title: Increased susceptibility of aged hearts to ventricular fibrillation during oxidative stress.
abstract: Oxidative stress with hydrogen peroxide (H(2)O(2)) readily promotes early afterdepolarizations (EADs) and triggered activity (TA) in isolated rat and rabbit ventricular myocytes. Here we examined the effects of H(2)O(2) 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(2)O(2) (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 H(2)O(2) 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 microM) but not by its inactive form (KN-92, 1 microM). There were no significant differences between action potential duration (APD) or APD restitution slope before or after H(2)O(2) 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 ( approximately 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.
authors.affiliation: Translational Arrhythmia Research Laboratory and Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, USA.
authors.forename: Norishige
authors.initials: N
authors.lastname: Morita
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Xie
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: William J
authors.initials: WJ
authors.lastname: Mandel
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Fuhua
authors.initials: F
authors.lastname: Chen
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000200:Action Potentials; D000367:Age Factors; D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002450:Cell Communication; D003198:Computer Simulation; D004195:Disease Models, Animal; D004562:Electrocardiography; D004789:Enzyme Activation; D005355:Fibrosis; D006352:Heart Ventricles / Q000378:metabolism; D006861:Hydrogen Peroxide; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016877:Oxidants; D018384:Oxidative Stress / Q000187:drug effects; D010477:Perfusion; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D000096926:Benzenesulfonamides
chemical_list: D000111:Acetylcysteine; D000975:Antioxidants; D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006861:Hydrogen Peroxide; D016877:Oxidants; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides