Vagus Nerve Stimulation in Early Stage of Acute Myocardial Infarction Prevent Ventricular Arrhythmias and Cardiac Remodeling

Abstract

Aims: To evaluate whether low level left vagus nerve stimulation (LLVNS) in early stage of myocardial infarction (MI) could effectively prevent ventricular arrhythmias (VAs) and protect cardiac function, and explore the underlying mechanisms.Methods and Results: After undergoing implantable cardioverter defibrillators (ICD) and left cervical vagal stimulators implantation and MI creation, 16 dogs were randomly divided into three groups: the MI (n = 6), MI+LLVNS (n = 5), and sham operation (n = 5) groups. LLVNS was performed for 3 weeks. VAs, the left ventricular function, the density of the nerve fibers in the infarction area and gene expression profiles were analyzed. Compared with the MI group, dogs in the MI+LLVNS group had a lower VAs incidence (p < 0.05) and better left ventricular function. LLVNS significantly inhibited excessive sympathetic nerve sprouting with the evidences of decreased density of TH, GAP43 and NF positive nerves (p < 0.05). The gene expression profiling found a total of 206 genes differentially expressed between MI+LLVNS and MI dogs, mainly involved in cardiac tissue remodeling, cardiac neural remodeling, immune response and apoptosis. These genes, including 55 up-regulated genes and 151 down-regulated genes, showed more protective expressions under LLVNS.Conclusions: This study suggests that LLVNS was delivered without altering heart rate, contributing to reduced incidences of VAs and improved left ventricular function. The potential mechanisms included suppressing cardiac neuronal sprouting, inhibiting excessive sympathetic nerve sprouting and subduing pro-inflammatory responses by regulating gene expressions from a canine experimental study.

Threshold adjusted vagus nerve stimulation after asphyxial cardiac arrest results in neuroprotection and improved survival

“…Recently, in dogs, mild left VNS without changes in HR has been shown to reduce ventricular arrhythmias and improved left ventricular function. This may be attributed to multiple potential mechanisms including reduced cardiac neuronal sprouting, inhibition of excessive sympathetic nerve sprouting, and reduced pro-inflammatory responses (Zhao et al, 2021 ). The decrease we observed in creatinine levels post-CA with tVNS are in agreement with a prior study which showed that VNS protects against kidney injury induced by ischemia-reperfusion injury through activation of the α7nAChR+ and decreasing pro-inflammatory markers (Inoue et al, 2016 ).…”

Closed-Loop Vagus Nerve Stimulation for the Treatment of Cardiovascular Diseases: State of the Art and Future Directions

“…Vagus nerve stimulation was also shown to decrease infarct size and to halt post-myocardial infarction phenomena such as the remodeling of both the myocytes and the intrinsic cardiac neuronal system. These cardioprotective mechanisms include anti-inflammatory effects, prevention of Connexin 40 and Connexin 43 loss, antioxidative effects, and antiapoptotic effects such as decrease in cytochrome c release and in the proapoptotic Bcl-2-associated X protein levels ( 28 , 89 , 103 – 106 ). When applied during myocardial reperfusion, VNS was shown to improve ventricular function and reduce arrhythmic episodes via antagonization of the cardiac sympathetic outflow, reduction of reactive oxygen species and of ventricular excitability ( 28 , 103 – 106 ).…”

“…These cardioprotective mechanisms include anti-inflammatory effects, prevention of Connexin 40 and Connexin 43 loss, antioxidative effects, and antiapoptotic effects such as decrease in cytochrome c release and in the proapoptotic Bcl-2-associated X protein levels ( 28 , 89 , 103 – 106 ). When applied during myocardial reperfusion, VNS was shown to improve ventricular function and reduce arrhythmic episodes via antagonization of the cardiac sympathetic outflow, reduction of reactive oxygen species and of ventricular excitability ( 28 , 103 – 106 ). VNS improves left ventricular ejection fraction post-myocardial infarction restoring subcellular levels of calcium-binding proteins (such as SERCA2a, NCX1, and PLB) and can reestablish baroreceptor reflex to the pre-infarction baseline ( 28 ).…”

“…Vagus nerve stimulation can slow the progression of myocardial remodeling and atrial and ventricular dysfunction in animal models of chronic HF with reduced ejection fraction ( 28 ). VNS beneficial effects in HF can be attributed to improvements in left ventricular mechanics, attenuation of the sympathetic drive, down-regulation of the renin-angiotensin-aldosterone system, reduction of proinflammatory cytokines, normalization of the nitric oxide pathway, increase in myocardial expression of gap junction proteins and capillary density and tempering of myocardial interstitial fibrosis ( 1 , 28 , 104 , 106 – 113 ). Optogenetic stimulation of cardioinhibitory neurons in the dorsal motor nucleus of the vagus can reduce myocardial expression of G-protein-coupled receptor kinase 2 (GRK2) and b-arrestin 2, which both contribute to the progressive decline of myocardial contractile function in HF ( 104 ).…”

The plasticity of cardiac sympathetic nerves and its clinical implication in cardiovascular disease

“…Moreover, other preclinical VNS studies have demonstrated that VNS reduces ventricular arrhythmias and increases ventricular electrical stability in dog and pig models of myocardial infarction (Vaseghi et al, 2017;Nasi-Er et al, 2019). Interestingly, the potential underlying mechanisms identified included suppressing cardiac neuronal sprouting, inhibiting excessive sympathetic nerve sprouting, and pro-inflammatory responses by regulating gene expression (Zhao et al, 2021). Recently, findings from animal studies have suggested that the cardioprotective effects of VNS in myocardial infarction are provided by the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages (Chung et al, 2020).…”