Role of Sarcoplasmic Reticulum Calcium in Development of Secondary Calcium Rise and Early Afterdepolarizations in Long QT Syndrome Rabbit Model

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_i) rise is associated with initiation of EADs.

Objective

To test whether inhibition of sarcoplasmic reticulum (SR) Ca²⁺ cycling suppresses secondary Ca_i rise and genesis of EADs.

Methods

Langendorff perfusion and dual voltage and Ca_i optical mapping were conducted in 10 rabbit hearts. Atrioventricular block (AVB) was created by radiofrequency ablation. After baseline studies, E4031, SR Ca²⁺ 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_i 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_i 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 Ca²⁺ cycyling reduces the inducibility of TdP. The mechanism might be suppression of secondary Ca_i rise and genesis of EADs.