Contents

📒 Zhou 2014

Effects of Regional Mitochondrial Depolarization on Electrical Propagation: Implications for Arrhythmogenesis1

Sciwheel

Introduction

  • 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.

Methods

Model

  • ECME-RIRR model as cardiomyocyte model
  • (2D) finite element model of ventricular tissue (5x5cm2). Monodomain equation. No-flux boundary conditions.

Numerical aspects

  • 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

Experimental protocol

  • Neonatal rat ventricular myocytes (NRVM)
  • Regional ΔΨm depolarization by local FCCP perfusion

Results

Regional ΔΨm depolarization forms a metabolic sink

https://www.ahajournals.org/cms/attachment/a80ab003-dfac-47c9-b048-6636ffaee778/143fig01.jpg

  • 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

https://www.ahajournals.org/cms/attachment/8be450d2-5113-4fc4-823f-4ad1420b865a/143fig02.jpg

  • 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

https://www.ahajournals.org/cms/attachment/d35179a2-13df-4659-a281-1f87d75c1412/143fig03.jpg

  • Recovery of ΔΨm during the repolarization phase => spontaneous wavefront generation from the back of the S1 wave( waveback breakthrough) https://www.ahajournals.org/cms/attachment/3ae14a37-1c09-4d05-b694-9395ed0a3395/143fig04.jpg
  • Rapid inactivation of KATP current reversed the current dissipation by the sink, thus lowering the threshold for re-excitation https://www.ahajournals.org/cms/attachment/01e573c2-1def-4f08-ba9c-36e421fba4fd/143fig05.jpg
  • The timing of metabolic sink recovery (relative to S1) affects the induction of spontaneous arrhythmias

https://www.ahajournals.org/cms/attachment/25758d67-6517-46fc-9cbf-c77b3fcbb5ef/143fig06.jpg

  • 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

https://www.ahajournals.org/cms/attachment/a5d3ca99-fead-472f-b8e6-8149f83eebe8/143fig07.jpg

  • 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.

Discussion

  • 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

  1. Zhou L, Solhjoo S, Millare B, et al. Effects of regional mitochondrial depolarization on electrical propagation: implications for arrhythmogenesis. Circ Arrhythm Electrophysiol. 2014;7(1):143-51. PMC4001739 ↩︎