Introduction
Drug-induced cardiac arrhythmias, especially proarrhythmic effects of class I and III antiarrhythmic drugs, are common in patients with structural heart diseases and remain an important issue for the development and clinical use of drugs. With the high prevalence of atrial fibrillation (AF), drug-induced AF becomes a problem worthy of clinical attention because of the potentially high incidence and poor understanding on the underlying mechanisms1, 2. Many cardiovascular and on-cardiovascular drugs are associated with increased risk of AF in clinic. Ivabradine (IVA), a class 0 antiarrhythmic agent in the modernized classification of cardiac antiarrhythmic drug3, selectively inhibits hyperpolarization-activated cyclic nucleotide (HCN) channel to reduce the pacemaker funny current (If) in the sinus node and is used to treat inappropriate sinus tachycardia in addition to or as an alternative to digitalis, β blockers or calcium channel inhibitors 4without affecting blood pressure, myocardial contractility and atrioventricular nodal conduction. However, clinical use of IVA caused no reduction in cardiovascular mortality even when the sinus heart rate was already decreased to 70 beat per minute or lower in patients with heart failure and/or coronary artery diseases5, 6.
HCN channels are highly expressed during embryonic atrial development, decrease gradually and are limited to the cardiac conduction system with age. HCN channels, especially the HCN2 and HCN4 channels, are re-expressed under pathophysiological conditions, including heart failure, myocardial infarction, hypertrophy and atrial arrhythmias7. Drug-induced AF is more common in patients with bradycardia from the use of drugs to slow heart rate or in patients with increased vagal tone than others 8. Clinical use of IVA is associated with a possibly 24% increase in the risk of developing AF 9. The mechanisms, risk factors and the correlation with the prognosis underlying the increased susceptibility to AF following IVA application remain underdetermined. In this study, the atrial proarrhythmic activity of IVA was reproduced and the underlying mechanisms were investigated in isolated rabbit hearts and left atrial myocytes (LAMs). To the best of our knowledge, this is the first report to demonstrate that IVA has atrial proarrhythmic activities in experimental animal models.