Autoimmune Basis for Postural Tachycardia Syndrome

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT02725060

Collaborator

University of Oklahoma (Other)

Enrollment

Locations

Arm

88.9

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to see if some people with postural tachycardia syndrome (POTS) have higher levels of immune proteins (autoantibodies) directed against receptors of the autonomic nervous system, and if these autoantibodies make a difference in their POTS symptoms. The investigators also want to see if the levels of these autoantibodies stay the same over time.

Condition or Disease	Intervention/Treatment	Phase
Postural Orthostatic Tachycardia Syndrome Postural Tachycardia Syndrome Tachycardia Arrhythmias, Cardiac Autonomic Nervous System Diseases Orthostatic Intolerance Cardiovascular Diseases Primary Dysautonomias	Drug: phenylephrine Drug: isoproterenol Radiation: 25 micro-Ci of radiation Procedure: Posture study with blood samples Procedure: 24-hour heart rhythm and blood pressure monitoring Procedure: Quantitative Axonal Sudomotor Reflex Testing Procedure: Autonomic function tests Other: Rebreathing test Other: Assessment of splanchnic capacitance Procedure: microneurography	N/A

Detailed Description

Postural tachycardia syndrome (POTS) is a debilitating disorder resulting from cardiovascular autonomic dysfunction, has many causes and is very difficult to treat effectively. The investigators have identified the presence of autoantibodies (immune proteins) directed against some receptors of the autonomic nervous system that can cause patient's symptoms on standing.

The present study is designed to test the hypothesis that patients with POTS harbor functional autoantibodies to adrenergic receptors that lead to an excessive tachycardia characteristic of POTS. For this purpose, this study will define the prevalence, burden, and the in vivo physiological significance of these adrenergic antibodies in a well-phenotyped and representative cohort of patients with POTS and a matched cohort of healthy control subjects, and will characterize the stability of these autoantibodies over time in affected POTS patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

58 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Autoimmune Basis for Postural Tachycardia Syndrome

Study Start Date :

Feb 1, 2016

Anticipated Primary Completion Date :

Apr 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autonomic and Antibody Assessments On up to 3 study days, POTS patients and control subjects will have several tests to assess autonomic function and to detect the presence of autoantibodies to adrenergic receptors. The following tests will de done but in some participants it may not be necessary to do all of them. The investigator will discuss with each participant which particular tests will be done in each particular case: Posture study with blood samples for autoantibody testing 24-hour heart rhythm and blood pressure monitoring autonomic function tests Quantitative Axonal Sudomotor Reflex Testing Total blood volume assessment Pharmacologic testing with phenylephrine Pharmacologic testing with isoproterenol Cardiac output with rebreathing Assessment of splanchnic capacitance Microneurography	Drug: phenylephrine Phenylephrine is a selective α1-adrenergic receptor agonist. It will be given in IV bolus injections starting from 12.5 ug. Incremental doses will be given every ~3 min up to 800 ug or until systolic blood pressure increases by 25 mmHg Drug: isoproterenol Isoproterenol is non-selective beta-adrenergic agonist. It will be given in IV bolus injections starting from 0.025 ug. Incremental doses will be given every ~3 min until heart rate increases by 25 bpm. This intervention is optional. Other Names: isuprel isoprenaline Radiation: 25 micro-Ci of radiation Using injection of iodinated I-131 tagged human serum albumin nominally 25 micro-Ci of radiation, blood samples are drawn before and 30 minutes after injection. Other Names: DAXOR Procedure: Posture study with blood samples Blood pressure and heart rate will be measured while supine and then while standing for up to 30 minutes. Blood will be drawn in each position to measure hormones that regulate blood pressure and blood volume. An additional sample will be collected in the supine position for the autoantibody assessment. Other Names: orthostatic challenge orthostatic stress test Procedure: 24-hour heart rhythm and blood pressure monitoring Blood pressure, heart rate and ECG monitoring for 24 hours Other Names: 24 Holter Procedure: Quantitative Axonal Sudomotor Reflex Testing The QSART assesses the ability of sympathetic nerve terminals in the skin to release acetylcholine and increase sweat production. The test is performed at 4 sites over the forearm, proximal lateral leg, medial distal leg and proximal foot. Other Names: QSART sweat test Procedure: Autonomic function tests The autonomic function tests will determine how well the autonomic nervous system regulates blood pressure and heart rate. These tests include breathing deeply for two minutes, breathing fast for 30 seconds, maintaining a handgrip for 3 minutes, breathing against pressure for 15 seconds, and placing the hand in ice water for 1 minute. In addition, participants will be tilted up on a tilt table for up to 10 minutes while recording their heart rate, blood pressure and cardiac output. Other: Rebreathing test Cardiac output will be measured using the rebreathing technique (Innocor) Other Names: cardiac output measurement Other: Assessment of splanchnic capacitance Splanchnic capacitance will be assessed using cpap and body impedance to construct pressure volume curves Procedure: microneurography microneurography will be measured in the peroneal nerve to assess sympathetic activity. Other Names: msna

