Abstract
Torsade de Pointes (TdP) is a ventricular tachycardia that can result in sudden death. Risk factors include the congenital long QT syndrome, but also acquired factors including drugs that prolong the repolarization (QT interval). If concerns exist about the cardiac safety of (novel) drug, an animal model can be used
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to further evaluate the cardiac safety. An example is the canine chronic complete AV-block model, which is used in this thesis. In this model, artificially complete AV-block is created by radiofrequency ablation. The resulting idioventricular rhythm is much slower than the sinus rate (bradycardia), but also causes an abnormal ventricular activation pattern and AV-dyssynchrony. This results in an acute drop in cardiac output. This is almost completely restored on the long-term, associated with ventricular remodeling. The ventricular remodeling includes structural, contractile and electrophysiological adaptations of the myocardium and is linked to an enhanced susceptibility to TdP. After remodeling, under general anesthesia, administration of a class III anti-arrhythmic drug (dofetilide) causes TdP in about 75% of the dogs. Only recently it was shown that not only bradycardia, but also the abnormal ventricular activation plays a role in electrical remodeling and arrhythmogenesis. Most important aim of this thesis was to further explore the role of abnormal ventricular activation. First, the proarrhythmic effect of the combination of bradycardia and chronic, dyssynchronous ventricular activation (DVA) was investigated. For this purpose AV-block was created, followed by right ventricular apical pacing at lowest captured rate. After a remodeling period, dofetilide induced TdP in 75% of the dogs, which is comparable to what is normally observed dogs with chronic idioventricular rhythm. In a subsequent study the effect of DVA in absence of chronic bradycardia was studied. This also increased the susceptibility to dofetilide-induced TdP. DVA adversely affects the mechanical function of the heart and therefore currently cardiac resynchronization therapy (CRT) is widely used as a treatment of DVA due to left bundle branch block in patients with chronic heart failure. CRT is applied by biventricular pacing using a conventional right ventricular lead and an additional lead positioned in the latest activated left ventricular area. This results in a more synchronous activation pattern and improves the left ventricular mechanical function. We studied the effects of CRT on electrical remodeling and arrhythmogenesis of TdP in the dogs with chronic DVA and found that chronic CRT could reverse the DVA induced increased susceptibility to TdP. The DVA-induced electrical remodeling was different than expected. The considerable increased susceptibility to TdP caused by the combination of DVA and bradycardia was not associated with a significant prolongation of QT interval and beat-to-beat variability of repolarization (an important predictor of TdP in the model of dogs with AV-block). However, in an additional mapping study prolongation of repolarization in the left ventricle was found, but this was limited to the early-activated regions. As a consequence this is masked if the QT is measured. Interestingly, the induction of ectopic beats in this experiment could be linked to large local (spatial) dispersion of repolarization, suggesting that spatial dispersion was involved in the arrhythmogenesis of the ectopic beats.
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