Electrical Vagal Nerve Stimulation Ameliorates Pulmonary Vascular Remodeling and Improves Survival in Rats With Severe Pulmonary Arterial Hypertension

Abstract

Visual Abstract

An implant for long-term cervical vagus nerve stimulation in mice

“…This is of particular importance when VNS is delivered therapeutically, wherein standardized doses are desirable within and in between animals, and across time. Previous reports from rat and large animal models implemented a similar approach to adjust stimulation intensity using respiratory twitching [15,71], and heart rate [40,72,73] to standardize stimulation protocols, but not on a dose-by-dose basis. Notably, electrical impedance, which is commonly used as a measure of electrode integrity and performance [74], did not correlate well with changes in HRT on an individual implant basis as implants aged (Fig 3E).…”

“…In addition to its approved use in treatment-resistant epilepsy [1] and depression [2], vagus nerve stimulation (VNS) may provide new treatment options for a wide range of illnesses. Long-term VNS is currently being explored in the treatment of brain disorders, such as tinnitus [3,4], stroke [5,6], and Alzheimer's disease [7,8], as well as peripheral organ and systemic diseases, including heart failure [9], cardiac arrhythmias [10][11][12][13], pulmonary hypertension [14,15], rheumatoid arthritis [16], Crohn's disease [17], and lupus [18]. The relatively recent discovery that the VN modulates the inflammatory response [19][20][21][22] might broaden the range of future indications for VNS, as inflammation is implicated in many common chronic diseases, such as type 2 diabetes, obesity, and atherosclerosis [23][24][25][26].…”

“…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].…”

Novel non-pharmacological therapy to modulate the autonomic tone in patients with heart failure with pulmonary hypertension

“…In recent years, clinical relevance of ANS disturbances in pulmonary arterial hypertension (PAH) has attracted attention as a new therapeutic target irrespective of the existence of HF (7,8). PAH is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure with associated ANS disturbances (9).…”

“…In most recent preclinical study using a rat model with PAH by Yoshida et al, the authors reported that VNS restored autonomic balance, decreased mean PA pressure, attenuated pulmonary vascular remodeling, and preserved RV function and also that VNS improved the survival rate in both the prevention and treatment protocols (8). Furthermore, in this study, acute VNS did not change nitric oxide synthesis or pulmonary vascular mechanics, despite acute as well as chronic VNS exhibiting significant inflammatory suppression in rats with PAH.…”