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

Figures

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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.