Abstract 17973: Chronic Fcγ Receptor II Stimulation by Immunization Leads to Dilated Cardiomyopathy
Introduction: Cardiotropic autoantibodies have been described in dilated cardiomyopathy (DCM). These antibodies can induce negative inotropic effects in cardiomyocytes by binding to the respective antigen via the Fab-part or by binding to Fcγ receptors. This study aimed to evaluate the role of activation by direct immunization against the Fcγ receptor II in the development of dilated cardiomyopathy.
Methods: 10 Lewis rats, age 4–6 weeks, were actively immunized by subcutaneous injection of an Fcγ receptor II peptide or vehicle and followed up by echocardiography. Isolated cardiomyocytes were cultured with IgG and Fcγ receptor II antibodies. Western blotting was performed to assess the phosphorylation status of Akt. Cellular contractility was measured in cardiomyocytes by field-stimulation using a video-imaging edge detector system.
Results: In contrast to control animals, actively immunized rats developed an increased level of Fcγ receptor II-antibodies after one month (1320ng/ml vs. <150ng/ml; p<0.01). Elevated levels persisted until the experimental endpoint. 5 months after the initial immunization, immunized animals developed progressive left ventricular dilatation (LVEDD: 0.36±0.01cm to 0.41±0.01cm; p<0.05) as well as reduced myocardial contractility (LVEF: baseline — 77.8±2.4% after 5 months – 52.9±3.5% p<0.001). Animals with Fcγ receptor II-antibodies showed increased mortality compared to the control group. Antibody level was negatively associated with left ventricular function (r=-0.596; p<0.001). Contractility analyses of isolated cardiomyocytes showed negative inotropy after incubation with anti-Fcγ receptor II antibodies, while goat IgG did not influence contractility in comparison to medium control (−18.1±4.5% vs. -2.6-±2.7% p<0.05). In isolated cardiomyocytes, phosphorylation of AKT was markedly reduced after addition of anti-Fcγ receptor II antibodies compared to control and goat IgG.
Conclusions: In this experimental setting, immunization against the Fcγ receptor II induces left ventricular dilatation and dysfunction. Activation of this receptor therefore seems to be involved in antibody-mediated DCM. Negative inotropy in this model might be mediated by reduced activation of AKT.
- © 2010 by American Heart Association, Inc.