<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03263819</url>
  </required_header>
  <id_info>
    <org_study_id>170052</org_study_id>
    <nct_id>NCT03263819</nct_id>
  </id_info>
  <brief_title>Gastrointestinal Symptoms in Postural Orthostatic Tachycardia Syndrome</brief_title>
  <acronym>POTS-GUT</acronym>
  <official_title>POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME AND GASTROINTESTINAL SYMPTOMS: Contribution of Gastrointestinal Peptides</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with POTS experience significant gastrointestinal symptoms. Current evidence&#xD;
      suggesting that abnormal post-ganglionic sympathetic function could play a role in the&#xD;
      pathophysiology of these GI abnormalities. Sympathetic fiber regulate motor and the&#xD;
      postprandial GI peptides secretion.&#xD;
&#xD;
      The focus of the present proposal is to determine glucose homeostasis, GI motility, and their&#xD;
      association with GI and cardiovascular symptoms in POTS patients versus healthy controls.&#xD;
      Furthermore, we will determine differences in these outcomes in POTS patients with and&#xD;
      without evidence of postganglionic sympathetic fiber neuropathy.&#xD;
&#xD;
      As a long-term goal, this study can lead us to understand the pathophysiology of common&#xD;
      co-morbidities in patients with POTS to provide new treatment approaches and prevention&#xD;
      strategies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Postural Tachycardia Syndrome (POTS) is a disabling condition that mostly affects young women&#xD;
      in their reproductive age. It is characterized by chronic (&gt;6 months) orthostatic intolerance&#xD;
      symptoms (palpitation, lightheadedness, blurred vision and mental clouding) triggered by&#xD;
      assuming an upright posture and that improved upon recumbency. These symptoms are associated&#xD;
      with a rapid increase in heart rate (≥30 bpm) that occur within 10 minutes upon standing.&#xD;
      POTS is estimated to affect up to 3 million persons in the United States and is considered a&#xD;
      syndrome rather than a single disease.&#xD;
&#xD;
      The pathophysiology of POTS is complex, and are related to abnormal cardiovascular autonomic&#xD;
      adaptation to postural changes. Under normal conditions, the assumption of upright posture&#xD;
      does not result in major changes in blood pressure due to the integration of complex&#xD;
      autonomic, circulatory and neurohumoral responses. Upright posture-induced a fluid shift of&#xD;
      approximately 700 mL of blood from the upper thorax to the splanchnic circulation and lower&#xD;
      extremities, which result in decrease in venous return to the heart, ventricular filling, and&#xD;
      stroke volume. These changes cause unloading of the arterial baroreceptors and increase in&#xD;
      sympathetic activity, vasoconstriction and restoration of stroke volume and cardiac output.&#xD;
&#xD;
      In POTS patients, multiple mechanisms have been proposed to explain the exaggerated increase&#xD;
      in heart rate. The orthostatic tachycardia could be a compensatory phenomenon to hypovolemia,&#xD;
      impaired sympathetic-mediated vasoconstriction or increased vascular compliance. The later&#xD;
      could induce an exaggerated fluid shift upon standing from thorax to lower body. Depending on&#xD;
      the mechanism involved different POTS phenotype has been described: (i) hypovolemic POTS;&#xD;
      (ii) neuropathic POTS; and (iii) POTS associated with Ehlers-Danlos and joint hypermobility&#xD;
      syndrome (EDS/JHS). Of note, there is overlapping in the pathophysiology of POTS with&#xD;
      patients having more than one etiology.&#xD;
&#xD;
      In addition to the cardiovascular symptoms, patients with POTS experience significant&#xD;
      gastrointestinal symptoms namely nausea, bloating, diarrhea or even severe constipation.&#xD;
      Furthermore, large meals or high carbohydrate meals exacerbates the feelings of palpitations,&#xD;
      weakness, and fatigue in these patients.&#xD;
&#xD;
      Multiple studies have reported the presence of alterations in the gastrointestinal motility.&#xD;
