title: Enhanced sensitivity of aged fibrotic hearts to angiotensin II- and hypokalemia-induced early afterdepolarization-mediated ventricular arrhythmias.
abstract: Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24-26 mo) and young (3-4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 μM) or ionic stress with hypokalemia (2.7 mM). ANG II caused EAD-mediated VF in 16 of 19 aged hearts (83%) after 32 ± 7 min but in 0 of 9 young hearts (0%). ANG II-mediated VF was suppressed with KN-93 (Ca(2+)/calmodulin-dependent kinase inhibitor) and the reducing agent N-acetylcysteine. Hypokalemia caused EAD-mediated VF in 11 of 11 aged hearts (100%) after 7.4 ± 0.4 min. In 14 young hearts, however, VF did not occur in 6 hearts (43%) or was delayed in onset (31 ± 22 min, P < 0.05) in 8 hearts (57%). In patch-clamped myocytes, ANG II and hypokalemia (n = 6) induced EADs and triggered activity in both age groups (P = not significant) at a cycle length of >0.5 s. When myocytes of either age group were coupled to a virtual fibroblast using the dynamic patch-clamp technique, EADs arose in both groups at a cycle length of <0.5 s. Aged ventricles had significantly greater fibrosis and reduced connexin43 gap junction density compared with young hearts. The lack of differential age-related sensitivity at the single cell level in EAD susceptibility indicates that increased ventricular fibrosis in the aged heart plays a key role in increasing vulnerability to VF induced by oxidative and ionic stress.
authors.affiliation: Translational Arrhythmia Research Section, University of California-Los Angeles Cardiovascular Research Laboratory, USA.
authors.forename: Aneesh
authors.initials: A
authors.lastname: Bapat
authors.forename: Thao P
authors.initials: TP
authors.lastname: Nguyen
authors.forename: Jong-Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
mesh_terms: D000375:Aging / Q000502:physiology*; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D007008:Hypokalemia / Q000150:complications* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000503:physiopathology
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D019255:NADPH Oxidases