Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress

Norishige Morita, Ali A. Sovari, Yuanfang Xie, Michael C. Fishbein, William J. Mandel, Alan Garfinkel, Shien Fong Lin, Peng Sheng Chen, Lai Hua Xie, Fuhua Chen, Zhilin Qu, James N. Weiss, Hrayr S. Karagueuzian

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Oxidative stress with hydrogen peroxide (H2O2) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H2O2 on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H 2O2 (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H2O2 caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 μM) but not by its inactive form (KN-92, 1 μM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H2O2 in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate (∼30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.

Original languageEnglish (US)
Pages (from-to)H1594-H1605
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume297
Issue number5
DOIs
StatePublished - Nov 1 2009

Fingerprint

Ventricular Fibrillation
Oxidative Stress
Fibrosis
Rabbits
Ventricular Tachycardia
Cardiac Arrhythmias
Young Adult
Action Potentials
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Intracellular Membranes
Reducing Agents
Acetylcysteine
Microelectrodes
Computer Simulation
Muscle Cells
Hydrogen Peroxide
Glass
Staining and Labeling
Calcium

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Keywords

  • Aging
  • Calcium transient
  • Early afterdepolarization
  • Fibrosis
  • Optical mapping
  • Triggered activity

Cite this

Morita, N., Sovari, A. A., Xie, Y., Fishbein, M. C., Mandel, W. J., Garfinkel, A., ... Karagueuzian, H. S. (2009). Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. American Journal of Physiology - Heart and Circulatory Physiology, 297(5), H1594-H1605. https://doi.org/10.1152/ajpheart.00579.2009
Morita, Norishige ; Sovari, Ali A. ; Xie, Yuanfang ; Fishbein, Michael C. ; Mandel, William J. ; Garfinkel, Alan ; Lin, Shien Fong ; Chen, Peng Sheng ; Xie, Lai Hua ; Chen, Fuhua ; Qu, Zhilin ; Weiss, James N. ; Karagueuzian, Hrayr S. / Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. In: American Journal of Physiology - Heart and Circulatory Physiology. 2009 ; Vol. 297, No. 5. pp. H1594-H1605.
@article{b40027d3708b46b5b84910aee3e17ada,
title = "Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress",
abstract = "Oxidative stress with hydrogen peroxide (H2O2) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H2O2 on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H 2O2 (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94{\%}) aged (24-26 mo) rat hearts, 0.1 mM H2O2 caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 μM) but not by its inactive form (KN-92, 1 μM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H2O2 in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90{\%}; middle-aged rabbit hearts had less fibrosis (5-35{\%}), whereas young adult rat and rabbit hearts had <4{\%} fibrosis. In aged rat hearts, EADs and TA arose most frequently (70{\%}) from the left ventricular base where fibrosis was intermediate (∼30{\%}). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.",
keywords = "Aging, Calcium transient, Early afterdepolarization, Fibrosis, Optical mapping, Triggered activity",
author = "Norishige Morita and Sovari, {Ali A.} and Yuanfang Xie and Fishbein, {Michael C.} and Mandel, {William J.} and Alan Garfinkel and Lin, {Shien Fong} and Chen, {Peng Sheng} and Xie, {Lai Hua} and Fuhua Chen and Zhilin Qu and Weiss, {James N.} and Karagueuzian, {Hrayr S.}",
year = "2009",
month = "11",
day = "1",
doi = "10.1152/ajpheart.00579.2009",
language = "English (US)",
volume = "297",
pages = "H1594--H1605",
journal = "American Journal of Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "5",

}

Morita, N, Sovari, AA, Xie, Y, Fishbein, MC, Mandel, WJ, Garfinkel, A, Lin, SF, Chen, PS, Xie, LH, Chen, F, Qu, Z, Weiss, JN & Karagueuzian, HS 2009, 'Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress', American Journal of Physiology - Heart and Circulatory Physiology, vol. 297, no. 5, pp. H1594-H1605. https://doi.org/10.1152/ajpheart.00579.2009

Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress. / Morita, Norishige; Sovari, Ali A.; Xie, Yuanfang; Fishbein, Michael C.; Mandel, William J.; Garfinkel, Alan; Lin, Shien Fong; Chen, Peng Sheng; Xie, Lai Hua; Chen, Fuhua; Qu, Zhilin; Weiss, James N.; Karagueuzian, Hrayr S.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 297, No. 5, 01.11.2009, p. H1594-H1605.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress

AU - Morita, Norishige

AU - Sovari, Ali A.

AU - Xie, Yuanfang

AU - Fishbein, Michael C.

AU - Mandel, William J.

AU - Garfinkel, Alan

AU - Lin, Shien Fong

AU - Chen, Peng Sheng

AU - Xie, Lai Hua

AU - Chen, Fuhua

AU - Qu, Zhilin

AU - Weiss, James N.

AU - Karagueuzian, Hrayr S.

PY - 2009/11/1

Y1 - 2009/11/1

N2 - Oxidative stress with hydrogen peroxide (H2O2) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H2O2 on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H 2O2 (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H2O2 caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 μM) but not by its inactive form (KN-92, 1 μM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H2O2 in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate (∼30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.

AB - Oxidative stress with hydrogen peroxide (H2O2) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H2O2 on arrhythmias in intact Langendorff rat and rabbit hearts using dual-membrane voltage and intracellular calcium optical mapping and glass microelectrode recordings. Young adult rat (3-5 mo, N = 25) and rabbit (3-5 mo, N = 6) hearts exhibited no arrhythmias when perfused with H 2O2 (0.1-2 mM) for up to 3 h. However, in 33 out of 35 (94%) aged (24-26 mo) rat hearts, 0.1 mM H2O2 caused EAD-mediated TA, leading to ventricular tachycardia (VT) and fibrillation (VF). Aged rabbits (life span, 8-12 yr) were not available, but 4 of 10 middle-aged rabbits (3-5 yr) developed EADs, TA, VT, and VF. These arrhythmias were suppressed by the reducing agent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1 μM) but not by its inactive form (KN-92, 1 μM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H2O2 in aged or young adult rat hearts. In histological sections, however, trichrome staining revealed that aged rat hearts exhibited extensive fibrosis, ranging from 10-90%; middle-aged rabbit hearts had less fibrosis (5-35%), whereas young adult rat and rabbit hearts had <4% fibrosis. In aged rat hearts, EADs and TA arose most frequently (70%) from the left ventricular base where fibrosis was intermediate (∼30%). Computer simulations in two-dimensional tissue incorporating variable degrees of fibrosis showed that intermediate (but not mild or severe) fibrosis promoted EADs and TA. We conclude that in aged ventricles exposed to oxidative stress, fibrosis facilitates the ability of cellular EADs to emerge and generate TA, VT, and VF at the tissue level.

KW - Aging

KW - Calcium transient

KW - Early afterdepolarization

KW - Fibrosis

KW - Optical mapping

KW - Triggered activity

UR - http://www.scopus.com/inward/record.url?scp=70350455536&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350455536&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00579.2009

DO - 10.1152/ajpheart.00579.2009

M3 - Article

C2 - 19767530

AN - SCOPUS:70350455536

VL - 297

SP - H1594-H1605

JO - American Journal of Physiology

JF - American Journal of Physiology

SN - 0363-6135

IS - 5

ER -