Autoimmune Basis for Postural Tachycardia Syndrome

Not Applicable

• Conditions: Cardiovascular Diseases; Postural Orthostatic Tachycardia Syndrome; Autonomic Nervous System Diseases; Orthostatic Intolerance; Postural Tachycardia Syndrome; Tachycardia; Arrhythmias, Cardiac; Primary Dysautonomias
• Interventions: 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

• Registration Number: NCT02725060
• Lead Sponsor: Vanderbilt University Medical Center

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.

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 Timeline

• Study Start: 2016-02
• Study First Submitted: 2016-02-22
• Study First Submitted QC: 2016-03-30
• Study First Posted: 2016-03-31
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-04
• Last Update Posted: 2024-11-06
• Primary Completion: 2025-10
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: ENROLLING_BY_INVITATION
• Sex: All
• Target Recruitment: 58

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Autonomic and Antibody Assessments	Assessment of splanchnic capacitance	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
Autonomic and Antibody Assessments	microneurography	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
Autonomic and Antibody Assessments	24-hour heart rhythm and blood pressure monitoring	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
Autonomic and Antibody Assessments	Rebreathing test	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
Autonomic and Antibody Assessments	25 micro-Ci of radiation	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
Autonomic and Antibody Assessments	Posture study with blood samples	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
Autonomic and Antibody Assessments	Quantitative Axonal Sudomotor Reflex Testing	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
Autonomic and Antibody Assessments	Autonomic function tests	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
Autonomic and Antibody Assessments	phenylephrine	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
Autonomic and Antibody Assessments	isoproterenol	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

Primary Outcome Measures

Name	Time	Method
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.
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

Secondary Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (2)

Autonomic Dysfunction Center; 🇺🇸 Nashville, Tennessee, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States