Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS
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|ClinicalTrials.gov Identifier: NCT03261570|
Recruitment Status : Recruiting
First Posted : August 25, 2017
Last Update Posted : July 16, 2019
|Condition or disease||Intervention/treatment||Phase|
|Postural Orthostatic Tachycardia Syndrome (POTS) POTS Orthostatic Intolerance||Drug: Pyridostigmine Drug: Digoxin Drug: Placebo||Early Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||80 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in Postural Tachycardia Syndrome|
|Actual Study Start Date :||July 1, 2017|
|Estimated Primary Completion Date :||June 30, 2021|
|Estimated Study Completion Date :||September 1, 2021|
Active Comparator: Pyridostigmine and Placebo
Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
60mg by mouth
Other Name: Mestinon
Lactulose 50mg by mouth
Active Comparator: Digoxin and Placebo
Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day
0.5 (500mcg) by mouth
Lactulose 50mg by mouth
- Cardiovagal Baroreflex during orthostatic stress [ Time Frame: 1 year ]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.
- Cognitive ability during orthostatic stress [ Time Frame: 1 year ]. 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.
- Cardiac output measure by inert gas breathing technique [ Time Frame: 1 year ]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.
- Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle [ Time Frame: 1 year ]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.
- Heart rate [ Time Frame: 1 year ]
- systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output [ Time Frame: 1 year ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03261570
|Contact: Courtney R. Terilli, RN, BSNfirstname.lastname@example.org|
|Contact: Julian M. Stewart, M.D., Ph.D.||email@example.com|
|United States, New York|
|New York Medical College/Bradhurst building||Recruiting|
|Hawthorne, New York, United States, 10532|
|Contact: Courtney R. Terilli, RN. BSN 914-593-8888 firstname.lastname@example.org|
|Contact: Julian M. Stewart, M.D., Ph.D. 914-593-8888 email@example.com|
|Principal Investigator: Julian M. Stewart, M.D., Ph.D.|
|Sub-Investigator: Marvin S. Medow, Ph.D.|
|Principal Investigator:||Julian M. Stewart, M.D., Ph.D.||New York Medical College|