209 EMF Preservation of Gap Junction Coupling Improves Transmural Conduction Velocity and Limits Epicardial Conduction Block During Global Myocardial Ischemia

Abstract

Study Objectives: Hypothermia and myocardial ischemia are both arrhythmogenic by several mechanisms, including transmural conduction slowing and increased dispersion of repolarization. However, therapeutic hypothermia has not been associated with increased arrhythmias after return of spontaneous circulation after cardiac arrest. Preliminary work in our lab suggests that therapeutic hypothermia may be antiarrhythmic by attenuating transmural slowing of ventricular conduction velocity, limiting epicardial conduction block, and attenuating ischemia-induced dispersion of repolarization. Preserving intracellular gap junction coupling has been shown to improve conduction during ischemia. Improving gap junction coupling may be a potential mechanism for the improved conduction velocity and decrease in epicardial conduction block observed with mild hypothermia in our canine model of global ischemia. Our aim was to investigate the effect of rotagaptide, a gap junction opener, on the transmural electrophysiologic effects of global ischemia in ventricular myocardium.Methods: Langendorff-perfused canine left ventricle wedge preparations were pre-treated with the gap junction opener rotigaptide (R) (50 nM, n=8) compared to historic control group (C) (n=7) at normal temp (36°C). Optical action potentials were recorded with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution from cells spanning the transmural wall of the left ventricle. Wedges underwent global no-flow ischemia for 15 min and subsequent reperfusion. Action potential duration, conduction velocity, dispersion of repolarization, and evidence of epicardial conduction block were recorded.Results: No difference in conduction velocity or mean APD was seen at baseline between the 2 groups. At 15 min ischemia, rotigaptide attenuated the ischemia induced conduction slowing, with a conduction velocity decrease of 31±8% versus 50±13% (p=.02) Mean APD was preserved in the R group (222±4 ms to 221±12 ms) versus APD shortening in the C group (230±6 ms to 178±13 ms, p=.01), and the severe epicardial APD shortening seen in the C group from baseline to 15 min of ischemia (211±7 ms to 142±15ms, p=.004) was attenuated in R group (209±5 ms to 193±20ms, p=NS). Epicardial conduction block was observed in only 2/8 preparations in the R group versus 6/7 in the C group. Conduction velocity and Mean APD returned to baseline upon reperfusion.Conclusion: Preservation of gap junction coupling attenuated ischemia-induced slowing of transmural conduction velocity, preserved mean APD, and limited ischemia-induced epicardial conduction block, and suggests a mechanism for the similar effect seen in therapeutic hypothermia. Study Objectives: Hypothermia and myocardial ischemia are both arrhythmogenic by several mechanisms, including transmural conduction slowing and increased dispersion of repolarization. However, therapeutic hypothermia has not been associated with increased arrhythmias after return of spontaneous circulation after cardiac arrest. Preliminary work in our lab suggests that therapeutic hypothermia may be antiarrhythmic by attenuating transmural slowing of ventricular conduction velocity, limiting epicardial conduction block, and attenuating ischemia-induced dispersion of repolarization. Preserving intracellular gap junction coupling has been shown to improve conduction during ischemia. Improving gap junction coupling may be a potential mechanism for the improved conduction velocity and decrease in epicardial conduction block observed with mild hypothermia in our canine model of global ischemia. Our aim was to investigate the effect of rotagaptide, a gap junction opener, on the transmural electrophysiologic effects of global ischemia in ventricular myocardium. Methods: Langendorff-perfused canine left ventricle wedge preparations were pre-treated with the gap junction opener rotigaptide (R) (50 nM, n=8) compared to historic control group (C) (n=7) at normal temp (36°C). Optical action potentials were recorded with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution from cells spanning the transmural wall of the left ventricle. Wedges underwent global no-flow ischemia for 15 min and subsequent reperfusion. Action potential duration, conduction velocity, dispersion of repolarization, and evidence of epicardial conduction block were recorded. Results: No difference in conduction velocity or mean APD was seen at baseline between the 2 groups. At 15 min ischemia, rotigaptide attenuated the ischemia induced conduction slowing, with a conduction velocity decrease of 31±8% versus 50±13% (p=.02) Mean APD was preserved in the R group (222±4 ms to 221±12 ms) versus APD shortening in the C group (230±6 ms to 178±13 ms, p=.01), and the severe epicardial APD shortening seen in the C group from baseline to 15 min of ischemia (211±7 ms to 142±15ms, p=.004) was attenuated in R group (209±5 ms to 193±20ms, p=NS). Epicardial conduction block was observed in only 2/8 preparations in the R group versus 6/7 in the C group. Conduction velocity and Mean APD returned to baseline upon reperfusion. Conclusion: Preservation of gap junction coupling attenuated ischemia-induced slowing of transmural conduction velocity, preserved mean APD, and limited ischemia-induced epicardial conduction block, and suggests a mechanism for the similar effect seen in therapeutic hypothermia.