Neuromodulation of Inflammation to Treat Heart Failure With Preserved Ejection Fraction: A Pilot Randomized Clinical Trial

Abstract

Background A systemic proinflammatory state plays a central role in the development of heart failure with preserved ejection fraction. Low‐level transcutaneous vagus nerve stimulation suppresses inflammation in humans. We conducted a sham‐controlled, double‐blind, randomized clinical trial to examine the effect of chronic low‐level transcutaneous vagus nerve stimulation on cardiac function, exercise capacity, and inflammation in patients with heart failure with preserved ejection fraction. Methods and Results Patients with heart failure with preserved ejection fraction and at least 2 additional comorbidities (obesity, diabetes, hypertension, or age ≥65 years) were randomized to either active (tragus) or sham (earlobe) low‐level transcutaneous vagus nerve stimulation (20 Hz, 1 mA below discomfort threshold), for 1 hour daily for 3 months. Echocardiography, 6‐minute walk test, quality of life, and serum cytokines were assessed at baseline and 3 months. Fifty‐two patients (mean age 70.4±9.2 years; 70% female) were included (active, n=26; sham, n=26). Baseline characteristics were balanced between the 2 arms. Adherence to the protocol of daily stimulation was >90% in both arms ( P >0.05). While the early mitral inflow Doppler velocity to the early diastolic mitral annulus velocity ratio did not differ between groups, global longitudinal strain and tumor necrosis factor‐α levels at 3 months were significantly improved in the active compared with the sham arm (−18.6%±2.5% versus −16.0%±2.4%, P =0.002; 8.9±2.8 pg/mL versus 11.3±2.9 pg/mL, P =0.007, respectively). The reduction in tumor necrosis factor‐α levels correlated with global longitudinal strain improvement (r=−0.73, P =0.001). Quality of life was better in the active arm. No device‐related side effects were observed. Conclusions Neuromodulation with low‐level transcutaneous vagus nerve stimulation over 3 months resulted in a significant improvement in global longitudinal strain, inflammatory cytokines, and quality of life in patients with heart failure with preserved ejection fraction. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03327649.

Transcutaneous Vagus Nerve Stimulation Ameliorates the Phenotype of Heart Failure With Preserved Ejection Fraction Through Its Anti-Inflammatory Effects

“…Notably, in a recent pilot randomized clinical trial, LLTS over 3 months improved global longitudinal strain, inflammatory cytokines, and quality of life in a selected group of patients with HFpEF. 31 The effect of LLTS on blood pressure is consistent with recent evidence suggesting that an α7nAChR-dependent cholinergic pathway is recruited by hypertensive stimuli to contribute to blood pressure regulation. 32 Attenuation of the LLTS effect on blood pressure with the α7nAchR blocker MLA in our study is consistent with these results and highlights the important role of hemodynamic loadinduced proinflammatory signaling in mediating myocardial inflammation and fibrosis, eventually leading to HFpEF.…”

Effects of Stimulus Frequency, Intensity, and Sex on the Autonomic Response to Transcutaneous Vagus Nerve Stimulation

“…Afferent information from the vagus nerve enters the nucleus tractus solitarius (NTS) and then spreads through the locus coeruleus (LC) to the various cortical regions, such as the sensorimotor cortex, anterior cingulate cortex (ACC), and insular cortex (Ins) [ 2 ]. Transcutaneous Vagus Nerve Stimulation (tVNS) enables noninvasive electrical stimulation of vagal afferents and has been reported to improve symptoms of seizures, depression, migraine headaches, COVID-19, cardiac disease, and stroke [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. Neurophysiological changes underpinning the effects of tVNS reveal that stimulation either to the tragus or cymba conchae, the auricular branches of the vagus nerve, changes heart rate (HR) and heart rate variability (HRV) [ 11 , 12 ].…”

Strategies for precision vagus neuromodulation

“…LLTS has been mainly tested in patients with HF with preserved ejection fraction (HFpEF). Recently, two randomized and double-blind clinical trials showed that LLTS reduces TNF-a, improves left ventricular strain and quality of life in this population (Stavrakis et al 2022 ). As treatments for HFpEF are lacking, LLTS promising preliminary results warrants further study in this disease.…”