Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart

Rebecca M. Smith, Saalini S. Velamakanni, Elena G. Tolkacheva

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μg glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.

Original languageEnglish (US)
Pages (from-to)H224-H233
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume303
Issue number2
DOIs
StatePublished - Jul 15 2012

Fingerprint

Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
Ventricular Fibrillation
Mitochondria
Ischemia
Heart Ventricles
Rabbits
Hydrazones
Glyburide
Action Potentials
Reperfusion
Myocardial Ischemia

Keywords

  • Carbonyl cyanide p-(trifluoromethoxy) phenyl-hydrazone
  • Interventricular heterogeneity
  • Mitochondria
  • Myocardial ischemia
  • Optical mapping

Cite this

Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart. / Smith, Rebecca M.; Velamakanni, Saalini S.; Tolkacheva, Elena G.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 303, No. 2, 15.07.2012, p. H224-H233.

Research output: Contribution to journalArticle

@article{f8ce6ea445e24f5eaa2e4af18fa122c2,
title = "Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart",
abstract = "Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μg glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.",
keywords = "Carbonyl cyanide p-(trifluoromethoxy) phenyl-hydrazone, Interventricular heterogeneity, Mitochondria, Myocardial ischemia, Optical mapping",
author = "Smith, {Rebecca M.} and Velamakanni, {Saalini S.} and Tolkacheva, {Elena G.}",
year = "2012",
month = "7",
day = "15",
doi = "10.1152/ajpheart.00017.2012",
language = "English (US)",
volume = "303",
pages = "H224--H233",
journal = "American Journal of Physiology - Cell Physiology",
issn = "0363-6143",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - Interventricular heterogeneity as a substrate for arrhythmogenesis of decoupled mitochondria during ischemia in the whole heart

AU - Smith, Rebecca M.

AU - Velamakanni, Saalini S.

AU - Tolkacheva, Elena G.

PY - 2012/7/15

Y1 - 2012/7/15

N2 - Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μg glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.

AB - Myocardial ischemia results in metabolic changes, which collapse the mitochondrial network, that increase the vulnerability of the heart to ventricular fibrillation (VF). It has been demonstrated at the single cell level that uncoupling the mitochondria using carbonyl cyanide p-(tri-fluoromethoxy)phenyl-hydrazone (FCCP) at low concentrations can be cardioprotective. The aim of our study was to investigate the effect of FCCP on arrhythmogenesis during ischemia in the whole rabbit heart. We performed optical mapping of isolated rabbit hearts (n = 33) during control and 20 min of global ischemia and reperfusion, both with and without pretreatment with the mitochondrial uncoupler FCCP at 100, 50, or 30 nM. No hearts went into VF during ischemia under the control condition, with or without the electromechanical uncoupler blebbistatin. We found that pretreatment with 100 (n = 4) and 50 (n = 6) nM FCCP, with or without blebbistatin, leads to VF during ischemia in all hearts, whereas pretreatment with 30 nM of FCCP led to three out of eight hearts going into VF during ischemia. We demonstrated that 30 nM of FCCP significantly increased interventricular (but not intraventricular) action potential duration and conduction velocity heterogeneity in the heart during ischemia, thus providing the substrate for VF. We showed that wavebreaks during VF occurred between the right and left ventricular junction. We also demonstrated that no VF occurred in the heart pretreated with 10 μg glibenclamide, which is known to abolish interventricular heterogeneity. Our results indicate that low concentrations of FCCP, although cardioprotective at the single cell level, are arrhythmogenic at the whole heart level. This is due to the fact that FCCP induces different electrophysiological changes to the right and left ventricle, thus increasing interventricular heterogeneity and providing the substrate for VF.

KW - Carbonyl cyanide p-(trifluoromethoxy) phenyl-hydrazone

KW - Interventricular heterogeneity

KW - Mitochondria

KW - Myocardial ischemia

KW - Optical mapping

UR - http://www.scopus.com/inward/record.url?scp=84863996908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863996908&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00017.2012

DO - 10.1152/ajpheart.00017.2012

M3 - Article

C2 - 22636678

AN - SCOPUS:84863996908

VL - 303

SP - H224-H233

JO - American Journal of Physiology - Cell Physiology

JF - American Journal of Physiology - Cell Physiology

SN - 0363-6143

IS - 2

ER -