Effects of Crataegus pentagyna on cardiomyocytes (CMs) differentiated from CPVT1 patient-derived induced pluripotent stem cells (iPSCs)

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. The discovery of induced pluripotent stem cells (iPSCs) was a milestone providing a great opportunity for modeling hereditary cardiac arrhythmias as well as developing new drugs or testing their toxicity [1, 2]. Human iPSC models have been described for the cardiac arrhythmia syndromes including LQTS and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). CPVT is a life-threatening arrhythmia with mortality rate of 30 – 35% at very young ages [3]. According to the bioactive natural products, Crataegus species (Hawthorn) are known as herbal supplement for cardiovascular system. Flavonoids and proanthocyanidins of Crataegus might induce its beneficial effects on the cardiovascular system [4]. In this study we aimed to test the effects of Crataegus pentagyna Waldst. & Kit. Ex Willld. (Family, Rosaceae) on cardiomyocytes (CMs) differentiated from CPVT1 patient-derived iPSC. The hydroalcoholic extract (50:50) of C. pentagyna was obtained using sonication and the extract was concentrated using rotary evaporator and finally became powder by freeze drying. The effect of C. pentagyna on electrophysiological properties of CPVT1-iPSC derived CMs was assessed using Multi Electrode Array (MEA) and Patch-clamp techniques. LD₅₀ of C. pentagyna for CPVT1-iPSCs was determined to be 1 µg/ml. Arrhythmia was observed in electrograms of iPSC-derived beating colonies. The occurrence of EAD and DAD in spontaneous action potentials of a single iPSC-derived CM was shown. β₁-adrenergic stimulation increased the arryhthmogenic events and EAD/DADs. Serial concentrations of C. pentagyna showed a biphasic effect on beating rate of ES-derived CMs. Beating frequency increased by 1.46 in 5 ng/ml and decreased in higher concentrations near LD₅₀. However, C. pentagyna could not reduce arrhythmic events in CPVT1 electrograms. We concluded that C. pentagyna exerts both positive and negative chronotropic effect and has to be consumed with more cautious. The more detail results has been shown in the Figure 1.

Fig. 1: Representative electrogram of cardiomyocyte at baseline and different concentration of hawthorn

Acknowledgements: The author wish to thank Royan Institute for Stem Cell Biology and Technology (RI-SCBT) for their financial and technical supports.

Keywords: Crataegus, drug discovery, cardiomyocytes, CPVT, MEA, patch clamp.

References:

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