Investigations on different aspects of cardiac ventricular repolarization: repolarization reserve and adaptation to heart rate

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Investigations on different aspects of cardiac ventricular repolarization: repolarization reserve and adaptation to heart rate Introduction 1. The proper assessment of the pro-arrhythmic potential of candidate compounds is a major concern for drug development, since drug-induced arrhythmias, including Torsades de Pointes (TdP), can lead to sudden cardiac death. The prediction of TdP in clinical setting is very difficult since the incidence of drug-induced TdP is very low (1:100 000), however, drug associated sudden cardiac deaths have led to the withdrawal of a number, otherwise successful, compounds in the past. Importantly, current cardiac electrophysiological safety methods concentrate mostly on testing the hERG blocking and/or ventricular repolarization prolonging effects of candidate compounds and they use mostly healthy tissues and animals. It is, therefore, not entirely surprising that these cardiac safety tests are not sensitive enough. A large and still growing number of animal experimental and clinical studies suggest that the degree of repolarization prolongation does not show a close correlation with subsequent ventricular arrhythmia development. In these cases, without marked prolongation of the QT interval, repolarization reserve may be reduced with a consequent increase in arrhythmia susceptibility. According to the concept of repolarization reserve, normal cardiac repolarization is controlled by different potassium currents in a redundant way, and congenital or acquired (e.g. mild potassium current inhibition by a non-cardiovascular drug) decrease in the function of a single repolarizing current does not always lead to marked repolarization prolongation, since other currents can compensate for the lost function. In the case of reduced repolarization reserve, additional inhibition of another repolarizing current can result in excessive prolongation of repolarization and can provoke serious ventricular arrhythmias. Evidence points to a critically important role for the slow component of the delayed rectifier potassium current (IKs) in ventricular repolarization reserve, however, other potassium currents may also significantly contribute to repolarization reserve. There is considerable variation in the expression of key repolarizing potassium channels in different mammalian species, including dog and rabbit that are frequently used species in pro-arrhythmia models. Therefore, it is reasonable to assume that species specific ion channel expression profiles may result in species dependent alterations in responses to potassium channel blockers. Such differences may significantly influence the value of data obtained in these models for human extrapolation, however, it is unclear how species specific potassium channel expressions translate into differences in arrhythmia development in dogs and rabbits. 2. Disturbances in another important aspect of cardiac ventricular repolarization adaptation can also play a significant role in the development of serious cardiac arrhythmias and sudden cardiac death. Clinical, animal experimental and theoretical studies have shown that abrupt changes in heart rate result in a progressive adaptation of the QT interval measured on the ECG due to short-term cardiac memory effects. Patients exhibiting protracted QT interval heart rate adaptation dynamics have been identified to be at greater risk of developing cardiac arrhythmias and sudden cardiac death. Furthermore, clinical data also suggest that the extent of amiodarone-induced acceleration of QT interval heart rate adaptation could be used as a therapeutic marker of antiarrhythmic drug efficacy. However, despite strong evidence suggesting an important role of short-term cardiac memory in arrhythmogenesis, the underlying ionic mechanisms are still controversial. Aims 1. It is not clear, how species specific potassium channel expressions translate into differences in arrhythmia development in dogs and rabbits, two species frequently used in pro-arrhythmia models. It has been shown previously that repolarization reserve impairment by inhibition of IKs increased arrhythmia susceptibility during subsequent IKr inhibition in dogs and rabbits in a similar degree. A possibly important role for IK1 has been suggested in repolarization reserve. In the first series of experiments we studied the effects of combined pharmacological inhibition of IK1 and IKs, as well as IK1 and IKr on ECG parameters and the incidence of TdP in conscious dogs and anesthetized rabbits. We also investigated whether TdP development was paralleled by increased short-term variability of the QT interval, a novel ECG parameter suggested for more reliable prediction of drug-induced ventricular arrhythmias. 2. The aim of the second series of experiments was to investigate another important aspect of cardiac venricular repolarization adaptation: we performed studies on the ionic mechanisms of QT interval heart rate adaptation in ventricular

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