Tilt Table With Suspected Postural Orthostatic Tachycardia Syndrome (POTS) Subjects
Condition: Postural Orthostatic Tachycardia Syndrome; Syncope, Vasovagal; Neurocardiogenic Syncope
MeSH terms: Syncope; Postural Orthostatic Tachycardia Syndrome; Syncope, Vasovagal; Tachycardia; Syndrome
Study type: Observational

Summary: 
      Dysautonomia, primarily defined as postural orthostatic tachycardia syndrome (POTS) can
      seriously disrupt a child's daily activities. It is most commonly associated with nausea or
      abdominal pain. In preliminary studies, when orthostatic intolerance was treated with
      fludrocortisone, a standard therapy for orthostatic intolerance (OI), symptomatic improvement
      in nausea was observed. However, children with POTS were also observed to have higher supine
      mean arterial pressure (MAP) (preliminary data) and greater suppression of the baroreceptor
      reflex sensitivity (BRS) occurred upon up-right tilt. While fludrocortisone alleviates nausea
      associated with OI, its long-term use may pose long term health risks to children including
      worsening hypertension. Therefore, it is the objective of this study to define the mechanism
      for OI as it relates to nausea. The investigators hypothesize that OI resulting from changes
      in the autonomic nervous system is the likely mechanism for the nausea observed in the
      patients in this study. The investigators further hypothesize that this is potentially an
      early marker for future cardiovascular problems such as early onset hypertension and cardiac
      hypertrophy. The general objective of this protocol is to address this gap in knowledge by
      determining the autonomic characteristics of children with OI as well as defining
      neurohumoral profiles for these subjects to better understand the cause of the elevated
      supine in these subjects. By better understanding the potential mechanism for this condition,
      it is the investigators future goal to develop a more focused and safer treatment strategy.
      The investigators will study subjects between 10 to 18 years of age utilizing the tilt table
      to mimic daily life stressors and also measure serum levels of epinephrine, norepinephrine,
      rennin, angiotensin II, aldosterone, and vasopressin at baseline and during tilt. This study
      will generate data with high impact in that more rational treatments for management of
      dysautonomia could be chosen on the basis of the profile of dysautonomia and neurohumoral
      markers.
    

Detailed description: 
      Dysautonomia resulting in decreased HRV and impaired BRS, which may be accompanied by supine
      hypertension, is known to play a role in the development and progression of hypertension,
      which can lead to hypertensive heart disease including left ventricular hypertrophy and
      congestive heart failure as well as cardiovascular problems such as stroke, 4-6. The
      long-term cardiovascular consequence of decreased HRV and impaired BRS when present in
      childhood is not known, but in experimental models of cardiovascular dysfunction, the BRS and
      HRV impairments precede the eventual elevation in MAP 7. Dysautonomia with symptoms of OI is
      found in nearly 500,000 Americans with approximately 15% of all children experiencing syncope
      before the end of adolescence 8, 9. The majority of these individuals will not develop severe
      autonomic failure disorders as adults (pure autonomic failure or multiple system atrophy),
      but whether they are at greater cardiovascular risk for hypertension, stroke or cardiac
      hypertrophy and heart failure is not known.

      Our preliminary findings in children presenting to our GI clinic with chronic unexplained
      nausea show that dysautonomia manifesting as OI triggered nausea in 15 of 17 patients, and
      that nausea in these subjects substantially improved after the aldosterone agonist
      fludrocortisones 1. These children exhibit predominately POTS1, in contrast to syncope and
      neurally mediated hypotension (NMH) typically seen in pediatric cardiology clinics10. POTS is
      an autonomic disorder characterized by excessive increase in heart rate (HR) upon upright
      posture 11. It may present with palpitations, shortness of breath, nausea, lightheadedness,
      and syncope. Fludrocortisone acetate is a standard treatment for the orthostatic symptoms
      associated with POTS, thought to be a volume expander and to offset the low aldosterone
      reported in adults with OI 12, 13 . This is not the first time an association between OI and
      gastrointestinal symptoms has been described. Posturally mediated heart rate (HR) changes
      resulting in abnormal gastric electrical activity in patients with functional abdominal pain
      has recently been shown in children14. While it may seem that nausea and other GI symptoms
      are not relevant to CV disease and the AHA, our preliminary data suggest that treatment to
      remedy the CV dysautomomia also reduces the chronic unexplained nausea in a majority of these
      children without correcting the gastric dysrhythmias, suggesting the nausea is secondary to
      the CV dysatuonomia. However, there is a significant knowledge and therapy gap in this field
      as the cause and pathophysiologic mechanism(s) of either the chronic nausea or the POTS in
      this group remains essentially undefined. Furthermore, we recognized that the treatment for
      OI associated nausea, such as alpha or aldosterone agonists, may alleviate gastrointestinal
      symptoms, but exacerbate undefined cardiovascular pathology through multiple mechanisms.

