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

Eur Heart J. 2010 Jun;31(12):1529-37. doi: 10.1093/eurheartj/ehp554. Epub 2009 Dec 21.

Abstract

Aims: To investigate the adaptations of left ventricular function and calcium handling to chronic heart rate reduction with ivabradine in the reperfused heart.

Methods and 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Benzazepines / pharmacology*
  • Blotting, Western
  • Calcium-Binding Proteins / metabolism
  • Coronary Occlusion / physiopathology
  • Heart Rate / drug effects*
  • Ivabradine
  • Myocardial Infarction / physiopathology
  • Myocardial Reperfusion / methods
  • Rabbits
  • Stroke Volume / drug effects
  • Tacrolimus Binding Protein 1A / metabolism*
  • Ventricular Dysfunction, Left / drug therapy
  • Ventricular Dysfunction, Left / physiopathology

Substances

  • Anti-Arrhythmia Agents
  • Benzazepines
  • Calcium-Binding Proteins
  • Ivabradine
  • Tacrolimus Binding Protein 1A