Vagal nerve stimulation protects the heart against myocardial ischemia-reperfusion injury

Despite significant improvements in medical therapy, acute myocardial infarction (MI) is still the major contributor to mortality and morbidity worldwide. (1) Although timely reperfusion of the occluded coronary artery is necessary for salvage of cardiac cells and function, reperfusion of the jeopardized myocardium results in a cascade of harmful events, referred to as reperfusion injury. (2) In addition, reperfusion-injury itself contributes to the increase of myocardial infarction, and consequently plays a major role in the progression of adverse left ventricular remodeling as well as chronic heart failure. (3) Of importance, the treatment of heart failure patients represents a huge socioeconomic burden on individuals and health care systems. Therefore, there is need to identify novel clinically feasible, cost-effective intervention(s) and targets which reduce infarct size as well as the progression of adverse left ventricular remodeling. Recent studies demonstrated that reduced parasympathetic activity and counterbalancing sympathetic hyperactivity in myocardial ischemia-reperfusion (IR) is associated with cell necrosis as well as contractile dysfunction. (4) In addition, there is considerable autonomic disturbance in heart failure; the excess of sympathetic activity and the withdrawal of vagal activity clearly contribute to the progression of ventricular remodeling as well as worse outcome of heart failure. (4) Therefore, therapeutic approaches acting on either reduced sympathetic hyperactivity or enhanced parasympathetic activity might represent novel strategies to reduce myocardial IR injury. Recent pioneering studies demonstrating a number of device-based neuromodulation interventions targeting specific aspects of autonomic imbalance (e.g. renal denervation, cardiac contractility modulation, spinal cord stimulation, and carotid sinus nerve and vagal nerve stimulation) are being actively investigated in experimental and clinical studies. (5) Vagal nerve stimulation (VNS) is a promising novel therapeutic approach to enhance cardiac parasympathetic activity. The safety and efficacy of VNS for the treatment of epilepsy and depression are well established. (6). Preclinical studies have shown the benefit of VNS to improve LV function and reduce infarct size and mortality in a variety of animal models of myocardial IR and heart failure. (7, 8) These studies have demonstrated the pleiotropic effects of this therapy, involving heart rate lowering, reduction of inflammation and apoptosis as well as inhibition of sympathetic hyperactivity. There is evidence that stimulation of the vagal nerve releases acetylcholine (Ach) which acts on both muscarinic and nicotinic receptors, initiating cellular and subcellular signaling pathways associated with cardioprotection, such as activation of the AktGSK-3β protection pathway. (7) In addition, similarly to VNS, ischemic preconditioning, which is one of the most powerful cardioprotective phenomena, whereby brief cycles of ischemia to a coronary bed renders it less susceptible to subsequent IR-injury, releases Ach as well as ultimately reducing infarct size. (9) Emerging evidence also points towards an immunomodulatory function of the vagal nerve in the regulation of cytokine production, termed the ‘cholinergic anti-inflammatory pathway. (10) Recently, it was demonstrated that electrical VNS decreased serum and cardiac TNF-α in wild type mice, but not in alpha-7 nicotinic acetylcholine receptor (α7 nAChR) deficient mice, emphasizing that the cholinergic anti-inflammatory pathway is strictly dependent on α7 nACh. (11) Of additional interest is the finding that electrical VNS protects from myocardial and remote vascular injury following myocardial IR via a mechanism that involves activation of the α7 nAChR. (12) Most of the studies above mentioned have investigated the potential effect of VNS, applied throughout the entire IR period to achieve maximal cardiovascular protection. There are controversial data on the efficacy of VNS in terms of 1) duration of the stimulation and 2) on the identification of the effects of ischemia and reperfusion regarding infarct size limitation. A recent study demonstrated that the infarct size limiting effect of VNS was abolished when VNS was started at the