      Pooled data from 352 patients recruited from 6 different studies, showed 21-80% prevalence of&#xD;
      nausea, vomiting, and abdominal pain. In four of these studies that measured gastric&#xD;
      motility, they found that 43% prevalence of rapid gastric emptying and 20% prevalence of&#xD;
      delayed gastric emptying. Furthermore, Al-Shekhlee et al. reported a high prevalence of&#xD;
      impaired sudomotor function in the POTS patients who reported GI symptoms suggesting that&#xD;
      abnormal post-ganglionic sympathetic function could play a role in the pathophysiology of&#xD;
      these GI abnormalities.&#xD;
&#xD;
      We previously defined a subgroup of POTS patients in whom we detected a partial peripheral&#xD;
      autonomic neuropathy primarily affecting lower extremities (neuropathic POTS). These subjects&#xD;
      had decreased norepinephrine spillover in response to sympathetic activation and abnormal&#xD;
      sweat volumes and prolonged latency detected by quantitative sudomotor axon reflex (QSART).&#xD;
      Recently, Gibbons and Freeman (2013) strengthen the definition by providing histological&#xD;
      evidence of neuronal damage with the inclusion of skin biopsies with specific staining for&#xD;
      autonomic dense fiber and sensitivity assessment.&#xD;
&#xD;
      In Neuropathic POTS there is evidence of impaired vasomotor tone in different specific&#xD;
      vascular bed, particularly the splanchnic circulation. Tani et al. reported reduced&#xD;
      splanchnic vascular resistance and increase in resting mesenteric blood flow providing&#xD;
      evidence of splanchnic denervation.&#xD;
&#xD;
      In summary, there is evidence of post-ganglionic sympathetic denervation is a subset of&#xD;
      patients with POTS. The most current definition are based on the presence of abnormal&#xD;
      sudomotor and sensitivity assessment.&#xD;
&#xD;
      The sympathetic nervous system (SNS) provide innervation to the enteric ganglia, the circular&#xD;
      muscles of sphincters, and the mucosa of the stomach and intestines. The SNS also negatively&#xD;
      regulate the motor and secretory functions of the gastrointestinal (GI) tract. Browning and&#xD;
      Travagli (2014) reported that the absence of sympathetic inhibitory innervation causes&#xD;
      excessive and uncoordinated activity in the GI tract. Indicating that a preserved ANS&#xD;
      (autonomic nervous system) regulation of the GI tract is crucial for the maintenance of&#xD;
      normal GI motility.&#xD;
&#xD;
      In addition to regulating the motor function, the SNS and parasympathetic nervous system&#xD;
      (PNS) regulate the postprandial GI peptides secretion by enteroendocrine cells (EEC). EECs&#xD;
      are the first line components of the Brain-Gut axis. Multiple peptides, such as incretins&#xD;
      (GLP-1, GLP-2, GIP), and PYY (peptide YY) are important for the maintenance of glucose&#xD;
      homeostasis. They are secreted by a different type of EEC in the GI tract. Prior to their&#xD;
      absorption, nutrients in the GI lumen are important stimuli for peptide secretion in the&#xD;
      ileum in rats, pigs , and humans. These peptides are secreted before the bulk of ingested&#xD;
      meal reaches to the ileum, suggesting the presence of a neuronal/endocrine pathway in GI&#xD;
      tract.&#xD;
&#xD;
      In summary, the SNS through innervation the gut smooth muscle; ENS (enteric nervous system)&#xD;
      and EECs negatively regulate the GI motor function and incretins secretion which impact&#xD;
      glucose homeostasis.&#xD;
&#xD;
      Evidence from animal models showed that when rats underwent removal of the superior autonomic&#xD;
      mesenteric ganglia that contains mostly SNS neurons and were challenged with an oral glucose&#xD;
      gavage; plasma insulin and C-peptide secretion were increased compared with controls&#xD;
      (non-ganglionectomised rats). Furthermore, glucose levels were much lower in the&#xD;
      ganglionectomised rats suggesting that the SNS splanchnic innervation plays a critical role&#xD;
      in the maintenance of glucose homeostasis. The increased secretion of insulin and C-peptide&#xD;
