Dr Elisabetta Burchi, MD, MBA
Translational Research Lead at Parasym.
Editor: Dr. Greta Dalle Luche, PhD, Head of R&D
Since the start of the coronavirus pandemic, a condition called POTS appears to be on the rise, affecting millions of people who recovered from the initial infection. Individuals afflicted by POTS often experience dizziness or light-headedness from changing posture, irregular heartbeats, fainting, chest pains and shortness of breath.
Emerging evidence also suggests that a great number of patients may experience lower urinary tract dysfunction, often manifesting as a very unpleasant and sudden urgency to pass urine without much prior warning 1,2.
POTS refers to the Postural Orthostatic Tachycardia Syndrome. It is primarily a disorder of the autonomic nervous system, characterised by the body’s abnormal response towards changes in the body posture that subsequently leads to orthostatic intolerance and excessive tachycardia but without concomitant orthostatic hypotension3.
“Essentially [when you change your posture], your blood pressure suddenly drops or your heart rate suddenly goes up, and you have all these symptoms [of POTS]. You have to pee all the time you feel weak,” said Dr Liesbeth Denef, a general practitioner at the OVIVE Medical Centre who has POTS as a consequence of coronavirus infection.
POTS can happen to anyone of any age, but women are disproportionately affected by the condition. Some women experience POTS during the few days leading up to their menstrual cycle, but the condition often begins after a pregnancy, major surgery or trauma4. Viral infections, such as COVID-19, could trigger POTS too. Recent studies indicate that 2%-14% of COVID-19 survivors develop POTS, and as much as 61% reported having POTS-like symptoms after SARS infection5.
Individuals with POTS often have a poor quality of life
Symptoms of POTS can vary greatly between individuals, and in some cases, they can be debilitating.
Studies have shown that people with POTS have significantly higher pain severity, poorer sleep quality and worse daytime fatigue. The majority of these people reported a feeling of losing control over their life. According to a recent survey, close to half (47.6%) of POTS patients were reported as being at a high risk of suicide, with almost a quarter of them having formed at least one suicide plan6. Moreover, the quality of life among people with POTS was lower than many chronic health conditions, such as chronic kidney disease, cancer, or diabetes7.
“I could not stand on my legs for more than two minutes because I had severe POTS,” recalled Dr Denef. “I would have to pee all the time. I couldn’t swallow. All my autonomic nervous system functions are just gone,”
The debilitating symptoms are not unique in Dr Denef’s cases. Poor quality of life is common among individuals diagnosed with POTS. Connie from Oxfordshire, another patient who was diagnosed several years ago, has also struggled with fatigue, insomnia and gastrointestinal issues. Her symptoms were very severe that she had to rely on a wheelchair and was bed bound for a prolonged period. “Many days I couldn’t even lift my head off the pillow due to my fatigue and POTS.”
A lack of treatment for POTS
As the underlying pathophysiology of POTS is still not fully understood, finding the right treatment becomes complicated and may take a long time to get it right.
Treatment is typically targeted at symptomatic relief, such as resolving low blood volume or regulating circulatory problems that may have contributed to the disorder. Simple interventions such as consuming more salt or wearing compression garments8 may help to control the symptoms, but these may not work with every individual.
Currently, there is no approved medication that can be used to treat POTS. Some medicines are prescribed off-label to help manage tachycardia and improve plasma volume. These medications may cause side effects and sometimes may be counterproductive to individuals who do not respond well to pharmacotherapy9.
Autonomic dysfunction and non-invasive vagus nerve stimulation
POTS has been considered a disorder of the autonomic nervous system. Some studies have demonstrated that a subset of people with POTS have distinct autonomic abnormalities that are consistent with impaired vagal and sympathetic cardiovascular control. These individuals have decreased vagal baroreflex sensitivity and blunted sympathetic nervous response10.
Vagus nerve stimulation (VNS) has been proposed as a promising treatment option for POTS. The proposal was motivated by the early success of treating POTS with an implanted VNS device11. Nonetheless, the intervention was invasive as the device must be implanted via surgery and the procedure carries certain risks that prohibit widespread adoption of the treatment.
On the other hand, low-level transcutaneous electrical stimulation of the tragus (LLTS) is a safe, non-invasive, and effective alternative to stimulate the auricular vagus nerve. It has demonstrated promising anti-arrhythmic and anti-inflammatory effects in both animal and human studies. Preliminary investigations showed that LLTS is effective in animal models of POTS.
Recently, scientists from the University of Oklahoma Health Sciences Center, led by Associate Professor Stavros Stavrakis, have successfully demonstrated the efficacy of LLTS in treating POTS through a randomized, double-blind, sham-controlled trial12.
During the trial, LLTS was delivered using the Nurosym device for one hour daily over 2 months. Important study parameters, such as heart rate, heart rate variability, serum cytokines and anti-autonomic autoantibodies were collected at baseline and the end-of-study visit.
The analysis showed that postural tachycardia (without a significant drop in blood pressure) was significantly less in subjects who received LLTS compared to control (postural increase in heart rate 18±10 bpm vs. 32±14 bpm, respectively, p=0.016; See Figure 1 below).
Figure 1: Effect of active LLTS vs sham stimulation on the postural change in heart rate [Δ(heart rate)] at 2 months. The mean difference between the two groups was approximately 14 bpm. The total sample size was 26 (active, n=12; sham, n=14)
In addition, anti-autonomic autoantibodies were significantly lower in the treatment arm at 2 months compared to the control arm. No device-related side effects were reported, and all subjects demonstrated excellent adherence to treatment protocol.
