Key result
In a long QT syndrome rabbit model, inhibition of sarcoplasmic reticulum calcium cycling with ryanodine and thapsigargin significantly reduced the inducibility of Torsades de pointes from 70% to 20%.
Why the study?
Does inhibition of sarcoplasmic reticulum calcium cycling suppress secondary calcium rise and the genesis of early afterdepolarizations in a long QT syndrome rabbit model?
Does inhibition of sarcoplasmic reticulum calcium cycling suppress secondary calcium rise and the genesis of early afterdepolarizations in a long QT syndrome rabbit model?
Inhibition of sarcoplasmic reticulum calcium cycling suppresses secondary calcium rise and reduces the inducibility of torsades de pointes in a long QT syndrome rabbit model.
Answers are grounded in this paper and cite their sources.
May inform novel LQTS antiarrhythmic targets; leaves open translation from rabbit models to patients.
BACKGROUND: L-type calcium current reactivation plays an important role in development of early afterdepolarizations (EADs) and torsades de pointes (TdP). Secondary intracellular calcium (Cai) rise is associated with initiation of EADs. OBJECTIVE: To test whether inhibition of sarcoplasmic reticulum (SR) Ca2+ cycling suppresses secondary Cai rise and genesis of EADs. METHODS: Langendorff perfusion and dual voltage and Cai 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 Cai 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 Cai 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 Cai rise and genesis of EADs.
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Chang et al. (2015) studied Long QT Syndrome (n=10). Ryanodine plus thapsigargin vs. E4031 alone was evaluated on Torsades de pointes (TdP) inducibility (p=0.03). In a long QT syndrome rabbit model, inhibition of sarcoplasmic reticulum calcium cycling with ryanodine and thapsigargin significantly reduced the inducibility of Torsades de pointes from 70% to 20%.
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