Chemoreflex and Baroreflex Alterations Causing Postural Tachycardia Syndrome With Orthostatic Hyperpnea and Hypocapnia

NCT05923840 | Unknown

• 1 other identifier: R56HL162752
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Postural tachycardia syndrome (POTS) is the most common chronic cause of postural lightheadedness, and upright confusion afflicting many Americans, mostly young women. Many POTS patients hyperventilate by increasing their depth of breathing that produces tachycardia, alters blood flow and blood pooling in the body and importantly reduces brain blood flow causing "brain fog". In this proposal the investigators will demonstrate in young women that abnormal repeated brief impairment of blood pressure and brain flow just after standing sensitizes the body's oxygen sensor in POTS to respond as if it were in a low oxygen environment causing hyperventilation and its consequences. In this project the investigators will use various drugs that will help to understand the mechanisms that cause POTS in this unique subset of POTS patients who hyperventilate.

Conditions

Postural Orthostatic Tachycardia Syndrome; Hypocapnia; Hyperventilation

Keywords

Postural Tachycardia Syndrome (POTS); Young Females; Tilt Table Testing; Initial Orthostatic Intolerance

Outcome Measures

Primary Outcomes (10)

• Orthostatic tachycardia

  Heart rate (beats per minute) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostatic Blood Pressure Changes

  Blood pressure (mmHg) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostatic Changes in Systemic Vascular Resistance

  Systemic vascular resistance (mmHg⋅min⋅mL-1) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostatic Blood Volume Changes

  Central Blood Volume in liters (L) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostatic Changes in Segmental Blood Flow

  Segmental Blood Flows (ml•min-1•100 ml tissue-1) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostatic Changes in Cerebral Blood Flow

  Cerebral Blood Flow (cm/s) delimit the orthostatic response. Two separate orthostatic tests are used: a standing test and a 70 degree upright tilt test. The standing test will delineate the carotid blood flow signal that sensitizes the carotid body chemoreflex. The tilt test will delineate the effects of sustained tachyardia (and hyperpnea) on systemic hemodynamics and breathing.

  Baseline in all subjects

• Orthostasis Induced Rate of Breathing

  Changes in the rate of breathing (breaths per minute) will be determined in all subjects before and after being tilted upright on a tilt table.

  Baseline in all subjects

• Orthostasis Induced Depth of Breathing

  Changes in the depth of breathing (L of inhaled air per minute) will be determined in all subjects before and after being tilted upright on a tilt table.

  Baseline in all subjects

• Measurement of chemoreflex sensitivity carotid body chemoreflex and central chemoreflex

  Paired hypoxia and isocapnic hyperoxia determine the carotid body chemoreflex sensitivity; measurements of ventilation and sympathetic activation using Muscle Sympathetic Nerve Activity (MSNA - mean burst frequency and normalized mean burst area and expressed as arbitrary units (AU) per minute) define the responses. Similarly, measurement of during isocapnic hyperoxia and hypercapnic hyperoxia determine central chemoreflex stressors - measure sympathetic activity as responses.

  Baseline in all subjects

• Effects of chemoreflex activation on baroreflexfunction and the effects of baroreflex on chemoreflex sensitivity

  Supine chemoreflex activation using controlled gas conditions which are: isocapnic hypoxia and isocapnic hyperoxia to measure carotid body reflex; hyperoxic isocapnia and hyperoxic hypercapnia to measure central chemoreflexes. Hyperoxia silences peripheral chemoreceptors and will normalize baroreflex and tilt responses) should alter baroreflex function measured as the change in RR Interval (reciprocal of heart rate) in milliseconds per millimeter of mercury change in systolic blood pressure). This will be performed both supine and during 45 degree tilting which will activate the baroreflexes and reduce chemoreflex responses.

  Baseline in all subjects

Secondary Outcomes (2)

• Systemic changes in leg blood volumes during orthostatic testing.

  Baseline in all subjects

• Systemic changes in abdominal blood volumes during orthostatic testing.

  Baseline in all subjects

Study Arms (3)

Female Postural Tachycardia Syndrome (POTS) patients without orthostatic hyperpneic hypocapnia

ACTIVE COMPARATOR

Female POTS patients without orthostatic hyperpneic hypocapnia identified by tilt table testing and respiratory monitoring.

