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.

Gene Therapy for Cardiac Arrhythmias

“…Using a transgenic mouse with a long QT phenotype (Kv1DN), a gene transfer of Kv1.5 reconstituted a 4-aminopyridinesensitive outward K+ current, shortened the APD and QT interval, and eliminated early after depolarizations. 63,64 However, arising from the limitations inherent in a study with small animals, there were few incidences of arrhythmias in this long QT model mouse. Thus, the antiarrhythmic effects should be further evaluated using another model.…”

Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System

“…155 A transgenic mouse model of the syndrome was created by overexpressing a truncated version of the Kv1.5 K + channel, exerting a dominant negative effect. After obtaining evidence that adenoviral expression of the wild-type channel shortens both the action potential duration and the QT interval, 156 the use of an AAV vector made it possible to validate the persistence of action potential normalization at 6 months after gene delivery. 157 Unfortunately, the incidence of arrhythmias in this model is low, and it is therefore difficult to infer the actual therapeutic potential of this strategy.…”

Biological Therapies for Cardiac Arrhythmias

“…27 A transgenic mouse model of the long QT syndrome has been used to test the feasibility of gene transfer to correct the phenotype. Wild-type Kv1.5 was delivered in either adenoviral 28 or adeno-associated viral vector 29 into the left ventricular base of transgenic mice bearing a dominant negative of Kv1.1 channel. In both studies, Kv1.5 overexpression and the resultant I Ks led to shortened APD and QT interval.…”