Suppression of Arrhythmia by Enhancing Mitochondrial Ca2+ Uptake in Catecholaminergic Ventricular Tachycardia Models
Maria K. Schweitzer, Fabiola Wilting, Simon Sedej, Lisa Dreizehnter, Nathan J. Dupper, Qinghai Tian, Alessandra Moretti, Ilaria My, Ohyun Kwon, Silvia G. Priori, Karl-Ludwig Laugwitz, Ursula Storch, Peter Lipp, Andreas Breit, Michael Mederos y Schnitzler, Thomas Gudermann and Johann Schredelseker
MiCUps Reduce Spontaneous Ca2+ Waves in Human iPSC-derived Cardiomyocytes
Confocal line scans of iPSC-derived human cardiomyocytes from a CPVT patient (RyR2S406L/WT) and a healthy individual are shown (control). (A) Confocal line scans across iPSC-derived human cardiomyocytes loaded with Fluo-4 AM to measure intracellular Ca2+ and intensity plots show that stimulation with ISO does not induce spontaneous, diastolic Ca2+ waves in control cells but induced waves in RyR2S406L/WT cardiomyocytes. These waves can be blocked with either 15 μM efsevin (upper right panel) or 10 μM kaempferol (lower right panel). (B) Quantitative analysis revealed a significant reduction in the number of RyR2S406L/WT cells showing ISO-induced Ca2+ waves upon treatment with MiCUps, to a level comparable to that of unstimulated cells (asterisks denote significance compared to RyR2S406L/WT +ISO by Fisher’s exact test). (C) Quantification of waves/min reveal a significant reduction from 3.78 ± 0.72 waves/min in RyR2S406L/WT cardiomyocytes treated with ISO to levels indistinguishable from control after treatment with efsevin (0.15 ± 0.15; p < 0.001 compared to ISO: p = 0.884 compared to vehicle, Kruskal-Wallis test) or kaempferol, respectively (0.21 ± 0.14, p < 0.001 compared to ISO; p = 0.980 compared to vehicle, Kruskal-Wallis test). CPVT = catecholaminergic polymorphic ventricular tachycardia; iPSC = induced pluripotent stem cell; other abbreviations as in Figure 1.