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

Primary Purpose

Postural Orthostatic Tachycardia Syndrome, Hypocapnia, Hyperventilation

Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Chemoreflex Testing
Baroreflex testing
Orthostatic stress testing
Sponsored by
New York Medical College
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Postural Orthostatic Tachycardia Syndrome focused on measuring Postural Tachycardia Syndrome (POTS), Young Females, Tilt Table Testing, Initial Orthostatic Intolerance

Eligibility Criteria

15 Years - 39 Years (Child, Adult)FemaleAccepts Healthy Volunteers

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

Sites / Locations

  • NewYork Medical CollegeRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

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

Female POTS patients with orthostatic hyperpneic hypocapnia

Healthy Female vounteers

Arm Description

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

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

Healthy Female vounteers

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

Systemic changes in leg blood volumes during orthostatic testing.
The investigators will measure changes in leg blood volume using impedance plethysmography methods which measures changes in electrical resistance (in Ohms) of the legs before and after tilt table testing which is expressed as ml•min-1•100 ml tissue-1.
Systemic changes in abdominal blood volumes during orthostatic testing.
The investigators will measure changes in abdominal blood volume using impedance plethysmography methods which measures changes in electrical resistance (in Ohms) of the abdomin before and after tilt table testing which is expressed as ml•min-1•100 ml tissue-1.

Full Information

First Posted
May 31, 2023
Last Updated
June 20, 2023
Sponsor
New York Medical College
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1. Study Identification

Unique Protocol Identification Number
NCT05923840
Brief Title
Chemoreflex and Baroreflex Alterations Causing Postural Tachycardia Syndrome With Orthostatic Hyperpnea and Hypocapnia
Official Title
Mechanism of Chemoreflex and Baroreflex Alterations Causing Postural Tachycardia Syndrome in POTS Patients With Orthostatic Hyperpnea and Hypocapnia
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 23, 2022 (Actual)
Primary Completion Date
August 31, 2023 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
New York Medical College

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.
Detailed Description
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 with the following two (2) specific aims: To test poikilocapnic (allowing carbon dioxide (CO2) to vary) orthostatic cardiorespiratory responses to determine whether prolonged initial orthostatic hypotension (IOH) precedes upright hypocapnia in hyperpneic POTS but not in controls or non-hyperpneic POTS. Subjects are instrumented for cerebral blood flow, respiratory and hemodynamic measurements, investigating splanchnic blood flow by indocyanine green infusion, and measuring changes of CBV, regional blood volumes, and cardiac output (CO) by impedance plethysmography during a 10 min stand to quantify IOH, and a 10 min tilt test to 70⁰ to quantitate cardiorespiratory changes. These changes during tilt stratify hyperpneic and non-hyperpneic POTS. To test if chemoreflex sensitization of ventilation and sympathetic activity (by microneurography) are abnormal when supine and tilted upright at 45o and how that interacts with Oxford measured cardiovagal and sympathetic baroreflexes under 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Postural Orthostatic Tachycardia Syndrome, Hypocapnia, Hyperventilation
Keywords
Postural Tachycardia Syndrome (POTS), Young Females, Tilt Table Testing, Initial Orthostatic Intolerance

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
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.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Female Postural Tachycardia Syndrome (POTS) patients without orthostatic hyperpneic hypocapnia
Arm Type
Active Comparator
Arm Description
Female POTS patients without orthostatic hyperpneic hypocapnia identified by tilt table testing and respiratory monitoring.
Arm Title
Female POTS patients with orthostatic hyperpneic hypocapnia
Arm Type
Active Comparator
Arm Description
Female POTS patients without orthostatic hyperpneic hypocapnia identified by tilt table testing and respiratory monitoring.
Arm Title
Healthy Female vounteers
Arm Type
Active Comparator
Arm Description
Healthy Female vounteers
Intervention Type
Diagnostic Test
Intervention Name(s)
Chemoreflex Testing
Intervention Description
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.
Intervention Type
Diagnostic Test
Intervention Name(s)
Baroreflex testing
Intervention Description
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.
Intervention Type
Diagnostic Test
Intervention Name(s)
Orthostatic stress testing
Intervention Description
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.
Primary Outcome Measure Information:
Title
Orthostatic tachycardia
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostatic Blood Pressure Changes
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostatic Changes in Systemic Vascular Resistance
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostatic Blood Volume Changes
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostatic Changes in Segmental Blood Flow
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostatic Changes in Cerebral Blood Flow
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostasis Induced Rate of Breathing
Description
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.
Time Frame
Baseline in all subjects
Title
Orthostasis Induced Depth of Breathing
Description
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.
Time Frame
Baseline in all subjects
Title
Measurement of chemoreflex sensitivity carotid body chemoreflex and central chemoreflex
Description
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.
Time Frame
Baseline in all subjects
Title
Effects of chemoreflex activation on baroreflexfunction and the effects of baroreflex on chemoreflex sensitivity
Description
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.
Time Frame
Baseline in all subjects
Secondary Outcome Measure Information:
Title
Systemic changes in leg blood volumes during orthostatic testing.
Description
The investigators will measure changes in leg blood volume using impedance plethysmography methods which measures changes in electrical resistance (in Ohms) of the legs before and after tilt table testing which is expressed as ml•min-1•100 ml tissue-1.
Time Frame
Baseline in all subjects
Title
Systemic changes in abdominal blood volumes during orthostatic testing.
Description
The investigators will measure changes in abdominal blood volume using impedance plethysmography methods which measures changes in electrical resistance (in Ohms) of the abdomin before and after tilt table testing which is expressed as ml•min-1•100 ml tissue-1.
Time Frame
Baseline in all subjects

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
15 Years
Maximum Age & Unit of Time
39 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: Any subjects with systemic disease or who cannot stop taking prescribed medications for at least 2 weeks prior to study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marvin S Medow, Ph.D.
Phone
914-594-2848
Email
marvin_medow@nymc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Julian M Stewart, M.D., Ph.D.
Phone
914-594-2849
Email
julian_stewart@nymc.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marvin S Medow, Ph.D.
Organizational Affiliation
New York Medical College
Official's Role
Principal Investigator
Facility Information:
Facility Name
NewYork Medical College
City
Hawthorne
State/Province
New York
ZIP/Postal Code
10532
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marvin S Medow, Ph.D.
Phone
914-594-2848
Email
marvin_medow@nymc.edu
First Name & Middle Initial & Last Name & Degree
Julian M Stewart, M.D.,Ph.D.
Phone
914-594=2849
Email
julian_stweart@nymc.edu
First Name & Middle Initial & Last Name & Degree
Marvin S. Medow, Ph.D.
First Name & Middle Initial & Last Name & Degree
Julian M. Stewart, M.D., Ph.D.

12. IPD Sharing Statement

Learn more about this trial

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

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