Adenylate-Cyclase VI Transforms Ventricular Cardiomyocytes into Biological Pacemaker Cells

Abstract

When sinus node or atrioventricular (AV) node cells are damaged by disease, the implantation of an artificial cardiac pacemaker becomes necessary. In search for a biological alternative, the objective 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 AV node block model. Genetic therapy of arrhythmic disorders of the heart has been subject of extensive studies. Cyclic AMP is generated in response to Beta-adrenergic receptor stimulation and also binds to HCN channels, where it regulates spontaneous rhythmic activity in the sinus node. Adenoviruses encoding either AC-VI or Beta-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/min (n = 5), whereas the escape rhythms in the control group (n = 4) originated from the right ventricle. Western blot analysis of the injection sites revealed significantly higher expression of AC-VI in the respective group as compared with the control group. Our study demonstrates that AC-VI gene transfer has the potential to create a biological pacemaker system.