Low‐level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction

Abstract

Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in 3 groups: low salt (LS, 0.3% NaCl; n=12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n=18) or sham (n=18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20Hz, 2mA, 0.2ms) was implemented for 30 minutes daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes [tumor necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A] were differentially altered in the 2 groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel noninvasive neuromodulation therapy in HFpEF.

Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury

“…However, the group that received low-level tragus stimulation exhibited reductions in plasma norepinephrine (NE) levels, suggesting that central sympathoinhibition may be responsible for the amelioration of the post-MI remodeling (Wang et al, 2014). In a study by Zhou et al (2019) on Dahl salt-sensitive rats, inflammatory responses within the LV were successfully abrogated following 4 weeks of tVNS (20 Hz, 0.2 ms, 2 mA). In this model, cardiac injury on the LV signifies maladaptive physiological reactions due to prolonged elevations in blood pressure (Zhou et al, 2019).…”

“…In humans, delivering transcutaneous VNS (tVNS) at the tragus provided equivalent cardioprotection in patients with ST elevated myocardial infarction (STEMI) treated with primary percutaneous coronary treatment (Yu et al, 2017). This therefore aids with generating an initial evidence base of the cardioprotective effects non-invasive vagal stimulation can confer in MI patients (Wang et al, 2014;Stavrakis et al, 2017;Zhou et al, 2019). While numerous studies reveal the therapeutic benefits of invasive and non-invasive VNS in I/R injured myocardium, the underlying cardioprotective mechanism remains to be elucidated.…”

The rise of bioelectric medicine sparks interest among researchers, patients, and industry

“…Within the next decade, researchers say, modulating the body's neural networks could become a mainstream therapy for many of today's greatest health issuesfrom arthritis (1), asthma (2), and Alzheimer's disease (3) to depression (4), diabetes (5), and digestive disorders (6,7). Stimulating nerves also shows promise in treating cardiovascular disease (8) and septic shock (9), even in improving cognition (10).…”

Messages from the auricle: Limiting progression of heart failure with preserved ejection fraction through transcutaneous nerve stimulation of nerves in the external ear

“…Effective treatments are therefore urgently required. Now, Zhou et al () provide evidence that a simple, non‐invasive and inexpensive neuromodulatory procedure can ameliorate the development of HFpEF in a rat model.…”

“…However, as this assumption relies on a single human cadaveric study, it has recently been questioned (Badran et al., ). Zhou et al () addressed this issue through a sham arm, in which stimulation of the auricular margin did not provide the same protection as concha stimulation. A greater understanding of what is being stimulated and the pathways underlying the effects might therefore enhance future studies.…”