Vagal Nerve Stimulation for Cardiovascular Diseases: From Hype to Hope

The autonomic nervous system (ANS) regulates every aspect of cardiac physiology in a very delicate and precise manner, and ANS dysregulation plays a central role in the pathogenesis of cardiovascular diseases, including hypertension, heart failure and arrhythmias 1 .Pharmacological therapies targeting the ANS, such as beta blockers and alpha agonists, have long been used in cardiovascular therapeutics.More recently, autonomic modulation, which targets the neural tissue to induce neural remodeling, has emerged as a promising therapeutic modality for cardiovascular diseases 1 .There are several targets for autonomic modulation, including spinal cord stimulation, baroreceptor activation, renal denervation and vagus nerve stimulation (VNS) 2 .VNS includes implantation of a cuff around the cervical vagus nerve through a neck incision similar to carotid endarterectomy.The cuff is then connected to a pulse generator implanted in the chest, similar to a pacemaker.Moreover, transcutaneous VNS (tVNS), by stimulating the auricular branch of the vagus nerve at the tragus of the external ear, is an emerging noninvasive alternative to VNS 2, 3 .Unlike most pharmacological therapies, which target a specific receptor or molecule, the mechanism of autonomic modulation is pleiotropic.Specifically, VNS has been shown to exert antiadrenergic, anti-fibrotic and anti-inflammatory effects, among others 1, 4 .To understand its potential in cardiovascular therapeutics, the salient characteristics of VNS will be expounded.First, VNS is characterized by "memory", whereby the effect markedly outlasts the duration of stimulation 1 .This notion is supported by several preclinical and clinical studies, showing that brief periods of stimulation result in long-lasting effects 3,4 .This phenomenon may be, in part, due to synaptic plasticity, which refers to the ability to modulate the strength of the synapses within the cardiac autonomic ganglia and other neural tissues 1 .Second, the benefits of VNS may not be solely due to direct effects on the heart but may involve neuroimmune communications along the brain-heart-splenic axis 5 .Specifically, the vagus nerve modulates immune responses via the cholinergic antiinflammatory pathway, which involves neural signals traveling in the splenic nerve, with subsequent activation of α7 nicotinic acetylcholine receptors on macrophages to suppress cytokine release.Consequently, VNS has been shown to exert prominent anti-inflammatory effects in multiple experimental models, as well as in clinical trials in humans 3,5 .