POTS NET mRNA Functional Correlation With NET Activity

Vanderbilt University Medical Center

Status: Active, not recruiting

Conditions: Postural Tachycardia Syndrome

Treatments: Diagnostic Test: Plasma catechols; Diagnostic Test: NET mRNA level; Diagnostic Test: Urine Catechols

Study type: Observational

Funder types: Other; NIH

Identifiers

NCT03218761

IRB#170714

Details and patient eligibility

About

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.

Full 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.

Enrollment: 200 estimated patients

Sex: All

Ages: 13 to 80 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

200 participants in 2 patient groups

POTS Patients

Description:

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.

Treatment:

Diagnostic Test: Urine Catechols

Diagnostic Test: NET mRNA level

Diagnostic Test: Plasma catechols

Control Subjects

Description:

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.

Treatment:

Diagnostic Test: Urine Catechols

Diagnostic Test: NET mRNA level

Diagnostic Test: Plasma catechols