Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias

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• 作者：Fu Siong Ng^a ; Iqbal T. Shadi^a ; Nicholas S. Peters^a ; ^{n.peters@imperial.ac.uk} ; Alexander R. Lyon^a ; ^b
• 关键词：Ischaemia&ndash ; reperfusion ; Reperfusion arrhythmias ; Ventricular arrhythmias ; Ivabradine ; Heart rate reduction
• 刊名：Journal of Molecular and Cellular Cardiology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：59
• 期：Complete
• 页码：67-75
• 全文大小：1360 K

文摘

Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective I_f current inhibitor, to assess the effects of heart rate reduction (HRR) during ischaemia-reperfusion on reperfusion ventricular arrhythmias and assessed potential anti-arrhythmic mechanisms by optical mapping. Five groups of rat hearts were subjected to regional ischaemia by left anterior descending artery occlusion for 8 min followed by 10 min of reperfusion: (1) Control n = 10; (2) 1 ¦ÌM of ivabradine perfusion n = 10; (3) 1 ¦ÌM of ivabradine + 5 Hz atrial pacing throughout ischaemia-reperfusion n = 5; (4) 1 ¦ÌM of ivabradine + 5 Hz pacing only at reperfusion; (5) 100 ¦ÌM of ivabradine was used as a 1 ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n = 5; 5 Hz pacing n = 5) were subjected to global ischaemia whilst transmembrane voltage transients were recorded. Epicardial activation was mapped, and the rate of development of ischaemia-induced electrophysiological changes was assessed. HRR observed in the ivabradine group during both ischaemia (195 ¡À 11 bpm vs. control 272 ¡À 14 bpm, p < 0.05) and at reperfusion (168 ¡À 13 bpm vs. 276 ¡À 14 bpm, p < 0.05) was associated with reduced reperfusion ventricular fibrillation (VF) incidence (20 % vs. 90 % , p < 0.05). Pacing throughout ischaemia-reperfusion abolished the protective effects of ivabradine (100 % VF), whereas pacing at reperfusion only partially attenuated this effect (40 % VF). Ivabradine, given as a bolus at reperfusion, did not significantly affect VF incidence (80 % VF). Optical mapping experiments showed a delay to ischaemia-induced conduction slowing (time to 50 % conduction slowing: 10.2 ¡À 1.3 min vs. 5.1 ¡À 0.7 min, p < 0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7 ¡À 4.3 min vs. 14.5 ¡À 0.6 min, p < 0.05). Ivabradine administered throughout ischaemia and reperfusion reduced reperfusion VF incidence through HRR. Heart rate during ischaemia is a major determinant of reperfusion arrhythmias. Heart rate at reperfusion alone was not a determinant of reperfusion VF, as neither a bolus of ivabradine nor pacing immediately prior to reperfusion significantly altered reperfusion VF incidence. This anti-arrhythmic effect of heart rate reduction during ischaemia may reflect slower development of ischaemia-induced electrophysiological changes.