POTS NET mRNA Functional Correlation With NET Activity

Postural Tachycardia Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT03218761
• Other study ID #: IRB#170714
• Status: Enrolling by invitation
• Start date: July 14, 2017
• Est. completion date: December 31, 2025

Study information

• Verified date: September 2023
• Source: Vanderbilt University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 200
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 13 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Postural Orthostatic Tachycardia Syndrome
• Postural Tachycardia Syndrome
• Syndrome
• Tachycardia

Intervention

Diagnostic Test:
• NET mRNA level
quantification of mRNA to the Norepinephrine Transporter (NET)
• Plasma catechols
plasma for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols
• Urine Catechols
urine for assay of norepinephrine (NE), DHPG (intraneuronal metabolite of NE), and other catechols

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee

Sponsors (4)

Lead Sponsor	Collaborator
Vanderbilt University Medical Center	Dysautonomia International, National Institute of Neurological Disorders and Stroke (NINDS), University of Calgary

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Supine Plasma DHPG:NE correlation	NET mRNA above and below median supine plasma DHPG:NE	1 day
Secondary	Standing Plasma DHPG:NE correlation	NET mRNA above and below median standing plasma DHPG:NE	1 day
Secondary	Urine DHPG:NE correlation	NET mRNA above and below median urine DHPG:NE	1 day