Objective. Cardiomyopathy has emerged as a leading cause of death in patients with systemic sclerosis (SSc). However, the pathogenesis of SSc-related cardiomyopathy is poorly understood, and new therapies as well as platforms for testing are needed. The aim of this study was to characterize the histopathologic features of cardiomyopathy in patients with SSc and in common mouse models of SSc.Methods. The histopathologic features of myocardial tissue specimens obtained at autopsy from 5 subjects with SSc and 5 control subjects matched for sex, age, and cardiovascular risk factors were evaluated and compared with those of myocardial tissue specimens obtained from 3 common mouse models of SSc with systemic manifestations: Fra-2-transgenic mice, mice with sclerodermatous chronic graft-versus-host disease (GVHD), and TSK-1 mice.Results. Myocardial tissue from autopsy subjects with SSc and no clinically manifest cardiac involvement showed endothelial cell apoptosis with reduced capillary density, perivascular inflammation, myofibroblast differentiation, and accumulation of collagen. Only selected features of SSc-related cardiomyopathy were observed in the mice with chronic GVHD and TSK-1 mice. However, the myocardial tissue of Fra-2-transgenic 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 autopsy subjects with SSc.Conclusion. We demonstrate that all typical manifestations of SSc-related cardiomyopathy are mimicked in Fra-2-transgenic mice. Moreover, overexpression of Fra-2 in the myocardium of autopsy subjects with SSc may suggest similar underlying pathogenic mechanisms. Thus, Fra-2-transgenic mice might be a suitable preclinical model with which to study the mechanisms of and therapeutic approaches to myocardial involvement in SSc.
The lack of decrease in the maximal vasodilatation response indicates that there is no irreversible functional damage at the level of the coronary arterioles. In patients with reduced CFR, the decreased basal IMR and higher velocity reflect compensatory vasodilatory mechanisms probably triggered by ischaemic signals deriving from abnormal myocardial microcirculation.
Cardiac involvement is among the leading causes of mortality in patients with systemic sclerosis (SSc). Previously, we demonstrated in a single-center, cross-sectional study the frequent coexistence of different forms of cardiac involvement in systemic sclerosis including pulmonary arterial hypertension (PAH), coronary artery disease (CAD), and microvascular dysfunction (MVD). The aim of the present study was to investigate the prognostic significance of cardiac involvement. One hundred twenty patients with SSc were enrolled. All cases underwent a non-invasive cardiovascular protocol. In 30 patients with suspected cardiac involvement, right heart catheterization and intra-coronary pressure-wire-supplemented coronary angiography were performed. Clinical follow-up was 5 years. Patients with CAD at the baseline showed a trend for higher cardiovascular mortality while in patients with MVD this difference was significant (26.7 % versus 9.5 %, p = 0.077 and 30 % versus 10.1 %, p < 0.05, respectively). Cardiovascular mortality of PAH cases was higher but, however, did not reach statistical significance 21.4 % versus 10.4 %, p = 0.261. Cardiovascular event-free survival was significantly lower among patients with combinations of two or three disorders (p < 0.05). Multivariate analysis of organ involvements and comorbidities showed that the diffuse cutaneous subset, the presence of kidney involvement, the velocity of the tricuspid regurgitation, as well as diabetes mellitus were independent predictors of overall mortality. MVD and CAD alone or in combination with PAH significantly affected the 5-year cardiovascular mortality. These findings highlight the prognostic importance of coronary disease in patients with SSc [ www.clinicaltrials.gov (Reg. Nr.: NCT00843102)].
Background Fibrosis and vasculopathy are the hallmarks of Systemic sclerosis (SSc). There was a shift over SSc-related death causes over last years. Cardiomyopathy was identified as a major cause of death. However, the pathogenesis of SSc-related cardiomyopathy is poorly understood. New therapies as well as platforms for testing are needed Objectives We aimed to characterize cardiomyopathy in patients and mice models of SSc, and identify the best animal model for SSc-related cardiomyopathy. Methods Four patients with definite systemic sclerosis were enrolled in the project. Disease duration was 5±2 year. Patients with clinical evidence for cardiovascular disease were excluded from the study. Three systemic disease models of scleroderma were chosen: Fra-2 transgenic mice model (Fra-2), sclerodermatous chronic Graft versus Host disease (cGvHD) model and tight skin 1 mutation model (Tsk-1). Formalin fixed and paraffin embedded heart sections used for IHC. Heart sections from SSc patients, controls and mouse models were stained for α-SMA, CD31, active caspase3, picrosirius and hematoxylin eosin. Results Significant collagen accumulation was observed in hearts of SSc patients. The fibrotic area was increased in 8.8±2.3 folds compared to controls (P<0.001). Same pattern was found in Fra-2 mice with 8.9±2.8 fold increase (P=0.0002). In contrast, no significant changes were observed in cGvHD and in Tsk-1 mice. To detect differentiation towards myofibroblasts we stained for the α-SMA. SSc samples presented with increased numbers of myofibroblasts 2.5±0.6 vs. 0.5±0.8 (P=0.01) per high power field in controls. Same pattern found in all mice models of SSc, though highest mimicry to SSc hearts observed in Fra-2 model (3.0±1.1 vs. 0.5±0.6 P=0.0005). CD31 stainings revealed significant loss of capillaries in SSc hearts (2.16±0.17 fold change vs. controls P<0.0001). A prominent capillary loss was also observed in Fra-2 tg and in cGvHD models (2.0±0.2 P<0.0001 and 2.1±0.3 P<0.0001 fold change, respectively). No changes were observed in Tsk-1 mice. Apoptosis of endothelial cells was increased in Fra-2 tg mice vs. controls (2.5±0.9 vs. 0.17±0.43 P=0.0001). Apoptosis was observed in cGvHD mice though it was also elevated in controls (2.6±0.7 vs. 1.2±0. 5 P=0.003). No apoptosis was detected in capillaries of Tsk-1 mice. Endothelial apoptosis was also elevated in SSc hearts with 1.2±0.4 vs. 0.2±0.4 (P=0.0018) in controls. Detected higher numbers of perivascular leukocytes in SSc patients (5.8±1.8 fold change, P=0.0001) strengthened the hypothesis of vascular damage. Conclusions We demonstrate that heart changes were detectable in all models of SSc, but the typical features of cardiac disease in SSc –loss of capillaries due to apoptosis of endothelial cell and fibrosis- were closely mimicked only by Fra-2 tg mice. The cGvHD and Tsk-1 mice lacked some features of scleroderma related cardiomyopathy and were less representative. Thus, Fra-2 tg mice are a promising preclinical model to study the mechanisms and therapeutic approaches of ...
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