Evaluating Inward Rectifier Current Inhibiton for Treatment of Atrial Fibrillation

Abstract

Atrial Fibrillation (AF) is one of the most common forms of cardiac arrhythmia and affects a large percentage of the human population, especially in the elderly. Currently, more than 6 million Europeans suffer from AF, and due to ageing this number will at least double in the next 50 years. Approximately 23-26% of men and women above the age of 40 will develop AF. Men are more often affected than women. In humans, AF is associated with strongly increased morbidity and mortality, including an increased risk for stroke (5 fold), heart failure (3 fold) and myocardial infarction (2 fold), that reduces the quality of life. Thus effective treatments of AF are necessary. There are many treatments available, for instance, cardioversion or rate control with pharmacological agents, pacemaker technology or catheter ablation, that primarily address controlling of the heart rhythm or the heart rate. However, the optimal treatment for AF management is unclear and improvements can be made. AF results in increased KIR2.1 ion channel expression at the mRNA and protein levels, that shortens the action potential duration and thereby drives reentry which maintains AF. Hence, IK1 inhibitors have been proposed as potential drugs for treating AF. From previous research, we demonstrated that Pentamidine analogue 6, named PA-6, is a promising lead compound as it presented high specificity for KIR2.x currents and did not affect IKv11.1, IKv7.1/MinK, IKv4.3, ICa−L and INav1.5 at 200 nM. PA-6 would be a potential drug for anti-AF therapy. In the work described in this thesis, we tested for efficacy of AF cardioversion and cardiac safety of PA-6 in dedicated large animal models consisting of the goat with rapid pacing induced AF and the dog with chronic AV block, respectively. Furthermore, we evaluated the success of cardioversion by PA-6 in awake dogs with naturally occurring AF. Additionally, we tested if PA-6 could be a useful therapeutic option for treating AF and/or SQT resulting from two KCNJ2 gain-of-function mutations.