Background: Ivabradine (IVA) inhibits hyperpolarization-activated cyclic nucleotide channel to reduce pacing current with a possible increasing risk of atrial fibrillation (AF). Objective: To determine the effects of IVA on atrial action potentials, atrial arrhythmic activities and intracellular calcium homeostasis. Methods: Langendorff-perfused hearts and atrial myocytes from New Zealand White rabbits were used to record 12-lead ECGs，left atrial monophasic APs and Ca2+ sparks. Ca2+ handing related protein from left atrium were tested using western blotting. Results: IVA (0.1-10 μM) slowed the HR and prolonged the atrial MAPD90 (n=8, p<0.05) and induced atrial arrhythmias in 26% and 77% of hearts paced at cycle lengths of 350 ms and 570 ms, respectively (n=23 and 13, p<0.05). In hearts treated with either 0.3 µM acetylcholine (ACh) or 2 nM ATX-II with modulated atrial MAPDs, IVA (0.1-10 µM) caused either shortening or prolongation of MAPD90, respectively (n=18 and 21, p<0.05) and atrial arrhythmias in 61.9% and 44.4% of hearts (p<0.05). IVA induced delayed afterdepolarizations in 41.7%, 62.5% and 50% of cells in the absence and presence of either ATX-II or ACh, respectively (n=12, 8 and 8, p<0.05). IVA (0.03-3 μM) increased the frequency, amplitude and full width at half-maximum (n=22, p<0.05), and the expression of ryanodine receptor and Na+/Ca2+ exchanger with decreased sarcoplasmic reticulum calcium pump (n=4-5, p<0.05). Conclusion: IVA caused a blunted HR reduction and increased atrial proarrhythmic risk in hearts with slow rate, enhanced vagal tone and late INa, and DADs resulting from enhanced Ca2+ release.

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.