Auricular Vagal Neuromodulation Therapy in Postural Orthostatic Tachycardia Syndrome: Physiological Mechanisms and Systemic Effects - A Pilot Study

Postural Orthostatic Tachycardia Syndrome (POTS) is a chronic disorder characterized by dysregulation of the cardiovascular autonomic nervous system, leading to an excessive increase in heart rate upon standing. The pathophysiology of POTS is multifactorial, involving systemic inflammation, dysfunctional autonomic modulation, cerebral hypoperfusion, and impaired cerebral autoregulation. Beyond the hallmark postural tachycardia, POTS is associated with numerous systemic, autonomic, and neurocognitive symptoms that severely impair quality of life (QoL). Current treatments for POTS are limited in number, tolerability, efficacy, and evidence base.1, 2 Auricular vagal neuromodulation therapy (aVNT), a noninvasive method of vagus nerve stimulation, has shown potential due to its autonomic neuromodulation and anti-inflammatory effects. The global hypothesis is that autonomic dysregulation and systemic inflammation underlie POTS and its chronic symptoms. We will test this hypothesis using the neuromodulation effects of chronic, intermittent aVNT in patients with POTS to restore autonomic balance and reduce systemic inflammation leading to improved hemodynamics cognition and symptoms. We will test this hypothesis with a sham-controlled, double-blind, randomized mechanistic study of aVNT in 80 patients with POTS.

POTS is a chronic, multisystem disorder with symptomatic orthostatic intolerance and an excessive increase in heart rate (HR) upon standing without significant orthostatic hypotension (Fig 1). Patients often have low cardiac filling pressures and low stroke volume that worsens with upright posture. These lead to symptoms such as palpitations, low energy, headaches, cognitive impairment, muscle fatigue, chest pain, and generalized weakness. POTS is a debilitating autonomic nervous system disorder affecting ~1% of the population (~400,000 Canadians).

POTS predominantly affects females, with a female-to-male ratio of 5:1. The impact of POTS is particularly significant because it affects adolescent and young adult females who are typically in critical stages of their education or early careers. This often leads to frequent absences from school or work and necessitates lifestyle adjustments that hinder social and professional opportunities. POTS delays/limits their education, and leads to both direct and indirect economic loss. Consequently, POTS presents a considerable public health challenge with extensive social and economic implications, given its effect on a predominantly young and productive segment of the population.

Our research considers POTS holistically, with research priorities developed through a partnered research approach. Our patient partners, including Dysautonomia International, have long prioritized consideration of symptoms and outcomes beyond orthostatic tachycardia. POTS patients frequently experience several noncardiac symptoms including low energy, fatigability, and anxiety. Most POTS patients suffer from sleep disturbances, and mild to moderate depression is common. Symptoms related to subjective cognitive dysfunction, often referred to as "brain fog", are disabling and reported by over >90% of patients with POTS. Many systemic, autonomic, and neurocognitive symptoms occur even when supine, but are worse with upright posture. Severe fatigue, sleep disturbances, and "brain fog" are reported in >90% of patients with POTS. These noncardiac symptoms of POTS are often debilitating, severely affecting daily functioning, and reducing quality of life (QoL) to levels comparable to patients with heart failure.

Many POTS patients report cognitive dysfunction and mental fatigue, experiencing symptoms that significantly impair intellectual functioning and interfere with daily activities. A questionnaire-based study revealed that over 95% of POTS patients reported cognitive impairment, with many experiencing daily symptoms, including difficulties with executive function. These cognitive deficits are comparable to those observed in chronic fatigue syndrome and multiple sclerosis, indicating their severity and impact. Cognitive dysfunction can occur even while lying down or seated. In our prior study of 28 female POTS patients and 24 matched healthy controls, significant reductions in selective attention, cognitive processing speed, and executive function were observed, indicating that tasks requiring planning, organizing, and adapting are particularly affected in POTS. Many patients report worsened symptoms when upright. Using the Cambridge Neuropsychological Test Automated Battery (CANTAB), we found that POTS patients had worse cognitive processing than controls while seated (375±9 vs. 337±18 ms, p=0.045), and more so when standing (382±18 vs. 320±11 ms, p=0.012). While the pathophysiology of cognitive impairment in POTS is not understood, decreased PNS tone has been linked to both aging-associated cognitive decline and transient cognitive impairment following orthostatic stress.