P130 Downregulation and reorganization of cardiac gap junctions in arrhythmogenic right ventricular cardiomyopathy.
1G.Plenz, 2V.Arps, 1H.Eschert, 1M.Paul, 1P.Gerdes, 1G.Breithardt, 1T.Wichter
1Department of Cardiology and Angiology, University Hospital, Muenster; 2Institute for Arteriosclerosis Research, Muenster.

Background: The propagation of the electrical impulse between cardiac myocytes is disturbed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and leads to life threatening arrhythmias. Gap junctions are transmembrane channels that mediate direct intercellular exchange of ions. However, nothing is known about the expression of gap junctions and their constituting molecules, the connexins (Cx), in ARVC.

Material and Methods: We studied the mRNA expression of the myocardial connexins (RT-PCR) and distribution of gap junctions (immunoconfocal analysis) in septal myocardial specimen obtained from patients undergoing evaluation of ARVC (n=11) and idiopathic dilated cardiomyopathy (DCM; n=13). Nonfailing myocardium (NF, control) was obtained from donor hearts (n=6). Expression and distribution patterns of gap junctions in patients with ARVC were compared to those of DCM and NF.

Results: In comparison with NF, ARVC showed a decreased expression of Cx40 (14,67±2.59 vs. 7,13±3.66; p=0,0002), Cx43 (17,17±1,72 vs. 12,13±3,46; p=0,003) and Cx45 (20,33±1,97 vs. 2,25±1,31; p=6,1x10-16). These alterations of expression levels were directly reflected on the protein level. Cx40 and Cx43 gap junctions were reduced, whereas Cx45 gap junctions were lost. Tissue from patients with DCM showed decreased expression of Cx43 (17.17±1.72 vs. 12.67±4.37; p=0,04) and Cx45 (20,33±1,97 vs. 5,12±1,55; 6,1x10-8) but not of Cx40. In comparison with ARVC, DCM showed higher levels of Cx40 (p=0,027) and Cx45 (p=0,0004).

Conclusions: ARVC is characterized by a dramatic reduction of cardiac connexins and gap junctions. The most pronounced effect was found in the “conducting tissue” connexins. Nevertheless, the working myocardium Cx43 was also affected. Thus, in ARVC failures both in the conduction of the electrical impulse to the working myocardium and in the distribution in the working myocardium ensue. In contrast, DCM patients demonstrated an impaired distribution of the electrical impulse only in the working myocardium.