Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Antiarrhythmic Effect of Artemisinin in an Ex-vivo Model of Brugada Syndrome Induced by NS5806

  • Hyung Ki Jeong (Division of Cardiology, Department of Internal Medicine, Wonkwang University School of Medicine) ;
  • Seo Na Hong (Department of Cardiology, Kwangju Christian Hospital) ;
  • Namsik Yoon (Division of Cardiology, Department of Internal Medicine, Chonnam National University Medical School) ;
  • Ki Hong Lee (Division of Cardiology, Department of Internal Medicine, Chonnam National University Medical School) ;
  • Hyung Wook Park (Division of Cardiology, Department of Internal Medicine, Chonnam National University Medical School) ;
  • Jeong Gwan Cho (Division of Cardiology, Department of Internal Medicine, Chonnam National University Medical School)
  • Received : 2022.11.11
  • Accepted : 2023.01.04
  • Published : 2023.04.01
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Abstract

Background and Objectives: Brugada syndrome (BrS) is an inherited arrhythmia syndrome that presents as sudden cardiac death (SCD) without structural heart disease. One of the mechanisms of SCD has been suggested to be related to the uneven dispersion of transient outward potassium current (Ito) channels between the epicardium and endocardium, thus inducing ventricular tachyarrhythmia. Artemisinin is widely used as an antimalarial drug. Its antiarrhythmic effect, which includes suppression of Ito channels, has been previously reported. We investigated the effect of artemisinin on the suppression of electrocardiographic manifestations in a canine experimental model of BrS. Methods: Transmural pseudo-electrocardiograms and epicardial/endocardial transmembrane action potentials (APs) were recorded from coronary-perfused canine right ventricular wedge preparations (n=8). To mimic the BrS phenotypes, acetylcholine (3 μM), calcium channel blocker verapamil (1 μM), and Ito agonist NS5806 (6-10 μM) were used. Artemisinin (100-150 μM) was then perfused to ameliorate the ventricular tachyarrhythmia in the BrS models. Results: The provocation agents induced prominent J waves in all the models on the pseudo-electrocardiograms. The epicardial AP dome was attenuated. Ventricular tachyarrhythmia was induced in six out of 8 preparations. Artemisinin suppressed ventricular tachyarrhythmia in all 6 of these preparations and recovered the AP dome of the right ventricular epicardium in all preparations (n=8). J wave areas and epicardial notch indexes were also significantly decreased after artemisinin perfusion. Conclusions: Our findings suggest that artemisinin has an antiarrhythmic effect on wedge preparation models of BrS. It might work by inhibition of potassium channels including Ito channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation.

