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Attenuation of I_K,slow1 and I_K,slow2 in Kv1/Kv2DN mice prolongs APD and QT intervals but does not suppress spontaneous or inducible arrhythmias

¹Bioelectricity Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston 02115; ²Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110; and ³Cardiovascular Engineering Inc., Holliston, Massachusetts 01746

Submitted 3 April 2003 ; accepted in final form 13 August 2003

Overexpression of a truncated Kv1.1 or Kv2.1 channel polypeptide in the heart (Kv1DN or Kv2DN) resulted in mice with a prolonged action potential duration (APD) due to marked attenuation of rapidly activating, slowly inactivating K⁺ current (I_K,slow1) or slowly inactivating outward K⁺ current (I_K,slow2) in ventricular myocytes. ECG monitoring, optical mapping, and programmed electrical stimulation of Kv1DN mice revealed spontaneous and inducible reentrant ventricular tachycardia due to spatial dispersion of repolarization and refractoriness. Recently, we demonstrated upregulation of I_K,slow2 in apical cardiomyocytes derived from Kv1DN mice. We therefore hypothesized that the selective upregulation of Kv2.1-encoded currents underlies the apex-to-base dispersion of repolarization and the reentrant arrhythmias. To test this hypothesis, the Kv1DN line was crossbred with the Kv2DN line to produce Kv1/Kv2DN lines. Whole cell voltage-clamp recordings from left ventricular cells of Kv1/Kv2DN confirmed that the 4-aminopyridine- and tetraethylammonium-sensitive components of I_K,slow were eliminated, resulting in marked APD prolongation compared with wild-type, Kv1DN, and Kv2DN cells. Telemetric ECG recordings revealed prolongation of the corrected QT in Kv1/Kv2DN compared with Kv1DN and Kv2DN mice. However, attenuation of Kv2.1-encoded currents in Kv1DN mice did not suppress the arrhythmias. Thus, the elimination of I_K,slow2 prolongs APD and the QT intervals, but does not have an antiarrhythmic effect.

cardiac arrhythmia; electrophysiology; potassium channels; long QT syndrome

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