Abstract 5933: Reduced Number of Gap Junctions at the Intercalated Disc in the Ventricles of Boxer Dogs Afflicted with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

Abstract

ARVC is an inherited myocardial disease associated with sustained monomorphic ventricular tachycardia, sudden cardiac death, and replacement of RV myocardium with fatty or fibro-fatty tissue. Lethal arrhythmias often occur in young patients, before apparent structural damage. It has been hypothesized that loss of Cx43 gap junctions (GJ) may act as a substrate for ventricular arrhythmias in these patients. An inherited form of ARVC is present in the boxer, with clinical symptoms and pathological features similar to those of humans. Here, we used transmission electron microscopy (TEM) to assess the ultrastructure of the intercalated disc (ID) in ARVC-afflicted boxers. Samples from the right and left ventricles (RV and LV) of 1 unafflicted beagle, and 3 ARVC afflicted boxers were examined by TEM. Samples from beagle tissue showed normal morphology, good alignment of the sarcomeres and myofibrils, and attachment of myofibrils to the ID. Samples from the ARVC-afflicted boxer lacked myofibril organization, with few attachments to the ID. Within RV and LV longitudinal sections from one afflicted and one control animal, three parameters were measured: ID length, individual GJ length, and number of GJ per ID. No significant differences were found in the length of IDs or of GJs from RV or LV samples of ARVC vs. control. ID length (μm) was 26.8 +/− 5.4 and 44.9+/− 10.6 in control RV and LV, respectively. ID length in afflicted samples was 31.2+/− 5.0 and 52.3+/−13.5 (pNS). GJ length (μm) was .5+/−.03 and .5+/.05 for RV and LV of the control group, and .4+/−.07 and .6+/−,13 in samples obtained from RV and LV of ARVC afflicted animals (pNS). However, our data indicated a significant (p<.01) decrease in the number of GJ per ID in the ARVC sample by over 80% (5.7+/−.4 RV, 5.8+/− 1.4 LV in control; 1.1+/−.16 RV, 1.5+/−.2 LV in ARVC). Our results suggest that ARVC, both in humans and in boxer dogs, associates with a loss of GJ, which may act as a substrate for lethal arrhythmias. In contrast to human ARVC, no desmosomal protein mutations have been linked to boxer ARVC. This suggests a different genetic basis and yet, a common molecular pathway for ARVC in both species. As such, boxers represent a valuable model to understand the mechanisms leading to malignant ventricular arrhythmias in ARVC patients. This research has received full or partial funding support from the American Heart Association, AHA Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).