title: Selective heart rate reduction with ivabradine slows ischaemia-induced electrophysiological changes and reduces ischaemia-reperfusion-induced ventricular arrhythmias.
abstract: Heart rates during ischaemia and reperfusion are possible determinants of reperfusion arrhythmias. We used ivabradine, a selective If 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 8min followed by 10min of reperfusion: (1) Control n=10; (2) 1μM of ivabradine perfusion n=10; (3) 1μM of ivabradine+5Hz atrial pacing throughout ischaemia-reperfusion n=5; (4) 1μM of ivabradine+5Hz pacing only at reperfusion; (5) 100μM of ivabradine was used as a 1ml bolus upon reperfusion. For optical mapping, 10 hearts (ivabradine n=5; 5Hz 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±11bpm vs. control 272±14bpm, p<0.05) and at reperfusion (168±13bpm vs. 276±14bpm, 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±1.3min vs. 5.1±0.7min, p<0.05) and to loss of electrical excitability in ivabradine-perfused hearts (27.7±4.3min vs. 14.5±0.6min, 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.
authors: National Heart & Lung Institute, Imperial College London, UK.
authors: Fu Siong
authors: FS
authors: Ng
authors: Iqbal T
authors: IT
authors: Shadi
authors: Nicholas S
authors: NS
authors: Peters
authors: Alexander R
authors: AR
authors: Lyon
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001552:Benzazepines / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects*; D000077550:Ivabradine; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014693:Ventricular Fibrillation / Q000188:drug therapy*
chemical_list: D000889:Anti-Arrhythmia Agents; D001552:Benzazepines; D000077550:Ivabradine
references: Cardiovasc Res. 1988 Jul;22(7):447-55
references: 3252968
references: Am J Physiol. 1989 Jan;256(1 Pt 2):H21-31
references: 2912184
references: Circ Res. 1997 Jan;80(1):124-38
references: 8978331
references: J Electrocardiol. 2007 Nov-Dec;40(6 Suppl):S37-41
references: 17993326
references: J Cardiovasc Pharmacol. 1987 Nov;10(5):489-97
references: 2447396
references: Circ Res. 2001 Oct 26;89(9):741-3
references: 11679400
references: Heart Rhythm. 2007 May;4(5):619-26
references: 17467631
references: Cardiovasc Res. 1996 Dec;32(6):1056-63
references: 9035900
references: J Mol Cell Cardiol. 1986 Dec;18(12):1255-66
references: 3820317
references: Circulation. 2012 Aug 7;126(6):697-706
references: 22732314
references: Cardiovasc Res. 1998 Mar;37(3):646-55
references: 9659448
references: Lancet. 2008 Sep 6;372(9641):807-16
references: 18757088
references: Circulation. 1981 Feb;63(2):333-40
references: 7449056
references: Circulation. 2003 Feb 18;107(6):817-23
references: 12591750
references: J Cardiovasc Pharmacol. 2008 Dec;52(6):548-54
references: 19034029
references: Eur Heart J. 2008 Sep;29(18):2265-75
references: 18621770
references: Am J Pathol. 1972 Jun;67(3):441-52
references: 5033258
references: Lancet. 2010 Sep 11;376(9744):875-85
references: 20801500
references: Am J Physiol Heart Circ Physiol. 2012 Oct 1;303(7):H753-65
references: 22821993
references: J Am Coll Cardiol. 2004 May 19;43(10):1765-72
references: 15145097
references: Cardiovasc Res. 2009 Oct 1;84(1):72-82
references: 19477966
references: Circ Res. 1987 Sep;61(3):429-35
references: 3621502
references: J Mol Cell Cardiol. 1990 Aug;22(8):843-58
references: 2231748
references: Am Heart J. 1983 Feb;105(2):323-5
references: 6823815
references: Resuscitation. 2011 Aug;82(8):1092-9
references: 21561702
references: Lancet. 2008 Sep 6;372(9641):817-21
references: 18757091
references: N Engl J Med. 2007 Sep 13;357(11):1121-35
references: 17855673
references: Circulation. 1983 Aug;68(2 Pt 2):I16-24
references: 6305533
references: J Clin Invest. 2005 Dec;115(12):3527-35
references: 16284648