Vagus nerve stimulation exerts cardioprotection against myocardial ischemia/reperfusion injury predominantly through its efferent vagal fibers

Abstract

Vagus nerve stimulation (VNS) has been shown to exert cardioprotection against myocardial ischemia/reperfusion (I/R) injury. However, whether the cardioprotection of VNS is mainly due to direct activation through its ipsilateral efferent fibers (motor) rather than indirect effects mediated by the afferent fibers (sensory) have not been clearly understood. We hypothesized that VNS exerts cardioprotection predominantly through its efferent vagal fibers. Thirty swine (30-35 kg) were randomized into five groups: I/R no VNS (I/R), and left mid-cervical VNS with both vagal trunks intact (LC-VNS), with left vagus nerve transection (LtVNX), with right vagus nerve transection (RtVNX) and with atropine pretreatment (Atropine), respectively. VNS was applied at the onset of ischemia (60 min) and continued until the end of reperfusion (120 min). Cardiac function, infarct size, arrhythmia score, myocardial connexin43 expression, apoptotic markers, oxidative stress markers, inflammatory markers (TNF-α and IL-10) and cardiac mitochondrial function, dynamics and fatty acid oxidation (MFN2, OPA1, DRP1, PGC1α and CPT1) were determined. LC-VNS exerted cardioprotection against myocardial I/R injury via improvement of mitochondrial function and dynamics and shifted cardiac fatty acid metabolism toward beta oxidation. However, LC-VNS and LtVNX, both efferent vagal fibers are intact, produced more profound cardioprotection, particularly infarct size reduction, decreased arrhythmia score, oxidative stress and apoptosis and attenuated mitochondrial dysfunction compared to RtVNX. These beneficial effects of VNS were abolished by atropine. Our findings suggest that selective efferent VNS may potentially be effective in attenuating myocardial I/R injury. Moreover, VNS required the contralateral efferent vagal activities to fully provide its cardioprotection.

An implant for long-term cervical vagus nerve stimulation in mice

“…Experimental testing of VNS as therapy for chronic diseases requires a long-term VN implant and, as of yet, has been mostly limited to neurological and cardiovascular diseases modeled in rats and large animals [11,13,15,[27][28][29][30][31][32][33][34]. Even though the mouse is the species of choice in the study of disease mechanisms and is considered the standard for pre-clinical therapeutic screening [35,36], translational VNS research in mice has been limited to acute delivery of stimulation [37][38][39][40][41][42][43][44][45].…”

Stimulating ideas for heart regeneration: the future of nerve-directed heart therapy

“…Initial reports of the cholinergic anti-inflammatory pathway in the cardiovascular system for clinical use investigated the protective effects of vagus nerve stimulation (VNS) in rats, dogs, rabbits, and pigs in chronic heart failure (Ando et al 2005;Calvillo et al 2011;Hamann et al 2013;Nuntaphum et al 2018;Uemura et al 2010;Vaseghi et al 2017). VNS demonstrated a wide range of effects on the heart following injury, including anti-arrhythmogenic effects following ischemia in rats and rabbits (Ando et al 2005;Brack et al 2011;Wu et al 2017), reduced inflammation and infarct size (Calvillo et al 2011;Wu et al 2017), prevention of remote vascular disfunction (Zhao et al 2013), improved redox status after MI (Shinlapawittayatorn et al 2014;Tsutsumi et al 2008), and has been demonstrated to be tolerable in humans with some efficacy in advanced heart failure states (Klein and Ferrari 2010;Schwartz et al 2008).…”

The effects of acetylcholinesterase inhibitors on the heart in acute myocardial infarction and heart failure: From cells to patient reports

“…76,78,82,132 As regards device therapy, VNS has been shown previously to reduce the infarct size and improve cardiac function in various animal models with cardiac I/R injury. 16,[133][134][135] In a heart transplantation model, Yuan and coworkers reported that donepezil decreased inflammatory cytokines, cardiac injury, fibrosis and apoptotic markers at 24 hours after heart transplantation. In that study, donepezil also improved cardiac function and survival of a cardiac graft by attenuation of tumour necrosis factor-alpha (TNF-α) and cardiac fibrosis through α7nAChR activation 1 month after heart transplantation.…”

“…In contrast, vagal nerve rarely innervates the ventricles and less affects to negative inotropic effects. [15][16][17] Since cervical VNS is invasive and required a surgical procedure to implant this electrical device and could cause adverse events such as neck pain or coughing, these limit its clinical use. 13 Emerging evidence has demonstrated that modulation of vagal activity provided beneficial effects in CVDs.…”

“…Direct activation of vagus nerve by electrical VNS have been shown to exert cardioprotection under various conditions. [15][16][17] Since cervical VNS is invasive and required a surgical procedure to implant this electrical device and could cause adverse events such as neck pain or coughing, these limit its clinical use. 18 Recent studies showed that non-invasive stimulation of the auricular branch of the vagus nerve by low-level tragus stimulation showed beneficial effects in CVDs in both animal 19,20 and clinical models.…”