P532Validation of a new in vitro proarrhythmia model based on reduced repolarization reserve

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Abstract

Background

Presently available screening tests of proarrhythmia are not sensitive and specific enough. Recently, we developed a new in vitro proarrhythmia model based on reduction of the repolarization reserve. We also developed new biomarkers of electric instability, called ‘absolute’ beat-to-beat variability and instability parameters of the ECG intervals (ABVI), which predicted drug-induced TdP in anaesthetized rabbits. The aims of the present study were to validate the sensitivity of our in vitro model with six reference proarrhythmic drugs and to examine whether new ABVI parameters predict TdP in the model.

Methods

Isolated, Langendorff perfused rabbit hearts were used. After 20 minutes of drug perfusion, the IKs inhibitor HMR1556 was added to the perfusate for 40 min in order to reduce the repolarization reserve. Test drugs were dofetilide, terfenadine, cisapride, sertindole, moxifloxacin and clofilium. We determined the incidence of torsades de pointes (TdP) and non-TdP-type ventricular tachycardia (VT). We also determined the ABVI parameters by measuring ECG intervals irrespective of the rhythm in 40 consecutive QRST complexes before TdP occurrence.

Results

Apart from terfenadine, all drugs exerted substantial proarrhythmic activity when repolarization reserve was reduced; all five drugs significantly increased the incidence of TdP and non-TdP-type VT when HMR 1556 was added to the perfusate. ABVI parameters increased significantly before TdP occurrence.

Conclusions

Reduction of repolarization reserve markedly increased the sensitivity of rabbit hearts to the proarrhythmic activity of drugs and allowed TdP to be regarded as a primary end point, which validated our new proarrhythmia model. Increased ABVI parameters predicted TdP occurrence, which suggest that ABVI parameters may be used as biomarkers of TdP. Further examinations are needed to work out why terfenadine did not evoke arrhythmias in the model.

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