential duration[24]. We aimed to study whether β3-AR overexpressing mice could be protected from cardiac remodeling induced by chronic exposure to β1-aabs

Methods

Results

Conclusion