POTS Adrenergic Ab (CIHR Aims #1&2)

Study Overview
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Brief Summary
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Objective: In this pilot study, we will test the hypothesis that patients with POTS (age 18-60 years) will have a higher percentage of functional antibodies to adrenergic receptors compared with control subjects without POTS.

Detailed Description
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Background & Rationale: Postural Tachycardia Syndrome (POTS) is a chronic state of orthostatic tachycardia (> 30 bpm increment from lying to standing) and typical symptoms that are worse on standing, and are relieved by lying down. Typical orthostatic symptoms include palpitation, lightheadedness, chest pains, dyspnea, tremulousness, blurred vision and mental clouding. POTS often occurs in younger individuals with a female predominance (4-5 fold). Using the RAND36 quality of life (QOL) tool, we showed that POTS patients had lower quality of life (QOL) scores than healthy subjects for both physical (26±9 vs. 54±6; P<0.0001) and mental health domains (43±11 vs. 52±10; P<0.0001). These QOL scores are similar to scores for chronic obstructive pulmonary disease and congestive heart failure. In collaboration with the Kem/Yu lab (Oklahoma University), the investigators sought to determine whether POTS patients had functionally significant adrenergic receptor (AR) Abs. Samples from 14 POTS patients (included 7 blinded, well-characterized samples from Vanderbilt) and 10 healthy control subjects. Using the rat cremaster artery assay, the sera/immunoglobulin (IgG) of the POTS patients demonstrated significantly greater arteriolar contractile activity (69±3% of baseline vessel diameter) compared to the control subjects (91±1% of baseline; P<0.001). This contractility was suppressed with prazosin, an α1-AR blocker. With the addition of POTS sera, the phenylephrine dose-response curve was shifted to the right. In other words, a higher dose of phenylephrine was required to achieve the same degree of vasoconstriction, suggests that the α1-AR Ab is actually a partial-agonist/antagonist. Using a cell-based cyclic AMP (cAMP) reporter assay, all POTS sera had dose-dependent β1-AR activation (max: +30±3% from buffer baseline) compared to control sera (-1±2% from buffer baseline; P<0.001), and 7/14 POTS patients (but no control subjects) had elevated β2-AR activation. The excessive β1-AR activation could be blocked with propranolol. With the addition of POTS sera, the isoproterenol dose-response curve was shifted to the left (a lower isoproterenol dose was required to achieve the same receptor activation in the presence of the POTS sera). These data suggest that the β1-AR Ab is actually a straight agonist. Big Picture: While exciting, these data are obtained from only 14 POTS patients. In this protocol (Aim#1; REB15-2434), the investigators will study a larger cohort of POTS patients and control subjects in order to have a better sense of the true prevalence of these antibodies, to determine their association with other autoimmune illnesses, and to see if they relate to the patient-reported onset of illness. In addition to this, the investigators seek to see whether this is physiologically significant in intact humans in vivo (Aim#2). The investigators propose to perform dose response studies for phenylephrine and isoproterenol in POTS patients and control subjects with blood pressure (BP) and heart rate (HR) as the output metric and will then determine if these are different between POTS patients and control subjects and, more importantly, based on the auto-antibody in vitro activity. Specifically, the investigators will give a series of injections of small doses of phenylephrine while monitoring their HR and continuous BP. After each injection, the investigators will note the peak BP increase and will monitor the patient until the BP returns to baseline. The investigators will give incrementally larger doses until the endpoint is achieved. The endpoint is the lowest test dose of phenylephrine that will increase the systolic BP by >25 mmHg (PHE-PD25). the investigators will then repeat the same process with small doses of isoproterenol with the same monitoring. After each injection, the investigators will note the peak HR increase and will monitor the patient until the HR returns to baseline. The investigators will give incrementally larger doses until the endpoint is achieved. The endpoint is the lowest test dose of isoproterenol that will increase the HR by >25 bpm (ISO-PD25).

