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Spontaneous atrial fibrillation initiated by triggered activity near the pulmonary veins in aged rats subjected to glycolytic inhibition

Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center, and the Department of Medicine and Physiology, David Geffen School of Medicine, University of California, Los Angeles, California

Submitted 3 May 2006 ; accepted in final form 17 August 2006

Aging and glycolytic inhibition (GI) are known to alter intracellular calcium ion (Ca_i²⁺) 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_i²⁺ 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_i²⁺ levels at the LA-PVJ, where the time constant of the Ca_i²⁺ 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_i²⁺ 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_i²⁺ handling abnormalities that facilitate EAD-mediated triggered activity and AF.

action potential; early afterdepolarization; calcium transient; interstitial fibrosis; atrial fibrillation

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