Diagnostic Test: Chemoreflex Testing; Diagnostic Test: Baroreflex testing; Diagnostic Test: Orthostatic stress testing

Female POTS patients with orthostatic hyperpneic hypocapnia

ACTIVE COMPARATOR

Female POTS patients without orthostatic hyperpneic hypocapnia identified by tilt table testing and respiratory monitoring.

Diagnostic Test: Chemoreflex Testing; Diagnostic Test: Baroreflex testing; Diagnostic Test: Orthostatic stress testing

Healthy Female vounteers

ACTIVE COMPARATOR

Healthy Female vounteers

Diagnostic Test: Chemoreflex Testing; Diagnostic Test: Baroreflex testing; Diagnostic Test: Orthostatic stress testing

Interventions

Chemoreflex Testing DIAGNOSTIC_TEST

The carotid body chemoreflex can be tested by holding carbon dioxide (CO2) constant (isocapnic) and applying hypoxia and hyperoxia. Measurements are then made of expiratory minute volume and of sympathetic activity. The central chemoreflex measures isocapnic and hypercapnic responses in the presence of hyperoxia to suppress the carotid body chemoreflex.

Female POTS patients with orthostatic hyperpneic hypocapnia; Female Postural Tachycardia Syndrome (POTS) patients without orthostatic hyperpneic hypocapnia; Healthy Female vounteers

Baroreflex testing DIAGNOSTIC_TEST

Baroreceptors are measured by the change of heart rate (HR) and sympathetic activity with changing blood pressure using the modified Oxford technique. Blood pressure is lowered an amount by a bolus of sodium nitroprusside and then raised by a bolus of phenylephrine. When standing baroreflexes are activated and the investigators will measure chemoreflex activity upright to see how baroreflex effects the chemoreflexes. Similarly chemoreflexes affect the baroreflexes best observed when the patients are supine.

Female POTS patients with orthostatic hyperpneic hypocapnia; Female Postural Tachycardia Syndrome (POTS) patients without orthostatic hyperpneic hypocapnia; Healthy Female vounteers

Orthostatic stress testing DIAGNOSTIC_TEST

Orthostatic Stress tests are administered in two forms: a standing test to evoke the initial orthostatic hypotensive response that sensitizes and triggers the carotid body chemoreflex by intermittent stagnant ischemia. And the 70 degree upright tilt test that best identifies causal changes in regional blood volumes and flows and in respiratory patterns of hyperpneic hypocapnia.

Female POTS patients with orthostatic hyperpneic hypocapnia; Female Postural Tachycardia Syndrome (POTS) patients without orthostatic hyperpneic hypocapnia; Healthy Female vounteers

Eligibility Criteria

• Age: 15 Years - 39 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• The investigators will recruit female POTS cases (N=80) and healthy female control subjects (N=40) aged 15-39 years, matched for BMI. POTS is a disease in which 80-90% are females. Therefore, the investigators will only recruit female POTS patients and controls.

You may not qualify if:

• Any subjects with systemic disease or who cannot stop taking prescribed medications for at least 2 weeks prior to study.

Sponsors & Collaborators

• New York Medical College: lead

Study Sites (1)

NewYork Medical College

Hawthorne, New York, 10532, United States

RECRUITING

MeSH Terms

Conditions

Postural Orthostatic Tachycardia Syndrome; Hypocapnia; Hyperventilation

Condition Hierarchy (Ancestors)

Orthostatic Intolerance; Primary Dysautonomias; Autonomic Nervous System Diseases; Nervous System Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Respiratory Tract Diseases

Study Officials

• Marvin S Medow, Ph.D.

  New York Medical College

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marvin S Medow, Ph.D.

CONTACT

914-594-2848; marvin_medow@nymc.edu

Julian M Stewart, M.D., Ph.D.

CONTACT

914-594-2849; julian_stewart@nymc.edu

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Model Details: The investigators will compare results from female POTS patients, free of known pulmonary or sleep disorders aged 15 to 39 years with, and without orthostatic hyperpneic hypocapnia, to healthy female volunteers.

Study Record Dates

• First Submitted: May 31, 2023
• First Posted: June 28, 2023
• Study Start: September 23, 2022
• Primary Completion: August 31, 2023
• Study Completion: August 31, 2024
• Last Updated: June 28, 2023

Record last verified: 2023-06

Locations

US (1)