Prolongation of cardiac repolarization is an undesired side effect of many non-antiarrhythmic drugs, independent of their intended therapeutic effect. Delayed repolarization has been linked to ventricular arrhythmias, including torsades de pointes, a potentially life-threatening polymorphic tachycardia that has been implicated in the occurence of sudden cardiac death. Yet, there is no scientific consensus on the preferred approach to, or internationally recognized guidance on, addressing risks for repolarization-associated ventricular tachyarrhythmias. Also, the precise relationship between pharmaceutical-induced delay of ventricular repolarization and risk of proarrhythmia is not known. Consequently, there is no available experimental model for predicting the effect that a drug-induced change in ion channel electrical properties may have on cardiac wave propagation. Phase I of this project will addree these risk assessment isusses using a combined experimental and computational approach.
The aims of Phase I are to develop 1) a standardized, comprehensive in vitro IKR assay in disaggregated cardiac myocites, 2) a highly automated test system for efficient data collection, 3) a database for archiving annotated raw data, 4) a software tool capable of data processing and integration for assay evaluation, and 5) a software tool for manipulation and transfer for input to a software platform for simulation of cardiac electrical activity. After feasibilty is established, Phase II will expand the data collection protocol to include other important ionic currents, and will improve the capability of the software tools by including additonal data analysis algorithms and a convienient graphical user interface.
| Rand, David G; Zhou, Qinlian; Buzzard, Gregery T et al. (2008) Computationally efficient strategy for modeling the effect of ion current modifiers. IEEE Trans Biomed Eng 55:3-13 |
