Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS

Study Overview
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Brief Summary
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Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance associated with excessive upright tachycardia, and occurs predominantly in young females (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory often called brain fog by patients. Task-related neurovascular coupling (NVC) links neural activity to an increase in CBF known as functional hyperemia. Although memory task performance and NVC deteriorated with angle of tilt in POTS but not healthy controls, cerebral blood flow (CBF) remained similar to control. Instead, the investigators observed extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples BP to HR to buffer BP changes. The investigators hypothesize that the cardiovagal baroreflex becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF and Brain Fog in POTS.

Detailed Description
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Orthostatic intolerance is defined by debilitating upright symptoms that are relieved by sitting or lying. Symptoms include upright lightheadedness, fatigue, confusion, and decreased memory called 'Brain Fog' by patients. The most common chronic form is Postural Tachycardia Syndrome (POTS), characterized by excessive upright tachycardia without hypotension. Of note, >85% of POTS patients are female. The proposal that Brain Fog was caused by reduced cerebral blood flow (CBF) has been disproven, because graded incremental upright tilt failed to demonstrate difference in mean CBF compared to healthy volunteers. Nevertheless, memory task performance deteriorates with angle of tilt as does task-related neurovascular coupling (NVC), which links neural activity to an increase in CBF known as functional hyperemia. The investigators have previously observed that large low frequency (0.07-0.13 Hz) oscillations in BP (OBP), which entrained and amplified oscillations in CBF (OCBF), increased with tilt angle and were associated with impaired working memory and reduced functional hyperemia. The sympathetic baroreflex remains intact and HR is excessively increased in the absence of parasympathetic counterregulation. The cardiovagal baroreflex couples BP to HR to buffer BP changes. Large low frequency BP oscillations, representing a resonance within the sympathetic baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and reduced parasympathetic buffering of BP by HR; conditions found in upright POTS. This leads to the following hypothetical paradigm: ↓Cardiovagal Baroreflex → ↑OBP → ↑↑OCBF → ↓NVC → ↓working memory. Therefore, in this application, the investigators hypothesize that the cardiovagal baroreflex is impaired in POTS while supine, becomes further impaired with orthostasis, and accounts for OBP, OCBF, and loss of NVC. Further, the investigators propose that improving the cardiovagal baroreflex improves hemodynamics and Brain Fog in POTS patients.

Official Title
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Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in Postural Tachycardia Syndrome

Conditions
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Postural Orthostatic Tachycardia Syndrome (POTS), POTS, Orthostatic Intolerance

Intervention / Treatment
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* Drug: Pyridostigmine
* Drug: Digoxin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for POTS patients: POTS patients referred for day to day orthostatic intolerance with greater than 3 symptoms for greater than 3 months and will have the diagnosis of symptomatic postural tachycardia made during a screening tilt table test : dizziness nausea and vomiting palpitations fatigue headache exercise intolerance blurred vision abnormal sweating heat. Healthy control subjects: normal physical examination, and normal electrocardiographic and echocardiographic evaluations. Only those free from heart disease, and from systemic illness will be eligible to participate. This excludes patients with illnesses and disease states known to be associated with endothelial cell dysfunction such as diabetes, renal disease, congestive heart failure, systemic hypertension, acute and chronic inflammatory diseases, neoplasm, immune mediated disease, trauma, morbid obesity and peripheral vascular disease. At the time of testing all patients and control subjects must refrain from vasoactive drugs for two weeks. Exclusion Criteria for both POTS and healthy controls: An active medical condition that may explain the diagnosis A previous medical condition with undocumented resolution that may explain the diagnosis any systemic or overt structural, arrhythmic or myopathic cardiovascular disease any illnesses known to produce autonomic dysfunction such as diabetes, heart disease, renal disease, systemic hypertension, acute and chronic inflammatory diseases, neoplastic disease, immune mediated disease, major trauma and burns, morbid obesity and peripheral vascular disease will also be excluded. Cigarette smokers will be excluded. Past or present major psychiatric disorder Substance abuse within 2 years before onset of symptoms.

Ages Eligible for Study
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Minimum Age: 15 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pyridostigmine and Placebo<br>Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day | Drug: Pyridostigmine<br>* 60mg by mouth<br>* Other names: Mestinon;Drug: Placebo<br>* Lactulose 50mg by mouth<br>|
| Active Comparator: Digoxin and Placebo<br>Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day | Drug: Digoxin<br>* 0.5 (500mcg) by mouth<br>Drug: Placebo<br>* Lactulose 50mg by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovagal Baroreflex during orthostatic stress | Cardiovagal Baroreflex during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. The unmedicated baroreflex measurement will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Baroreflex measurements will be obtained using the standard modified Oxford technique. | 1 year | 
| Cognitive ability during orthostatic stress | . Cognitive ability during orthostatic stress in unmedicated POTS patients compared to unmedicated control subjects during each angle of incremental tilt. Cognitive ability will be repeated in POTS patients to similar measurements after treatment with placebo, pyridostigmine or digoxin. Cognitive ability will be assessed with a standard 2-Back test in which patients identify identical alphabetic characters appearing 2 characters before the current displayed character in a sequence of 29 characters. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiac output measure by inert gas breathing technique | Cardiac output measure by inert gas breathing technique. Cardiac output is the amount of blood pumped by the heart in one minute. The technique uses the Innocor system in which the relative levels of two inert gases - one blood soluble and one insoluble component - are measured over a few respirations (about 5 breaths or 15 seconds). The rate of disappearance of the soluble gas from the alveolar space is proportional to the flow of blood perfusing the lungs and equals the cardiac output. | 1 year | 
| Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle | Arterial blood pressure in mmHg over each cardiac cycle will be collected using finger photoplethysmography. The arterial pressure is reported as an aggregate of 3 extracted quantities: the systolic blood pressure which is the maximum blood pressure over a cardiac cycle; the diastolic blood pressure which is the minimum blood pressure over a cardiac cycle; and the mean blood pressure which is the average blood pressure over a cardiac cycle. | 1 year | 
| Heart rate |  | 1 year | 
| systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output |  | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Postural Orthostatic Tachycardia Syndrome (POTS), POTS, Orthostatic Intolerance, Digoxin, Pyridostigmine, Mestinon