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Ivabradine causes abnormal intracellular calcium handlings and delayed afterdepolarizations to induce atrial fibrillation in rabbit hearts
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  • Chengyu Wang,
  • Bingxun Li,
  • Mingjie Lin,
  • Qiaomei Yang,
  • Gang Li,
  • Xiaoyan Liu,
  • Qing Zhang,
  • Shandong Yu,
  • Lin Wu
Chengyu Wang
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Bingxun Li
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Mingjie Lin
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Qiaomei Yang
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Xiaoyan Liu
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Qing Zhang
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Shandong Yu
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Lin Wu

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Objective: The present paper is to determine the effects and underlying mechanisms of ivabradine (IVA) on atrial fibrillation (AF). Methods: Electrophysiological changes were determined using Langendorff-perfused hearts and patch-clamp techniques. Parameters of Ca2+ handling were evaluated by using calcium imaging and western blotting. Results: IVA (0.1-10 μM) slowed HR in a concentration-dependent manner in isolated hearts of rabbit. IVA induced atrial arrhythmias in 26.1% and 76.9% of hearts paced at a basic cycle length of 350 and 570 ms, respectively. In hearts pretreated with either acetylcholine (ACh) or anemone toxin-II (ATX-II) which caused no inducible atrial arrhythmias, adding to IVA administration caused atrial arrhythmias in 61.9% (13/21) and 44.4% (8/18) of hearts, respectively. In atrial myocytes, IVA induced DADs by 41.7%, 62.5% and 50.0%, respectively, in the absence and presence of either ACh or ATX-II. IVA increased the frequency, amplitude and full width at half-maximum (FWHM) of Ca2+ sparks and decreased Ca2+ transport in association with increased protein expression of RyR2 and NCX1 and decreased SERCA2. Conclusion: IVA increases atrial proarrhythmic risk in hearts with a slow HR, enhanced vagal tone and increased late sodium current by inducing DADs resulting from an enhanced intracellular Ca2+ inhomeostasis.