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1 Medicine, Cedars-Sinai, Los Angeles, California, United States
2 Medicine, Cedars-Sinai Medical Center, Los Angeles, United States
3 Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States; Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California, 90048, United States
4 Division of Cardiology, University of California School of Medicine, Los Angeles, California, United States
5 Cardiology Division, Cedar Sinai Medical Center, Los Angeles, California, United States
6 Medicine, Cedars-Sinai Med Ctr, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: karagueuzian{at}cshs.org.
Aging and glycolytic inhibition (GI) are known to alter intracellular calcium ion (Cai2+) handling in cardiac myocytes causing early and delayed afterpotentials (EADs and DADs respectively). 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 months, N=8) and old (age, 27-29 months, N=14) rats subjected to GI (0 glucose +10 mmol/L pyruvate). Epicardial atrial activation maps were constructed using optical action potentials (AP) while simultaneously monitoring Cai2+ by means of dual voltage- and calcium-sensitive fluorescent dyes. During GI, spontaneous AF occurred in 13/14 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 wavefront, but within 1 sec degenerated into multiple wavelets. The EADs and triggered activity in the old atria were associated with significantly elevated diastolic Cai2+ levels at the LA-PVJ, where the time constant, 
, of the Cai2+ transient decline and AP duration were significantly (P<0.01) prolonged compared to atrial sites 5 mm away from LA-PVJ. During GI and rapid atrial pacing spatially discordant APD and Cai2+ 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 Cai2+ handling abnormalities that facilitates EAD-mediated triggered activity and AF.
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