Arm

Intervention/Treatment

Experimental: Autonomic and Antibody Assessments

On up to 3 study days, POTS patients and control subjects will have several tests to assess autonomic function and to detect the presence of autoantibodies to adrenergic receptors. The following tests will de done but in some participants it may not be necessary to do all of them. The investigator will discuss with each participant which particular tests will be done in each particular case: Posture study with blood samples for autoantibody testing 24-hour heart rhythm and blood pressure monitoring autonomic function tests Quantitative Axonal Sudomotor Reflex Testing Total blood volume assessment Pharmacologic testing with phenylephrine Pharmacologic testing with isoproterenol Cardiac output with rebreathing Assessment of splanchnic capacitance Microneurography

Drug: phenylephrine

Phenylephrine is a selective α1-adrenergic receptor agonist. It will be given in IV bolus injections starting from 12.5 ug. Incremental doses will be given every ~3 min up to 800 ug or until systolic blood pressure increases by 25 mmHg

Drug: isoproterenol

Isoproterenol is non-selective beta-adrenergic agonist. It will be given in IV bolus injections starting from 0.025 ug. Incremental doses will be given every ~3 min until heart rate increases by 25 bpm. This intervention is optional.

Other Names:

isuprel

isoprenaline

Radiation: 25 micro-Ci of radiation

Using injection of iodinated I-131 tagged human serum albumin nominally 25 micro-Ci of radiation, blood samples are drawn before and 30 minutes after injection.

Other Names:

DAXOR

Procedure: Posture study with blood samples

Blood pressure and heart rate will be measured while supine and then while standing for up to 30 minutes. Blood will be drawn in each position to measure hormones that regulate blood pressure and blood volume. An additional sample will be collected in the supine position for the autoantibody assessment.

Other Names:

orthostatic challenge

orthostatic stress test

Procedure: 24-hour heart rhythm and blood pressure monitoring

Blood pressure, heart rate and ECG monitoring for 24 hours

Other Names:

24 Holter

Procedure: Quantitative Axonal Sudomotor Reflex Testing

The QSART assesses the ability of sympathetic nerve terminals in the skin to release acetylcholine and increase sweat production. The test is performed at 4 sites over the forearm, proximal lateral leg, medial distal leg and proximal foot.

Other Names:

QSART

sweat test

Procedure: Autonomic function tests

The autonomic function tests will determine how well the autonomic nervous system regulates blood pressure and heart rate. These tests include breathing deeply for two minutes, breathing fast for 30 seconds, maintaining a handgrip for 3 minutes, breathing against pressure for 15 seconds, and placing the hand in ice water for 1 minute. In addition, participants will be tilted up on a tilt table for up to 10 minutes while recording their heart rate, blood pressure and cardiac output.

Other: Rebreathing test

Cardiac output will be measured using the rebreathing technique (Innocor)

Other Names:

cardiac output measurement

Other: Assessment of splanchnic capacitance

Splanchnic capacitance will be assessed using cpap and body impedance to construct pressure volume curves

Procedure: microneurography

microneurography will be measured in the peroneal nerve to assess sympathetic activity.

Other Names:

msna

Outcome Measures

Primary Outcome Measures

Autoantibody levels [up to 10 minutes]
Blood samples collected while supine during the posture study will be analyzed for autoantibody positivity in POTS patients and control subjects.
Blood pressure after phenylephrine boluses [1-2 minutes after bolus injections]
Heart rate after isoproterenol boluses [1-2 minutes after bolus injections]
Orthostatic change in heart rate [up to 10 minutes]
Difference between standing and supine heart rates.

Secondary Outcome Measures

Blood pressure response during phase IV of the Valsalva maneuver [up to 10 minutes]
Hear rate response during phase IV of the Valsalva maneuver [up to 10 minutes]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

18-50 years old
Postural Tachycardia Syndrome: Heart rate increase >30 bpm from supine within 10 min of standing, in the absence of orthostatic hypotension (>20/10 mmHg fall in blood pressure), with chronic symptoms (> 6 months), and in the absence of other acute cause of orthostatic tachycardia.
Able and willing to provide informed consent
Female premenopausal subjects must utilize adequate birth control and willingness to undergo serum beta-hCG testing
The subject must understand and be able to comply with the study procedures and restrictions.

Exclusion Criteria:

Hypertension (>150 mmHg systolic and >100 mmHg diastolic) based on history or findings at screening.
Orthostatic hypotension (consistent drop in blood pressure >20/10 mmHg with 10 min stand)
Pregnancy
Cardiovascular disease, such as myocardial infarction within 6 months, angina pectoris, significant arrhythmia (sinus tachycardia is not excluded), deep vein thrombosis, pulmonary embolism
History of serious neurologic disease
History or presence of significant immunological or hematological disorders
Clinically significant gastrointestinal impairment that could interfere with dietary compliance or drug absorption
Impaired hepatic function (aspartate amino transaminase and/or alanine amino transaminase >1.5 x upper limit of normal range)
Impaired renal function (serum creatinine >1.5 mg/dL)
Hematocrit <28%
Current or concurrent disease that could affect the absorption, action or disposition of the drug, or clinical or laboratory assessments.
Any underlying or acute disease requiring regular medication that could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
Inability to comply with the protocol

Healthy control subjects will be healthy, non-smoking and on no chronic medications at the time of the study. Healthy control subjects will be group-matched to the POTS patients for age and gender. We will attempt to study female patients in the first half of their menstrual cycle to minimize cyclical variability.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73117-1213
2	Autonomic Dysfunction Center	Nashville	Tennessee	United States	37232