title: Adenylate-cyclase VI transforms ventricular cardiomyocytes into biological pacemaker cells.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our study demonstrates that AC-VI gene transfer has the potential to create a biological pacemaker system.
authors.affiliation: Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany. arjang.ruhparwar@med.uni-heidelberg.de
authors.forename: Arjang
authors.initials: A
authors.lastname: Ruhparwar
authors.forename: Klaus
authors.initials: K
authors.lastname: Kallenbach
authors.forename: Gunnar
authors.initials: G
authors.lastname: Klein
authors.forename: Christoph
authors.initials: C
authors.lastname: Bara
authors.forename: Ali
authors.initials: A
authors.lastname: Ghodsizad
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sigg
authors.forename: Matthias
authors.initials: M
authors.lastname: Karck
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Michael
authors.initials: M
authors.lastname: Niehaus
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology*; D015153:Blotting, Western; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D013552:Swine; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D001616:beta-Galactosidase; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6