title: Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation.
abstract: BACKGROUND
  The need for new treatment strategies for cardiac arrhythmias has motivated our continuing development of gene therapeutic options. Previously, we reported a decreased heart rate in an acute model of atrial fibrillation after atrioventricular nodal gene transfer. Here, we expand those observations to persistent atrial fibrillation and severe heart failure.
  
  
  RESULTS
  After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding beta-galactosidase (beta-gal), wild-type Galpha(i2) (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by beta-gal or wtGi. cGi caused a sustained 15% to 25% decrease in heart rate. The wtGi effect became evident with sedation. A tachycardia-induced cardiomyopathy was present before gene transfer. In the beta-gal group, cardiomyopathy worsened over time. In the wtGi group, the condition improved slightly, and in the cGi group, ejection fraction was near normal at the end of the study. TUNEL staining results corroborated this finding.
  
  
  CONCLUSIONS
  cGi overexpression in the porcine atrioventricular node causes physiologically relevant heart rate control in persistent atrial fibrillation. These data advance the development of gene therapy as a potential treatment for common cardiac arrhythmias.
authors.affiliation: Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bauer
authors.forename: Amy D
authors.initials: AD
authors.lastname: McDonald
authors.forename: Khurram
authors.initials: K
authors.lastname: Nasir
authors.forename: Leah
authors.initials: L
authors.lastname: Peller
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rade
authors.forename: Julie M
authors.initials: JM
authors.lastname: Miller
authors.forename: Alan W
authors.initials: AW
authors.lastname: Heldman
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Donahue
mesh_terms: D000208:Acute Disease; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D001283:Atrioventricular Node; D002304:Cardiac Pacing, Artificial; D004077:Digoxin / Q000494:pharmacology / Q000627:therapeutic use; D004110:Diltiazem / Q000494:pharmacology / Q000627:therapeutic use; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D006339:Heart Rate; D011412:Propanolamines / Q000494:pharmacology / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D013318:Stroke Volume; D034421:Sus scrofa; D014463:Ultrasonography
chemical_list: D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D004077:Digoxin; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D004110:Diltiazem; C036604:esmolol