Models to study the potential for drug-induced torsades de pointes
| Model | Initial Descriptions by | Advantages | Disadvantages |
|---|---|---|---|
| Block of heterologously expressed KCNH2 current | Snyders and Chaudhary, 1996 | Dose-response relationship for potential arrhythmogenic effects can be defined; high throughput is feasible; relatively inexpensive | No relationship to arrhythmias; effects on other currents (e.g., sodium or L-type calcium) not taken into account |
| Block of IKr in cardiomyocytes | Sanguinetti and Jurkiewicz, 1990 | Dose-response relationship for potential arrhythmogenic effects can be defined. | No relationship to arrhythmias; effects on other currents (e.g., sodium or L-type calcium) not taken into account; myocyte preparation may not be uniform |
| Action potential prolongation in canine (or rabbit) Purkinje fibers | Dangman and Hoffman, 1981; Roden and Hoffman, 1985 | Arrhythmogenic EADs can be elicited | Canine repolarization may differ from that in humans; drug effects may be greater in isolated fibers than in whole heart |
| Perfused canine left ventricular “wedge” preparation | Strauss et al., 1970; Antzelevitch et al., 1991 Yan et al., 1998 | Enables mechanistic studies of the arrhythmia; allows evaluation of multiple cell types to the arrhythmia | Complex, low throughput; role of M cells is disputed |
| Isolated perfused female rabbit hearts | Hondeghem and Hoffmann, 2003 | Validated across large numbers of drugs; may be able to identify agents with arrhythmogenic potential even without marked QT prolongation | Complex, low throughput, although automated methods have been developed |
| Anesthetized methoxamine-treated rabbits | Carlsson et al., 1990 | Simple whole-heart model; methoxamine required although role uncertain | Complex, low throughput |
| Dogs with long-term atrioventricular block | Chézalviel-Guilbert et al., 1995; Vos et al., 1998 | Enables mechanistic studies of the arrhythmia; studies of mechanisms over time in the whole heart | Complex, low throughput |