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

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 Na2+/Ca2+ 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.