071 Procoralan, an If current inhibitor, improves systolic function and enhances FKBP12 expression after myocardial infarction and 3 weeks of reperfusion in conscious rabbits

Abstract

Purpose It remains unknown whether heart rate reduction by the I f current inhibitor ivabradine (IVA) improves left ventricular (LV) function of the infarcted and reperfused myocardium. Accordingly, our goal was to investigate the effect of IVA on global and regional LV function following myocardial infarction and long term reperfusion in rabbits. Methods Myocardial systolic function was assessed before a 20 min coronary artery occlusion and during the subsequent 3 weeks of reperfusion by echocardiography and tissue tracking imaging. Throughout reperfusion, rabbits received either IVA (10 mg/kg/day, n=9) or vehicle (Control, n=8) using implanted osmotic pumps. At 3 weeks reperfusion, LV remodeling was investigated by histology and expression of several proteins (SERCA2a, RyR2-P, phospholamban, FKBP12) involved in calcium handling. Results After 3 weeks, IVA induced a significant decrease in heart rate by ≈20% as compared to Control (214±9 vs 266±14 bpm, respectively). In Control rabbits, ejection fraction and regional systolic displacement were significantly decreased as compared to baseline values (43±4% vs 63±2% and 1.4±0.2 vs 2.8±0.2 mm, respectively) and were associated with LV enlargement and interstitial fibrosis within the reperfused zone (risk zone: 30±2% of LV and infarct size: 8% of LV). Chronic administration of IVA prevented the reduction in ejection fraction (58±3% vs 66±3% in baseline) and the decrease in regional systolic displacement (1.9±0.3 vs 2.6±0.3 mm). This improvement was not related to a difference in infarct size and interstitial fibrosis. Interestingly, this was associated with a significant increase in FKBP12 expression in the reperfused area without any changes in SERCA2a, RyR2-P and phospholamban. Conclusion Heart rate reduction with IVA significantly improves systolic function after 3 weeks of reperfusion. This beneficial effect might result from an adaptation of calcium handling as suggested by the increase in FKBP12 expression.