      levels in this model could be explained by an increase in incretin hormonal release.&#xD;
      Additional studies using isolated guineas pig ileum (in vitro model) showed that GLP-1&#xD;
      secretion is inhibited by SNS nerve stimulation which is mediated by α-adrenergic receptors.&#xD;
&#xD;
      In summary, in the absence of sympathetic tone on ENS and EECs the incretins secretion&#xD;
      increases which may cause low levels of plasma glucose.&#xD;
&#xD;
      The focus of the present proposal is to determine glucose homeostasis, GI motility, and their&#xD;
      association with GI and cardiovascular symptoms in POTS patients versus healthy controls.&#xD;
      Furthermore, we will determine differences in these outcomes in POTS patients with and&#xD;
      without evidence of postganglionic sympathetic fiber neuropathy.&#xD;
&#xD;
      The glucose homeostasis will be evaluated by a modified oral glucose tolerance test (OGTT).&#xD;
      In addition, we will assess GI symptoms and hemodynamics before and after oral glucose (at&#xD;
      minute 0, 30, 60, 90, and 120). The plasma levels of GI peptides (GLP-1, GLP-2, PYY,&#xD;
      glucagon, C-peptide, insulin) will be measured in different time points after oral glucose.&#xD;
      Gastric emptying will be evaluated by acetaminophen absorption test (AAT). The LPS&#xD;
      (lipopolysaccharide), LBP (lipopolysaccharid-binding protein), sCD14, and I-FABP (faty&#xD;
      acid-binding protein) as GUT cells damage markers will be measured at baseline. The following&#xD;
      technics will be used in this study:&#xD;
&#xD;
        1. Oral glucose tolerance test (OGTT): In the case of OGTT, subjects will be given a&#xD;
           ready-to-use test solution (TRUTOL® 75, Thermo Scientific, USA) containing 75 g glucose&#xD;
           dissolved in 300 mL water, immediately after fasting blood sampling. They will be&#xD;
           instructed to drink the test solution within 5 mins. Blood samples will be drawn at 5,&#xD;
           10, 15, 30, 60, 90, and 120 minutes after drinking the ready-to-use test solution.&#xD;
           Gastric emptying will be measured by acetaminophen absorption test.&#xD;
&#xD;
        2. Acetaminophen absorption test (AAT): Acetaminophen (20 mg/kg) will be given to patients.&#xD;
           Serum acetaminophen will be determined by fluorescence polarization immunoassay. This&#xD;
           assay uses a six-point calibration curve, and the detection limit is 4 µmol/L. The&#xD;
           coefficient of variation is less than 5%. Estimation of the rate of gastric emptying was&#xD;
           based on serum concentrations of acetaminophen in the blood samples collected. An&#xD;
           algorithm that transforms serum concentrations of paracetamol into estimates of gastric&#xD;
           emptying was applied. This algorithm adjusts for first-pass metabolism, unequal&#xD;
           distribution and individual rate of elimination, and provides estimates for the&#xD;
           percentage of meal emptied from the stomach as a function of time.&#xD;
&#xD;
        3. Gastrointestinal symptoms scoring: The 2-page questionnaire is based on elements from a&#xD;
           questionnaire that have been validated with some modifications. The questionnaire&#xD;
           contains 17 questions on the frequency of GI symptoms that have been troublesome in the&#xD;
           preceding 6 months. The frequency of each symptom is rated on seven-point Likert scale&#xD;
           from no discomfort to very severe discomfort.&#xD;
&#xD;
        4. Hemodynamic symptoms scoring: Hemodynamic symptoms will be measured by using the&#xD;
           Vanderbilt POTS Symptom Score. The patients will be asked to rate the severity of 9&#xD;
           symptoms on a 0-10 scale (with 0 reflecting an absence of symptoms). The sum of the&#xD;
           scores at each time point will be used as a measure of symptom burden. The 9 symptoms&#xD;
           are: mental clouding, blurred vision, shortness of breath, rapid heartbeat,&#xD;
           tremulousness, chest discomfort, headache, lightheadedness, and nausea. This symptom&#xD;
           score has been previously used by our center, and the symptoms were chosen as they&#xD;
