📒 Zhou 2014
Effects of Regional Mitochondrial Depolarization on Electrical Propagation: Implications for Arrhythmogenesis1
- Effective refractory period (ERP) of the tissue depends on both differences in the action potential duration (APD) of the individual cardiomyocytes and the conduction velocity.
- The timing of ΔΨm depolarization during reperfusion7 and ventricular fibrillation (VF) coincide.
- KATP channels are rapidly activated upon energy depletion to cause APD shortening and the concomitant elevation of the ST-segment.
- KATP antagonists can also prevent arrhythmias elicited by reperfusion
- Self-organized slow oscillations of ΔΨm (period≈100seconds) from RIRR. Decreased ATP/ADP ratio, activating KATP channels and shortening the APD.
- ECME-RIRR model as cardiomyocyte model
- (2D) finite element model of ventricular tissue (5x5cm2). Monodomain equation. No-flux boundary conditions.
- PDE was discretized at 200μm spatial resolution with operator splitting scheme
- Forward Euler to solve PDE, Rush-Larsen to solve ODE.
- The PDE was integrated using a time step of 20μs and the set of ODEs was split into groups of variables that operated at similar time scales
- Neonatal rat ventricular myocytes (NRVM)
- Regional ΔΨm depolarization by local FCCP perfusion
Regional ΔΨm depolarization forms a metabolic sink
- Changing KATP channel density alone had no effect on ΔΨm, but a huge effect on APD and exicibility.
Regional mitochondrial depolarization forms a substrate for arrhythmias
- Premature S2 at or near the border of the central zone to induce reentry. S1–S2 coupling interval window (~150–205ms) within which S2 induced reentrant activity.
- Phase singularities sustaining the turbulent electrical behavior arose initially at the border of the central zone
- Requires larger metabolic sinks (r > 2cm)
Recovery of mitochondrial energetics induces spontaneous arrhythmias
- Recovery of ΔΨm during the repolarization phase => spontaneous wavefront generation from the back of the S1 wave( waveback breakthrough)
- Rapid inactivation of KATP current reversed the current dissipation by the sink, thus lowering the threshold for re-excitation
- The timing of metabolic sink recovery (relative to S1) affects the induction of spontaneous arrhythmias
- Induction of reentry during recovery of ΔΨm under the conditions of reduced tissue conductivity (gap junction uncoupling) in the metabolic sink. (conductivity decreased from 0.1S/m in normal tissue to 0.03S/m in the central region)
Regional ΔΨm depolarization induces abnormal electrical activity in NVRM monolayers
- Within ΔΨm depolarization, wavelength shortened, and wave slowing was also observed: KATP–dependent coupling and decreased gap junctional conductance closely matched these results.
- occasionally led to reentry, spiral waves.
- heterogeneity in refractoriness and conduction due to metabolic sink.
- Glibenclamide (10μM), a KATP inhibitor, blunted the APA decrease and largely prevented the APD shortening.
- metabolic sink, induced by regional mitochondrial depolarization, profoundly affects electrical activity in the tissue, with decrease APA and APD.
- premature beats at locations surrounding the metabolic sink resulted in spiral wave reentry and fibrillation
- spontaneous electrical instability through a novel mechanism involving waveback breakthrough
- Mitochondrial ΔΨm depolarization can potentiate KATP channel opening via reversal of ATP synthase.
- evidenced by the ability of KATP channel inhibitors such as glibenclamide to prevent shortening of the AP duration over the first 10min of ischemia.
- reperfusion after 30minutes of global ischemia evokes reentrant arrhythmias, and that treatment with a compound that prevents or reverses RIRR-mediated mitochondrial depolarization (4′-chlorodiazepam) eliminates post-ischemic VF and improves AP recovery
- mitochondrial ΔΨm collapse impacts the AP and the propagating wavefront in a manner that is more complex than expected simply from KATP channel activation