      Therefore, our immediate goal is a better understanding of the specific autonomic
      disturbances in patients with chronic unexplained nausea to allow more timely and better
      selection of drugs to manage both the GI and CV symptoms in these subjects. In the past year,
      we have used the combination of tilt table and continuous autonomic assessment to provide
      more complete data on autonomic profile of these subjects, including baroreflex sensitivity
      for control of HR (BRS), heart rate variability (HRV) and blood pressure variability (BPV).
      The head-up tilt mimics daily life stressors (upright posture/standing) and the response
      pattern provides additional diagnostic information important for patient management. Our
      preliminary findings show that supine MAP is elevated in the subjects with POTS compared with
      the control group (those with nausea but having a normal tilt test). In addition, during
      upright posture BRS and HRV are impaired ~50% in normal subjects, whereas >80% suppression of
      BRS occurs in the POTS subjects 2, 3, suggesting that BRS suppression may lead to or at least
      play a permissive role in the inappropriate orthostatic blood pressure and HR regulation in
      these children.

      The use of non-invasive hemodynamic monitoring devices has proven to increase the sensitivity
      of tilt table testing in children with unexplained syncope10. Indeed, both BRS and HRV were
      suppressed to a greater degree in subjects with OI. Interestingly, in this series in which
      children were recruited from a pediatric cardiology clinic, the majority of patients (61%)
      were diagnosed with neurally mediated hypotension (NMH); whereas, in our series, most
      patients (68%) had POTS. Therefore, for this proposal, patients will be recruited from both
      pediatric gastroenterology and cardiology clinics to maximize the number of patients in each
      respective CV dysautonomia subgroup: POTS, NMH, or neurocardiogenic syncope.

      While fludrocortisone treatment resulted in symptomatic relief of both nausea and OI in our
      patients, it may not be the optimal long-term agent for children with OI particularly because
      indefinite use of fludrocortisone may pose musculoskeletal and endocrine risks, chronic
      headaches and electrolyte problems such as hypokalemia 15, 16. The cardiovascular effects
      associated with long-term use of fludrocortisone in children are not known, but experimental
      data clearly implicate excess aldosterone with and without elevated angiotensin II with
      increased fibrosis in heart and kidney and cardiac hypertrophy, as well as hypertension 6 .
      Elevated levels of aldosterone have been associated with secondary hypertension as well as
      impaired baroreflex sensitivity in the hypertensive state17, 18. Our preliminary findings
      suggest abnormalities in BRS during the tilt in the children with POTS, which improves but
      does not correct with fludrocortisone. Of greater concern is the higher supine MAP in
      children with POTS compared to those without POTS. While our data do not show further
      elevation in supine MAP with fludrocortisone treatment in our small sample, other blood
      pressure elevating treatments, such as vasoconstrictors that have also been empirically used
      to treat OI do elevate the supine MAP 15, 19. However, blockade of aldosterone has
      cardiovascular benefits independent of lowering blood pressure 20 suggesting that even if
      aldosterone does not further elevate supine MAP, excess aldosterone may be detrimental to
      cardiovascular health. In adults, increasing evidence suggests that angiotensin II
      concentrations in plasma may be elevated in OI 21, which could contribute to suppression of
      the BRS. The abnormalities in the renin-angiotensin-aldosterone axis and in the levels of
      catecholamines in adult patients12, 21 are used to direct treatments, including use of
      beta-blockers or exercise for the tachycardia seen with POTS 22 Because we do not have a
      neurohumoral profile defined in these children, an evidence-based choice of medications is
      often absent. Therefore, in addition to elucidating the specific role of the sympathetic
      versus parasympathetic nervous system by HR changes and differences in BRS, BPV and HRV
      during tilt, we believe it is essential to better define neurohumoral characteristics of
      patients with CV dysautonomia to attempt to understand the mechanism for OI. While this has
      been performed in adults, it has not been described in children to date23. Perhaps, more
      importantly, understanding the autonomic neurohumoral profile in patients with CV
      dysautonomia may allow more directed and safer treatment with less risk for cardiovascular
      side effects, such as exacerbation of supine hypertension.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Children between the ages of 10-21 years whose diagnostic workup for chronic unexplained
        nausea has unexpectedly revealed underlying cardiovascular instability manifesting as
        dysautonomia, primary defined as postural orthostatic tachycardia syndrome (POTS).