           reflect common complaints of patients with POTS.&#xD;
&#xD;
        5. Glucose and insulin levels: Glucose levels will be measured with a glucose analyzer (YSI&#xD;
           Life Sciences, Yellow Springs, OH).&#xD;
&#xD;
        6. GI peptides measurements: The plasma designated for GLP-1 measurement will be&#xD;
           supplemented with aprotinin (1,000 kallikrein inactivation unit (KIU)/ml) and dipeptidyl&#xD;
           peptidase-4 inhibitor (20 μl/ml plasma; Millipore, St. Charles, MO). Plasma insulin,&#xD;
           c-peptide, glucagon, GIP, active GLP-1 (7-37 and 7-36 amide), peptide YY, pancreatic&#xD;
           polypeptide, and leptin were measured by multiplex immunoassays (Luminex, Millipore).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 20, 2017</start_date>
  <completion_date type="Actual">December 31, 2020</completion_date>
  <primary_completion_date type="Actual">December 31, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Gastrointestinal hormones plasma levels after oral glucose tolerance test</measure>
    <time_frame>0-120 minutes.</time_frame>
    <description>The plasma levels of GI peptides (GLP-1, GLP-2, PPY, glucagon, C-peptide, insulin) and their pattern of secretion after ingestion of 75 g glucose.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Gastric emptying after oral glucose</measure>
    <time_frame>0-120 minutes.</time_frame>
    <description>Gastric emptying time will be measured by acetaminophen absorption test after ingestion of 75 grams glucose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastrointestinal symptoms</measure>
    <time_frame>0-120 minutes</time_frame>
    <description>The gastrointestinal symptoms will be evaluated by questionnaire after ingestion of 75 grams glucose.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>POTS related symptoms</measure>
    <time_frame>0-120 minutes.</time_frame>
    <description>Symptoms related to postural orthostatic tachycardia symptoms will be evaluated by specific questionnaire after ingestion of 75 grams glucose.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">25</enrollment>
  <condition>Postural Tachycardia Syndrome</condition>
  <arm_group>
    <arm_group_label>POTS</arm_group_label>
    <description>patients with postural orthostatic tachycardia syndrome diagnosis.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy controls</arm_group_label>
    <description>Patients with Postural orthostatic tachycardia syndrome who has peripheral neuropathy</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Oral glucose tolerance test</intervention_name>
    <description>75 grams of glucose</description>
    <arm_group_label>Healthy controls</arm_group_label>
    <arm_group_label>POTS</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood will be retain for DNA extraction.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The participants with POTS and &quot;complete autonomic failure&quot; will be recruited from patients&#xD;
        referred to the Vanderbilt University Autonomic Dysfunction Center. Additional patients&#xD;
        will be recruited from the POTS registry in ResearchMatch, and information about the study&#xD;
        will be posted on websites associated with POTS support groups. Healthy volunteers will be&#xD;
        recruited from a population of previous participants in autonomic studies, through the&#xD;
        ResearchMatch.org database, Subject Locator, and through advertising and emails around the&#xD;
        Vanderbilt community.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18-60 years old&#xD;
&#xD;
          -  Postural Tachycardia Syndrome: Heart rate increase &gt;30 bpm from supine within 10 min&#xD;
             of standing, in the absence of orthostatic hypotension (&gt;20/10 mmHg fall in blood&#xD;
             pressure), with chronic symptoms (&gt; 6 months), and in the absence of other acute cause&#xD;
             of orthostatic tachycardia.&#xD;
&#xD;
          -  Able and willing to provide informed consent&#xD;
&#xD;
          -  Female premenopausal subjects must utilize adequate birth control and willingness to&#xD;
