Chronic Intermittent Low-Level Transcutaneous Electrical Stimulation of Auricular Branch of Vagus Nerve Improves Left Ventricular Remodeling in Conscious Dogs With Healed Myocardial Infarction

Abstract

Background-Vagus nerve stimulation attenuates left ventricular (LV) remodeling after myocardial infarction (MI).Our previous study found a noninvasive approach to deliver vagus nerve stimulation by transcutaneous electric stimulation of auricular branch of vagus nerve. So we hypothesize that chronic intermittent low-level tragus stimulation (LL-TS) could attenuate LV remodeling in conscious dogs with healed MI. Methods and Results-Thirty beagle dogs were randomly divided into 3 groups, MI group (left anterior descending artery and major diagonal branches ligation to introduce MI, n=10), LL-TS group (MI plus chronic intermittent LL-TS, n=10), and control group (sham surgery without stimulation, n=10). Tragus stimulation was delivered to bilateral tragus with earclips connected to a custom-made stimulator. The voltage slowing sinus rate was used as the threshold for setting LL-TS at 80% below that. LL-TS group was given 4 hours stimulation at 7-9 AM and 4-6 pM on conscious dogs. At the end of 90-day follow-up, LL-TS group significantly reduced LA and LV dilatation, improved LV contractile and diastolic function, reduced infarct size by ≈50% compared with MI group. LL-TS treatment alleviated cardiac fibrosis and significantly decreased protein expression level of collagen I, collagen III, transforming growth factor β1, and matrix metallopeptidase 9 in LV tissues. The plasma level of high-specific C-reactive protein, norepinephrine, N-terminal pro-B-type-natriuretic peptide in LL-TS group was significantly lower than those in MI group from the 7th day to the end of follow-up. Conclusions-Chronic

The strange case of the ear and the heart: The auricular vagus nerve and its influence on cardiac control

“…When the same stimulation protocol was applied to the left and right tragus of conscious dogs with healed myocardial infarction, tVNS was improved cardiac function, alleviated cardiac fibrosis and attenuated left ventricular remodelling (Wang et al, 2014;Wang et al, 2015). This low-level tVNS reduced the plasma concentration of non-specific inflammatory markers such as C-reactive protein and decreased the expression of various factors which regulate cellular remodelling such as transforming growth factor beta 1 and matrix metalloproteinase 9 (Wang et al, 2014;Wang et al, 2015). A decrease in the concentration of plasma noradrenaline was further observed, suggesting that lowlevel tVNS may decrease sympathetic nerve activity.…”

“…In healthy human volunteers with no history of cardiovascular disease, tVNS on the inner and outer surface of the tragus significantly improved heart rate variability (through a shift in cardiac autonomic activity towards relative parasympathetic/vagal dominance) and caused a significant decrease in muscle sympathetic nerve activity as recorded by microneurography (Clancy et al, 2014). Further evidence that electrical stimulation of the ABVN can elicit a decrease in sympathetic activity comes from a study by Wang et al (2014), where a reduction in plasma noradrenaline concentration was observed following bilateral tragus stimulation in conscious dogs with healed myocardial infarction (Wang et al, 2014). Zhou et al (2016) also showed that in anesthetized dogs, 3 hours of right tragus stimulation significantly attenuated the sinus rate acceleration in response to right stellate ganglion stimulation and decreased activity in the right stellate ganglion.…”

“…Subsequent studies stimulating the right or left tragus suppressed atrial fibrillation when performed alongside 9 hours of atrial pacing by preventing the loss of the connexin proteins Cx40 and Cx43 in the atrial tissue (Chen et al, 2015a;Chen et al, 2015b). When the same stimulation protocol was applied to the left and right tragus of conscious dogs with healed myocardial infarction, tVNS was improved cardiac function, alleviated cardiac fibrosis and attenuated left ventricular remodelling (Wang et al, 2014;Wang et al, 2015). This low-level tVNS reduced the plasma concentration of non-specific inflammatory markers such as C-reactive protein and decreased the expression of various factors which regulate cellular remodelling such as transforming growth factor beta 1 and matrix metalloproteinase 9 (Wang et al, 2014;Wang et al, 2015).…”

“…A key consideration is that tVNS increases heart rate variability and, critically, decreases muscle sympathetic nerve activity in healthy humans (Clancy et al, 2014). Further, such cardiovascular diseases are associated with increased inflammation and tVNS reduced plasma levels of non-specific inflammatory markers in conscious dogs with healed myocardial infarction (Wang et al, 2014;Wang et al, 2015), as well as in patients with paroxysmal atrial fibrillation (Stavrakis et al, 2015). Finally, the pathways through which tVNS functions are not yet known (see Figure 2) -it is conceivable that they provide a more selective route of action than those activated through cervical vagus stimulation.…”

Toward Bioelectronic Medicine—Neuromodulation of Small Peripheral Nerves Using Flexible Neural Clip

“…Furthermore, VNS has shown other clinical benefits in diseases such as hypertension and rheumatoid arthritis 14, 22, 33. Recently, VNS has been proposed as a promising therapeutic approach such as heart failure34 and cardiac arrhythmia35 as it provides cardiac autonomic responses such as chronotropic, inotropic, and dromotropic effects 23, 33, 36. For the clinical applications, several VNS factors such as pulse width, current amplitude, number of pulses, interpulse period, and electrode configurations still need to be verified with the physiological effects, though the therapeutic effect has been recognized in preclinical and pilot clinical studies 23.…”