253 Effects of the selective heart rate-reducing agent ivabradine on the risk of onset of ventricular fibrillation during myocardial ischemia in pigs: involved mechanisms

Abstract

A major risk of myocardial ischemia (MI) is the onset of ventricular fibrillation (VF). Our study evaluated the effect of heart rate reduction (HRR) induce by ivabradine (IVA), the first selective inhibitor of the pacemaker current If, on the risk of onset of VF, and study the possible mechanisms involved. MI was induced in pigs by total occlusion of the anterior interventricular artery until onset of VF, which was assessed by the VF threshold (VFT; protocol 1) or the time to onset of VF (TOF; protocol 2), with or without IVA (0.25 mg/kg, i.v.). Electrophysiological, hemodynamic parameters and ischemic area were assessed in these two protocols. The impact of IVA was evaluated on: i) ultrastructure of mitochondria (by electron microscopy) in protocol 1; ii) myocardial energetic status compared with a β-blocker, propranolol (PROP) in protocol 2; iii) regional myocardial blood flow (RMBF) after 1 min-ischemia followed (without VF) by reperfusion by positrons emission tomography in protocol 3. IVA induced a significant HRR (∼25%), increased the VFT and the TOF. When compare to control, IVA prevented the apparition of mitochondrial alterations due to repetitive sequences of MI/VF and reperfusion. IVA improved the RMBF during reperfusion (after 1 min-occlusion). Also, the myocardial energetic status evaluated by the concentrations of high energy phosphates, was in part preserved with IVA. All of these changes were correlated with IVA-induced HRR and were not associated with modifications in the dP/dtmax. Our results showed that IVA decreases the risk of the onset of ischemia-induced VF. This effect can be explained by a preservation of ultrastructure of mitochondria, an improvement in the RMBF and a better conservation of myocardial energetic status. Although further work is needed to determine the mechanisms underlying these effects, this might give a place of choice to IVA in the prevention of ischemia-induced VF.