Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition.
Aging and glycolytic inhibition (GI) are known to alter intracellular calcium ion (Ca(i)(2+)) handling in cardiac myocytes, causing early afterpotentials (EADs) and delayed afterpotentials. We hypothesized that aging and GI interact synergistically in intact hearts to generate EADs and triggered activity leading to atrial fibrillation (AF). We studied isolated and Langendorff-perfused hearts of young (age 3-5 mo, N = 8) and old (age 27-29 mo, N = 14) rats subjected to GI (0 glucose + 10 mmol/l pyruvate). Epicardial atrial activation maps were constructed using optical action potentials, while simultaneously monitoring Ca(i)(2+) by means of dual-voltage and calcium-sensitive fluorescent dyes. During GI, spontaneous AF occurred in 13 of 14 old but in no young rats. AF was initiated by EAD-induced triggered activity at the left atrial pulmonary vein junction (LA-PVJ). The triggered activity initially propagated as single wave front, but within 1 s degenerated into multiple wavelets. The EADs and triggered activity in the old atria were associated with significantly elevated diastolic Ca(i)(2+) levels at the LA-PVJ, where the time constant tau of the Ca(i)(2+) transient decline and action potential duration were significantly (P < 0.01) prolonged compared with atrial sites 5 mm away from LA-PVJ. During GI and rapid atrial pacing, spatially discordant APD and Ca(i)(2+) transient alternans developed in the old but not young atria, leading to AF. Atria in old rats had significantly more fibrotic tissue than atria in young rats. We conclude that GI interacts with the aged and fibrotic atria to amplify Ca(i)(2+) handling abnormalities that facilitate EAD-mediated triggered activity and AF.
Ono
Norihiko
N
Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hayashi
Hideki
H
Kawase
Ayaka
A
Lin
Shien-Fong
SF
Li
Hongmei
H
Weiss
James N
JN
Chen
Peng-Sheng
PS
Karagueuzian
Hrayr S
HS
D000200:Action Potentials; D000375:Aging; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006325:Heart Atria / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology*; D008297:Male; D011667:Pulmonary Veins / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344
D005947:Glucose