title: Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.
abstract: OBJECTIVE
  Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown.
  
  
  METHODS
  LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d).
  
  
  RESULTS
  Long- and short-term HRR reduced LV end-diastolic pressure, LV relaxation, and LV end-diastolic pressure-volume relation. Simultaneously, LV hypoxia-inducible factor-1α expression was reduced. Long-term and, to a more marked extent, short-term HRR increased endothelial cell proliferation, associated after long-term HRR with the prevention of CHF-related LV capillary rarefaction. Long-term and, to a lesser extent, short-term HRR increased endothelial nitric oxide synthase expression, associated after long-term HRR with improved nitric oxide-dependent coronary vasodilatation.
  
  
  CONCLUSIONS
  Long-term HRR induced by ivabradine improves diastolic LV function probably involving attenuated hypoxia, reduced remodeling, and/or preserved nitric oxide bioavailability, resulting from processes triggered early after HRR initiation: angiogenesis and/or preservation of endothelial nitric oxide synthase expression.
authors.affiliation: INSERM U644, Institut Hospitalier Recherche BioMedicale Normandie, IFRMP n°23, UFR de Médecine et de Pharmacie, Rouen, France.
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Fang
authors.forename: Manuelle
authors.initials: M
authors.lastname: Debunne
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.forename: Ebba
authors.initials: E
authors.lastname: Brakenhielm
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Francoise
authors.initials: F
authors.lastname: Lallemand
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003971:Diastole; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D000077550:Ivabradine; D008297:Male; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000473:pathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009569:Nitric Oxide; D000077550:Ivabradine