—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 α 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 α 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 (Kv4.2W362F×Kv1.4^−/−) were generated. Histological and echocardiographic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362F×Kv1.4^−/− mouse hearts. Electrophysiological recordings from the majority (≈80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362F×Kv1.4^−/− 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 Kv4.2W362F×Kv1.4^−/− 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. (Circ Res. 2000;87:73-79.)