Cardiomyopathy in murine models of systemic sclerosis

Abstract

Objectives. Cardiomyopathy has emerged as a leading cause of death in systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood and new therapies as well as platforms for testing are needed. Here, we aimed to characterize the histopathological features of cardiomyopathy in SSc patients and in common mouse models of SSc. Methods. The histopathological features in myocardial tissues of five patients with SSc and five controls matched for sex, age and cardiovascular risk factors were evaluated and compared to those of three common mouse models of SSc with systemic manifestations: Fra-2 transgenic (Fra-2 tg) mice, mice with sclerodermatous chronic Graft versus Host disease (cGvHD) and tight skin 1 (Tsk-1) mice. Results: Myocardial tissues of SSc patients without clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation and accumulation of collagen. The cGvHD and Tsk-1 models displayed only selected features of SSc-related cardiomyopathy. However, myocardial tissue of Fra-2 tg mice mimicked all features of SSc-related cardiomyopathy and also demonstrated comparable vascular, inflammatory and fibrotic manifestations. Of note, the expression of Fra-2 was also increased in the myocardium of SSc patients. Conclusions. We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked by Fra-2 tg mice. Moreover, the overexpression of Fra-2 in the myocardium of SSc patients may suggest similar underlying pathomechanisms. Thus, Fra-2 tg mice might be a suitable preclinical model to study the mechanisms and therapeutic approaches of myocardial involvement in SSc. \ © 2014 American College of Rheumatology.