Abstract 1407: Spatial Heterogeneity of the Mitochondrial Membrane Potential Underlies Reperfusion Related Arrhythmias
Previously, we demonstrated a mechanism by which depolarization of the mitochondrial membrane potential (ΔΨm) causes conduction block (i.e. ‘metabolic sink’). However, a direct relationship between ΔΨm dynamics and post ischemic VF remained unknown. Here, we developed a novel system capable of directly measuring ΔΨm and calcium transients (CaT) in the same hearts.
Methods: Guinea pig hearts, double stained with TMRM (ΔΨm) and Rhod2am (CaT) were subjected to a standard protocol of ischemia reperfusion. CaT and ΔΨm were optically measured and correlated from 464 sites spanning a 0.4cm area of the LV.
Results: Despite overlapping emission spectra, differences in CaT and ΔΨm kinetics allowed for separation of the 2 signals. ΔΨm was markedly reduced during the first minute of ischemia, followed by a more gradual decay (Figure⇓, top). ΔΨm depolarization was associated with significant CaT shortening. Reperfusion caused the rapid increase in ΔΨm signals to pre ischemic levels. However, despite recovery of average ΔΨm, there was a marked (+42%) increase in the spatial heterogeneity of ΔΨm across the mapping field (Figure⇓ bottom). Interestingly, ΔΨm heterogeneity was greatest during early reperfusion coinciding with the onset of VF. Finally, regions of conduction block were characterized by significantly lower ΔΨm levels compared to neighboring regions exhibiting high frequency Ca2+ oscillations.
Conclusion: These data demonstrate that: 1. ΔΨm depolarization during ischemia leads to membrane inexcitability, and 2. the heterogeneous recovery of ΔΨm during early reperfusion underlies spatial heterogeneities in tissue excitability underlying conduction block and arrhythmias.