title: If inhibition in the atrioventricular node by ivabradine causes rate-dependent slowing of conduction and reduces ventricular rate during atrial fibrillation.
abstract: BACKGROUND
  If channels are functionally expressed in atrioventricular (AV) nodal tissue.
  
  
  OBJECTIVE
  The purpose of this study was to address whether the prototypical If inhibitor, ivabradine, at clinically safe concentrations can slow AV node conduction to reduce ventricular rate (VR) during atrial fibrillation (AF).
  
  
  METHODS
  Effects of ivabradine (0.1 mg/kg i.v. bolus) were studied in an anesthetized Yorkshire pig (N = 7) model of AF and in isolated guinea pig hearts (N = 7).
  
  
  RESULTS
  Ivabradine reduced heart rate (P = .0001) without affecting mean arterial pressure during sinus rhythm. The agent lengthened PR intervals in a rate-dependent manner (P = .0009) by 14 ± 2.7 ms (P = .003) and 25 ± 3.0 ms (P = .0004) and increased atrial-His (A-H) intervals in a rate-dependent manner (P = .020) by 10 ± 1.7 ms and 17 ± 2.8 ms during pacing at 130 and 180 bpm, respectively (both P = .0008). Similar rate-dependent effects were observed in isolated guinea pig hearts. Ivabradine slowed VR during AF from 240 ± 21 bpm to 211 ± 25 bpm (P = .041). The ivabradine-induced increase in A-H interval was inversely correlated with VR (r = -0.85, P = .03, at 130 bpm; r = -0.95, P = .003, at 180 bpm). QT and HV intervals, AF dominant frequency (8.5 ± 0.9 to 8.7 ± 1.1 Hz, P = NS), mean arterial pressure, and left ventricular dP/dt (1672 ± 222 to 1889 ± 229 mm Hg/s, P = NS) during AF were unaffected.
  
  
  CONCLUSIONS
  Ivabradine's rate-dependent increase in A-H interval is highly correlated with VR during AF. As dominant frequency was unaltered, AV node conduction slowing during high nodal activation rates appears to be the main mechanism of ivabradine's VR reduction. If inhibition in the AV node may provide a promising target to slow VR during AF without depression in contractility.
authors.affiliation: Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Verrier
authors.affiliation: Beth Israel Deaconess Medical Center; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bonatti
authors.affiliation: Beth Israel Deaconess Medical Center; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Ana F G
authors.initials: AF
authors.lastname: Silva
authors.affiliation: Beth Israel Deaconess Medical Center; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Julio A P
authors.initials: JA
authors.lastname: Batatinha
authors.affiliation: Beth Israel Deaconess Medical Center; Harvard Medical School, Boston, Massachusetts.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Nearing
authors.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Gongxin
authors.initials: G
authors.lastname: Liu
authors.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.affiliation: Gilead Sciences, Inc., Foster City, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D001283:Atrioventricular Node / Q000187:drug effects* / Q000503:physiopathology; D001552:Benzazepines / Q000493:pharmacokinetics / Q000494:pharmacology*; D006328:Cardiac Catheterization; D002317:Cardiovascular Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004562:Electrocardiography; D005471:Fluoroscopy / Q000379:methods; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D000077550:Ivabradine; D008297:Male; D020551:Pulse Therapy, Drug; D011897:Random Allocation; D012016:Reference Values; D034421:Sus scrofa; D013552:Swine; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D001552:Benzazepines; D002317:Cardiovascular Agents; D000077550:Ivabradine
keywords: Atrial fibrillation; Atrioventricular node; I(f) current; Ivabradine; Ventricular rate