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

Abstract

Aim Transient outward potassium current (Ito) is thought to be central to the activator has not been pathogenesis of the Brugada syndrome (BrS). However, an Ito available with which to validate this hypothesis. Here we provide a direct test of the hypothesis using a novel Ito activator, NS5806. Methods Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Results 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 increased of inactivation from 12.6±3.2 to 20.3±2.9 ms, n=7. Total charge carried by Ito 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 (AP) in epicardium, but not endocardium, and accentuated the ECG J-wave, leading to the development of phase 2 reentry and polymorphic ventricular tachycardia (n=9). While sodium and calcium channel blockers are capable of inducing BrS only in right ventricular 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. Conclusions 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.

Modulation of the Voltage-gated Potassium Channel (Kv4.3) and the Auxiliary Protein (KChIP3) Interactions by the Current Activator NS5806

“…This drug was shown to reverse the effect of induced heart failure in canine models (17,19). On the other hand, Witzel et al (11) hypothesized that the observed current inhibition in hippocampal neuronal cells was likely due to a higher concentration of NS5806 used (20 M) compared with the concentration used in canine cardiomyocytes.…”

“…The formation of Kv4-KChIP complex has been shown to be necessary for proper regulation of the fast component of the I TO currents in the heart (4) and I SA in the brain (10). Demod-* This work was supported, in whole or in part, by National Institutes of Health ulation of I TO currents is a characteristic trait in hypertrophied and failing hearts (16) as well as in Brugada syndrome (17). Normal functioning heart tissue displays an increasing I TO current density gradient from endocardium to epicardium, which has been shown to correlate with a transmural KChIP density (18).…”

“…Recently, Calloe et al (17) introduced a new compound named NS5806, which was shown to modulate the I TO current kinetics and reverse the I TO current decrease induced by heart failure in canine models (20). Interestingly, this I TO activator has also been shown to decrease I SA currents in cultured hippocampal neurons where its effects on gating kinetics are comparable to those observed in heart tissue (11).…”

Abnormal Atrial Repolarization and Depolarization Contribute to the Inducibility of Atrial Fibrillation in Brugada Syndrome

“…We have reported that intravenous administration of quinidine increased RV MAPD 90 at the shortest diastolic interval and decreased the maximum slope of the RV action potential duration restitution curve. 33) Thus, we hypothesized that shorter RA MAPD 80 and a steeper restitution curve at the shorter diastolic interval in Brugada syndrome might also be related to the smaller late sodium current 2) or greater transient outward current 34) at the shorter diastolic interval in Brugada patients. The inducibility of reentrant arrhythmias to a large extent is dependent on the wavelength (conduction velocity × refractory period) of the atrial impulse.…”

Ionic and Cellular Mechanisms Underlying the Development of Acquired Brugada Syndrome in Patients Treated with Antidepressants

“…Single myocytes were enzymatically dissociated from the left ventricle as previously described 23 and allowed to settle and attach to the polylysine-coated floor of a 0.5 mL chamber mounted on a stage heater (Model PDMI-2, Harvard Apparatus, Holliston, MA, USA) on a Nikon Eclipse microscope. This chamber was perfused with Tyrode's solution at a rate of 2-3 mL/min prior to and during gigaseal formation.…”