title: Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis.
abstract: OBJECTIVE
  To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I(f) current, prevents cardiac dysfunction associated with dyslipidemia.
  
  
  METHODS
  New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays.
  
  
  RESULTS
  IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008).
  
  
  CONCLUSIONS
  Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.
authors.affiliation: Research Center, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Busseuil
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.forename: Mélanie
authors.initials: M
authors.lastname: Mecteau
authors.forename: Geneviève
authors.initials: G
authors.lastname: Brand
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Caroline
authors.initials: C
authors.lastname: Asselin
authors.forename: Philippe
authors.initials: P
authors.lastname: Roméo
authors.forename: Tack Ki
authors.initials: TK
authors.lastname: Leung
authors.forename: Jean-Gilles
authors.initials: JG
authors.lastname: Latour
authors.forename: Christine
authors.initials: C
authors.lastname: Des Rosiers
authors.forename: Muriel
authors.initials: M
authors.lastname: Bouly
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
mesh_terms: D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000494:pharmacology*; D003971:Diastole / Q000187:drug effects; D018619:Echocardiography, Doppler, Pulsed; D005355:Fibrosis; D006325:Heart Atria / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects*; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D006937:Hypercholesterolemia / Q000503:physiopathology*; D000077550:Ivabradine; D018384:Oxidative Stress; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology*
chemical_list: D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D000804:Angiotensin II; D000077550:Ivabradine; D000450:Aldosterone