Abstract 2563: Description of a Local Cardiac Adiponectin System and its Deregulation in Dilated Cardiomyopathy
Despite recent advances in medical therapy heart failure is a leading cause for cardiovascular mortality and its complex pathogenesis is incompletely understood. In order to identify new therapeutic targets in dilated cardiomyopathy (DCM), oligonucleotide microarray analysis was performed on endomyocardial biopsy specimens of patients with early DCM (LVEDP>55mm, LVEF>60%, n=6) and control subjects (LVEDP<55mm, LV-EF>60%, no cardiac pathology, n=5). Adiponectin, an adipocytokine involved in cellular metabolism, survival and immun-modulation that very recently has been shown to be synthetized in cardiac myocytes, was 6.2fold downregulated in the DCM group. Microarray data for adiponectin were confirmed by Taq-Man-PCR (8.6fold downregulation, control n=12 vs. DCM n=15, respectively, p<0,05). Immunohistological analysis of myocardial biopsies showed a significant downregulation of adiponectin protein expression. Changes of cardiac adiponectin expression in early DCM were independent of serum adiponectin (p=0,36, NS) or serum TNFα concentrations (p=0,46, NS). Both receptors, Adipo-R1 and Adipo-R2, were not regulated in early DCM. Adiponectin downregulation was confirmed in patients with advanced heart failure. Explanted hearts of patients with end-stage DCM (LV-EF<30%, n=5) showed an 5.8fold downregulation of adiponectin mRNA and protein expression when compared with explanted hearts from healthy donors (n=6, p<0,05). Moreover, Adipo-R1 and Adipo-R2 were significantly upregulated in late DCM. In vitro, adiponectin incubation of NRVM led to an activation of the pro-survival protein kinase PKB/Akt as well as increased eNOS-phosphorylation and NO-synthesis. Adiponectin prevented apoptosis of cardiac myocytes caused by prolonged serum starvation in vitro and this effect could be blocked by transduction of NRVM with a dominant negative form of PKB/Akt. Our data describe the importance of a novel local cardiac adiponectin system and its deregulation in cardiac pathology. The study suggests a role for adiponectin in the pathogenesis of dilated cardiomyopathy and implicates the adipocytokine as a possible future therapeutic target in heart failure.