Abstract 14809: Macrophages Contribute to Diastolic Dysfunction in Systemic Sclerosis

Abstract

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by aberrant inflammation and internal organ fibrosis, resulting in irreversible scarring and organ failure. In patients with SSc, primary cardiac involvement heralds a poor prognosis, and accounts for one-third of SSc-related deaths. No effective treatments are available for this lethal disorder. However, preclinical investigations are hindered by the scarcity of animal models recapitulating human SSc-associated cardiac disease. Methods: 5-7-week-old C57BL/6J female wild type mice were injected with PBS (control) or 100 μL bleomycin subcutaneously every other day for 4 weeks. Endpoints include body weight, exercise capacity, echocardiography, and histologic quantification of fibrosis in heart (Masson’s trichrome staining). Results: At study endpoint, animals receiving bleomycin exhibited body weight loss (p<0.005) and lower exercise capacity compared to vehicle (p<0.0002). Echocardiographic assessment revealed diastolic dysfunction (measured by E/E’ ratio) in bleomycin exposed mice (38.35 vs 21.38 control; p<0.001), with no changes in systolic function. By Masson’s trichrome staining, cardiac fibrosis was significantly greater in SSc animals compared to controls (p<0.001). Transcriptomic analysis of left ventricular tissue from SSc mice showed enrichment of macrophage signaling pathways. Furthermore, macrophage depletion (for 4 weeks post bleomycin) with clodronate liposomes attenuated diastolic dysfunction (-10.48; p p<0.01) and cardiac fibrosis (p<0.05) in SSc mice compared to vehicle. Conclusions: The bleomycin model of systemic sclerosis also exhibits signs of systemic sclerosis with cardiac involvement, namely diastolic dysfunction and myocardial fibrosis. The clodronate data implicate inflammation and specifically macrophages as drivers of cardiac abnormalities in this preclinical model of SSc.