Effects Of AAP10 On Ventricular Arrhythmia In Rabbit LQT2 Model

Background Gap junctions (GJs) are intercellular channels that permit the transfer of electrical current and small molecules between neighbouring cells. In the heart, cardiac gap junctions play a critical role in propagation, repolarization and arrhythmias. Long QT syndromes (LQTS) is often associated with torsade de pointes (TdP), a lethal ventricular arrhythmia (VA) characterized by its unique manifestation on electrocardiography (ECG). Increased transmural dispersion of repolarization (TDR) has been shown to contribute to initiation and maintenance of TdP in addition to QT interval prolongation in LQTS. Recent studies by Poelzing et al. demonstrated that intercellular uncoupling through gap junctions is an important mechanism for maintaining transmural heterogeneities of repolarization in both intact and diseased heart. Moreover, computer simulation study by Conrath et al also showed that effective intercellular coupling eradicated disparity of repolarization.Therefore, we hypothesized that improving gap junction communication reduces and prevents ventricular arrhythmia in LQTS.Aim The present study was to test the hypothesis that improving gap junction communication reduces TDR and prevents ventricular arrhythmia in rabbit ventricular model of LQT2Materials and Methods Thirty female New Zealand White rabbit weighing 1800~2200g were studied. An arterially-perfused rabbit left ventricular preparation and an Ikr blocker, E-4031 (0.5μM), were used to establish a model of LQT2. Antiarrhythmic peptide 10 (AAP10, H-Gly-Ala-Gly-4Hyp-Pro-Tyr-NH(2)), a specific gap junction stimulator, was used to improve gap junction conductance in the experiment. Preparations were randomly assigned to control (LQT-2+saline), AAP-100nM (LQT2+100nM AAP10) and AAP-500nM (LQT2+500nM AAP10) group. Perfusate containing antiarrhythmic peptide 10 (AAP10)/Saline were introduced 15mins prior to establishment of LQT2 model. Transmural ECG as well as action potential (AP) and stimulus-response interval (SRI) from both endocardium and epicardium were simultaneously recorded in the whole process in all experiments..Results 1) Rabbit body, heart, wedge weight, wedge/heart ratio and wedge/left ventricle (LV) ratio were of no significant difference compared across all groups (P>0.05). 2) No significant differences were observed in QT interval, endocardial and epicardial APD90, TDR, endocardial and epicardial SRI at baseline for all groups (P>0.05). 3) In LQT2 model, presence of 500nM AAP10 reduced endocardial action potential and TDR and prevented ventricular arrhythmia comparing to the control and AAP-100nM group (p<0.05) where no significant different were observed between control and AAP-100nM group (P>0.05).Conclusion The presence of 500nM AAP10 reduces TDR and prevents ventricular arrhythmia in rabbit ventricular model of LQT2. This study provides an indirect evidence of possible role of GJs in TDR in rabbit LQT2 model and indicates a new clinical approach to LQTS.