Ivabradine causes abnormal intracellular calcium handlings and delayed afterdepolarizations to induce atrial fibrillation in rabbit hearts

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 Ca ²⁺ 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 Ca ²⁺ sparks and decreased Ca ²⁺ 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 Ca ²⁺ inhomeostasis.