             undergo serum beta-hCG (human chorionic gonadotropin) testing&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of acetaminophen or acetaminophen-related drugs (over-the-counter) in the 24 hours&#xD;
             prior to the study.&#xD;
&#xD;
          -  Hypertension (&gt;150 mmHg systolic and &gt;100 mmHg diastolic) based on history or findings&#xD;
             on screening.&#xD;
&#xD;
          -  Orthostatic hypotension (consistent decrease in BP &gt;20/10 mmHg with 10 min stand)&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  History of type 1 or type 2 diabetes mellitus&#xD;
&#xD;
          -  Cardiovascular disease, such as myocardial infarction within 6 months, angina&#xD;
             pectoris, significant arrhythmia (sinus tachycardia is not excluded), deep vein&#xD;
             thrombosis, pulmonary embolism&#xD;
&#xD;
          -  History of serious neurologic disease&#xD;
&#xD;
          -  Impaired hepatic function (aspartate amino transaminase and/or alanine amino&#xD;
             transaminase &gt;1.5 x upper limit of normal range)&#xD;
&#xD;
          -  Impaired renal function (serum creatinine &gt;1.5 mg/dL)&#xD;
&#xD;
          -  Hematocrit &lt;28%&#xD;
&#xD;
          -  Any underlying or acute disease requiring regular medication that could possibly pose&#xD;
             a threat to the subject or make implementation of the protocol or interpretation of&#xD;
             the study results difficult&#xD;
&#xD;
          -  Inability to comply with the protocol&#xD;
&#xD;
        Healthy control subjects&#xD;
&#xD;
        Defined as subjects without any significant past medical history, non-smokers, and on no&#xD;
        chronic medications at the time of the study. Healthy control subjects will be age- and&#xD;
        BMI-matched to the POTS patients.&#xD;
&#xD;
        Positive control&#xD;
&#xD;
        Patients with complete autonomic neuropathy (pure autonomic failure) will be enrolled as&#xD;
        positive control. This condition is defined as complete autonomic failure based on AFT&#xD;
        (autonomic function test) and norepinephrine plasma levels less than 100 pg/ml.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>cyndya shibao</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Agarwal AK, Garg R, Ritch A, Sarkar P. Postural orthostatic tachycardia syndrome. Postgrad Med J. 2007 Jul;83(981):478-80. doi: 10.1136/pgmj.2006.055046.</citation>
    <PMID>17621618</PMID>
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  <reference>
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  <reference>
    <citation>Dysautonomia International: Postural Orthostatic Tachycardia Syndrome [Internet]. [cited 2016 Aug 15]. Available from: http://www.dysautonomiainternational.org/page.php?ID=30</citation>
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  <reference>
    <citation>Zhang Q, Chen X, Li J, Du J. Clinical features of hyperadrenergic postural tachycardia syndrome in children. Pediatr Int. 2014 Dec;56(6):813-816. doi: 10.1111/ped.12392. Epub 2014 Oct 15.</citation>
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    <PMID>22143364</PMID>
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    <citation>Lawal A, Barboi A, Krasnow A, Hellman R, Jaradeh S, Massey BT. Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol. 2007 Mar;102(3):618-23. doi: 10.1111/j.1572-0241.2006.00946.x.</citation>
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    <citation>Antiel RM, Risma JM, Grothe RM, Brands CK, Fischer PR. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):285-8. doi: 10.1097/MPG.0b013e318145a70c.</citation>
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    <citation>Loavenbruck A, Iturrino J, Singer W, Sletten DM, Low PA, Zinsmeister AR, Bharucha AE. Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome. Neurogastroenterol Motil. 2015 Jan;27(1):92-8. doi: 10.1111/nmo.12480. Epub 2014 Dec 6.</citation>
    <PMID>25483980</PMID>
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    <PMID>23708963</PMID>
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  </reference>
  <reference>
    <citation>Hansen L, Lampert S, Mineo H, Holst JJ. Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E939-47. doi: 10.1152/ajpendo.00197.2004.</citation>
    <PMID>15475512</PMID>
