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Vanderbilt Autonomic Dysfunction Center

POTS Related Research Information

Estimation of sleep disturbances using wrist actigraphy in patients

with postural tachycardia syndrome.

  • Investigators conducted a questionnaire study to assess sleep disturbances and quality of life in patients with POTS and healthy subjects.  Patients with POTS and healthy volunteers were given several surveys to assess their sleep (Epworth Sleepiness Index & Medical Outcomes Study [MOS] Sleep Survey), level of fatigue (a visual analogue scale) and health related quality of life (RAND36 and EQ5D).
  • Patients with POTS reported more sleep problems, daytime sleepiness and fatigue, and worse health related quality of life than the healthy volunteers.
  • Patients with POTS had a markedly diminished quality of life in both physical health and mental/social health domains compared to the healthy volunteers.  The scores were comparable to previously published scores for patients with kidney failure requiring hemodialysis.  The Vanderbilt data were similar to a prior publication from the Mayo Clinic {PMID: 12059122} that also found diminished quality of life in patients with POTS.
  • There was a strong correlation between sleep problems and physical and mental health related quality of life. In fact, 60% of the variability in score for each of the physical health domain and the mental health domains could be accounted for by the Sleep Problems Index (a summary score from the MOS Sleep Survey).

Psychiatric profile and attention deficits in

postural tachycardia syndrome

  • There was no increased prevalence of major depression or anxiety disorders in patients with POTS compared with the general population, based on DSM4-TR criteria.
  • On formal psychometric testing patients with POTS had:
  • Mild depressive symptoms;
    • Increased anxiety scores compared to healthy controls according to the Beck Anxiety Inventory; however, this anxiety score incorporates both physical and psychological symptoms of anxiety.
    • A trend toward decreased anxiety scores compared to general population norms according to the Anxiety Sensitivity Index. This index measures psychological fear of anxiety-provoking sensations. This result means that it is possible that the increased anxiety detected by the Beck Anxiety Inventory might be due to a misinterpretation of their physical symptoms of POTS and not due to true increased “cognitive anxiety”.
    • Significantly more inattention measured on adult ADHD questionnaires than general population.  This may explain some of the complaints of “memory problems”. It may be that the memory problems as much as inattention and an inability to process the memory.

Orthostatic intolerance and tachycardia associated with

norepinephrine-transporter deficiency.

Lack of Function of the Norepinephrine Transporter (NET) can Cause POTS

 Some years ago, a patient with POTS was found to be heterozygous (had one copy of the mutant allele) for a mutation in the norepinephrine transporter gene that caused a single amino acid (protein building block) change in the protein (A457P). The mutation was “dominant negative” and resulted in an almost complete “loss of function” of the norepinephrine transporter compared to the normal gene. Since the transporter is involved in clearance of norepinephrine from the sympathetic nerve synapse (area between nerve terminals), this mutation likely led to an increase in norepinephrine in the synapse, and in excessive sympathetic activation. This likely resulted in the excessive heart rate seen in this patient, which was worse on standing (when there would be more sympathetic nervous system activation). Other members of this patient’s family that had this genetic mutation also had a greater increase in heart rate with standing and elevated plasma norepinephrine compared to those without this genetic mutation. This demonstrates that orthostatic intolerance and tachycardia are associated with norepinephrine transporter deficiency.

 Do Other Non-Related Patients have this NET Mutation?

For several years, we looked for this mutation in other POTS patients.  We have not found any other non-related patients to have this same loss of function mutation.

 Decreased NET Protein Expression in Some POTS Patients
 

We had just about lost hope in NET deficiency as an important contributor to POTS in many patients. More recently, colleagues from Melbourne Australia published a very nice paper in which they performed forearm vein biopsy in a handful of POTS patients and healthy volunteers.  They then assessed the amount of NET protein in the vein tissue.  They found that several patients, but not all, had low levels of NET protein expression compared to the healthy volunteers,  These data suggest that even though most POTS patients do not have a genetic mutation causing dysfunctional NET protein, it may be more common to have decreased protein expression.  Further work from their group has suggested that the relevant DNA may not “uncoil” properly in some POTS patients.  This would be required to make it available for transcription to RNA to then make the protein.  In another very elegant paper from the Czech Republic, the authors performed MIBG heart scans in 20 POTS patients.  MIBG is a radiotracer that is taken up by sympathetic nerves via NET.  They found that 20% of the patients had markedly diminished heart uptake of MIBG.  They concluded that these hearts were denervated.  An alternative explanation could be that these patients had decreased NET expression (as shown in the Melbourne studies) and could not take up the MIBG tracer.

 NET Blocking Medications

Many drugs can block NET as one of their mechanisms of action.  Several of these medications are used to treat depression, anxiety, ADHD and fibromyalgia.  They are sometimes called norepinephrine reuptake inhibitors (NRI) or serotonin-norepinephrine reuptake inhibitors (SNRI) as opposed to selective serotonin reuptake inhibitors.

In one study conducted at Vanderbilt, duloxetine (a SNRI medication) was given to healthy volunteers in increasing large doses.  At doses higher than are typically used clinically today, these healthy volunteers developed orthostatic tachycardia and symptoms that mimicked those of patients with POTS.  Colleagues in Germany have shown that they could cause healthy volunteers to develop tachycardia with reboxetine {PMID: 11804991} an anti-depressant that blocks NET. These studies demonstrate that blocking norepinephrine reuptake can produce a human model of orthostatic intolerance. While the doses used in these studies was likely higher than most patients will ingest, POTS patients may be more sensitive to the tachycardia-inducing effects of NET inhibiting drugs than most people.  We often recommend that these drugs not be used or used with caution.

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