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

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 Ca(2+)-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 Ca(2+) overload and/or abnormal spontaneous openings of ryanodine receptors in diastole. A drug promoting alterations of Ca(2+) handling may be pro-arrhythmogenic without QT interval change at rest.


CONCLUSION
Ca(2+)-dependent arrhythmia should be investigation matter in drug safety evaluation.