Targeted Pharmacological Reversal of Electrical Remodeling After Cardioversion.

Details of the trial are described in a design paper published in the American Heart Journal (1).

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with approximately one million affected patients in Germany. Current estimates suggest that the life-time risk for AF is 30% for men and slightly less for women at the age of 40 years. Due to demographic changes in the German population, the incidence and prevalence of AF is expected to double within the next 30 years. AF almost doubles mortality and causes important morbidity, mainly due to thrombo-embolic complications and stroke. In addition, the arrhythmia in itself reduces the chronotropic adaptation of the heart to increased work load and reduces cardiac output, especially in patients with heart failure or other cardiac disease. Restoration of sinus rhythm would reduce this burden of disease.

Acute termination of AF is almost always successful by external electrical cardioversion, especially using recently optimized techniques [biphasic shock wave forms, anterior-posterior electrode position, sintered steel electrode paddles. Maintaining sinus rhythm, however, is a more difficult task. Antiarrhythmic, ion channel-blocking drugs are effective in preventing a part of recurrent episodes of AF. Their long-term use, however, is limited by pro-arrhythmic side effects which are especially apparent during long-term therapy. AF initiates major changes in atrial electrophysiology per se which have been summarized as "electrical remodeling". The main consequence of these changes is a shortening of the atrial refractory period and action potential duration. Electrical remodeling maintains AF and is related to recurrence of AF after successful cardioversion. Electrical remodeling is reversed when sinus rhythm is maintained over approximately 4 weeks after successful cardioversion. Interestingly, the vast majority of AF recurrences occur during these first few weeks after cardioversion.

Conceptually, the initial phase of "reversal" of electrical remodeling can be separated from the long-term treatment aimed at modifying the underlying substrate of AF. Classical sodium- or potassium channel blocking antiarrhythmic drugs prolong the atrial action potential even in the fibrillating atrium and may therefore support or even anticipate reversal of electrical remodeling. Such pharmacological reversal of electrical remodeling may only transiently be required, i.e. until electrical remodeling is in itself reversed by the natural restoration of normal atrial electrophysiology. Atrial action potential prolongation beyond normal values may indeed even be pro-arrhythmic. Therefore, it is tempting to treat the main electrophysiological end point of electrical remodeling, shortening of atrial action potential duration, by a limited short-term use of action potential-prolonging antiarrhythmic drugs.

Hypothesis: Targeted "pharmacological reversal" of atrial remodeling by short-term administration of action potential prolonging antiarrhythmic drugs (4 weeks therapy duration) is equally efficient and potentially safer to prevent recurrent AF after cardioversion when compared to current long-term antiarrhythmic drug therapy.