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.


OBJECTIVE
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.


CONCLUSIONS
Ca(2+)-dependent arrhythmia should be investigation matter in drug safety evaluation.
Pasquié
Jean-Luc
JL
INSERM U637, Université Montpellier1 and 2, CHU Montpellier, Département de Cardiologie, F34295 Montpellier, France.
Richard
Sylvain
S
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002118:Calcium / Q000502:physiology*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology; D016276:Ventricular Function / Q000187:drug effects / Q000502:physiology
D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium