POTS NET mRNA Functional Correlation With NET Activity

NCT ID: NCT03218761

Last Updated: 2025-10-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-07-14
• Study Completion Date: 2029-12-31

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.

Conditions

Postural Tachycardia Syndrome

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

NET mRNA level

Intervention Type: DIAGNOSTIC_TEST

quantification of mRNA to the Norepinephrine Transporter (NET)

Plasma catechols

Intervention Type: DIAGNOSTIC_TEST

plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Urine Catechols

Intervention Type: DIAGNOSTIC_TEST

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.

NET mRNA level

Intervention Type: DIAGNOSTIC_TEST

quantification of mRNA to the Norepinephrine Transporter (NET)

Plasma catechols

Intervention Type: DIAGNOSTIC_TEST

plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Urine Catechols

Intervention Type: DIAGNOSTIC_TEST

urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Interventions

NET mRNA level

quantification of mRNA to the Norepinephrine Transporter (NET)

Intervention Type: DIAGNOSTIC_TEST

Plasma catechols

plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Intervention Type: DIAGNOSTIC_TEST

Urine Catechols

urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Intervention Type: DIAGNOSTIC_TEST

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.

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Calgary

OTHER

Sponsor Role: collaborator

Dysautonomia International

OTHER

Sponsor Role: collaborator

Vanderbilt University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Satish R. Raj

Adjunct Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Satish R Raj, MD MSCI

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University

Locations

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

IRB#170714

Identifier Type: -

Identifier Source: org_study_id