Abstract 1744: Adenylate-Cyclase VI Transforms Ventricular Cardiomyocytes Into Biological Pacemaker Cells

Abstract

Background- Genetic therapy of arrhythmic disorders of the heart has been subject of extensive studies. Cyclic AMP (cAMP) is generated in response to β-adrenergic receptor stimulation and also binds to HCN channels, where it regulates spontaneous rhythmic activity in the heart. Aim of this study was to demonstrate whether in-vivo adenoviral gene transfer of Adenylate-Cyclase type VI (AC VI ) can create biological pacemaker activity in a porcine atrioventricular node (AV-node) block model. Methods and Results- Adenovirus encoding either AC VI or β-Galactosidase (lacZ) gene were injected into the lateral wall of the left ventricle of adult pigs via anterolateral thoracotomy at a dose of 10 10 virus particles each. After 12 days, the AV-node was ablated and three-dimensional electrophysiological cardiac mapping was performed using the Ensite™ electro-anatomical system. After rapid ventricular pacing and administration of Isoprenalin all animals of the AC-VI group exhibited an escape rhythm originating from the area of the left ventricular injection site at a rate of 100 ± 7 beats/minute (n = 5), while the escape rhythms in the control group (n = 4) originated from the right ventricle. Western blot analysis of the injection sites revealed a significantly higher expression of AC-VI in the respective group as compared to the control group. Conclusions- Our study demonstrates that AC-VI gene transfer may be a novel method to create a biological pacemaker