Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial

Abstract

Background: Low-level transcutaneous stimulation of the auricular branch of the vagus nerve at the tragus is antiarrhythmic and anti-inflammatory in animals and humans. Preliminary studies show that transcutaneous vagus nerve stimulation (tVNS) is beneficial in animal models of postural tachycardia syndrome (POTS).

Objectives: In this study the authors conducted a sham-controlled, double-blind, randomized clinical trial to examine the effect of tVNS on POTS over a 2-month period relative to sham stimulation.

Methods: tVNS (20 Hz, 1 mA below discomfort threshold) was delivered using an ear clip attached to either the tragus (active; n = 12) or the ear lobe (sham; n = 14) for 1 hour daily over a 2-month period. Postural tachycardia was assessed during the baseline and 2-month visit. Heart rate variability based on 5-minute electrocardiogram, serum cytokines, and antiautonomic autoantibodies were measured at the respective time points.

Results: Mean age was 34 ± 11 years (100% female; 81% Caucasian). Adherence to daily stimulation was 83% in the active arm and 86% in the sham arm (P > 0.05). Postural tachycardia was significantly less in the active arm compared with the sham arm at 2 months (mean postural increase in heart rate 17.6 ± 9.9 beats/min vs 31.7 ± 14.4 beats/min; P = 0.01). Antiadrenergic autoantibodies and inflammatory cytokines were lower in the active arm compared with the sham arm at 2 months (P < 0.05). Heart rate variability was better in the active arm. No device-related side effects were observed.

Conclusions: Our results support the emerging paradigm of noninvasive neuromodulation to treat POTS. Mechanistically, this effect appears to be related to reduction of antiautonomic autoantibodies and inflammatory cytokines, and improvement in autonomic tone. Further studies are warranted. (Autoimmune Basis for Postural Tachycardia Syndrome; NCT05043051).

Keywords: autoantibodies; autonomic modulation; inflammation; postural tachycardia syndrome.

FIGURE 1. Schematic Representation of the Study Design and Timeline of Events

A representative example of active stimulation, with the ear clip attached to the tragus is shown in the inset. BP blood pressure; COMPASS-31 = Composite Autonomic Symptom Scale 31; ECG = electrocardiogram; HR = heart rate; HRV = heart rate variability; VNS = vagal nerve stimulation.

FIGURE 2. Flow Diagram of Participant Recruitment and Follow-Up

tVNS = transcutaneous vagus nerve stimulation.

FIGURE 3. Effect of Transcutaneous Vagus Nerve Stimulation on Orthostatic Tachycardia

(A) Comparison of orthostatic tachycardia between the 2 groups. (B) Representative examples of systolic blood pressure (SBP) and heart rate (HR) changes during tilt test in patients from each group. *P < 0.05.

FIGURE 4. Comparison of Antiautonomic Autoantibody Activity Between the 2 Groups

(A) β1-adrenergic receptor (β1AR) autoantibody activity. (B) α1-adrenergic receptor (α1AR) autoantibody activity. *P < 0.05. Ab = antibody.

FIGURE 5. Comparison of Heart Rate Variability Measures Between the 2 Groups

(A) Low frequency (LF). (B) High frequency (HF). (C) LF/HF ratio. *P < 0.05.

CENTRAL ILLUSTRATION. Summary of Study Design and Primary and Secondary Endpoints

In a double-blind, sham-controlled, RCT, noninvasive vagus nerve stimulation improved orthostatic tachycardia compared to sham stimulation at 2 months (inset). This effect appears to be related to decrease in antiadrenergic autoantibodies and inflammatory cytokines, and improvement in cardiac autonomic tone (assessed by HRV). HRV = heart rate variability; RCT = randomized controlled trial.