A transient outward potassium current activator recapitulates the electrocardiographic manifestations of Brugada syndrome

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Abstract
Transient outward potassium current (Ito) is thought to be central to the pathogenesis of the Brugada syndrome (BrS). However, an Ito activator has not been available with which to validate this hypothesis. Here, we provide a direct test of the hypothesis using a novel Ito activator, NS5806. Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 µM) increased peak Ito at +40 mV by 79 ± 4% (24.5 ± 2.2 to 43.6 ± 3.4 pA/pF, n = 7) and slowed the time constant of inactivation from 12.6 ± 3.2 to 20.3 ± 2.9 ms (n = 7). The total charge carried by Ito increased by 186% (from 363.9 ± 40.0 to 1042.0 ± 103.5 pA·ms/pF, n = 7). In ventricular wedge preparations, NS5806 increased phase 1 and notch amplitude of the action potential in the epicardium, but not in the endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 re-entry and polymorphic ventricular tachycardia (n = 9). Although sodium and calcium channel blockers are capable of inducing BrS only in right ventricular (RV) wedge preparations, the Ito activator was able to induce the phenotype in wedges from both ventricles. NS5806 induced BrS in 4/6 right and 2/10 left ventricular wedge preparations. The Ito activator NS5806 recapitulates the electrographic and arrhythmic manifestation of BrS, providing evidence in support of its pivotal role in the genesis of the disease. Our findings also suggest that a genetic defect leading to a gain of function of Ito could explain variants of BrS, in which ST-segment elevation or J-waves are evident in both right and left ECG leads.

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