Ionic Currents in Human Atrial Fibrillation

It is the aim of this research project to characterize the role of the pacemaker current If and the ATP-dependent current IK(ATP) in atrial tachycardia and atrial fibrillation (AF) in isolated human atrial myocytes. Atrial fibrillation is the most common arrhythmia. Millions of people worldwide are afflicted with this disease. The incidence of the disease increases significantly with age. AF is characterized by disorganized high rate (300- 500/min) atrial electrical activity which leads to impaired contractility, increases the risk of stroke by thrombus formation and is an independent risk factor for mortality. Commonly used antiarrhythmic drugs have only low success rate, and only a minority of cases is amenable to surgical therapies like ablation. Thus, development of novel pharmacological treatments would have a substantial public health impact. Predisposing factors for AF are advanced age, hypertension, valvular disease, hyperthyroidism, pulmonary disease, and heart failure. AF typically progresses from paroxysmal self-terminating episodes to a persistent state. AF results from cumulative electrophysiological and structural changes which have been termed "remodeling". The changes affecting primarily excitability and electrical activity have been termed "electrophysiological or ionic remodeling". AF is associated with long-term electrophysiological changes which facilitate the maintenance and perpetuation of AF. In animal models rapid atrial pacing reproduced the pathophysiological changes associated with AF. In this research project the role of the pacemaker current If as well as the ATP-dependent K+ current IK(ATP) in the genesis of AF and/or in the transformation from paroxysmal to persistent AF by ionic remodeling will be studied. The presence of both current components could be verified in human atrial myocytes and a role of If in the genesis of cardiac arrhythmias was discussed since its detection in cardiac tissues outside the sinus node.The K(ATP) channels are also known to play a role in cardiac arrhythmias. Recently it was demonstrated that If channel mRNA was significantly higher in patients with AF and mRNA of the gene encoding K(ATP) channel was significantly reduced in the chronic persistent form of atrial fibrillation compared with paroxysmal AF and controls in sinus rhythm. Studies of drug influences and computer simulations of current influence on the excitation process will complement this study.

The FWF Austrian Science Fund project 15403-Med was dealing with atrial fibrillation (AF) the most common arrhythmia in heart. Because this topic of the project was evaluated by the Austrian National Bank (OeNB) potentially suited to act innovation- and technology- promoting the financial resources were refunded by the OeNB to the FWF (letter of July 9, 2002). Millions of people worldwide are afflicted with AF. The disease is characterized by disorganized high rate (300- 500/min) electrical activity which leads to impaired contractility thereby increasing the risk of stroke by thrombus formation. Commonly used antiarrhythmic drugs have only low success rate, and only a minority of cases is amenable to surgical therapies like ablation. Automaticity, the property of generating spontaneous electrical activity is a very common feature of the heart. Under physiological conditions generation of spontaneous electrical activity is restricted to cells of the sinoatrial and atrioventricular nodes. The activity of such "pacemaker cells" is considered as "normal automaticity" to distinguish it from the "abnormal automaticity" that can occur in all types of cardiac myocytes depolarized by pathological conditions. It was the main topic of this research project to study a possible role of the pacemaker current If, one of the most prominent current components involved in the spontaneous excitation of the sinus node, in the genesis of AF. The presence of If could be verified in human atrial myocytes in earlier investigations and a role of If in the genesis of cardiac arrhythmias was discussed since its detection in cardiac tissues outside the sinus node. The study was performed in left-atrial myocytes from tissue probes obtained during open heart surgery in patients with AF and in controls. The most important result of this study performed with patch clamp techniques is the finding of single cells with extremely high If amplitudes in the left atrium. The current characteristics of these cells could be implemented in a mathematical model of the atrium which was brought to spontaneous activity by this current indicating its arrhythmogenic potency. Because of the still relatively small number of experiments up to now a clear association between If occurrence and atrial fibrillation was not possible. In an editorial in Cardiovascular Research dedicated to a publication dealing with these results our group was encouraged to continue with studies of this non-uniform distribution of pacemaker current.