Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress

doi:10.1152/ajpheart.00579.2009

Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress

Norishige Morita,¹ Ali A. Sovari,¹ Yuanfang Xie,¹ Michael C. Fishbein,² William J. Mandel,³ Alan Garfinkel,¹ Shien-Fong Lin,⁴ Peng-Sheng Chen,⁴ Lai-Hua Xie,⁵ Fuhua Chen,¹ Zhilin Qu,¹ James N. Weiss,¹ and Hrayr S. Karagueuzian¹

¹Translational Arrhythmia Research Laboratory and Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, ²Department of Pathology, David Geffen School of Medicine at the University of California, Los Angeles, and ³Division of Cardiology, Department of Medicine, Cedars-Sinai Health System, David Geffen School of Medicine at University of California, Los Angeles, California; ⁴Division of Cardiology, Department of Medicine, The Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana; and ⁵Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry New Jersey, Newark, New Jersey

Submitted June 30, 2009 ; accepted in final form September 14, 2009

Oxidative stress with hydrogen peroxide (H₂O₂) readily promotesearly afterdepolarizations (EADs) and triggered activity (TA)in isolated rat and rabbit ventricular myocytes. Here we examinedthe effects of H₂O₂ on arrhythmias in intact Langendorff ratand rabbit hearts using dual-membrane voltage and intracellularcalcium optical mapping and glass microelectrode recordings.Young adult rat (3–5 mo, N = 25) and rabbit (3–5mo, N = 6) hearts exhibited no arrhythmias when perfused withH₂O₂ (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-mediatedTA, 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 reducingagent N-acetylcysteine (2 mM) and CaMKII inhibitor KN-93 (1µM) but not by its inactive form (KN-92, 1 µM).There were no significant differences between action potentialduration (APD) or APD restitution slope before or after H₂O₂in aged or young adult rat hearts. In histological sections,however, trichrome staining revealed that aged rat hearts exhibitedextensive fibrosis, ranging from 10–90%; middle-aged rabbithearts had less fibrosis (5–35%), whereas young adultrat and rabbit hearts had <4% fibrosis. In aged rat hearts,EADs and TA arose most frequently (70%) from the left ventricularbase where fibrosis was intermediate ( $~$ 30%). Computer simulationsin two-dimensional tissue incorporating variable degrees offibrosis showed that intermediate (but not mild or severe) fibrosispromoted EADs and TA. We conclude that in aged ventricles exposedto oxidative stress, fibrosis facilitates the ability of cellularEADs to emerge and generate TA, VT, and VF at the tissue level.

optical mapping; aging; fibrosis; calcium transient; triggered activity; early afterdepolarization

Address for reprint requests and other correspondence: H. S. Karagueuzian, Translational Arrhythmia Research Lab., David Geffen School of Medicine at UCLA, 675 Charles E. Young Dr. S., MRL 3645 Mail Code: 176022, Los Angeles, CA 90095 (e-mail: hkaragueuzian{at}mednet.ucla.edu).