Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

Heart Involvement in Patients with Systemic Sclerosis Is Mimicked by Fra-2 Transgenic Mice.

Venalis1,  Paulius, Cziriak2,  Laszlo, Akhmetshina3,  Alfiya, Dees3,  Clara, Zerr3,  Pawel, Mackevic4,  Zygmunt, Lundberg1,  Ingrid E.

Karolinska Institutet, Stockholm, Sweden
University of Pécs, Budapest, Hungary
University of Erlangen-Nuremberg, Erlangen, Germany
State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
University Hospital Zurich, Zurich, Switzerland


Systemic sclerosis (SSc) is a systemic autoimmune disease with vascular and fibrotic components. SSc-related cardiomyopathy is increasingly recognized 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. Here, we aimed to characterize different murine models of SSc and identify the best animal model for SSc-related cardiomyopathy.


Six patients with definite systemic sclerosis were enrolled in the project. Age- and sex- matched patients autopsies served as controls. Patients with a medical record for cardiovascular disease were excluded from the study. We have chosen three systemic disease models of scleroderma: 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 of SSc were stained for a-SMA, CD31 and active caspase3 as well as with picrosirius and hematoxylin eosin.


Significant fibrotic changes with accumulation of collagen were 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 increases in fibrotic area were observed in cGvHD mice and in Tsk-1 mice. To detect differentiation towards myofibroblasts we stained for the a-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 (HPF) in controls. As expected 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). Slight increases in the numbers of myofibroblasts were also obtained in the cGvHD and in the Tsk-1 model. 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 = 0003). No apoptosis was detected in capillaries of Tsk-1 mice. Endothelial cell 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.


We demonstrate that the typical features of cardiac disease in SSc –loss of capillaries due to apoptosis of endothelial cell and fibrosis- are closely mimicked by Fra-2 tg mice. In contrast, the changes in the hearts of mice with sclerodermatous cGvHD and in Tsk-1 mice were less representative. Thus, Fra-2 tg mice are a promising preclinical model to study the mechanisms and therapeutic approaches of heart involvement in systemic sclerosis.

To cite this abstract, please use the following information:
Venalis, Paulius, Cziriak, Laszlo, Akhmetshina, Alfiya, Dees, Clara, Zerr, Pawel, Mackevic, Zygmunt, et al; Heart Involvement in Patients with Systemic Sclerosis Is Mimicked by Fra-2 Transgenic Mice. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2606

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