Vagal Stimulation in POTS

This study will test the hypothesis that impairment of the parasympathetic nervous system contributes to the symptoms of POTS and that stimulation of this part of the nervous system improves the excessive increase in heart rate, standing tolerance and inflammation in patients with POTS. For this purpose, the investigators will use electrical stimulation of a nerve in the skin of the earlobe (transcutaneous vagal nerve stimulation) and two medications that increase the levels of acetylcholine (a neurotransmitter) in the central or peripheral nervous system (galantamine and pyridostigmine, respectively) to increase the activity of the parasympathetic nervous system.

Screening Procedures: Potential participants will be screened in the Vanderbilt Autonomic Dysfunction Center (ADC). Medications affecting heart rate, blood pressure, blood volume, inflammatory markers and the autonomic nervous system will be withdrawn for at least five half-lives before studies. Patients will undergo a complete history and physical examination, ECG, routine clinical laboratory analyses and a blood pregnancy test for women of childbearing potential. Autonomic testing including a posture study with plasma catecholamines is then performed to determine if they meet the inclusion/exclusion criteria.

Eligible participants will be studied on three separate days in a randomized, double-blind, crossover fashion. On each testing day, patients will be given one dose of the study medication (either pyridostigmine, galantamine or placebo pill), and then will have two tilt table tests (a motorized table with a footboard that moves to an upright position): one with the vagal stimulation and one with sham electrical stimulation. Heart rhythm, blood pressure and the amount of fluid in the body (body impedance) will be monitored during studies. Blood samples (up to a total of 2 tablespoons per study day) will also be collected. The order of the study days and tilt tests will be decided at random, like the toss of a coin. Each study day will last about 5 hours.

• placebo sugar pill (Drug), also known as placebo: placebo single oral dose
• Pyridostigmine Pill (Drug), also known as pyridostigmine bromide, Mestinon: pyridostigmine bromide 30 mg single oral dose
• Galantamine Pill (Drug), also known as Galantamine hydrobromide, Razadyne: Galantamine hydrobromide 8mg single oral dose
• Vagal stimulation (Device), also known as Transcutaneous vagal nerve stimulation: Vagal stimulation will be given at 50 Hz during the tilt table tests
• Sham vagal stimulation (Device): Sham vagal stimulation will be given at 0.01 mA during the tilt table tests

Primary outcomes

• High frequency variability of heart rate [Up to 15 min of head up tilt]: Average of high frequency variability of heart rate during the head up tilt

Sex: Female, ages: 18 Years to 45 Years

Inclusion Criteria:

* Female subjects of 18-45 years, with Postural Tachycardia Syndrome (POTS) as defined by a heart rate increase ≥30 bpm from supine within 10 min of standing or head-up tilt in the absence of orthostatic hypotension, with chronic symptoms (> 6 months), and in the absence of other acute cause of orthostatic tachycardia.
* Subjects able and willing to provide informed consent

Exclusion Criteria:

* Pregnancy.
* Medical conditions that can explain postural tachycardia (e.g., dehydration, medications).
* Patients who are bedridden or chair-ridden
* Subjects taking any medication known to affect autonomic function or inflammatory markers (e.g. corticosteroids) who could not discontinue them before study participation.
* Conditions associated with chronic inflammatory processes which in the investigator's opinion would affect the interpretation of the results. Examples may include smoking, diabetes, BMI>30 kg/m2, current infections or cancer.
* Other factors which in the investigator's opinion would prevent the subject from completing the protocol.

• Italo Biaggioni, MD, Principal investigator, Vanderbilt University Medical Center