In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype.
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.
Brunner
Michael
M
Bioelectricity Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Kodirov
Sodikdjon A
SA
Mitchell
Gary F
GF
Buckett
Peter D
PD
Shibata
Katsushi
K
Folco
Eduardo J
EJ
Baker
Linda
L
Salama
Guy
G
Chan
Danny P
DP
Zhou
Jun
J
Koren
Gideon
G
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
C496982:Kcna5 protein, mouse; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015761:4-Aminopyridine