title: Heart rate reduction with ivabradine increases ischaemia-induced ventricular fibrillation threshold: role of myocyte structure and myocardial perfusion.
abstract: OBJECTIVE
  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.
  
  
  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 dP/dt(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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: INSERM ERI22, Université Claude Bernard de Lyon, 8 Avenue Rockefeller, 69373 Lyon cedex 08, France. fanny.vaillant45@gmail.com
authors.forename: Fanny
authors.initials: F
authors.lastname: Vaillant
authors.forename: Leila
authors.initials: L
authors.lastname: Dehina
authors.forename: Alejandro
authors.initials: A
authors.lastname: Mazzadi
authors.forename: Jacques
authors.initials: J
authors.lastname: Descotes
authors.forename: Philippe
authors.initials: P
authors.lastname: Chevalier
authors.forename: Alain
authors.initials: A
authors.lastname: Tabib
authors.forename: Bernard
authors.initials: B
authors.lastname: Bui-Xuan
authors.forename: Cécile
authors.initials: C
authors.lastname: Riera
authors.forename: Dalila
authors.initials: D
authors.lastname: Belhani
authors.forename: Quadiri
authors.initials: Q
authors.lastname: Timour
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D032342:Muscle Cells / Q000187:drug effects / Q000648:ultrastructure; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D049268:Positron-Emission Tomography; D013552:Swine; D014693:Ventricular Fibrillation / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D001552:Benzazepines; D000077550:Ivabradine