title: In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.
abstract: Mutations in cardiac voltage-gated K+ channels cause long QT syndrome (LQTS) and sudden death. We created a transgenic mouse with a long QT phenotype (Kv1DN) by overexpression of a truncated K+ channel in the heart and investigated whether the dominant negative effect of the transgene would be overcome by the direct injection of adenoviral vectors expressing wild-type Kv1.5 (AV-Kv1.5) into the myocardium. End points at 3-10 days included electrophysiology in isolated cardiomyocytes, surface ECG, programmed stimulation of the right ventricle, and in vivo optical mapping of action potentials and repolarization gradients in Langendorff-perfused hearts. Overexpression of Kv1.5 reconstituted a 4-aminopyridine-sensitive outward K+ current, shortened the action potential duration, eliminated early afterdepolarizations, shortened the QT interval, decreased dispersion of repolarization, and increased the heart rate. Each of these changes is consistent with a physiologically significant primary effect of adenoviral expression of Kv1.5 on ventricular repolarization of Kv1DN mice.
authors.affiliation: Bioelectricity Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Brunner
authors.forename: Sodikdjon A
authors.initials: SA
authors.lastname: Kodirov
authors.forename: Gary F
authors.initials: GF
authors.lastname: Mitchell
authors.forename: Peter D
authors.initials: PD
authors.lastname: Buckett
authors.forename: Katsushi
authors.initials: K
authors.lastname: Shibata
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.forename: Linda
authors.initials: L
authors.lastname: Baker
authors.forename: Guy
authors.initials: G
authors.lastname: Salama
authors.forename: Danny P
authors.initials: DP
authors.lastname: Chan
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004562:Electrocardiography; D004594:Electrophysiology; D018014:Gene Transfer Techniques; D051666:Kv1.5 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010641:Phenotype; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
chemical_list: C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015761:4-Aminopyridine