Effects of VNS FREQ on HR and heart period.

<p>Mean percent drop in HR for <b>(A)</b> P-VNS, <b>(B)</b> S-VNS (10%), and <b>(C)</b> S-VNS (20%) at different FREQ. Mean percent drop in Heart Period for <b>(D)</b> P-VNS, <b>(E)</b> S-VNS (10%), and <b>(F)</b> S-VNS (20%) at different FREQ. Note data reported here for P-VNS is the mean and SEM of the average of P-VNS #1 and P-VNS #2 protocols (n = 8). (*p < 0.05).</p

Effects of VNS on HRV using Poincaré analysis.

<p>Representative Poincaré plots of <b>(A)</b> P-VNS and <b>(B)</b> S-VNS (10%) during VNS stimulation (<b>ON</b>) at 10 Hz and 30 Hz demonstrating the elliptical fitting of the beat-distribution cloud and the standard deviation of short-term (SD1) and long-term (SD2) variability. <b>(C)</b> Mean SD1/SD2 ratio for <b>PRE</b>, <b>ON</b> and <b>POST</b> across different FREQ. (*p < 0.05).</p

Effects of STOCH on the chronotropic effects of VNS.

Mean percent drop in HR for (A) S-VNS (10%) and (B) S-VNS (20%) being compared to its immediate preceding P-VNS protocol at different FREQ. (C) Comparison of mean relative drop in HR between P-VNS protocols and (D) S-VNS (20%) and its subsequent P-VNS protocol at different FREQ. (*p < 0.05).</p

Stochastic vagus nerve stimulation affects acute heart rate dynamics in rats

<div><p>Vagus nerve stimulation (VNS) is an approved therapy for treatment of epilepsy and depression. While also shown to be promising in several preclinical and clinical studies to treat cardiovascular diseases, optimal therapeutic stimulation paradigms are still under investigation. Traditionally, parameters such as frequency, current, and duty cycle are used to adjust the efficacy of VNS therapy. This study explored the effect of novel stochastic VNS (S-VNS) on acute heart rate (HR) dynamics. The effect of S-VNS was evaluated in Sprague Dawley rats by comparing the acute HR and HR variability (HRV) responses to standard, periodic VNS (P-VNS) across different frequencies (FREQs, 10–30 Hz). Our results demonstrate that both S-VNS and P-VNS produced negative chronotropic effects in a FREQ-dependent manner with S-VNS inducing a significantly smaller drop in HR at 10 Hz and 20 Hz compared to P-VNS (p<0.05). S-VNS demonstrated a FREQ-dependent drop in the SD1/SD2 ratio, a measure of HRV, which was absent in P-VNS, suggesting that S-VNS may acutely modulate the nonlinear relationship between short- and long-term HRV. In conclusion, S-VNS is a novel stimulation procedure that may provide different physiological outcomes from standard P-VNS, as indicated by our analysis of HR dynamics. Our study provides a rationale for further detailed investigations into the therapeutic potential of S-VNS as a novel neuromodulation technique.</p></div

Detailed schematic of the experimental VNS protocol.

<p>Standard P-VNS or S-VNS with different degree of stochasticity (STOCH, 10% and 20%) was administered across different frequencies (FREQ, 20, 30, and 10 Hz) with stabilization times between protocols and conditions. P-VNS, periodic vagus nerve stimulation; S-VNS, stochastic vagus nerve stimulation; STOCH, stochasticity; <b>PRE</b>, baseline recording; <b>ON</b>, continuous VNS; <b>POST</b>, recovery.</p

ECG recordings and corresponding HR responses.

<p>Representative segments of ECG recordings and corresponding heart rate (HR) response for an anesthetized rat for <b>PRE</b>, <b>ON</b>, and <b>POST</b> during <b>(A)</b> P-VNS, <b>(B)</b> S-VNS (10%), and <b>(C)</b> S-VNS (20%) of the right cervical vagus nerve. Zoomed-in snapshots of <b>PRE</b> (black), <b>ON</b> (red), and <b>POST</b> (yellow) highlights VNS artifacts during stimulation. Here, VNS was continuously delivered at 20 Hz, 500 µs pulse width, and 1.0 mA for 2 minutes.</p

Effects of VNS FREQ on HR recovery.

<p><b>(A)</b> Schematic representation of different scenarios of HR recovery based on the value of <i>HR</i>_{<i>POST Ratio</i>}. Mean <i>HR</i>_{<i>POST Ratio</i>} values for <b>(B)</b> P-VNS, <b>(C)</b> S-VNS (10%), and <b>(D)</b> S-VNS (20%) at different FREQ. # p<0.05 compared to a mean theoretical value of 1.</p

Data_Sheet_1_Chronic Low-Level Vagus Nerve Stimulation Improves Long-Term Survival in Salt-Sensitive Hypertensive Rats.docx

Chronic hypertension (HTN) affects more than 1 billion people worldwide, and is associated with an increased risk of cardiovascular disease. Despite decades of promising research, effective treatment of HTN remains challenging. This work investigates vagus nerve stimulation (VNS) as a novel, device-based therapy for HTN treatment, and specifically evaluates its effects on long-term survival and HTN-associated adverse effects. HTN was induced in Dahl salt-sensitive rats using a high-salt diet, and the rats were randomly divided into two groups: VNS (n = 9) and Sham (n = 8), which were implanted with functional or non-functional VNS stimulators, respectively. Acute and chronic effects of VNS therapy were evaluated through continuous monitoring of blood pressure (BP) and ECG via telemetry devices. Autonomic tone was quantified using heart rate (HR), HR variability (HRV) and baroreflex sensitivity (BRS) analysis. Structural cardiac changes were quantified through gross morphology and histology studies. VNS significantly improved the long-term survival of hypertensive rats, increasing median event-free survival by 78% in comparison to Sham rats. Acutely, VNS improved autonomic balance by significantly increasing HRV during stimulation, which may lead to beneficial chronic effects of VNS therapy. Chronic VNS therapy slowed the progression of HTN through an attenuation of SBP and by preserving HRV. Finally, VNS significantly altered cardiac structure, increasing heart weight, but did not alter the amount of fibrosis in the hypertensive hearts. These results suggest that VNS has the potential to improve outcomes in subjects with severe HTN.</p