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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) 1?M of ivabradine perfusion n=10; (3) 1?M of ivabradine+5Hz atrial pacing throughout ischaemia-reperfusion n=5; (4) 1?M of ivabradine+5Hz pacing only at reperfusion; (5) 100?M 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.

SUBMITTER: Ng FS

PROVIDER: S-EPMC3654199 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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

Ng Fu Siong FS Shadi Iqbal T IT Peters Nicholas S NS Lyon Alexander R AR

Journal of molecular and cellular cardiology 20130209

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) Co ...[more]

PMID: 23402927

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Project description:Cardiac sympathetic tone overdrive is a key mechanism of arrhythmia. Cardiac sympathetic nerves denervation, such as LSG ablation or renal sympathetic denervation, suppressed both the prevalence of VAs and the incidence of SCD. Accumulating evidence demonstrates the ligament of Marshall (LOM) is a key component of the sympathetic conduit between the left stellate ganglion (LSG) and the ventricles. The present study aimed to investigate the roles of the distal segment of LOM (LOMLSPV) denervation in ischemia and reperfusion (IR)-induced VAs, and compared that LSG denervation. Thirty-three canines were randomly divided into group 1 (IR group, n = 11), group 2 (LOMLSPV Denervation + IR, n = 9), and group 3 (LSG Denervation + IR, n = 13). Hematoxylin-Eosin (HE) and Immunohistochemistry staining revealed that LOMLSPV contained bundles of sympathetic but not parasympathetic nerves. IR increased the cardiac sympathetic tone [serum concentrations of noradrenaline (NE) and epinephrine (E)] and induced the prevalence of VAs [ventricular premature beat (VPB), salvo of VPB, ventricular tachycardia (VT), VT duration (VTD) and ventricular fibrillation (VF)]. Both LOMLSPV denervation and LSG denervation could reduce the cardiac sympathetic tone in Baseline (BS) [heart rate variability (HRV)]. Compared with group 1, LOMLSPV denervation and LSG denervation similarly reduced sympathetic tone [NE (1.39±0.068 ng/ml in group 2, 1.29±0.081 ng/ml in group 3 vs 2.32±0.17 ng/ml in group 1, P<0.05) and E (114.64±9.22 pg/ml in group 2, 112.60±9.69 pg/ml in group 3 vs 166.18±15.78 pg/ml in group 1, P<0.05),] and VAs [VT (0±3.00 in group 2, 0±1.75 in group 3 vs 8.00±11.00 in group 1, P<0.05) and VTD (0 ± 4 s in group 2, 0±0.88s in group 3 vs 10.0 ± 22.00s in group 1, P<0.05)] after 2h reperfusion. These findings indicated LOMLSPV denervation reduced the prevalence of VT by suppressing SNS activity. These effects are comparable to those of LSG denervation. In myocardial IR, the anti-arrhythmic effects of LOMLSPV Denervation may be related to the inhibition of the expression of NE and E.

Project description:ObjectiveTo explore the cardiac electrophysiological characteristics of cardiac hypertrophy and its influence on the occurrence of ventricular tachyarrhythmias.MethodsAdult C57BL6 mice were randomly divided into a surgery group and a control group. Thoracic aortic constriction was performed on mice in the surgery group, and cardiac anatomical and ultrasonic evaluations were performed to confirm the success of the cardiac hypertrophy model 4 weeks after the operation. Using the Langendorff method of isolated heart perfusion, monophasic action potentials (MAPs) and the effective refractory period (ERP) at different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles) were measured, and the induction rate of ventricular tachyarrhythmias was observed under programmed electrical stimulus (PES) and burst stimulus. Whole-cell patch-clamp was used to obtain the I-V characteristics of voltage-gated potassium channels in cardiomyocytes of different parts of the heart (including the epi- and endo-myocardium of the left and right ventricles) as well as the channels' properties of steady-state inactivation and recovery from inactivation.ResultsThe ratio of heart weight to body weight and the ratio of left ventricular weight to body weight in the surgery group were significantly higher than those in the control group (P < 0.05). Ultrasonic evaluation revealed that both interventricular septal diameter (IVSD) and left ventricle posterior wall diameter (LVPWD) in the surgery group were significantly larger than those in the control group (P < 0.05). Under PES and burst stimuli, the induction rates of arrhythmias in the surgery group significantly increased, reaching 41.2% and 23.5%, respectively. Both the QT interval and action potential duration (APD) in the surgery group were significantly longer than in the control group (P<0.01), and the changes showed obvious spatial heterogeneity. Whole-cell patch-clamp recordings demonstrated that the surgery group had significantly lower potassium current densities (IPeak, Ito, IKur, Iss, and IK1) at different parts of the heart than the control group (P < 0.01), and there were significant differences in the half-inactivation voltage (V1/2) and the inactivation-recovery time constant (τ) of Ito and IKur at different parts of the heart (P < 0.01) between the surgery group and the control group. In addition, the surgery group had significantly lower densities of IPeak, Ito, and IKur in cells of the endo-myocardium (P < 0.05), and the changes showed obvious spatial heterogeneity.ConclusionChanges in the current density and function of potassium channels contributed to irregular repolarization in cardiac hypertrophy, and the spatially heterogeneous changes of the channels may increase the occurrence of ventricular arrhythmias that accompany cardiac hypertrophy.

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Dataset Information

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

Publications

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

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