POTS NET mRNA Functional Correlation With NET Activity

Study Overview
=================
Brief Summary
-----------------
DNA Acetylation can be responsible for significant down-regulation of transcription of the Norepinephrine Transporter (NET). NET is an important clearance transporter that removes norepinephrine (NE) from sympathetic neuronal synapses. Very low levels of NET can cause Postural Tachycardia Syndrome (POTS) or make these patients more susceptible to certain medications. Quantified NET messenger RNA (mRNA) levels from a peripheral blood sample may be able to assess NET availability, which is simpler than older methods. This has not been validated against NET function. In this protocol, the investigators seek to assess whether these NET mRNA levels correlate with NET function. The investigators will assess the DHPG (NET dependent NE metabolite):NE ratio in POTS patients and control subjects from both plasma and urine samples.

Detailed Description
-----------------
Work from The Baker Institute in Melbourne, Australia has shown that there can be significant epigenetic modification of the Norepinephrine Transporter (NET). DNA Acetylation can be responsible for significant down-regulation of transcription. NET is an important clearance transporter that removes norepinephrine (NE) from sympathetic neuronal synapses.Very low levels of NET can produce a hyperadrenergic phenotype and can cause Postural Tachycardia Syndrome (POTS). The Baker Institute researchers have started using quantified NET mRNA levels from a peripheral blood sample to assess NET availability. This is a huge advance due to its simplicity, in contrast to a prior method which involved a vein biopsy to look at the level of protein expression. In this protocol, the investigators seek to assess whether these NET messenger RNA (mRNA) levels correlate with NET function. When NET transports NE back into presynaptic neurons, a high percentage gets converted to a metabolite (DHPG) and then released into the blood stream. Therefore, the ratio of DHPG:NE ratio is decreased with reduced NET activity. The investigators will assess this DHPG:NE ratio in POTS patients and control subjects from both plasma and urine samples.

Official Title
-----------------
Validation of Norepinephrine Transporter (NET) mRNA as a Measure of Functional NET Expression in Postural Tachycardia Syndrome (POTS)

Conditions
-----------------
Postural Tachycardia Syndrome

Intervention / Treatment
-----------------
* Diagnostic Test: NET mRNA level
* Diagnostic Test: Plasma catechols
* Diagnostic Test: Urine Catechols


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: • Postural Tachycardia Syndrome Previously diagnosed with POTS • Control Subjects Not diagnosed with POTS Age between 13-80 years Male and female subjects are eligible. Able and willing to provide informed consent (if ≥18 years) or assent with parental consent (if age 13-17 years) Exclusion Criteria: • Inability to give, or withdrawal of, informed consent Use of serotonin-norepinephrine reuptake inhibitors (SNRI) or NET inhibitors within 1 month o These drugs pharmacologically block NET activity Use of Tricyclic antidepressants within 1 week o Many tricyclic antidepressants pharmacologically block NET activity Other factors which in the investigator's opinion would prevent the subject from completing the protocol.

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| POTS Patients<br>Patients who self-identify as having Postural Tachycardia Syndrome. They will have assessment of NET mRNA levels, supine plasma catechols, standing plasma catechols, and urine catechols. | Diagnostic Test: NET mRNA level<br>* quantification of mRNA to the Norepinephrine Transporter (NET)<br>Diagnostic Test: Plasma catechols<br>* plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols<br>Diagnostic Test: Urine Catechols<br>* urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols<br>|
| Control Subjects<br>Subjects who do not have Postural Tachycardia Syndrome. They will have assessment of NET mRNA levels, supine plasma catechols, standing plasma catechols, and urine catechols. | Diagnostic Test: NET mRNA level<br>* quantification of mRNA to the Norepinephrine Transporter (NET)<br>Diagnostic Test: Plasma catechols<br>* plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols<br>Diagnostic Test: Urine Catechols<br>* urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Supine Plasma DHPG:NE correlation | NET mRNA above and below median supine plasma DHPG:NE | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standing Plasma DHPG:NE correlation | NET mRNA above and below median standing plasma DHPG:NE | 1 day | 
| Urine DHPG:NE correlation | NET mRNA above and below median urine DHPG:NE | 1 day | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
norepinephrine, norepinephrine transporter