  </reference>
  <reference>
    <citation>Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000 Oct 5;343(14):1008-14. doi: 10.1056/NEJM200010053431404.</citation>
    <PMID>11018167</PMID>
  </reference>
  <reference>
    <citation>Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993 Jan;43(1):132-7. doi: 10.1212/wnl.43.1_part_1.132.</citation>
    <PMID>8423877</PMID>
  </reference>
  <reference>
    <citation>Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One. 2013 Dec 27;8(12):e84716. doi: 10.1371/journal.pone.0084716. eCollection 2013.</citation>
    <PMID>24386408</PMID>
  </reference>
  <reference>
    <citation>Fujimura J, Camilleri M, Low PA, Novak V, Novak P, Opfer-Gehrking TL. Effect of perturbations and a meal on superior mesenteric artery flow in patients with orthostatic hypotension. J Auton Nerv Syst. 1997 Dec 3;67(1-2):15-23. doi: 10.1016/s0165-1838(97)00087-8.</citation>
    <PMID>9470140</PMID>
  </reference>
  <reference>
    <citation>Chaudhuri KR, Thomaides T, Mathias CJ. Abnormality of superior mesenteric artery blood flow responses in human sympathetic failure. J Physiol. 1992 Nov;457:477-89. doi: 10.1113/jphysiol.1992.sp019388.</citation>
    <PMID>1297840</PMID>
  </reference>
  <reference>
    <citation>Tani H, Singer W, McPhee BR, Opfer-Gehrking TL, Haruma K, Kajiyama G, Low PA. Splanchnic-mesenteric capacitance bed in the postural tachycardia syndrome (POTS). Auton Neurosci. 2000 Dec 28;86(1-2):107-13. doi: 10.1016/S1566-0702(00)00205-8.</citation>
    <PMID>11269915</PMID>
  </reference>
  <reference>
    <citation>Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res. 1998 Jan;7(1):75-83. doi: 10.1023/a:1008841022998.</citation>
    <PMID>9481153</PMID>
  </reference>
  <verification_date>February 2021</verification_date>
  <study_first_submitted>August 24, 2017</study_first_submitted>
  <study_first_submitted_qc>August 24, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 28, 2017</study_first_posted>
  <last_update_submitted>February 5, 2021</last_update_submitted>
  <last_update_submitted_qc>February 5, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Cyndya Shibao</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>gastrointestinal hormones</keyword>
  <keyword>Postural Orthostatic Tachycardia Syndrome</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Postural Orthostatic Tachycardia Syndrome</mesh_term>
    <mesh_term>Tachycardia</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>April 19, 2022</submitted>
    <returned>January 18, 2023</returned>
    <submitted>January 25, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03263819
org study id: 170052
nct id: NCT03263819
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Patients with POTS experience significant gastrointestinal symptoms. Current evidence
      suggesting that abnormal post-ganglionic sympathetic function could play a role in the
      pathophysiology of these GI abnormalities. Sympathetic fiber regulate motor and the
      postprandial GI peptides secretion.

      The focus of the present proposal is to determine glucose homeostasis, GI motility, and their
      association with GI and cardiovascular symptoms in POTS patients versus healthy controls.
      Furthermore, we will determine differences in these outcomes in POTS patients with and
      without evidence of postganglionic sympathetic fiber neuropathy.

      As a long-term goal, this study can lead us to understand the pathophysiology of common
      co-morbidities in patients with POTS to provide new treatment approaches and prevention
      strategies.
Postural Tachycardia Syndrome (POTS) is a disabling condition that mostly affects young women
      in their reproductive age. It is characterized by chronic (>6 months) orthostatic intolerance
      symptoms (palpitation, lightheadedness, blurred vision and mental clouding) triggered by
      assuming an upright posture and that improved upon recumbency. These symptoms are associated
      with a rapid increase in heart rate (≥30 bpm) that occur within 10 minutes upon standing.
      POTS is estimated to affect up to 3 million persons in the United States and is considered a
      syndrome rather than a single disease.

