title: Biological Heart Rate Reduction Through Genetic Suppression of Gα(s) Protein in the Sinoatrial Node.
abstract: BACKGROUND
  Elevated heart rate represents an independent risk factor for cardiovascular outcome in patients with heart disease. In the sinoatrial node, rate increase is mediated by β(1) adrenoceptor mediated activation of the Gα(s) pathway. We hypothesized that genetic inactivation of the stimulatory Gα(s) protein in the sinoatrial node would provide sinus rate control and would prevent inappropriate heart rate acceleration during β-adrenergic activation.
  
  
  RESULTS
  Domestic pigs (n=10) were evenly assigned to receive either Ad-small interfering RNA (siRNA)-Gα(s) gene therapy to inactivate Gα(s) or adenovirus encoding for green fluorescent protein (Ad-GFP) as control. Adenoviruses were applied through virus injection into the sinoatrial node followed by epicardial electroporation, and heart rates were evaluated for 7 days. Genetic inhibition of Gα(s) protein significantly reduced mean heart rates on day 7 by 16.5% compared with control animals (110±8.8 vs 131±9.4 beats per minute; P<0.01). On β-adrenergic stimulation with isoproterenol, we observed a tendency toward diminished rate response in the Ad-siRNA-Gα(s) group (Ad-siRNA-Gα(s), +79.3%; Ad-GFP, +61.7%; n=3 animals per group; P= 0.294). Adverse effects of gene transfer on left ventricular ejection fraction (LVEF) were not detected following treatment (LVEF(Ad-siRNA-Gαs), 66%; LVEF(Ad-GFP), 60%).
  
  
  CONCLUSIONS
  In this preclinical proof-of-concept study targeted Ad-siRNA-Gα(s) gene therapy reduced heart rates during normal sinus rhythm compared with Ad-GFP treatment and prevented inappropriate rate increase after β-adrenergic stimulation. Gene therapy may provide an additional therapeutic option for heart rate reduction in cardiac disease. (J Am Heart Assoc. 2012;1:jah3-e000372 doi: 10.1161/JAHA.111.000372).
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lugenbiel
authors.forename: Alexander
authors.initials: A
authors.lastname: Bauer
authors.forename: Kamilla
authors.initials: K
authors.lastname: Kelemen
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Schweizer
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Becker
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Dierk
authors.initials: D
authors.lastname: Thomas
keywords: electrophysiology; gene therapy; heart failure; heart rate; sinoatrial node