The Comprehensive In Vitro Proarrhythmia Assay (CiPA) Guide: A New Approach to Cardiac Risk Assessment

Historic Overview – Delayed Repolarization Hazard The association of certain cardiovascular drugs such as quinidine with risk of sudden cardiac death (quinidine syncope) was recognized nearly 100 years ago, but the mechanism was obscure until the 1960s, when quinidine syncope was found to be associated with prolongation of the electrocardiographic QT interval and a cardiac arrhythmia that displayed a distinctive electrocardiographic signature known as Torsade de Pointes (TdP, “twisting of the points”), a polymorphic ventricular arrhythmia which is potentially fatal (Figure 1). In the same era, congenital long QT syndromes (LQTS), rare familial diseases with similar cardiac phenotypes (i.e., QTc intervals in excess of 500 ms, episodes of TdP, and in some cases sudden cardiac death) were described. Figure 1. Human electrocardiograms illustrating normal and torsadogenic activity