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.