Inhibition of CINC-1 Decreases Right Ventricular Damage Caused by Experimental Pulmonary Embolism in Rats

Abstract

Right ventricular (RV) dysfunction is a strong risk factor for poor clinical outcome following pulmonary embolism (PE), the third most prevalent cardiovascular disease. Previous studies in our laboratory demonstrated that RV failure during PE is mediated, in part, by neutrophil-dependant cardiac inflammation. In this study we use DNA microarray analysis of gene expression to demonstrate that PE results in increased expression of the CXC chemokines CINC-1 and CINC-2 between 6 and 18 h after the start of PE in a rat model of PE. Neutrophils accumulate in RV tissue by 18 h, and this inflammation is associated with decreased right heart function. Treatment of rats with Abs to CINC-1 significantly suppressed neutrophil accumulation in RVs during PE (52% reduction in tissue myeloperoxidase) and ameliorated RV failure. In addition, plasma concentration of cardiac troponin I, an established diagnostic marker for cardiac damage, was reduced by 90%. These results suggest that selective anti-inflammatory therapies targeted at neutrophil chemoattractants will reduce cardiac inflammation and reduce RV damage in the setting of PE.

Involvement of inflammatory markers in pathogenesis of venous thromboembolism

“…It was demonstrated that patients with high serum levels of these inflammatory cytokines present a risk 2-3 times higher to develop venous thrombosis [1,17,[19][20][21][22]. Moreover, plasma concentrations of these immune mediators were increased in patients with recurrent venous thrombosis.…”

“…Secondly, IL-8 induces leukocyte recruitment, the first cells that adhere to the vein endothelium in deep venous thrombosis. Moreover, IL-8 might contribute to the generation of a procoagulant surface through monocyte adhesion to the vascular endothelium [22].…”

“…Histological analysis of the right ventricular muscle in subjects with fatal pulmonary thromboembolism show a massive accumulation of neutrophils and monocytes/macrophages, but no histological proof of infarction. Selective anti-inflammatory therapies targeted against neutrophil chemo-attractants lead to a reduction in cardiac inflammation and in right ventricular dysfunction in pulmonary embolism [22].…”

Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension

“…28 The mechanistic importance of RV inflammation was demonstrated because suppression of the inflammatory response after acute pulmonary embolism limited RV damage and prevented right heart failure. 29 In these studies, it was suggested that RV inflammation could have been triggered by ischemic injury of the RV or local and/or systemic overproduction of catecholamines.…”

“…28 The mechanistic importance of RV inflammation was demonstrated because suppression of the inflammatory response after acute pulmonary embolism limited RV damage and prevented right heart failure. 29 In these studies, it was suggested that RV inflammation could have been triggered by ischemic injury of the RV or local and/or systemic overproduction of catecholamines.High RV wall stress might be an alternative explanation, as recently shown in a model of chronic LV pressure overload. 9,30 We observed a similar amount of RV hypertrophy in all PH groups.…”