Elimination of both I(to,f) and I(to,s) in Kv4.2W362FxKv1.4(-/-) mice caused significant action potential prolongation, marked QT prolongation, atrioventricular block, and ventricular tachycardia.
Elimination of both fast and slow transient outward potassium currents in mice leads to severe electrical remodeling and arrhythmias without structural heart disease.
It was recently reported that the slow transient outward K(+) current, I(to, s), that is evident in mouse left ventricular septal cells is eliminated in mice with a targeted deletion of the Kv1.4 gene (Kv1.4(-/-)). The rapidly inactivating transient outward K(+) current, I(to, f), in contrast, is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing a dominant-negative Kv4 alpha subunit, Kv4.2W362F. Expression of Kv4. 2W362F results in marked prolongation of action potentials and QT intervals. In addition, a slow transient outward K(+) current, that is similar to I(to,s) in wild-type mouse left ventricular septal cells, is evident in all Kv4.2W362F-expressing (left and right) ventricular cells. To test directly the hypothesis that upregulation of Kv1.4 alpha subunit underlies the appearance of this slow transient outward K(+) current in Kv4.2W362F-expressing ventricular cells and to explore the functional consequences of elimination of I(to,f) and I(to,s), mice expressing Kv4.2W362F in the Kv1.4(-/-) background (Kv4.2W362FxKv1.4(-/-)) were generated. Histological and echocardiographic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362FxKv1.4(-/-) mouse hearts. Electrophysiological recordings from the majority (approximately 80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362FxKv1.4(-/-) animals demonstrated that both I(to, f) and I(to,s) are eliminated; action potentials are prolonged significantly; and, in some cells, early afterdepolarizations were observed. In addition, in vivo telemetric ECG recordings from Kv4.2W362FxKv1.4(-/-) animals revealed marked QT prolongation, atrioventricular block, and ventricular tachycardia. These observations demonstrate that upregulation of Kv1.4 contributes to the electrical remodeling evident in the ventricles of Kv4.2W362F-expressing mice and that elimination of both I(to,f) and I(to,s) has dramatic functional consequences.
Guo et al. (2000) studied Electrical remodeling and functional consequences of I(to,f) and I(to,s) elimination. Targeted deletion of Kv1.4 gene and expression of dominant-negative Kv4 alpha subunit (Kv4.2W362F) was evaluated on Electrophysiological recordings and in vivo telemetric ECG. Elimination of both I(to,f) and I(to,s) in Kv4.2W362FxKv1.4(-/-) mice caused significant action potential prolongation, marked QT prolongation, atrioventricular block, and ventricular tachycardia.