title: Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and β-receptor blockade.
abstract: To investigate whether heart rate reduction via I(f)-channel blockade and β-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II-induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P<0.05) and diastolic (LV relaxation, LV end diastolic pressure, τ, and stiffness constant β; P<0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (P<0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (P<0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with I(f)-channel inhibition.
authors.affiliation: Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Peter Moritz
authors.initials: PM
authors.lastname: Becher
authors.forename: Diana
authors.initials: D
authors.lastname: Lindner
authors.forename: Kapka
authors.initials: K
authors.lastname: Miteva
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Savvatis
authors.forename: Christin
authors.initials: C
authors.lastname: Zietsch
authors.forename: Bastian
authors.initials: B
authors.lastname: Schmack
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000008:administration & dosage*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000008:administration & dosage; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077550:Ivabradine; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D015999:Multivariate Analysis; D011897:Random Allocation; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013610:Tachycardia / Q000517:prevention & control*; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000473:pathology* / Q000517:prevention & control*; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D001552:Benzazepines; D054815:Cyclic Nucleotide-Gated Cation Channels; D016207:Cytokines; D000804:Angiotensin II; D000077550:Ivabradine; D008790:Metoprolol