Prolongation in QT interval is not predictive of Ca²⁺-dependent arrhythmias: implications for drug safety

Abstract

Background: Voltage-gated ion channels are the main providers of drug-induced delayed repolarization and, therefore, first line targets in cardiac safety assessments. Objectives/methods: We review mechanisms of drug-induced ventricular arrhythmias that may be associated with sudden cardiac death. We focus on Ca²⁺-dependent mechanisms with drug safety concerns. Results: Early afterdepolarizations occur during abnormally prolonged action potential repolarization. QT interval measurement is commonly used to assess the proarrhythmic risk of a drug. However, delayed afterdepolarizations are triggered by intracellular Ca²⁺ overload and/or abnormal spontaneous openings of ryanodine receptors in diastole. A drug promoting alterations of Ca²⁺ handling may be pro-arrhythmogenic without QT interval change at rest. Conclusion: Ca²⁺-dependent arrhythmia should be investigation matter in drug safety evaluation.

Keywords::

• Ca²⁺-dependent arrhythmia
• delayed afterdepolarization
• long QT
• repolarization
• RyR₂
• sudden cardiac death
• Torsade de Pointes

Acknowledgments

Our research is funded by Inserm and, in part, by a grant from the European Union (FPG, Life Science Genomics and Biotechnology for Health, contract CT 2005 N°018802, CONTICA) to SR.