Protective effects of heart rate reduction induced by ivabradine on the risk of ventricular fibrillation during acute myocardial ischemia in pigs
Q. Timour
Laboratoire de Pharmacologie Médicale
INSERM ERI 22
8, av. Rockefeller 69373 Lyon cedex 08
Paris, France
Abstract:
Aim: A major risk of acute myocardial ischemia is the onset of ventricular fibrillation (VF). Our study evaluated the effect of heart rate reduction (HRR) induce by ivabradine (IVA), a selective inhibitor of the pacemaker current If, on the risk of onset of VF, and on the possible mechanisms involved.
Methods: Myocardial ischemia was induced in pigs by total occlusion of the anterior descending coronary 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 and hemodynamic parameters were assessed during these two protocols. Moreover, the impact of IVA was evaluated on: i) extend of ischemic area (protocol 1), ii) ultrastructure of mitochondria by electron microscopy (protocol 1); iii) myocardial energetic status compared with a ß-blocker, propranolol (PROP) in protocol 2; iv) regional myocardial blood flow (RMBF) after 1 min-ischemia followed (without VF) by reperfusion by positrons emission tomography in protocol 3.
Results: IVA induced a significant HRR (~25%) in all the protocol; this was associated with a reduction of the risk of the onset of VF (by increase in the VFT (protocol 1) and the TOF (protocol 2)). When compared to control, IVA prevented the apparition of mitochondrial alterations due to repetitive sequences of acute myocardial ischemia/VF and reperfusion. Moreover, IVA improved of the RMBF at reperfusion (protocol 3). Also, the myocardial energetic status evaluated by the concentrations of high energy phosphates, was in part preserved with IVA at the onset of VF due to acute myocardial ischemia. All of these changes were abolished by the application of pacing, which demonstrate the role of IVA-induced HRR in cardiac protection. These observations were not associated with modifications in the dP/dtmax.
Conclusions: 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.
