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

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.

Acute cardiovascular and hemodynamic effects of vagus nerve stimulation in conscious hypertensive rats.

Hypertension (HTN) affects over 1 billion people worldwide, with a significant number who are unable to control their blood pressure (BP) with conventional therapies. Recently, novel device-based therapies targeting the autonomic nervous system have been evaluated for treating HTN, including vagus nerve stimulation (VNS). Numerous studies have indicated the beneficial effects of chronic VNS in various models of HTN, however the acute effects of VNS on physiological responses have not been widely investigated. To better understand the acute effects of VNS, this study evaluates cardiovascular and hemodynamic responses from conscious hypertensive rats implanted with VNS stimulators and physiological telemeters for simultaneous monitoring of BP and heart rate (HR) as therapy is applied. We demonstrated that there are no acute changes in mean BP, HR and contractility measures as a result of VNS stimulation. However, there were significant increases in both HR variability and BP variability during VNS, which returned to baseline levels immediately at the cessation of therapy. The small acute changes observed during intermittent VNS could be additive, leading to beneficial chronic changes in BP and HR control, and may help in furthering the understanding of beneficial effects demonstrated in chronic use of VNS therapy.

Evaluation of Multiscale Frequency Approach for Visualizing Rotors in Patients with Atrial Fibrillation.

Atrial Fibrillation (AF) is most common cardiac arrhythmia. It is associated with increased risk of stroke, heart failure and sudden cardiac death. Catheter ablation is a treatment used to control AF and has had suboptimal success for patients with persistent AF, which is primarily maintained by rotors outside of the pulmonary veins (PV) region. The pivot point (core) of the rotor is considered an efficient target for ablation. Currently available electro-anatomical mapping systems cannot accurately predict the exact location of the pivot point of rotors outside of the PV region, so there is a need for novel approaches to accurately identify and distinguish sites for ablation. Recently, a multiscale frequency (MSF) technique was developed for accurate identification of the pivot point of rotors and validated using optical mapping experiments in exvivo rabbit hearts, where electrical activity can be directly visualized. However, the nature of optical signals and its spatial resolution are very different from clinical intracardiac electrograms (iEGM). Here we extend the MSF approach to 3D iEGM and compare its prediction with the traditional dominant frequency (DF) approach, using Pearson's correlation and earth mover's distance methods. Our results demonstrate that the similarity between MSF and DF are high in some regions, but very low in other spatial regions of the human atria. This indicates the inconsistency in the traditional DF approach in identifying pivot points and identifying such low similarity regions can be used to find sites for successful ablation.

Modified Sequence Method to Assess Baroreflex Sensitivity in Rats.

Baroreceptors respond to fluctuations in blood pressure (BP) by modifying physiology in order to maintain a homeostatic set point. Baroreflex sensitivity (BRS) is used to quantify baroreceptor function and is a useful metric for tracking cardiovascular disease state and treatment effects. Pathological conditions such as hypertension (HTN) alter baroreflex function and reduce BRS. Traditionally, the sequence method is used to measure BRS, in which the linear slope of concomitant changes in BP and RR intervals are assessed. However, in rats, a high respiratory rate reduces the reliability of the sequence method. Here, we present a modified sequence method that captures BRS at lower frequencies and decreases the variability of the BRS estimate. This method was demonstrated using ECG and BP data from two groups of HTN rats: Sham rats and rats treated with vagus nerve stimulation. The modified sequence method resulted in lower BRS estimates than the traditional sequence technique when applied to the same data sets. Additionally, the modified sequence method resulted in lower BRS estimate variability.

Stochastic vagus nerve stimulation affects acute heart rate dynamics in rats.

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.

Novel Quantitative Analytical Approaches for Rotor Identification and Associated Implications for Mapping.

