Abstract 256: Therapeutic Hypothermia Decreases Arrhythmia Substrates by Attenuating Repolarization Current I K,ATP During Myocardial Ischemia

Abstract

Background: While hypothermia is arrhythmogenic, the effect of therapeutic hypothermia (TH) performed after cardiac arrest on susceptibility to arrhythmias is not well understood. Clinically, patients do not have an increase in arrhythmias, and it is possible that TH may be cardioprotective. The repolarization current I K,ATP is activated only during ischemia where it heterogeneously shortens action potentials increasing dispersion of repolarization (DOR). Since I K,ATP is attenuated at cooler temperatures, we hypothesized that the antiarrhythmic effect of TH during ischemia may be mediated by attenuation of I K,ATP activation. To test this hypothesis, a model of no flow global ischemia in the canine wedge preparation was created to study the effects of ischemia on all cell types spanning the transmural wall. Methods: Optical action potentials were recorded transmurally with high spatial (1 mm), temporal (.5 ms) and voltage (.5mv) resolution. To block I K,ATP, glibenclamide (10 µmol) was used at both 36 o C (normal temperature, NT+ I K,ATP block, n=3) and 32 o C (TH+ I K,ATP block, n=3) during 15 min of no flow global ischemia. I K,ATP blockade was compared to prior controls (NT=7, TH=6). Action potential duration (APD) for epicardial, mid-myocardial, and epicardial cells, DOR, and conduction velocity (CV) were measured for all conditions. Results: There was no difference in DOR between the 4 groups prior to ischemia. NT+ I K,ATP block attenuated ischemia-induced increase in DOR compared to NT controls (22±4 ms to 25±5 ms vs. 30±5 to 57±5 ms, p=.002). NT+ I K,ATP block also attenuated ischemia-induced conduction slowing (44±2 to 30±3 cm/s vs 34±5 to 18±3 cm/s, p=.03). Addition of I K,ATP block to TH did not further attenuate the DOR or CV vs. TH alone (p>0.05). Ischemia-induced epicardial conduction bock was attenuated by I K,ATP blockade, (0/3 I K,ATP block vs. 6/7 NT) Epicardial block was attenuated in both TH groups. Conclusions: I K,ATP blockade attenuates ischemia-induced DOR, conduction slowing, and epicardial conduction block, reproducing the effect of TH. This suggests that hypothermia-induced attenuation of I K,ATP may play a role in the mechanism of attenuation of ischemia-induced arrhythmias observed in TH.