Abstract 212: Fractalkine Neutralization Improves Cardiac Function After Myocardial Infarction

Abstract

Background: Circulating levels of the chemokine fractalkine (FKN) are increased in patients with chronic heart failure (HF) and our studies show that aged mice lacking the prostaglandin E2 EP4 receptor subtype (EP4 KO) have increased cardiac FKN coupled with a phenotype of dilated cardiomyopathy. However, whether FKN is a causal factor for HF is not well established. Hypothesis: FKN contributes to the pathogenesis of HF post myocardial infarction (MI) and EP4 KO mice have a better response to anti-FKN treatment due to elevated FKN levels. Methods: Male EP4 KO mice and wild type (WT) littermates underwent surgery to induce MI. Mice were treated with an anti-FKN antibody (40μg/kg/day, ip) or IgG immediately after MI and echocardiography was performed 2 wks post MI. Hearts were excised for infarct size determination, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) determined by morphometric analysis and macrophage infiltration using immunohistochemistry. Results: Anti-FKN treatment improved cardiac function and prevented remodeling (Table). In situ zymography revealed that gelatinase activity was markedly reduced by anti-FKN treatment in both strains. Moreover, anti-FKN treatment tended to improve survival in EP4 KO mice (p = 0.06, n=20). Conclusions: (1) FKN contributes to the pathogenesis of HF and anti-FKN treatment improves cardiac function and reduces cardiac remodeling. This may be related to reduced macrophage infiltration and decreased gelatinase activity.(2) Contrary to our hypothesis, EP4 KO mice do not have an enhanced response to anti-FKN treatment.