title: β-Blockers and ivabradine differentially affect cardiopulmonary function and left ventricular filling index.
abstract: OBJECTIVE
  Patients with left ventricular (LV) diastolic dysfunction are characterized by exertional dyspnoea. Heart rate (HR) reduction by β-blockers can improve exercise tolerance by prolonging LV filling, but their negative inotropic and lusitropic properties can be detrimental in this disease. We tested the effects of administering ivabradine, a HR-lowering drug without impact on cardiac kinetics that may favorably affect diastolic function.
  
  
  METHODS
  Twenty-four patients with coronary artery disease (CAD) and normal LV ejection fraction on chronic β-blocker therapy were included. NT-proBNP serum levels were determined prior to and after cardiopulmonary exercise. β-Blockers were then replaced by ivabradine and patients were re-tested after 6 weeks. Patients were initially classified as having a low (E/e' ≤ 8; n = 11) or high (E/e' > 8; n = 13) LV filling index.
  
  
  RESULTS
  E/e' significantly decreased during ivabradine therapy in patients with high E/e' (10.7 ± 2.9 vs. 8.9 ± 1.7; p < 0.01), whereas no difference occurred in patients with low E/e' (6.4 ± 0.7 vs. 6.5 ± 1.1; p = ns). With ivabradine, patients with high E/e' had an increased oxygen uptake at the anaerobic threshold (from 10.8 ± 1.4 to 11.8 ± 1.9 ml/min/kg; p < 0.05) and a steeper slope of the initial oxygen pulse curve (from 293 ± 109 to 359 ± 117 µl/beat/kg/W; p < 0.05). Moreover, patients with high E/e' had lower NT-proBNP serum levels at rest (169 ± 207 vs. 126 ± 146 pg/ml; p < 0.05) and after exercise (190 ± 256 vs. 136 ± 162 pg/ml; p < 0.05) during ivabradine therapy.
  
  
  CONCLUSIONS
  In patients with CAD and elevated E/e', switching therapy from β-blockers to ivabradine may cause a reduction in LV filling pressures and an improved stroke volume response to exercise.
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany. fischer-rasokat@gmx.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Fischer-Rasokat
authors.affiliation: Department of Cardiology, University Hospital of the Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Honold
authors.affiliation: Department of Cardiology, University Hospital of the Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Lochmann
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Wolter
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Liebetrau
authors.affiliation: Department of Cardiology, University Hospital of the Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Fichtlscherer
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany.
authors.forename: Helge
authors.initials: H
authors.lastname: Möllmann
authors.affiliation: Department of Cardiology, University Hospital of the Goethe University, Theodor-Stern-Kai 7, 60596, Frankfurt/Main, Germany.
authors.forename: Ioakim
authors.initials: I
authors.lastname: Spyridopoulos
authors.affiliation: Department of Cardiology, Kerckhoff Heart Center, Benekestr. 2-8, 61231, Bad Nauheim, Germany.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Hamm
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001552:Benzazepines / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D057915:Drug Substitution; D004417:Dyspnea / Q000503:physiopathology; D005080:Exercise Test; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D000077550:Ivabradine; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010865:Pilot Projects; D013318:Stroke Volume / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D015415:Biomarkers; D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000077550:Ivabradine
keywords: Diastolic dysfunction; Exercise testing; Ivabradine; Left ventricular filling pressure; NT-proBNP