Korean Circ J.  2023 Apr;53(4):239-250. 10.4070/kcj.2022.0312.

Antiarrhythmic Effect of Artemisinin in an Ex-vivo Model of Brugada Syndrome Induced by NS5806

• Jeong HK
• Hong SN
• Yoon N
• Lee KH
• Park HW
• Cho JG

• KMID: 2542294
• DOI: http://doi.org/10.4070/kcj.2022.0312

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 (I_to ) 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 I_to 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 I_to 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 pseudoelectrocardiograms. 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 I_to channels, subsequently suppressing ventricular tachycardia/ventricular fibrillation.

Keyword

Brugada syndrome; Sudden cardiac death; Anti-arrhythmia agents

Figure

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  Figure 1 A right ventricular coronary-perfused preparation model. (A) Scheme of a right ventricular canine coronary-perfused preparation. Transmembrane APs are recorded simultaneously at the epicardial and endocardial sites with floating microelectrodes. A pseudo-ECG is recorded using AgCl electrodes placed across the bath, positioned transmurally along the midline of the preparation. (B) A right ventricle wedge preparation in a tissue bath. Pacing on the endocardial surface is depicted by the red arrow, and the floating microelectrodes on the endocardium and epicardium are highlighted by the yellow arrows. Two pseudo-ECG leads are placed approximately 1–1.5 cm from the endocardium and epicardium (yellow arrowheads). The coronary artery is perfused with oxygenated Tyrode’s solution (red arrowhead).AP = action potential; Endo = endocardium; Epi = epicardium; ECG = electrocardiogram.

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  Figure 2 Measurement of AP. (A) Measurement of J wave parameters. (B) Measurement of AP parameters and transmural dispersion of repolarization when the AP dome is maintained or lost. The J wave area was calculated as mV×ms.AP = action potential; APD90 = action potential duration at 90% repolarization; AUC = area under curve; ECG = electrocardiogram; Endo = endocardium; Epi = epicardium; TDR = transmural dispersion of repolarization.

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  Figure 3 AP and ECG findings in the wedge preparations. (A) Baseline AP. (B) The provocation agents (NS5806, verapamil, and acetylcholine) induce Brugada syndrome phenotypes. After perfusion with artemisinin, epicardial AP notching is prominent (blue arrowhead) and the J wave is augmented (black arrowhead) at 10 minutes. The provocation agents induce a loss of dome (red arrowhead) at 15 minutes. At 25 minutes, a concealed phase 2 reentry (blue arrow) is identified. (C) Eventually, a polymorphic ventricular tachycardia is induced with a phase 2 reentry (red arrows). (D) After artemisinin administration, the epicardial AP dome is restored and the J wave is decreased, but a premature ventricular contraction is still detected at 20 minutes (black arrow). Finally, artemisinin offsets the provocation agents. (E) After washing out artemisinin, the provocation made prominent J wave and epicardial notch. Finally, ventricular tachyarrhythmia was induced again.ACh = acetylcholine; AP = action potential; ECG = electrocardiogram; Endo = endocardium; Epi = epicardium; Vera = verapamil.

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  Figure 4 AP and ECG findings in the wedge preparations. (A) Baseline AP. (B) The provocation agents (NS5806, verapamil, and acetylcholine) induce Brugada syndrome phenotypes. A polymorphic ventricular tachycardia is induced with a phase 2 reentry. (C) After 100 μM of artemisinin perfusion, premature ventricular contraction or ventricular tachyarrhythmia were not detected.ACh = acetylcholine; AP = action potential; ECG = electrocardiogram; Endo = endocardium; Epi = epicardium; Vera = verapamil.

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  Figure 5 AP and ECG findings in the wedge preparations. (A) Baseline AP. (B) The provocation agents (NS5806, verapamil, and acetylcholine) induce Brugada syndrome phenotypes. The epicardial AP notch is more prominent at 20 minutes. (C) The provocation agents caused polymorphic ventricular tachycardia at 30 minutes after the administration of the agents. (D) Then, 100 μM of artemisinin was infused. However, non-sustained ventricular tachyarrhythmias were still detected 30 minutes after artemisinin administration. (E) An additional dose of artemisinin of up to 50 μM (total 150 μM) effectively suppressed the non-sustained ventricular tachyarrhythmia and restored repolarization homogeneity.ACh = acetylcholine; AP = action potential; ECG = electrocardiogram; Endo = endocardium; Epi = epicardium; Vera = verapamil.

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  Figure 6 The effects of artemisinin on repolarization parameters. (A, C) APD90, (B, D) APD50, (E) notch magnitude, (F) notch index, (G) J wave area, and (H) TDR. The notch magnitude, notch index, J wave, and TDR were significantly reduced after artemisinin perfusion. Values are represented as the mean ± standard error.APD50 = action potential duration at 50% repolarization; APD90 = action potential duration at 90% repolarization; Endo = endocardium; Epi = epicardium; TDR = transmural dispersion of repolarization.*p<0.05.

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