Assessment of efficacy of proarrhythmia biomarkers in isolated rabbit hearts with attenuated repolarization reserve
Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estim...
Elmentve itt :
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| Dokumentumtípus: | Cikk |
| Megjelent: |
2014
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| Sorozat: | JOURNAL OF CARDIOVASCULAR PHARMACOLOGY
64 No. 3 |
| Tárgyszavak: | |
| doi: | 10.1097/FJC.0000000000000116 |
| mtmt: | 2598088 |
| Online Access: | http://publicatio.bibl.u-szeged.hu/22858 |
| Tartalmi kivonat: | Isolated hearts with reduced repolarization reserve would be suitable for assessing the proarrhythmic liability of drugs. However, it is not known which proarrhythmia biomarkers indicate the increased susceptibility to torsades de pointes arrhythmia (TdP) in such experimental setting. Thus, we estimated the efficacy of proarrhythmia biomarkers in isolated hearts with attenuated repolarization reserve.Langendorff-perfused rabbit hearts were used. Repolarization reserve was reduced by concomitant inhibition of the rapid (IKr) and slow (IKs) delayed rectifier potassium currents by dofetilide and HMR-1556, respectively. Rate corrected QT (QTc) interval and beat-to-beat variability of the QT interval measured in sinus rhythm or irrespective of rhythm even during arrhythmias (sinus and absolute QT variability, respectively) were tested.QTc failed to predict increased proarrhythmic risk. Sinus QT variability indicated proarrhythmic liability when low concentration of dofetilide was used. However, when arrhythmias compromised sinus variability measurement during co-perfusion of catecholamines and elevated concentration of dofetilide, only absolute QT variability indicated increased proarrhythmic risk. ABSOLUTE: QT variability parameters appear to be the most practical and sensitive biomarkers of proarrhythmic liability in rabbit hearts with reduced repolarization reserve. Absolute QT variability parameters could serve as surrogates for TdP in drug-safety investigations in isolated rabbit hearts with attenuated repolarization reserve. |
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| Terjedelem/Fizikai jellemzők: | 266-276 |
| ISSN: | 0160-2446 |