Abstract 2866: Identification of Spatio-Temporal Patterns of the Mitochondrial Membrane Potential That Promote Arrhythmias
Depolarization of the mitochondrial membrane potential (ΔΨm) suppresses cellular excitability by activating the surface K-ATP current. The relationship between spatio-temporal dynamics of ΔΨm and arrhythmias in the intact heart remains unknown. Here we investigate the ‘metabolic signature’ of the heart during conditions that promote (hyperglycemia) or inhibit (pre and post-conditioning) oxidative stress during ischemia reperfusion (IR) injury.
Methods: Ex-vivo perfused guinea pig hearts (n=55) were subjected to global ischemia (30min) followed by reperfusion. Oxidant burden was increased by perfusion under hyperglycemic (30mM glucose) conditions (HG) or reduced using pre- (PRE) and post-conditioning (POST) protocols. In PRE hearts (n=10) short repetitive episodes of ischemia preceded the main ischemic interval whereas in POST hearts (n=10) a brief (5min) secondary ischemic episode followed early (1min) reperfusion. Spatiotemporal changes in ΔΨm were measured using a novel approach of optical ™RM mapping, which we developed.
Results: HG delayed repolarization without affecting conduction or ΔΨm during steady state perfusion. However, HG was associated with a high (100%) incidence of IR mediated VF. Surprisingly, PRE failed to reduce the incidence of VF as 19/22 control and 9/10 PRE hearts exhibited VF upon reperfusion (p=0.6). In contrast, POST markedly suppressed VF to <40% in normal (4/11, p<0.02) and only 20% (p<0.01) in HG hearts. Global ischemia caused sustained ΔΨm depolarization, which could not be reversed by reperfusion in all groups. However, POST caused a blunted response to reperfusion compared to HG as ΔΨm repolarization following POST was smaller (6.6% POST vs 20.4% HG) and the subsequent rate of ΔΨm decay was slower (−0.8 %/min POST vs −3.6 %/min HG). Spatially discordant out of phase ΔΨm oscillations were observed prior to onset of inexcitability in 40% of HG hearts. While VF typically occurred following reperfusion, 20% of HG hearts exhibited arrhythmias during ischemia.
Conclusions: We demonstrate a pronounced anti-arrhythmic effect of POST- but not PRE-conditioning in normal and HG hearts subjected to IR. Out of phase ΔΨm oscillations during ischemia and accelerated ΔΨm decay during early reperfusion promote arrhythmias.
This research has received full or partial funding support from the American Heart Association, National Center.