Atrial arrhythmogenesis in ex vivo aged mouse hearts with hypokalemia and right atrial stretch

Abstract

Introduction: Atrial Fibrillation (AF) and atrial flutter (AFL) are the two most common cardiac arrhythmias in the United States. While advanced age has been correlated to AF/AFL, the lack of an appropriate animal model has hindered progress on better understanding the pathophysiology of atrial arrhythmogenesis. Both hypokalemic conditions and hemodynamic stretch have been associated with atrial tachyarrhythmias in patient populations. The purpose of this study was to examine the incidence of atrial tachyarrhythmias in an ex vivo aging C57BL/6 mouse model following hypokalemia and stretch challenges. Methods: Hearts were isolated with combined cannulation of the aorta and superior vena cava in a modified right-sided working heart perfusion technique. Isolated hearts of Aged (26-29 month) male (n=14) and female (n=14) mice were subjected to normokalemic and hypokalemic conditions +/- atrial preload elevation to 12 cmH20 to induce atrial stretch. Heart rate, right ventricular (RV) pressure development, and incidence of atrial tachyarrhythmias were monitored using a pressure catheter and intracardiac electrocardiogram. Results: In response to hypokalemia, there were no changes in mean heart rate, RV pressure development, or RV Rate-Pressure Product (Rate x RV peak pressure). Atrial tachyarrhythmias were not observed under baseline conditions, and only 1 of 8 hearts exhibited atrial tachycardia following the hypokalemia challenge. In response to atrial preload elevation, there was an increase in heart rate (P=0.0006 versus baseline) with no change in RV pressure development. RV Rate-Pressure Product was significantly elevated (P=0.013 versus baseline) with atrial preload due to the increase in heart rate. Atrial tachyarrhythmias were not observed under both baseline conditions and following atrial preload elevation. In response to the combined hypokalemia and preload challenges, there was an increase in heart rate (P=0.008 versus baseline) with no change in RV pressure development or RV Rate Pressure product. Atrial tachyarrhythmias were not observed under baseline conditions, yet after the combined challenges 50% of aged hearts exhibited atrial tachycardia or AF/AFL. During bouts of AF/AFL, the AF/AFL led to a variable ventricular response and concomitant contractile dysfunction in the form of variable RV pressure development. Conclusion: Ex vivo aged mouse hearts exhibit atrial tachyarrhythmias in response to combined hypokalemia and right atrial stretch conditions. The aged C57BL/6 mouse model is therefore useful for pre-clinical studies of atrial arrhythmogenesis.