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Trial record 14 of 63 for:    Postural Tachycardia Syndrome

POTS NET mRNA Functional Correlation With NET Activity

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ClinicalTrials.gov Identifier: NCT03218761
Recruitment Status : Enrolling by invitation
First Posted : July 17, 2017
Last Update Posted : August 10, 2018
Sponsor:
Collaborators:
National Institute of Neurological Disorders and Stroke (NINDS)
University of Calgary
Dysautonomia International
Information provided by (Responsible Party):
Satish R. Raj, Vanderbilt University Medical Center

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.

Condition or disease Intervention/treatment
Postural Tachycardia Syndrome 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 [Patient Registry]
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 2 Days
Official Title: Validation of Norepinephrine Transporter (NET) mRNA as a Measure of Functional NET Expression in Postural Tachycardia Syndrome (POTS)
Actual Study Start Date : July 14, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Supine Plasma DHPG:NE correlation [ Time Frame: 1 day ]
    NET mRNA above and below median supine plasma DHPG:NE


Secondary Outcome Measures :
  1. Standing Plasma DHPG:NE correlation [ Time Frame: 1 day ]
    NET mRNA above and below median standing plasma DHPG:NE

  2. Urine DHPG:NE correlation [ Time Frame: 1 day ]
    NET mRNA above and below median urine DHPG:NE


Biospecimen Retention:   Samples Without DNA
Plasma samples supine and upright catechol levels Urine for catechol levels PAXgene tubes for RNA assessment plasma/serum aliquots


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Ages Eligible for Study:   13 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
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.
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03218761


Locations
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
National Institute of Neurological Disorders and Stroke (NINDS)
University of Calgary
Dysautonomia International
Investigators
Principal Investigator: Satish R Raj, MD MSCI Vanderbilt University

Responsible Party: Satish R. Raj, Adjunct Associate Professor of Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT03218761     History of Changes
Other Study ID Numbers: IRB#170714
First Posted: July 17, 2017    Key Record Dates
Last Update Posted: August 10, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Satish R. Raj, Vanderbilt University Medical Center:
norepinephrine
norepinephrine transporter

Additional relevant MeSH terms:
Syndrome
Tachycardia
Postural Orthostatic Tachycardia Syndrome
Disease
Pathologic Processes
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Norepinephrine
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Sympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents