Abstract 2664: Arrhythmia Protection Insights From a Hibernating Animal
Hibernating animals are resistant to either hypothermia- or nonhypothermia-induced cardiac arrhythmias. However, their resistance to ischemia-induced arrhythmias at the time of hibernation is not known. Our goal was to investigate susceptibility to arrhythmias during coronary artery occlusion (CAO) in woodchucks in the winter during hibernation season, in comparison to that in the summer. We hypothesized the susceptibility to reactive oxygen species (ROS)-induced early afterdepolarizations (EADs) and triggered activities (TAs) may be modified in hibernating mammalian hearts during winter. Permanent CAO was performed in woodchucks (Marmota monax) in winter and in summer. Mortality was significantly lower, p<0.05, in woodchucks in winter (5%) than in summer (45%). By monitoring ECG with telemetry, ventricular fibrillation (VF) and sudden cardiac death (SCD) were found in 5 of 13 woodchucks in summer, while none of 8 woodchucks showed VF or SCD in winter. Western blotting was carried out on the tissue adjacent to the ischemic area 24 hours following CAO. The level of manganese superoxide dismutase (MnSOD) was increased by 40% and the ratio of oxidized (active) CaMKII/CaMKII was reduced by 66%, p<0.05, in woodchucks in winter compared to those in summer. Action potentials were recorded from isolated ventricular myocytes using patch-clamp technique. Perfusion with 0.2 mM or higher H2O2 only induced EADs in 1 out of 10 cells isolated form woodchuck in winter. In contrast, EADs were induced consistently with H2O2 (0.2 mM) at a shorter perfusion period (3.15±0.25 min) in 20 of 20 myocytes isolated from woodchucks in summer. The EADs were eliminated by inhibiting CaMK II (KN-93 1 microM, n=6), blocking L-type Ca current (10 microM Nifedipine, n=5), or inhibiting late Na current (10 microM ranolazine, n=4). Intracellular Ca transients were also evaluated. Thus, the heart of a hibernating animal in winter is more resistant to ischemia-induced arrhythmias and SCD. The mechanism involves reduced oxidative stress and thus ROS-oxidized CaMKII activity levels, which confers resistance against ROS-induced EADs and TAs. The profound protection conferred may provide insights into clinical directions for therapy of arrhythmias.
This research has received full or partial funding support from the American Heart Association, National Center.