Journal
CARDIOVASCULAR RESEARCH
Volume 81, Issue 4, Pages 686-694Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn339
Keywords
Transient outward potassium current; Ito; Brugada syndrome; Re-entry; Arrhythmia
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Funding
- Carlsberg Foundation [2006010173]
- American Health Assistance Foundation
- Danish National Research Foundation
- National Institutes of Health [HL 47678]
- Masons of New York State and Florida
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Transient outward potassium current (I-to) is thought to be central to the pathogenesis of the Brugada syndrome (BrS). However, an I-to activator has not been available with which to validate this hypothesis. Here, we provide a direct test of the hypothesis using a novel I-to activator, NS5806. Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 mu M) increased peak I-to 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 I-to 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 I-to 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 I-to 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 I-to 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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