J Korean Med Sci.  2025 Jan;40(1):e2. 10.3346/jkms.2025.40.e2.

Artemisinin-Quinidine Combination for Suppressing Ventricular Tachyarrhythmia in an Ex Vivo Model of Brugada Syndrome

• Jeong HK
• Yoon N
• Kim YR
• Lee KH
• Park HW

• KMID: 2564207
• DOI: http://doi.org/10.3346/jkms.2025.40.e2

Abstract

Background
The ionic mechanism underlying Brugada syndrome (BrS) arises from an imbalance in transient outward current flow between the epicardium and endocardium. Previous studies report that artemisinin, originally derived from a Chinese herb for antimalarial use, inhibits the Ito current in canines. In a prior study, we showed the antiarrhythmic effects of artemisinin in BrS wedge preparation models. However, quinidine remains a well-established antiarrhythmic agent for treating BrS. Therefore, this study aims to investigate the efficacy of combining artemisinin with low-dose quinidine in suppressing ventricular tachyarrhythmia (VTA) in experimental canine BrS models.
Methods
Transmural pseudo-electrocardiogram and epicardial/endocardial action potential (AP) were recorded from coronary-perfused canine right ventricular wedge preparation. To mimic the BrS model, acetylcholine (3 μM), calcium channel blocker verapamil (1 μM), and Ito agonist NS5806 (6–10 μM) were administered until VTA was induced. Subsequently, lowdose quinidine (1–2 μM) combined with artemisinin (100 μM) was perfused to mitigate VTA. Key parameters, including AP duration, J wave area, notch index, and T wave dispersion, were measured.
Results
After administering the provocation agents, all sample models exhibited prominent J waves and VTA. Artemisinin alone (100–150 μM) suppressed VTA and restored the AP dome in all three preparations. Its infusion resulted in reductions in the J wave area and epicardial notch index. Consequently, low-dose quinidine (1–2 μM) did not fully restore the AP dome in all six sample models. However, when combined with additional artemisinin (100 μM), lowdose quinidine effectively suppressed VTA in all six models and restored the AP dome while also decreasing the J wave area and epicardial notch index.
Conclusion
Low-dose quinidine alone fails to fully alleviate VTA in the BrS wedge model. However, its combination with artemisinin effectively suppresses VTA. Artemisinin may reduce the therapeutic dose of quinidine, potentially minimizing its associated adverse effects.

Keyword

Brugada Syndrome; Anti-Arrhythmia Agents; Sudden Cardiac Death; Quinidine; Artemisinin

Figure

• 

  Fig. 1 A right ventricular wedge preparation in a tissue bath. The red arrowhead indicates pacing on the endocardial surface, while the yellow arrows indicate the floating microelectrodes on the Endo and Epi. Two pseudo-ECG leads are placed approximately 1–1.5 cm from the Endo and Epi (red arrowheads). The coronary artery is perfused with oxygenated Tyrode’s solution (yellow arrowhead).ECG = electrocardiogram, Endo = endocardium, Epi = epicardium.

• 

  Fig. 2 AP and ECG findings of artemisinin alone (100 μM) in model 1. (A) Baseline AP. (B) Provocation agents (NS5806, Vera, and ACh) induce BrS phenotypes. After perfusion with artemisinin, Epi AP notching becomes prominent (blue arrowhead), and the J wave is augmented (black arrowhead). The provocation agents induce a loss of dome (red arrowhead). (C) PVT is eventually induced through a phase 2 reentry (red arrows). (D) Following artemisinin administration, the Epi AP dome is restored, and the J wave decreases, but PVC is still detected (black arrow). Finally, artemisinin offsets the effects of the provocation agents. (E) After washing out artemisinin, VTA is induced again.Endo = endocardium, Epi = epicardium, ECG = electrocardiogram, Vera = verapamil, ACh = acetylcholine, AP = action potential, BrS = Brugada syndrome, PVT = polymorphic ventricular tachycardia, PVC = premature ventricular contraction, VTA = ventricular tachyarrhythmia.

• 

  Fig. 5 AP and ECG findings of low-dose quinidine combined with artemisinin in models 6–11. (A) Baseline AP. (B) Provocation agents (NS5806, Vera, and ACh) induce BrS phenotypes. (C) The provocation agents induce PVT. (D) After the infusion of 1–2 μM quinidine, non-sustained VTA and phase 2 reentry are still detected. (E) The 100 μM of Artemisinin was added to perfusate, and it effectively suppresses the VTA and restores repolarization homogeneity.Endo = endocardium, Epi = epicardium, ECG = electrocardiogram, Vera = verapamil, ACh = acetylcholine, AP = action potential, BrS = Brugada syndrome, PVT = polymorphic ventricular tachycardia, VTA = ventricular tachyarrhythmia.

• 

  Fig. 3 AP and ECG findings of artemisinin alone (150 μM) in models 2 and 3. (A) Baseline AP. (B) Provocation agents (NS5806, Vera, and ACh) induce BrS phenotypes. The Epi AP notch becomes more prominent over time. (C) The provocation agents trigger PVT. (D) Then, 100 μM of artemisinin is infused. However, non-sustained VTA is still detected after the infusion. (E) An additional dose of artemisinin of up to 50 μM (total 150 μM) effectively suppresses the non-sustained VTA and restores repolarization homogeneity. After washing out artemisinin, VTA is induced again (not illustrated in this figure).Endo = endocardium, Epi = epicardium, ECG = electrocardiogram, Vera = verapamil, ACh = acetylcholine, AP = action potential, BrS = Brugada syndrome, PVT = polymorphic ventricular tachycardia, VTA = ventricular tachyarrhythmia.

• 

  Fig. 4 AP and ECG findings of full-dose quinidine alone in models 4 and 5. (A) Baseline AP. (B) Provocation agents (NS5806, Vera, and ACh) induce BrS phenotypes. Epi AP notching is prominent, and the J wave is augmented. The provocation agents induce a phase 2 reentry (red arrow). (C) Eventually, PVT is induced via a phase 2 reentry. (D) After quinidine (10 μM) administration, the Epi AP dome is restored, and the J wave decreases. Finally, quinidine offsets the provocation agents.Endo = endocardium, Epi = epicardium, ECG = electrocardiogram, Vera = verapamil, ACh = acetylcholine, AP = action potential, BrS = Brugada syndrome, PVT = polymorphic ventricular tachycardia.

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  Fig. 6 Serial changes in AP parameters during provocation, low-dose quinidine, and the combination of low-dose quinidine with artemisinin. Values are presented as mean ± standard error.Endo = endocardium, APD90 = action potential duration at 90% repolarization, Epi = epicardium, TDR = transmural dispersion of repolarization, AP = action potential.*P < 0.05.

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