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(Circulation Research. 2008;103:845.)
© 2008 American Heart Association, Inc.

Cellular Biology

Cellular Signaling Underlying Atrial Tachycardia Remodeling of L-type Calcium Current

Xiao Yan Qi, Yung-Hsin Yeh, Ling Xiao, Brett Burstein, Ange Maguy, Denis Chartier, Louis R. Villeneuve, Bianca J.J.M. Brundel, Dobromir Dobrev, Stanley Nattel

From the Montreal Heart Institute and Department of Medicine (X.Y.Q., Y.-H.Y., L.X., B.B., A.M., D.C., L.R.V., S.N.), Université de Montréal, Quebec, Canada; Department of Pharmacology and Therapeutics (L.X., B.J.J.M.B., S.N.), McGill University, Montreal, Quebec, Canada; Chang Gung Memorial Hospital and Chang Gung University (Y.H.Y.) Tao-Yuan, Taiwan; Department of Radiation and Stress Cell Biology, Department of Clinical Pharmacology (B.J.J.M.B.), University Groningen, The Netherlands; and Department of Pharmacology and Toxicology (D.D.), Dresden University of Technology, Germany.

Correspondence to Stanley Nattel, Montreal Heart Institute/University of Montreal, Department of Medicine and Research Center, 5000 Belanger St East, Montreal, Quebec, H1T 1C8, Canada. E-mail stanley.nattel{at}icm-mhi.org

Atrial tachycardia (AT) downregulates L-type Ca²⁺ current (I_CaL) and causes atrial fibrillation–promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I_CaL and transient outward current (I_to), unchanged I_CaT, I_Kr, and I_Ks, and reduced action potential duration (APD). I_CaL was unchanged in P3 at 2 and 8 hours but decreased by 55±6% at 24 hours. Tachypacing caused Ca²⁺_i accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca²⁺i returned to baseline. Ca_v1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32±4% and 48±4%, respectively) and protein expression was decreased (47±8%) at 24 hours only. Suppressing Ca²⁺_i increases during tachypacing with the I_CaL blocker nimodipine or the Ca²⁺ chelator BAPTA-AM prevented I_CaL downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca²⁺-dependent signaling was probed with inhibitors of Ca²⁺/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I_CaL downregulation. Significant APD reductions (30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca²⁺ loading, which activates the Ca²⁺-dependent calmodulin–calcineurin–NFAT system to cause transcriptional downregulation of I_CaL, restoring Ca²⁺i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.

Key Words: atrial fibrillation • electrophysiological remodeling • arrhythmia mechanisms • antiarrhythmic therapy

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