Paradoxical Effects of Sodium–Calcium Exchanger Inhibition on Torsade de Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model

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Abstract

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium–calcium exchanger (NCX) inhibition in genesis of secondary Ca2+ rise and EAD-TdP is still debated. Dual voltage and intracellular Ca2+ optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca2+ rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca2+ rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

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