The study provided robust clinical evidence to support the use of noninvasive LLTS in treating POTS. Moreover, the reduction in anti-autonomic autoantibodies offered significant mechanistic insight into the pathophysiology of POTS.
An autoimmune disorder?
There is a growing body of evidence that suggests POTS is an autoimmune disorder. Studies have reported increased expression of ganglionic, adrenergic, and muscarinic acetylcholine receptor antibodies in POTS13.
Specifically, it has been shown that the alpha-1 adrenergic receptor (α-1 AR) autoantibody was significantly elevated in most people with POTS. Approximately one-fifth of these individuals would have elevation in both the a1-AR and a2-AR antibodies13.
The clinical trial shows that the Nurosym device successfully lowered the expression of these antibodies after 2 months of continuous treatment. This result is highly motivating as it corroborates the previously known pathophysiology of POTS. Adrenergic receptor autoantibodies have been reported to significantly correlate with orthostatic intolerance – a major feature of POTS14–17.
“Within a week of using it, I felt inflammation going down. Much better mood, it was mostly on the mood that it was incredible,” explained Dr Denef, speaking about her experience of using the Nurosym device for her POTS and long-COVID syndrome.
Connie, too, has found the device useful to manage her symptoms. “With the Parasym [company behind Nurosym] I now have a tool I can use myself at home which doesn’t have the nasty side effects medications do. My PoTS, although still present, is much more manageable,” she said.
Vagus nerve stimulation, including LLTS, has demonstrated promising efficacy in slowing heart rate, improving heart rate variability, as well as reducing inflammation. These clinical improvements by LLTS are well-suited for people with POTS, who typically reported sympathetic overactivity, reduced cardiac vagal drive and systemic inflammation3.
In addition, the evidence generated from the Nurosym randomized controlled trial can be considered as Level IB evidence based on the recommendation by the Centre for Evidence-Based Medicine18, further providing strong support for wider utilization of LLTS to manage POTS.
For more information about how LLTS can help to manage symptoms of POTS, please visit the Nurosym website https://nurosym.com/products/nurosym
- Kaufman, M. R. et al. Overactive Bladder and Autonomic Dysfunction: Lower Urinary Tract Symptoms in Females with Postural Tachycardia Syndrome. Neurourol. Urodyn. 36, 610–613 (2017).
- PoTS UK. PoTS and Bladder Issues. PoTS UK https://www.potsuk.org/pots-and-bladder-issues/.
- Diedrich, A. et al. Transdermal Auricular Vagus Stimulation for the Treatment of Postural Tachycardia Syndrome. Auton. Neurosci. Basic Clin. 236, 102886 (2021).
- National Institute of Neurological Disorders and Stroke. Postural Tachycardia Syndrome (POTS). National Institute of Neurological Disorders and Stroke https://www.ninds.nih.gov/health-information/disorders/postural-tachycardia-syndrome-pots.
- Ormiston, C. K., Świątkiewicz, I. & Taub, P. R. Postural orthostatic tachycardia syndrome as a sequela of COVID-19. Heart Rhythm 19, 1880–1889 (2022).
- Pederson, C. L. & Brook, J. B. Health-related quality of life and suicide risk in postural tachycardia syndrome. Clin. Auton. Res. Off. J. Clin. Auton. Res. Soc. 27, 75–81 (2017).
- Seeley, M.-C. et al. Poor health-related quality of life in postural orthostatic tachycardia syndrome in comparison with a sex- and age-matched normative population. Clin. Auton. Res. (2023) doi:10.1007/s10286-023-00955-9.
- NHS. Postural tachycardia syndrome (PoTS). nhs.uk https://www.nhs.uk/conditions/postural-tachycardia-syndrome/ (2017).
- Abed, H., Ball, P. A. & Wang, L.-X. Diagnosis and management of postural orthostatic tachycardia syndrome: A brief review. J. Geriatr. Cardiol. JGC 9, 61–67 (2012).
- Jacob, G. et al. Vagal and Sympathetic Function in Neuropathic Postural Tachycardia Syndrome. Hypertension 73, 1087–1096 (2019).
- Gadze, Z. P., Kovac, A. B., Adamec, I., Milekic, N. & Sulentic, V. Vagal nerve stimulation is beneficial in postural orthostatic tachycardia syndrome and epilepsy. Seizure - Eur. J. Epilepsy 57, 11–13 (2018).
- Stavrakis, S. et al. LB-456640-4 Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. Heart Rhythm 20, 1090 (2023).
- Gunning, W. T., Kvale, H., Kramer, P. M., Karabin, B. L. & Grubb, B. P. Postural Orthostatic Tachycardia Syndrome Is Associated With Elevated G‐Protein Coupled Receptor Autoantibodies. J. Am. Heart Assoc. 8, e013602 (2019).
- Li, H. et al. Autoimmune Basis for Postural Tachycardia Syndrome. J. Am. Heart Assoc. 3, e000755.
- Li, H. et al. Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension. Hypertension 59, 402–408 (2012).
- Yu, X. et al. Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an “autoimmune” orthostatic hypotension. J. Am. Soc. Hypertens. 6, 40–47 (2012).
- Galloway, A. et al. Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism. Endocrine 49, 457–463 (2015).
- Burns, P. B., Rohrich, R. J. & Chung, K. C. The Levels of Evidence and their role in Evidence-Based Medicine. Plast. Reconstr. Surg. 128, 305–310 (2011).