Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: Role of myocyte structure and myocardial perfusion

Abstract

Aims We showed previously that ivabradine (IVA), a selective inhibitor of the cardiac pacemaker I f current, achieved protection against ischaemia-induced ventricular fibrillation (VF) in pigs by increasing the VF threshold (VFT). This was correlated to the heart rate reduction (HRR), the limitation of monophasic action potential shortening and the reduction of the hypoxic area. This study investigated myocyte ultrastructure and regional myocardial blood flow (RMBF), potentially involved in these cardioprotective effects of IVA. Methods and results Myocardial ischaemia was induced in pigs by total 1-min occlusion of the left anterior descending coronary artery following i.v. administration of saline ( n = 6) or IVA (0.25 mg/kg, n = 6). Electrophysiological and haemodynamic parameters, the hypoxic area and the presence of myocyte ultrastructural lesions were evaluated. The RMBF was assessed using positron emission tomography following ischaemia/reperfusion in IVA (0.25 mg/kg, i.v., n = 6) or vagal stimulation ( n = 4) groups. Compared with saline, IVA induced a 32% HRR ( p < 0.01), a 2.9-fold increase in the VFT ( p < 0.001) and a reduction of the hypoxic area without any change in left ventricular d P/d t max. IVA preserved cardiomyocyte morphology, particularly mitochondrial ultrastructure. Compared with baseline, RMBF during reperfusion was increased in the hypoxic area following IVA administration (+218% vs. +97%, p < 0.05) or vagal stimulation (+195% vs. +127%, p < 0.05). This increase was sharply reduced by atrial pacing in IVA-group. Conclusion IVA exerts a cardioprotection from ischaemia-induced VF by increasing RMBF and preserving cardiomyocyte and mitochondrial ultrastructure, which opens new perspectives regarding potential targets that would be involved in the anti-ischaemic effects of IVA.