Keywords

Acknowledgement

This research was supported from the Korean Cardiac Research Foundation (202002-02) and Korean Heart Rhythm Society (KHRS2020-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  1. Brugada J, Campuzano O, Arbelo E, Sarquella-Brugada G, Brugada R. Present status of Brugada syndrome: JACC state-of-the-art review. J Am Coll Cardiol 2018;72:1046-59.
  2. Antzelevitch C, Yan GX. J wave syndromes. Heart Rhythm 2010;7:549-58.
  3. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol 2006;29:1130-59.
  4. Szel T, Antzelevitch C. Abnormal repolarization as the basis for late potentials and fractionated electrograms recorded from epicardium in experimental models of Brugada syndrome. J Am Coll Cardiol 2014;63:2037-45.
  5. Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2018;138:e272-391.
  6. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022;43:3997-4126.
  7. Yang BF, Li YR, Xu CQ, et al. Mechanisms of artemisinin antiarrhythmic action. Chin J Pharm Toxicol 1999;13:169-75. 
  8. Yang BF, Luo DL, Bao LH, Zhang YC, Wang HZ. Artemisinin blocks activating and slowly activating K+ current in guinea pig ventricular myocytes. Acta Pharmacologica Sinica 1998;19:269-72.
  9. So EC, Wu SN, Wu PC, Chen HZ, Yang CJ. Synergistic inhibition of delayed rectifier K+ and voltage-gated Na+ currents by artemisinin in pituitary tumor (GH3) cells. Cell Physiol Biochem 2017;41:2053-66.
  10. Qiao G, Li S, Yang B, Li B. Inhibitory effects of artemisinin on voltage-gated ion channels in intact nodose ganglion neurones of adult rats. Basic Clin Pharmacol Toxicol 2007;100:217-24.
  11. Di Diego JM, Sicouri S, Myles RC, Burton FL, Smith GL, Antzelevitch C. Optical and electrical recordings from isolated coronary-perfused ventricular wedge preparations. J Mol Cell Cardiol 2013;54:53-64.
  12. Fish JM, Welchons DR, Kim YS, Lee SH, Ho WK, Antzelevitch C. Dimethyl lithospermate B, an extract of Danshen, suppresses arrhythmogenesis associated with the Brugada syndrome. Circulation 2006;113:1393-400.
  13. Gurabi Z, Koncz I, Patocskai B, Nesterenko VV, Antzelevitch C. Cellular mechanism underlying hypothermia-induced ventricular tachycardia/ventricular fibrillation in the setting of early repolarization and the protective effect of quinidine, cilostazol, and milrinone. Circ Arrhythm Electrophysiol 2014;7:134-42.
  14. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 1999;100:1660-6.
  15. Wilde AA, Postema PG, Di Diego JM, et al. The pathophysiological mechanism underlying Brugada syndrome: depolarization versus repolarization. J Mol Cell Cardiol 2010;49:543-53.
  16. Yoon N, Jeong HK, Lee KH, Park HW, Cho JG. Right ventricular longitudinal conduction delay in patients with Brugada syndrome. J Korean Med Sci 2021;36:e75.
  17. Lambiase PD, Ahmed AK, Ciaccio EJ, et al. High-density substrate mapping in Brugada syndrome: combined role of conduction and repolarization heterogeneities in arrhythmogenesis. Circulation 2009;120:106-17, 1-4.
  18. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011;123:1270-9.
  19. Malhi N, Cheung CC, Deif B, et al. Challenge and impact of quinidine access in sudden death syndromes: a national experience. JACC Clin Electrophysiol 2019;5:376-82.
  20. Andorin A, Gourraud JB, Mansourati J, et al. The QUIDAM study: hydroquinidine therapy for the management of Brugada syndrome patients at high arrhythmic risk. Heart Rhythm 2017;14:1147-54.
  21. Behr ER, Ben-Haim Y, Ackerman MJ, Krahn AD, Wilde AA. Brugada syndrome and reduced right ventricular outflow tract conduction reserve: a final common pathway? Eur Heart J 2021;42:1073-81.
  22. Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science 1985;228:1049-55.
  23. Di Diego JM, Sun ZQ, Antzelevitch C. I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol 1996;271:H548-61.
  24. Di Diego JM, Patocskai B, Barajas-Martinez H, et al. Acacetin suppresses the electrocardiographic and arrhythmic manifestations of the J wave syndromes. PLoS One 2020;15:e0242747.
  25. Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current Ito gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm 2011;8:1024-32.
  26. Litovsky SH, Antzelevitch C. Differences in the electrophysiological response of canine ventricular subendocardium and subepicardium to acetylcholine and isoproterenol. A direct effect of acetylcholine in ventricular myocardium. Circ Res 1990;67:615-27.
  27. Szel T, Koncz I, Antzelevitch C. Cellular mechanisms underlying the effects of milrinone and cilostazol to suppress arrhythmogenesis associated with Brugada syndrome. Heart Rhythm 2013;10:1720-7.
  28. Li GR, Wang HB, Qin GW, et al. Acacetin, a natural flavone, selectively inhibits human atrial repolarization potassium currents and prevents atrial fibrillation in dogs. Circulation 2008;117:2449-57.
  29. Patocskai B, Yoon N, Antzelevitch C. Mechanisms underlying epicardial radiofrequency ablation to suppress arrhythmogenesis in experimental models of Brugada syndrome. JACC Clin Electrophysiol 2017;3:353-63.