Official Title
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The Pathophysiological Role of Adrenergic Antibodies in Postural Tachycardia Syndrome (Aims #1&2)

Conditions
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Postural Tachycardia Syndrome

Intervention / Treatment
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* Drug: Phenylephrine
* Drug: Isoproterenol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who have been previously diagnosed with POTS Control subjects (patients not diagnosed with POTS) Age between 18 - 60 years Males and Females (Give that >80% of POTS patients are female, we will attempt to enroll a similar percentage of female control subjects) Able and willing to provide consent Exclusion Criteria: Smokers Overt cause for postural tachycardia, i.e., acute dehydration Significant cardiovascular, pulmonary, hepatic, or hematological disease by history or prior testing Highly trained athletes Subjects with somatization or severe anxiety symptoms will be excluded Use of drospirenone (a spironolactone analogue) containing oral contraceptive agent Hypertension defined as supine resting BP>145/95 mmHg off medications or needing antihypertensive medication Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule Unable to give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Postural Tachycardia Syndrome (POTS)<br>Patients with postural tachycardia syndrome; patients will receive both IV phenylephrine and IV isoproterenol | Drug: Phenylephrine<br>* incremental small doses of IV phenylephrine to find the dose that transiently raises systolic blood pressure by 25 mmHg<br>* Other names: NeoSynephrine;Drug: Isoproterenol<br>* incremental small doses of IV isoproterenol to find the dose that transiently raises heart rate by 25 bpm<br>* Other names: Isuprel;|
| Healthy (control) Subjects<br>Healthy volunteers that are gender and age-matched (by groups) to the POTS patients; healthy subjects will receive both IV phenylephrine and IV isoproterenol | Drug: Phenylephrine<br>* incremental small doses of IV phenylephrine to find the dose that transiently raises systolic blood pressure by 25 mmHg<br>* Other names: NeoSynephrine;Drug: Isoproterenol<br>* incremental small doses of IV isoproterenol to find the dose that transiently raises heart rate by 25 bpm<br>* Other names: Isuprel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of alpha-1 Ab titer positive subjects | The primary comparison will be the proportion of Ab titers between POTS patients compared to control subjects. | 1 Year (to measure Adrenergic antibody assay) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antibody Positivity by Joint Hypermobility Status | These comparisons include proportions of POTS patients with +va adrenergic Ab with a co-diagnosis of joint hypermobility syndrome (EDS III) vs without joint hypermobility syndrome (EDS III). | 1 Year (to measure Adrenergic antibody assay) | 
| Antibody Positivity by Clinical Autoimmune Syndromes | These comparisons include proportions of POTS patients with +ve adrenergic Ab with a co-diagnosis of a clinical autoimmune disorder vs without a clinical autoimmune disorder. | 1 Year (to measure Adrenergic antibody assay) | 
| Antibody Positivity by Viral Onset of POTS | These comparisons include proportions of POTS patients with +ve adrenergic Ab with a viral onset to their POTS vs without a viral onset to their POTS. | 1 Year (to measure Adrenergic Antibody assay) | 
| Isoproterenol HR Increase (PD25) | A comparison of the dose of isoproterenol required to acutely increase the Heart Rate by 25 bpm from a pre-injection baseline (as a measure of beta-receptor sensitivity) in antibody positive vs. antibody negative subjects. | 1 Year (to measure Adrenergic Antibody assay) | 
| Phenylephrine Systolic BP Increase (PD25) | A comparison of the dose of phenylephrine required to acutely increase the Systolic Blood Pressure by 25 mmHg from a pre-injection baseline (as a measure of alpha-receptor sensitivity) in antibody positive vs. antibody negative subjects. | 1 Year (to measure Adrenergic Antibody assay) | 
| The proportion of beta adrenergic Ab titer positive subjects | The primary comparison will be the proportion of Ab titers between POTS patients | 1 Year (to measure Adrenergic Antibody assay) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antibody, autoimmune, adrenergic, autonomic