POTS NET mRNA Functional Correlation With NET Activity

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Postural Tachycardia Syndrome
• Intervention / Treatment: Diagnostic test: NET mRNA level; Diagnostic test: Plasma catechols; Diagnostic test: Urine Catechols

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.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Patients with POTS and Subjects without POTS who are not on drugs that inhibit the norepinephrine transporter and are willing to give their informed consent (or assent and parental consent) to participate in the project.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
POTS Patients; 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; quantification of mRNA to the Norepinephrine Transporter (NET); Diagnostic test: Plasma catechols; plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols; Diagnostic test: Urine Catechols; urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols
Control Subjects; 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; quantification of mRNA to the Norepinephrine Transporter (NET); Diagnostic test: Plasma catechols; plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols; Diagnostic test: Urine Catechols; urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: University of Calgary; Dysautonomia International
• Investigators: Principal Investigator: Satish R Raj, MD MSCI, Vanderbilt University

Study record dates

Study Major Dates

• Study Start (Actual): July 14, 2017
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: July 12, 2017
• First Submitted That Met QC Criteria: July 12, 2017
• First Posted (Actual): July 17, 2017

Study Record Updates

• Last Update Posted (Estimated): October 14, 2025
• Last Update Submitted That Met QC Criteria: October 8, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: norepinephrine; norepinephrine transporter
• Additional Relevant MeSH Terms: Nervous System Diseases; Primary Dysautonomias; Autonomic Nervous System Diseases; Orthostatic Intolerance; Postural Orthostatic Tachycardia Syndrome
• Other Study ID Numbers: IRB#170714

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No