Jacobson Ingemar, Carlsson Leif, Duker Göran
AstraZeneca R&D Mölndal, Bioscience, Mölndal, Sweden.
J Pharmacol Toxicol Methods. 2011 Jan-Feb;63(1):40-6. doi: 10.1016/j.vascn.2010.04.010. Epub 2010 May 6.
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.
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.
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).
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.
越来越多的证据表明，药物诱导的QT间期延长本身并不能很好地预测复极相关的致心律失常风险。我们研究了QT间期逐搏变异性是否可能是QT延长的一种补充性致心律失常标志物。
对易发生尖端扭转型室速（TdP）的麻醉兔，最大输注30分钟探索性抗心律失常化合物，这些化合物被表征为混合离子通道阻滞剂。根据该模型中的结果，将这些化合物分类为具有低（TdPlow；n = 5）、中（TdPintermediate；n = 7）或高（TdPhigh；n = 10）致心律失常潜力。多非利特（n = 4）作为具有已知高致心律失常潜力的选择性IKr阻滞剂抗心律失常药物的代表被纳入研究。在输注过程中或直至诱发室性心律失常时，持续评估QT间期延长和QT间期逐搏变异性（量化为短期变异性，STV）。
所有化合物均显著延长QT间期。对于TdPlow和TdPhigh化合物，QT间期分别从169±14毫秒最大增加至225±28毫秒（p<0.05）和从186±21毫秒最大增加至268±42毫秒（p<0.01）。同样，在输注多非利特的兔中，QT间期从177±11毫秒最大增加至243±25毫秒（p<0.01）。相比之下，在给予TdPhigh化合物或多非利特的兔中，STV在心律失常诱发前显著增加（从1.6±0.4毫秒增加至10.5±5.6毫秒和从1.6±0.5毫秒增加至5.9±1.8毫秒，p<0.01），而在TdPlow组中保持不变（从1.3±0.6毫秒增加至2.2±0.9毫秒）。在TdPintermediate组中，发生TdP的兔与未发生TdP的兔的最大QT延长相似，而STV的变化显著不同（从0.9±0.5毫秒增加至8.7±7.3毫秒对从0.8±0.3毫秒增加至2.5±1.1毫秒）。
从本系列在敏感的TdP兔模型中的实验得出结论，药物诱导的TdP之前QT间期逐搏变异性增加。此外，评估这种潜在的致心律失常标志物可能有助于区分高致心律失常化合物和低致心律失常潜力的化合物。
