Chronic heart rate reduction with ivabradine improves systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term increase in FKBP12/12.6 expression.
OBJECTIVE
To investigate the adaptations of left ventricular function and calcium handling to chronic heart rate reduction with ivabradine in the reperfused heart.


RESULTS
Rabbits underwent 20 min coronary artery occlusion followed by 3 weeks of reperfusion. Throughout reperfusion, rabbits received ivabradine (10 mg/kg/day) or vehicle (control). Ivabradine reduced heart rate by about 20% and improved both ejection fraction (+35%) and systolic displacement (+26%) after 3 weeks of treatment. Interestingly, this was associated with a two-fold increase expression of FKBP12/12.6. There was no difference in the expressions of phospholamban, SERCA2a, calsequestrin, ryanodine, phospho-ryanodine, and Na(2+)/Ca(2+) exchanger in the two groups. Infarct scar and vascular density were similar in both groups. Administration of a single intravenous bolus of ivabradine (1 mg/kg) in control rabbits at 3 weeks of reperfusion also significantly improved acutely ejection fraction and systolic displacement.


CONCLUSIONS
Chronic heart rate reduction protects the myocardium against ventricular dysfunction induced by myocardial ischaemia followed by 3 weeks of reperfusion. Beyond pure heart rate reduction, ivabradine improves global and regional systolic function of the reperfused heart through a dual mechanism involving a direct mechanical effect and a long-term adaptation in calcium handling, as supported by the increase in FKBP12/12.6 expression.
Couvreur
Nicolas
N
INSERM U955 Equipe 03, 8, rue du Général Sarrail, Créteil F-94010, France.
Tissier
Renaud
R
Pons
Sandrine
S
Chetboul
Valérie
V
Gouni
Vassiliky
V
Bruneval
Patrick
P
Mandet
Chantal
C
Pouchelon
Jean-Louis
JL
Berdeaux
Alain
A
Ghaleh
Bijan
B
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000378:metabolism; D054059:Coronary Occlusion / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D009203:Myocardial Infarction / Q000503:physiopathology; D015425:Myocardial Reperfusion / Q000379:methods; D011817:Rabbits; D013318:Stroke Volume / Q000187:drug effects; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D002135:Calcium-Binding Proteins; D000077550:Ivabradine; D022061:Tacrolimus Binding Protein 1A