A Transient Outward Potassium Current Activator Recapitulates the Electrocardiographic Manifestations of Brugada Syndrome

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2008 Dec 17

PMID 19073629

Citations 48

Authors

Kirstine Calloe

Jonathan M Cordeiro

Jose M Di Diego

Rie S Hansen

Morten Grunnet

Soren Peter Olesen

Charles Antzelevitch

Affiliations

Soon will be listed here.

Abstract

Aims: 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.

Methods And Results: Isolated canine ventricular myocytes and coronary-perfused wedge preparations were used. Whole-cell patch-clamp studies showed that NS5806 (10 microM) 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 x 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.

Conclusion: 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.

Citing Articles

Impact of hypokalemia on Brugada syndrome: case report unveiling mechanisms beyond QT interval prolongation.

Siregar M, Wahidji V Egypt Heart J. 2024; 76(1):143.

PMID: 39436493 PMC: 11496434. DOI: 10.1186/s43044-024-00574-3.

Short QT intervals in African lions.

Scharling F, Sandgreen D, Stagegaard J, Elbrond V, Vincenti S, Isaksen J Exp Physiol. 2024; 109(12):2088-2099.

PMID: 39388603 PMC: 11607619. DOI: 10.1113/EP092203.

The Kv4 potassium channel modulator NS5806 attenuates cardiac hypertrophy in vivo and in vitro.

Cai Y, Zhang J, Zhang H, Qi J, Shi C, Xu Y Sci Rep. 2024; 14(1):19839.

PMID: 39191928 PMC: 11349892. DOI: 10.1038/s41598-024-70962-x.

Automated Patch-Clamp and Induced Pluripotent Stem Cell-Derived Cardiomyocytes: A Synergistic Approach in the Study of Brugada Syndrome.

Melgari D, Calamaio S, Frosio A, Prevostini R, Anastasia L, Pappone C Int J Mol Sci. 2023; 24(7).

PMID: 37047659 PMC: 10095337. DOI: 10.3390/ijms24076687.

Improved Ca release synchrony following selective modification of I and phase 1 repolarization in normal and failing ventricular myocytes.

Fowler E, Wang N, Hezzell M, Chanoit G, Hancox J, Cannell M J Mol Cell Cardiol. 2022; 172:52-62.

PMID: 35908686 PMC: 11773631. DOI: 10.1016/j.yjmcc.2022.07.009.

References

Ogawa R, Kishi R, Mihara K, Takahashi H, Takagi A, Matsumoto N . Population pharmacokinetic and pharmacodynamic analysis of a class IC antiarrhythmic, pilsicainide, in patients with cardiac arrhythmias. J Clin Pharmacol. 2006; 46(1):59-68. DOI: 10.1177/0091270005283281. View

Chen Q, Kirsch G, Zhang D, Brugada R, Brugada J, Brugada P . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998; 392(6673):293-6. DOI: 10.1038/32675. View

Fish J, Antzelevitch C . Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm. 2005; 1(2):210-7. PMC: 1524822. DOI: 10.1016/j.hrthm.2004.03.061. View

Watanabe H, Koopmann T, Scouarnec S, Yang T, Ingram C, Schott J . Sodium channel β1 subunit mutations associated with Brugada syndrome and cardiac conduction disease in humans. J Clin Invest. 2008; 118(6):2260-8. PMC: 2373423. DOI: 10.1172/JCI33891. View

Horigome H, Shigeta O, Kuga K, Isobe T, Sakakibara Y, Yamaguchi I . Ventricular fibrillation during anesthesia in association with J waves in the left precordial leads in a child with coarctation of the aorta. J Electrocardiol. 2003; 36(4):339-43. DOI: 10.1016/s0022-0736(03)00079-7. View

