Background: L-type calcium current reactivation plays an important role in development of early afterdepolarizations (EADs) and torsades de pointes (TdP). Secondary intracellular calcium (Ca<inf>i</inf>) rise is associated with initiation of EADs. Objective: To test whether inhibition of sarcoplasmic reticulum (SR) Ca<sup>2+</sup> cycling suppresses secondary Ca<inf>i</inf> rise and genesis of EADs. Methods: Langendorff perfusion and dual voltage and Ca<inf>i</inf> optical mapping were conducted in 10 rabbit hearts. Atrioventricular block (AVB) was created by radiofrequency ablation. After baseline studies, E4031, SR Ca<sup>2+</sup> cycling inhibitors (ryanodine plus thapsigargin) and nifedipine were then administrated subsequently, and the protocols were repeated. Results: At baseline, there was no spontaneous or pacing-induced TdP. After E4031 administration, action potential duration (APD) was significantly prolonged and the amplitude of secondary Ca<inf>i</inf> rise was enhanced, and 7 (70%) rabbits developed spontaneous or pacing-induced TdP. In the presence of ryanodine plus thapsigargin, TdP inducibility was significantly reduced (2 hearts, 20%, p = 0.03). Although APD was significantly prolonged (from 298 ± 30 ms to 457 ± 75 ms at pacing cycle length of 1000 m, p = 0.007) by ryanodine plus thapsigargin, the secondary Ca<inf>i</inf> rise was suppressed (from 8.8 ± 2.6%to 1.2 ± 0.9%, p = 0.02). Nifedipine inhibited TdP inducibility in all rabbit hearts. Conclusion: In this AVB and long QT rabbit model, inhibition of SR Ca<sup>2+</sup> cycyling reduces the inducibility of TdP. The mechanism might be suppression of secondary Ca<inf>i</inf> rise and genesis of EADs.
Chang, P. C., Wo, H. T., Lee, H. L., Lin, S. F., Wen, M. S., Chu, Y., … Chou, C. C. (2015). Role of sarcoplasmic reticulum calcium in development of secondary calcium rise and early afterdepolarizations in long QT syndrome rabbit model. PLoS ONE, 10(4). https://doi.org/10.1371/journal.pone.0123868