Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS

NCT03261570 | Completed Early Phase 1 DMC FDA Drug

• 1 other identifier: 1R01HL134674-01A1
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Postural Orthostatic Tachycardia Syndrome (POTS); POTS; Orthostatic Intolerance

Keywords

Postural Orthostatic Tachycardia Syndrome (POTS); POTS; Orthostatic Intolerance; Digoxin; Pyridostigmine; Mestinon

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Cardiac output measure by inert gas breathing technique

  1 year

• Arterial blood pressure, and mean arterial pressure defined by the time average blood pressure over the cardiac cycle

  1 year

• Heart rate

  1 year

• systemic vascular resistance defined by the ratio of mean arterial pressure to cardiac output

  1 year

Study Arms (2)

Pyridostigmine and Placebo

ACTIVE COMPARATOR

Pyridostigmine 60mg by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day

Drug: Pyridostigmine; Drug: Placebo

Digoxin and Placebo

ACTIVE COMPARATOR

Digoxin 0.5mg (500mcg) by mouth one day and Placebo (Lactulose 50mg) by mouth on a different day

Drug: Digoxin; Drug: Placebo

Interventions

Pyridostigmine DRUG

60mg by mouth

Also known as: Mestinon

Pyridostigmine and Placebo

Digoxin DRUG

0.5 (500mcg) by mouth

Digoxin and Placebo

Placebo DRUG

Lactulose 50mg by mouth

Digoxin and Placebo; Pyridostigmine and Placebo

Eligibility Criteria

• Age: 15 Years - 30 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• New York Medical College: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

New York Medical College/Bradhurst building

Hawthorne, New York, 10532, United States

Location

MeSH Terms

Conditions

Postural Orthostatic Tachycardia Syndrome; Orthostatic Intolerance

Interventions

Pyridostigmine Bromide; Digoxin

Condition Hierarchy (Ancestors)

Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pyridinium Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Glycosides; Carbohydrates

Study Officials

• Julian M. Stewart, M.D., Ph.D.

  New York Medical College

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: August 14, 2017
• First Posted: August 25, 2017
• Study Start: July 1, 2017
• Primary Completion: June 1, 2022
• Study Completion: June 1, 2022
• Last Updated: September 28, 2022

Record last verified: 2021-08

Locations

US (1)