Tilt Table With Suspected Postural Orthostatic Tachycardia Syndrome (POTS) Subjects

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.

Inclusion Criteria:

- Patients 10-21 years of age

- Must meet Rome III criteria for childhood functional dyspepsia with nausea as the
predominant symptom

- Must complete nausea and anxiety questionnaires

- Patients from the pediatric cardiac clinic who present with symptoms of unexplained
syncope not associated with cardiac anatomic anomalies or other identified cardiac
pathology

Exclusion Criteria:

- Patients with gastrointestinal symptoms due to metabolic, mechanical or mucosal
inflammation, including a diagnosis of inflammatory bowel disease, celiac disease,
liver or pancreatic disease, hiatal hernia, or bowel obstruction.

- Patients who are incapable or unwilling to discontinue medications affecting
autonomic function.

- Patients with significant cardiac or cardiovascular disease, malignancy, or other
co-morbid conditions precluding successful completion of a 45 minute tilt test.

- Patients with diabetes.