Hype or hope: Vagus nerve stimulation against acute myocardial ischemia-reperfusion injury

Abstract

Acute myocardial infarction (MI) is a major cause of death worldwide. Although timely and successful reperfusion could reduce myocardial ischemia injury, limit infarct size, and improve ventricular dysfunction and reduce acute mortality, restoring blood flow might also lead to unwanted myocardial ischemic-reperfusion (I/R) injury. Pre-clinical studies have demonstrated that multiple approaches are capable of attenuating the myocardial I/R injury. However, there is still no effective therapy for preventing myocardial I/R injury for the clinical setting. It is known that myocardial I/R injury could induce cardiac autonomic imbalance with over-activated sympathetic tone and reduced vagal activity, in turn, contributing to pathogenesis of myocardial I/R injury. Cumulative evidence shows that the enhancement of vagal activity, so called vagus nerve stimulation (VNS), is able to reduce injury and promote recovery of injured myocardium. Therefore, VNS might be a potentially novel strategy choice for preventing/attenuating myocardial I/R injury. In this review, we describe the protective role of VNS in myocardial I/R injury and related potential mechanisms. Then, we discuss the challenge and the opportunity of VNS in the treatment of acute myocardial I/R injury.

Introduction

Acute myocardial infarction (AMI) is a major cause of death and disability worldwide [1]. In patients with AMI, timely and successful reperfusion of ischemic myocardium with the thrombolytic therapy or primary percutaneous coronary intervention (PPCI) as well as surgical coronary artery bypass graft is the most effective treatment option for limiting the infarct size, improving cardiac function and clinical outcomes [2]. Unfortunately, the process of myocardial reperfusion could also induce unwanted cardiac injury, so-called myocardial ischemia-reperfusion (I/R) injury. Occurrence of myocardial I/R injury might offset part of the beneficial effects of restoring blood flow [3].

In 1960, Jennings et al. first presented the histological features and pathological characteristics of myocardial I/R injury in the canine model [4]. The site of myocardial I/R injury was characterized by myocyte swelling, contracture of myofibrils, disruption of the sarcolemma and the appearance of intra-mitochondrial calcium phosphate particles. Several critical factors might contribute to mediate the detrimental effects of myocardial reperfusion injury including mitochondrial dysfunction, oxidative stress, intracellular Ca²⁺ overload, inflammation and apoptosis [5], [6], [7], [8]. Briefly, upon myocardial perfusion, restoration of a physiologic pH and Ca²⁺ overload could lead to the disruption of mitochondrial membrane potential and ATP depletion. The opening of the mitochondrial permeability transition pore (mPTP) could result in the generation of reactive oxygen species (ROS). ROS could directly cause cellular DNA damage in addition to inducing apoptosis. ROS accumulation is also capable of stimulating the secretion of pro-inflammatory cytokines and chemokines in the course of I/R injury [9]. Finally, the chemoattractants might contribute to the neutrophils accumulation [10]. Therefore, targets on these detrimental mediators serve as the therapeutic focus in an effort to protect the heart against acute I/R injury [11]. However, there is still no effective option for preventing myocardial I/R injury in the complex clinical settings [12].

Previous clinical studies have shown that cardiac autonomic imbalances, in terms of reduced vagal activity and over-activated sympathetic activity, are involved in the pathogenesis of myocardial I/R injury [13]. Moreover, cumulative experimental and clinical studies demonstrate that vagus nerve stimulation (VNS) has a positive effect on reducing injury and promoting recovery of myocardial function [14,15]. Therefore, the enhancement of vagal activity may be a potential strategy for the treatment of myocardial I/R injury [16,17]. In this review, we described the potential usefulness of an emerging therapeutic strategy, VNS, on the protection of the heart against myocardial I/R injury [Fig. 1]. We further summarized the potential mechanisms underlying the cardioprotective effects and potential clinical prospect of VNS.