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Natural Medicine Journal

December 3, 2024

Vagus Nerve Stimulation for POTS

A promising, noninvasive treatment for postural tachycardia syndrome

Corey B. Schuler

FNP, MS, CNS, CNSC, DC
In a small study of patients with postural orthostatic tachycardia syndrome (POTS), stimulation of the tragus of the ear improved heart rate, heart rate variability, and inflammatory markers but did not significantly improve overall autonomic symptom burden.

Reference

Stavrakis S, Chakraborty P, Farhat K, et al. Noninvasive vagus nerve stimulation in postural tachycardia syndrome: a randomized clinical trial. JACC Clin Electrophysiol. 2024;10(2):346-355. 

Study Objective

To examine the effects of transcutaneous vagus nerve stimulation (tVNS) on postural orthostatic tachycardia syndrome (POTS) over a 2-month period

Key Takeaway

Transcutaneous vagus nerve stimulation via the tragus of the ear attenuates tachycardic events as well as inflammatory and autoimmune markers in patients with POTS.

Design

Sham-controlled, double-blind, randomized clinical trial

Participants

The study enrolled a total of 26 women (12 in the active group and 14 in the sham group), with a mean age of 34 ± 11 years. The majority (81%) were White. 

Inclusion criteria included diagnosis of POTS (defined as a heart rate increase of more than 30 beats per minute within 10 minutes of standing) in the absence of orthostatic hypotension, with chronic symptoms lasting more than 6 months and significant functional impairment at baseline, as evidenced by a Composite Autonomic Symptom Score 31 (COMPASS 31) score of more than 40.

Exclusion criteria included those with significant hypertension, orthostatic hypotension, recent stroke, myocardial infarction, severe anemia, or significant immunological or hematological disorders and those who were pregnant or nursing.

Intervention

Participants were randomly assigned to receive either active tVNS or sham stimulation.

The active group received tVNS at the tragus (20 Hz, 1 mA below discomfort threshold), while the sham group received stimulation at the ear lobe, which lacks vagal innervation; tVNS was administered for 1 hour daily over a 2-month period. Investigators monitored adherence with a daily log.

Study Parameters Assessed

Investigators monitored participants for 2 months. Subjective data in the study focused on assessing autonomic symptoms using the COMPASS 31 questionnaire.

Objective data included orthostatic tachycardia evaluation via a tilt test conducted at both baseline and after the 2-month intervention period; heart rate variability (HRV), assessed using a 5-minute electrocardiogram; serum cytokines, including tumor necrosis factor–alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interferon-gamma (IFN-γ); and the activity of anti-autonomic autoantibodies targeting beta-1 adrenergic receptors (β1AR) and alpha-1 adrenergic receptors (α1AR), using a fluorescence resonance energy transfer (FRET)–based beta-lactamase reporter assay.

Primary Outcome

The study assessed the reduction in orthostatic tachycardia at the 2-month time point. This was measured as the difference in heart rate between the supine and standing positions, evaluated during a tilt test. The goal was to determine whether tVNS could significantly attenuate the increase in heart rate associated with standing compared to sham stimulation.

Key Findings

The study found that tVNS significantly reduced orthostatic tachycardia in patients with POTS. At the 2-month mark, the increase in heart rate during the postural test was markedly lower in the tVNS group compared to the sham group, with an average increase of 17.6 ± 9.9 beats per minute vs 31.7 ± 14.4 beats per minute, respectively (P=0.01).

The study also observed significant reductions in autoantibody activity in the active group, including β1AR autoantibody levels (P=0.01) and α1AR autoantibody levels (P=0.04).

TNF-α levels were significantly reduced in the tVNS group compared to the sham group, with mean levels of 8.3 ± 4.6 pg/mL vs 13.9 ± 5.1 pg/mL, respectively (P=0.01). However, other cytokines, such as IL-6, IL-8, and IFN-γ, did not show significant changes.

HRV measures also improved significantly in the tVNS group (P<0.05).

Overall subjective autonomic symptom burden, measured by the COMPASS 31 questionnaire, did not show a statistically significant difference between groups (P=0.07); however, secretomotor scores were significantly better in the active group, with a mean score of 2.9 ± 3.3 compared to 6.1 ± 3.7 in the sham group (P=0.001).

Transparency

The study was funded by the National Institutes of Health National Heart, Lung, and Blood Institute (NIH NHLBI) The authors have declared that they have no conflicts of interest to disclose.

Practice Implications & Limitations

Postural orthostatic tachycardia syndrome significantly impacts patients’ quality of life, and traditional management strategies, including pharmacologic treatments and lifestyle modifications, often yield inconsistent results, with a significant risk of self-harm among patients.1 This study offers early evidence that transcutaneous vagus nerve stimulation, a low-risk intervention, can effectively, yet modestly, reduce key symptoms of POTS, providing practitioners with a novel therapeutic tool that may complement existing treatments. Interestingly, auricular therapy—specifically, tragus stimulation—has anatomical and traditional foundations for autonomic support.2 Conditions such as migraine, major depressive disorder, mild cognitive impairment, chronic pain, polycystic ovarian syndrome, and seizure disorder have been the subject of tVNS intervention.3-8

