title: Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis.
abstract: BACKGROUND
  Sudden cardiac death often involves arrhythmias triggered by metabolic stress. Loss of mitochondrial function is thought to contribute to the arrhythmogenic substrate, but how mitochondria contribute to uncoordinated electrical activity is poorly understood. It has been proposed that the formation of metabolic current sinks, caused by the nonuniform collapse of mitochondrial inner membrane potential (ΔΨm), contributes to re-entrant arrhythmias because ΔΨm depolarization is tightly coupled to the activation of sarcolemmal ATP-sensitive K(+) channels, hastening action potential repolarization and shortening the refractory period.
  
  
  RESULTS
  Here, we use computational and experimental methods to investigate how ΔΨm instability can induce re-entrant arrhythmias. We develop the first tissue-level model of cardiac electrical propagation incorporating cellular electrophysiology, excitation-contraction coupling, mitochondrial energetics, and reactive oxygen species balance. Simulations show that re-entry and fibrillation can be initiated by regional ΔΨm loss because of the disparity of refractory periods inside and outside the metabolic sink. Computational results are compared with the effects of a metabolic sink generated experimentally by local perfusion of a mitochondrial uncoupler in a monolayer of cardiac myocytes.
  
  
  CONCLUSIONS
  The results demonstrate that regional mitochondrial depolarization triggered by oxidative stress activates sarcolemmal ATP-sensitive K(+) currents to form a metabolic sink. Consequent shortening of the action potential inside, but not outside, the sink increases the propensity for re-entry. ΔΨm recovery during pacing can lead to novel mechanisms of ectopic activation. The findings highlight the importance of mitochondria as potential therapeutic targets for sudden death associated with cardiovascular disease.
authors.affiliation: Departments of Medicine.
authors.forename: Lufang
authors.initials: L
authors.lastname: Zhou
authors.forename: Soroosh
authors.initials: S
authors.lastname: Solhjoo
authors.forename: Brent
authors.initials: B
authors.lastname: Millare
authors.forename: Gernot
authors.initials: G
authors.lastname: Plank
authors.forename: M Roselle
authors.initials: MR
authors.lastname: Abraham
authors.forename: Sonia
authors.initials: S
authors.lastname: Cortassa
authors.forename: Natalia
authors.initials: N
authors.lastname: Trayanova
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D016757:Death, Sudden, Cardiac / Q000209:etiology; D056966:Excitation Contraction Coupling; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D054086:KATP Channels / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008929:Mitochondria, Heart / Q000378:metabolism*; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009716:Numerical Analysis, Computer-Assisted; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D012508:Sarcolemma / Q000378:metabolism; D013997:Time Factors
chemical_list: D054086:KATP Channels; D017382:Reactive Oxygen Species
keywords: KATP channels; arrhythmias, cardiac; mitochondria; reactive oxygen species