Elsevier

Heart Rhythm

Volume 10, Issue 11, November 2013, Pages 1700-1707
Heart Rhythm

Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury

https://doi.org/10.1016/j.hrthm.2013.08.009Get rights and content

Background

Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported.

Objective

To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury.

Methods

Thirty-two isoflurane-anesthetized swine (25–30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment.

Results

VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine.

Conclusions

During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion.

Introduction

Acute myocardial infarction is one of the leading causes of death worldwide.1 Early and successful myocardial reperfusion with either thrombolytic therapy or primary percutaneous coronary intervention is the most effective modality for reducing the infarct size and improving clinical outcomes.2 However, the process of abruptly restoring blood flow to the ischemic tissue during primary percutaneous coronary intervention may result in a devastating cascade of biological processes, leading to the production of several toxic compounds.3, 4 This phenomenon, so-called myocardial ischemia-reperfusion injury, can paradoxically reduce the beneficial effects of myocardial reperfusion.3 Therefore, myocardial ischemia-reperfusion injury is considered a major concern in patients with acute myocardial infarction or those undergoing coronary artery bypass grafting and transplantation.5, 6

Over the past decade, vagus nerve stimulation (VNS) has been shown to exert cardioprotection in both chronic heart failure and ischemic heart diseases.7, 8, 9, 10, 11, 12 In ischemic hearts, the effects of VNS have been shown to improve cardiac function, limit dispersion of repolarization, prevent reperfusion injury, attenuate cardiac remodeling, improve defibrillation efficacy, and decrease the infarct size.13, 14 Despite these well-documented beneficial effects of VNS, inconsistent findings have been reported. Currently, more than 100,000 patients worldwide have already been implanted with the left cervical VNS system for suppression of epilepsy and depression.15 Left cervical VNS is preferred over the right because of the greater number of cardiac efferent fibers from the right vagus nerve,16 whose stimulation may elicit more frequent undesirable effects. Furthermore, the effect of low-amplitude VNS on cardiac mitochondria has been rarely investigated. Since cardiac mitochondria have been indicated as a major determinant of both cardiac cell survival and arrhythmias, it is important that the effect of left cervical VNS on cardiac mitochondria during ischemia-reperfusion be explored. Therefore, in the present study, we sought to determine whether left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury in a swine model.

Section snippets

Animal preparation

All experiments were approved by the Institutional Animal Care and Use Committees of the Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Thirty-two domestic pigs (25–30 kg) were anesthetized by intramuscular injection of a combination of 4.4 mg/kg of Zoletil (Vibbac Laboratories, Carros, France) and 2.2 mg/kg of xylazine (Laboratorios Calier, SA, Barcelona, Spain). After endotracheal intubation, anesthesia was maintained by 1.5%–3.0% isoflurane (Abbott Laboratories Ltd,

Effect of VNS on ECG parameters and left ventricular function during the ischemia-reperfusion period

The electrophysiological effects of VNS were examined in 32 pigs in which HR, PR interval, and left ventricular (LV) function were measured continuously during the ischemia-reperfusion period. In the control group, the HR during the ischemic period increased significantly when compared with the baseline (Figure 2A). Interestingly, HRs at baseline and during ischemia and reperfusion periods were not different in VNS-treated groups (n = 8 per group), either in the presence or absence of

Discussion

To our knowledge, this is the first demonstration that I-VNS provides more robust efficacy than C-VNS with respect to the prevention of cardiac mitochondrial dysfunction during the ischemia-reperfusion period. Moreover, our finding confirms previous reports,9, 14, 23, 24 which also indicated that VNS exerted cardioprotection and improved LV function during ischemia-reperfusion period. Our findings on the better efficacy of I-VNS than C-VNS suggest that intermittent VNS may prevent adaptation of

Study limitations

There are several limitations in the present study. Our study was conducted in anesthetized healthy animals, whereas most victims of cardiac arrest have significant coronary lesions. Furthermore, VNS treatment was conducted immediately after LAD artery occlusion. The time schedule of treatment in this experimental study may differ from the clinical condition.

Conclusions

We have thus provided compelling evidence that during acute ischemia-reperfusion period, both C-VNS and I-VNS provide significant cardioprotection and improve LV function in a large animal model of ischemia-reperfusion injury. However, I-VNS provides more robust efficacy than C-VNS with respect to infarct size reduction and reperfusion arrhythmia prevention. A potential mechanism of such cardioprotection of VNS is associated with its prevention of cardiac mitochondrial dysfunction during

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    This work was supported in part by the Thailand Research Fund and Commission on Higher Education TRF-CHE Research Grant for New Scholar MRG5580125 (to Dr Shinlapawittayatorn), BRG5480003 (to Dr Chattipakorn), and RTA5580006 (to Dr Chattipakorn) and by Cyberonics.

    Dr Chattipakorn has served as a member of scientific advisory board for Cyberonics. Dr. KenKnight is an employee of Cyberonics.

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