Cordeiro J, Malone J, Di Diego J, Scornik F, Aistrup G, Antzelevitch C . Cellular and subcellular alternans in the canine left ventricle. Am J Physiol Heart Circ Physiol. 2007; 293(6):H3506-16. PMC: 2366895. DOI: 10.1152/ajpheart.00757.2007. View

Tanaka H, Kinoshita O, Uchikawa S, Kasai H, Nakamura M, Izawa A . Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2001; 24(8 Pt 1):1293-4. DOI: 10.1046/j.1460-9592.2001.01293.x. View

Antzelevitch C, Pollevick G, Cordeiro J, Casis O, Sanguinetti M, Aizawa Y . Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation. 2007; 115(4):442-9. PMC: 1952683. DOI: 10.1161/CIRCULATIONAHA.106.668392. View

Antzelevitch C . Brugada syndrome. Pacing Clin Electrophysiol. 2006; 29(10):1130-59. PMC: 1978482. DOI: 10.1111/j.1540-8159.2006.00507.x. View

10.

Lundby A, Olesen S . KCNE3 is an inhibitory subunit of the Kv4.3 potassium channel. Biochem Biophys Res Commun. 2006; 346(3):958-67. DOI: 10.1016/j.bbrc.2006.06.004. View

11.

Ozeke O, Aras D, Celenk M, Deveci B, Yildiz A, Topaloglu S . Exercise-induced ventricular tachycardia associated with J point ST-segment elevation in inferior leads in a patient without apparent heart disease: a variant form of Brugada syndrome?. J Electrocardiol. 2006; 39(4):409-12. DOI: 10.1016/j.jelectrocard.2005.10.004. View

12.

Brugada P, Brugada J . Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992; 20(6):1391-6. DOI: 10.1016/0735-1097(92)90253-j. View

13.

Di Diego J, Cordeiro J, Goodrow R, Fish J, Zygmunt A, Perez G . Ionic and cellular basis for the predominance of the Brugada syndrome phenotype in males. Circulation. 2002; 106(15):2004-11. DOI: 10.1161/01.cir.0000032002.22105.7a. View

14.

Ogawa M, Kumagai K, Yamanouchi Y, Saku K . Spontaneous onset of ventricular fibrillation in Brugada syndrome with J wave and ST-segment elevation in the inferior leads. Heart Rhythm. 2005; 2(1):97-9. DOI: 10.1016/j.hrthm.2004.09.005. View

15.

Gordon E, Lozinskaya I, Lin Z, Semus S, Blaney F, Willette R . 2-[2-(3,4-dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD-307243) causes instantaneous current through human ether-a-go-go-related gene potassium channels. Mol Pharmacol. 2007; 73(3):639-51. DOI: 10.1124/mol.107.041152. View

16.

Aiba T, Shimizu W, Hidaka I, Uemura K, Noda T, Zheng C . Cellular basis for trigger and maintenance of ventricular fibrillation in the Brugada syndrome model: high-resolution optical mapping study. J Am Coll Cardiol. 2006; 47(10):2074-85. DOI: 10.1016/j.jacc.2005.12.064. View

17.

Potet F, Mabo P, Le Coq G, Probst V, Schott J, Airaud F . Novel brugada SCN5A mutation leading to ST segment elevation in the inferior or the right precordial leads. J Cardiovasc Electrophysiol. 2003; 14(2):200-3. DOI: 10.1046/j.1540-8167.2003.02382.x. View

18.

Yan G, Antzelevitch C . Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. 1999; 100(15):1660-6. DOI: 10.1161/01.cir.100.15.1660. View

19.

Di Diego J, Sun Z, Antzelevitch C . I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol. 1996; 271(2 Pt 2):H548-61. DOI: 10.1152/ajpheart.1996.271.2.H548. View

20.

Delpon E, Cordeiro J, Nunez L, Thomsen P, Guerchicoff A, Pollevick G . Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2009; 1(3):209-18. PMC: 2585750. DOI: 10.1161/CIRCEP.107.748103. View