GOAL: Clinical studies identifying rotors and confirming these sites for ablation in treating cardiac arrhythmias have had inconsistent results with the currently available analysis techniques. The aim of this study is to evaluate four new signal analysis approaches-multiscale frequency (MSF), Shannon entropy (SE), Kurtosis (Kt), and multiscale entropy (MSE)-in their ability to identify the pivot point of rotors. METHODS: Optical mapping movies of ventricular tachycardia were used to evaluate the performance and robustness of SE, Kt, MSF, and MSE techniques with respect to several clinical limitations: decreased time duration, reduced spatial resolution, and the presence of meandering rotors. To quantitatively assess the robustness of the four techniques, results were compared to the "true" rotor(s) identified using optical mapping-based phase maps. RESULTS: The results demonstrate that MSF, Kt, and MSE accurately identified both stationary and meandering rotors. In addition, these techniques remained accurate under simulated clinical limitations: shortened electrogram duration and decreased spatial resolution. Artifacts mildly affected the performance of MSF, Kt, and MSE, but strongly impacted the performance of SE. CONCLUSION: These results motivate further validation using intracardiac electrograms to see if these approaches can map rotors in a clinical setting and whether they apply to more complex arrhythmias including atrial or ventricular fibrillation. SIGNIFICANCE: New techniques providing more accurate rotor localization could improve characterization of arrhythmias and, in turn, offer a means to accurately evaluate whether rotor ablation is a viable and effective treatment for chaotic cardiac arrhythmias.

Kurtosis as a statistical approach to identify the pivot point of the rotor.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that causes stroke affecting more than 2.3 million people in the US. Catheter ablation to terminate AF is successful for paroxysmal AF but suffers limitations with persistent AF patients as current mapping methods cannot identify AF active substrates outside of pulmonary vein region. In this work, we developed a novel Kurtosis based mapping technique that can accurately identify pivot points of the rotors that were induced in ex-vivo isolated rabbit heart. The results indicate that the chaotic nature of rotor pivot point results in higher Kurtosis compared to the periphery thereby enabling its accurate identification. Our results suggest that Kurtosis technique can be further applied to intra-atrial electrograms from AF patients with rotors to accurately identify the rotor pivot point by generating 3-dimensional (3D) patient-specific Kurtosis maps. Validation of this new Kurtosis based mapping technology is required through clinical studies with both paroxysmal and persistent AF patient data.

Intermittent electrical stimulation of the right cervical vagus nerve in salt-sensitive hypertensive rats: effects on blood pressure, arrhythmias, and ventricular electrophysiology.

Hypertension (HTN) is the single greatest risk factor for potentially fatal cardiovascular diseases. One cause of HTN is inappropriately increased sympathetic nervous system activity, suggesting that restoring the autonomic nervous balance may be an effective means of HTN treatment. Here, we studied the potential of vagus nerve stimulation (VNS) to treat chronic HTN and cardiac arrhythmias through stimulation of the right cervical vagus nerve in hypertensive rats. Dahl salt-sensitive rats (n = 12) were given a high salt diet to induce HTN. After 6 weeks, rats were randomized into two groups: HTN-Sham and HTN-VNS, in which VNS was provided to HTN-VNS group for 4 weeks. In vivo blood pressure and electrocardiogram activities were monitored continuously by an implantable telemetry system. After 10 weeks, rats were euthanized and their hearts were extracted for ex vivo electrophysiological studies using high-resolution optical mapping. Six weeks of high salt diet significantly increased both mean arterial pressure (MAP) and pulse pressure, demonstrating successful induction of HTN in all rats. After 4 weeks of VNS treatment, the increase in MAP and the number of arrhythmia episodes in HTN-VNS rats was significantly attenuated when compared to those observed in HTN-Sham rats. VNS treatment also induced changes in electrophysiological properties of the heart, such as reduction in action potential duration (APD) during rapid drive pacing, slope of APD restitution, spatial dispersion of APD, and increase in conduction velocity of impulse propagation. Overall, these results provide further evidence for the therapeutic efficacy of VNS in HTN and HTN-related heart diseases.