Medications that may be helpful for POTS include midodrine (alpha-1 agonist), fludrocortisone (corticosteroid), propranolol (nonselective beta-adrenoceptor antagonist), and ivabradine (hyperpolarization-activated cyclic nucleotide-gated [HCN] channel blocker).9

Practitioners can also consider dietary supplements for this population, including licorice root containing glycyrrhizin, which inhibits 11β-hydroxysteroid dehydrogenase, an enzyme that converts active cortisol to its inactive form.10 This inhibition results in higher cortisol-like effects in the body. Curcumin from turmeric inhibits inflammatory pathways.11 Evidence suggests resveratrol may inhibit beta-adrenergic-signaling pathways in certain tissues.12 Hawthorns (Crataegus spp) have mild cardiomodulatory effects, potentially reducing the stress on the heart through beta-adrenergic-pathway modulation, though it is not a true beta-blocker.13 L-theanine indirectly modulates sympathetic activity, calming the nervous system and mimicking some effects of beta-blockade on heart rate variability.14

This study underscores the importance of addressing the underlying pathophysiology of POTS, including autoimmune activity and inflammation, rather than merely managing symptoms. Approximately 20% of POTS patients have an identifiable autoimmune comorbidity.15

The observed reductions in β1AR and α1AR autoantibodies and TNF-α levels further support the mechanistic benefits of tVNS. These findings provide a potential explanation for its efficacy. For clinicians, this suggests that tVNS could be especially beneficial for patients with a suspected autoimmune or inflammatory component to their condition. It also opens the door for using tVNS in other autonomic or inflammatory conditions, such as fibromyalgia, chronic fatigue syndrome, and post-acute sequelae of SARS-CoV-2 infection, which may overlap with POTS.16,17

The improvements in heart rate variability (HRV) metrics are also noteworthy. These findings align with the hypothesis that tVNS enhances parasympathetic tone and reduces sympathetic overactivity. Clinicians who use HRV as a monitoring tool can leverage these data to evaluate the efficacy of tVNS in their patients.

However, the study also highlights the importance of setting realistic expectations. Although tVNS significantly improved objective measures like heart rate, HRV, and inflammatory markers, the overall autonomic symptom burden, as measured by the COMPASS 31 score, did not show a statistically significant difference between the tVNS and sham groups. This suggests that while tVNS addresses certain physiological aspects of POTS, it may not lead to immediate or dramatic improvements in all symptom domains. Clinicians should communicate this to patients to foster realistic goals and adherence.

Despite its promising findings, the study has several limitations that affect the interpretation and application of it in practice. The small sample size limits the generalizability of the results. Larger, multicenter studies are needed to confirm these findings and explore whether the benefits of tVNS extend across diverse patient populations, including males and individuals from different ethnic backgrounds.

Approximately 20% of POTS patients have an identifiable autoimmune comorbidity.

The short duration of the study (2 months) also restricts insights into the long-term efficacy and safety of tVNS. Chronic conditions like POTS often require prolonged management, and it remains unclear whether the benefits of tVNS are sustained over time or if continued treatment is necessary. Practitioners should approach tVNS as a potential adjunct therapy while monitoring its effects over an extended period.

Another limitation is the lack of phenotyping among participants. POTS is a heterogeneous condition with different subtypes (eg, hyperadrenergic, neuropathic, or hypovolemic).18 The study did not stratify participants based on these subtypes, which might influence the responsiveness to tVNS. This gap highlights the need for further research to identify which patients are most likely to benefit from this therapy. For example, with medications, midodrine may be more useful for neuropathic subtype than hyperadrenergic subtype,19 whereas ivabradine better suits hyperadrenergic presentations.20 

The study also relies on objective measures and a single-symptom questionnaire, COMPASS 31, which may not capture all facets of POTS-related symptomatology. COMPASS 31 is an easy-to-administer, 31-question survey available in the public domain that provides a broad measure of autonomic severity with a global score ranging from 0 to 100, where higher scores indicate greater symptom severity. The questionnaire evaluates 6 specific domains of autonomic function, including orthostatic intolerance, vasomotor function, secretomotor function, gastrointestinal function, bladder function, and pupillomotor function.21 Practitioners should consider supplementing this tool with additional patient-reported outcomes to get a more comprehensive understanding of the therapy’s impact.

This study was limited to tragus (auricular) tVNS, whereas other devices may use different placement. Because tVNS is relatively easy to administer and has minimal risks, it may also appeal to patients who are hesitant about or unable to tolerate pharmacologic options. However, clinicians must emphasize the experimental nature of tVNS and the need for careful monitoring. Unit costs range considerably but are often several hundred dollars (USD), so cost may be a barrier in some cases.

Your Conflict of Interest Disclosure

The author discloses no relevant conflicts of interest.

Categorized Under

Corey B. Schuler

FNP, MS, CNS, CNSC, DC

Corey B Schuler, PhD, FNP, CNS, DC, serves as director of medical affairs for Allergy Research Group (ARG). He is a family nurse practitioner and certified nutrition specialist. He earned a PhD in health sciences, MS in human nutrition, and master of science in nursing. He has additionally earned an executive MBA, doctor of chiropractic, and an undergraduate degree in chemistry. Schuler serves as an adjunct professor at Augsburg University and practices holistic primary care in Minnesota.

References

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