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

Abstract

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.

Development and characterization of a chronic implant mouse model for vagus nerve stimulation

“…Optimal preclinical studies of VNS in models of chronic disease require long-term implantation of a VNS device optimized for small animals, but to date the majority of chronically implanted VN devices have been limited to neurological and cardiovascular diseases in rats, pigs, dogs, and other large animals ( Nasi-Er et al, 2019 ; Yamaguchi et al, 2018 ; Yoshida et al, 2018 ; Annoni et al, 2019 ; Beaumont et al, 2016 ; Chinda et al, 2016 ; Farrand et al, 2017 ; Li et al, 2004 ; Meyers et al, 2018 ; Nuntaphum et al, 2018 ; Yamakawa et al, 2015 ; Ganzer et al, 2018 ). The mouse is currently the species of choice in the study of disease pathophysiology, genetic mechanisms, and drug screening ( Bryda, 2013 ; Perlman, 2016 ).…”

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].…”

Blood Pressure Modulation With Low-Intensity Focused Ultrasound Stimulation to the Vagus Nerve: A Pilot Animal Study

“…This suggested that the FUS approach could be promising as an alternative non-drug treatment method for hypertension, similar to the FES. In comparison with applying the FES for BP regulation, which requires the implantation of the stimulator into the targeted nerve by invasive surgery ( Scheffers et al, 2010 ; Bisognano et al, 2011 ; Lohmeier and Iliescu, 2011 ; Bakris et al, 2012 ; Hoppe et al, 2012 ; Plachta et al, 2014 ; Gierthmuehlen et al, 2016 ; Annoni et al, 2019 ), ultrasound energy could penetrate into the deep tissue in a non-invasive way, which has been proven in a lot of previous studies ( Bystritsky et al, 2011 ; Gavrilov and Tsirulnikov, 2012 ; Baek et al, 2017 ), that may make the proposed FUS approach outperform the existing device-based methods for BP regulation. In addition, unlike the high-intensity focused ultrasound stimulation used to ablate the renal sympathetic nerve for drug-resistant hypertension treatment ( Wang et al, 2013 ), FUS could induce an antihypertensive effect without damaging the nerve or tissues surrounding it.…”

“…Thus, novel neuromodulation approaches targeting sympathetic nerve inhibition might be potential for the treatment of resistant hypertension. Tremendous evidences have proved that neuromodulation techniques such as functional electrical stimulation (FES) of the carotid baroreceptor ( Scheffers et al, 2010 ; Bisognano et al, 2011 ; Lohmeier and Iliescu, 2011 ; Bakris et al, 2012 ; Hoppe et al, 2012 )/vagus nerve ( Plachta et al, 2014 ; Gierthmuehlen et al, 2016 ; Annoni et al, 2019 ) and renal sympathetic denervation (RSD) by different devices and techniques [including surgical sympathectomy ( Smithwick, 1948 ), laparoscopic sympathectomy ( Gao et al, 2019 ), catheter-based radiofrequency ablation ( Krum et al, 2009 ), endovascular ultrasound ( Fengler et al, 2019 ), injection of neurotoxic agents ( Lohmeier and Hall, 2019 ), external stereotactic radiofrequency ( Cai et al, 2019 ), external high-intensity focused ultrasound ( Wang et al, 2013 ), etc.,] might reduce BP through sympathetic nerve activity inhibition. However, these procedures of current neuromodulation methods are either invasive or associated with complete nerve damage.…”

“…One previous animal study suggested that using focused pulsed ultrasound for vagus nerve modulation could induce the change of its compound action potential (CAP) ( Juan et al, 2014 ). As it is well known, the BP value is regulated by the vagus nerve ( Plachta et al, 2014 ; Annoni et al, 2019 ). Hence, we hypothesized that it might be feasible to control the BP by stimulating the vagus nerve via low-intensity FUS.…”