Beat-by-beat QT interval variability, but not QT prolongation per se, predicts drug-induced torsades de pointes in the anaesthetised methoxamine-sensitized rabbit.
BACKGROUND
Accumulating evidence suggest that drug-induced QT prolongation per se poorly predicts repolarisation-related proarrhythmia liability. We examined whether beat-by-beat variability of the QT interval may be a complementary proarrhythmia marker to QT prolongation.


METHODS
Anaesthetised rabbits sensitized towards developing torsades de pointes (TdP) were infused for 30 min maximum with explorative antiarrhythmic compounds characterised as mixed ion channel blockers. Based on the outcome in this model the compounds were classified as having a low (TdPlow; n=5), intermediate (TdPintermediate; n=7) or high (TdPhigh; n=10) proarrhythmic potential. Dofetilide (n=4) was included as a representative of a selective IKr-blocking antiarrhythmic with known high proarrhythmic potential. QT interval prolongation and beat-by-beat QT variability (quantified as the short-term variability, STV) were continuously assessed during the infusion or up to the point where ventricular proarrhythmias were induced.


RESULTS
All compounds significantly prolonged the QT interval. For TdPlow and TdPhigh compounds the QT interval maximally increased from 169 ± 14 to 225 ± 28 ms (p<0.05) and from 186 ± 21 to 268 ± 42 ms (p<0.01), respectively. Likewise, in the dofetilide-infused rabbits the QT interval maximally increased from 177 ± 11 to 243 ± 25 ms (p<0.01). In contrast, whereas the STV in rabbits administered the TdPhigh compounds or dofetilide significantly increased prior to proarrhythmia induction (from 1.6 ± 0.4 to 10.5 ± 5.6 ms and from 1.6 ± 0.5 to 5.9 ± 1.8 ms, p<0.01) it remained unaltered in the TdPlow group (1.3 ± 0.6 to 2.2 ± 0.9 ms). In the TdPintermediate group, rabbits experiencing TdP had a similar maximal QT prolongation as the non-susceptible rabbits whereas the change in the STV was significantly different (from 0.9 ± 0.5 to 8.7 ± 7.3 ms vs 0.8 ± 0.3 to 2.5 ± 1.1 ms).


CONCLUSIONS
It is concluded from the present series of experiments in a sensitive rabbit model of TdP that increased beat-by-beat QT interval variability precedes drug-induced TdP. In addition, assessment of this potential proarrhythmia marker may be useful in discriminating highly proarrhythmic compounds from compounds with a low proarrhythmic potential.
Jacobson
Ingemar
I
AstraZeneca R&D Mölndal, Bioscience, Mölndal, Sweden.
Carlsson
Leif
L
Duker
Göran
G
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D004622:Embryo, Mammalian; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors; D007668:Kidney; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D015233:Models, Statistical; D010627:Phenethylamines / Q000494:pharmacology / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology / Q000633:toxicity; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; D010627:Phenethylamines; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide