Abstract
Sudden cardiac death represents a major cause of mortality in Western countries and is often caused by ventricular fibrillation. This life-threatening arrhythmia can occur upon maladaptive cardiac remodelling like in heart failure, or can be favoured by drug-induced adverse effects such as Torsade de Pointes arrhythmia (TdP). Recently, the new
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proposal Comprehensive In vitro Proarrhythmia Assay has been designed to prevent the commercialization of drugs with a potential proarrhythmic risk. These guidelines, despite representing a major breakthrough in the landscape of safety pharmacology, are associated with a number of shortcomings (Chapter 2). As an example, the proarrhythmic adverse effects often limit the use of positive inotropic agents in clinical conditions. We demonstrate however in Chapter 3 that istaroxime, a novel positive inotropic, increases cardiac contractility without inducing ventricular arrhythmic episodes. In principle, the incidence of ventricular arrhythmias can be predicted by improving our understanding of the underlying mechanisms. In Chapters 4 and 5, the role of spatial dispersion of repolarization and the driving mechanisms of continuation of TdP arrhythmias are respectively investigated in the sensitive chronic atrioventricular block (CAVB) dog model. We show that spatial dispersion is higher in animals that develop TdP (Chapter 4). In Chapter 5, we demonstrate that re-entry mechanism is responsible for longer lasting and non-terminating arrhythmic episodes. In addition, The CAVB dog model has been also used to evaluate the antiarrhythmic efficacy of a number of interventions. In Chapter 6, we review and rank these strategies. In Chapters 7, 8 and 9, we respectively investigate the antiarrhythmic efficacies of the sodium channel blockers GS-458967, eleclazine and A-803467. In CAVB dogs with TdP, we show that GS-458967 provides a complete antiarrhythmic efficacy associated with the reduction of spatial dispersion of repolarization. However, in a similar setting, eleclazine, selective for the cardiac sodium channel, exerts no antiarrhythmic effect. A-803467, a selective inhibitor for a peripheral sodium channel shows moderate antiarrhythmic properties. In Chapter 9, modulation of the autonomic nervous system is investigated as a potential antiarrhythmic strategy. Pharmacological approach is not effective. However, sympathetic denervation demonstrates strong antiarrhythmic properties. The final Chapter 11 discusses the findings from previous chapters and concludes the thesis.
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