      The pathophysiology of POTS is complex, and are related to abnormal cardiovascular autonomic
      adaptation to postural changes. Under normal conditions, the assumption of upright posture
      does not result in major changes in blood pressure due to the integration of complex
      autonomic, circulatory and neurohumoral responses. Upright posture-induced a fluid shift of
      approximately 700 mL of blood from the upper thorax to the splanchnic circulation and lower
      extremities, which result in decrease in venous return to the heart, ventricular filling, and
      stroke volume. These changes cause unloading of the arterial baroreceptors and increase in
      sympathetic activity, vasoconstriction and restoration of stroke volume and cardiac output.

      In POTS patients, multiple mechanisms have been proposed to explain the exaggerated increase
      in heart rate. The orthostatic tachycardia could be a compensatory phenomenon to hypovolemia,
      impaired sympathetic-mediated vasoconstriction or increased vascular compliance. The later
      could induce an exaggerated fluid shift upon standing from thorax to lower body. Depending on
      the mechanism involved different POTS phenotype has been described: (i) hypovolemic POTS;
      (ii) neuropathic POTS; and (iii) POTS associated with Ehlers-Danlos and joint hypermobility
      syndrome (EDS/JHS). Of note, there is overlapping in the pathophysiology of POTS with
      patients having more than one etiology.

      In addition to the cardiovascular symptoms, patients with POTS experience significant
      gastrointestinal symptoms namely nausea, bloating, diarrhea or even severe constipation.
      Furthermore, large meals or high carbohydrate meals exacerbates the feelings of palpitations,
      weakness, and fatigue in these patients.

      Multiple studies have reported the presence of alterations in the gastrointestinal motility.
      Pooled data from 352 patients recruited from 6 different studies, showed 21-80% prevalence of
      nausea, vomiting, and abdominal pain. In four of these studies that measured gastric
      motility, they found that 43% prevalence of rapid gastric emptying and 20% prevalence of
      delayed gastric emptying. Furthermore, Al-Shekhlee et al. reported a high prevalence of
      impaired sudomotor function in the POTS patients who reported GI symptoms suggesting that
      abnormal post-ganglionic sympathetic function could play a role in the pathophysiology of
      these GI abnormalities.

      We previously defined a subgroup of POTS patients in whom we detected a partial peripheral
      autonomic neuropathy primarily affecting lower extremities (neuropathic POTS). These subjects
      had decreased norepinephrine spillover in response to sympathetic activation and abnormal
      sweat volumes and prolonged latency detected by quantitative sudomotor axon reflex (QSART).
      Recently, Gibbons and Freeman (2013) strengthen the definition by providing histological
      evidence of neuronal damage with the inclusion of skin biopsies with specific staining for
      autonomic dense fiber and sensitivity assessment.

      In Neuropathic POTS there is evidence of impaired vasomotor tone in different specific
      vascular bed, particularly the splanchnic circulation. Tani et al. reported reduced
      splanchnic vascular resistance and increase in resting mesenteric blood flow providing
      evidence of splanchnic denervation.

      In summary, there is evidence of post-ganglionic sympathetic denervation is a subset of
      patients with POTS. The most current definition are based on the presence of abnormal
      sudomotor and sensitivity assessment.

      The sympathetic nervous system (SNS) provide innervation to the enteric ganglia, the circular
      muscles of sphincters, and the mucosa of the stomach and intestines. The SNS also negatively
      regulate the motor and secretory functions of the gastrointestinal (GI) tract. Browning and
      Travagli (2014) reported that the absence of sympathetic inhibitory innervation causes
      excessive and uncoordinated activity in the GI tract. Indicating that a preserved ANS
      (autonomic nervous system) regulation of the GI tract is crucial for the maintenance of
      normal GI motility.

      In addition to regulating the motor function, the SNS and parasympathetic nervous system
      (PNS) regulate the postprandial GI peptides secretion by enteroendocrine cells (EEC). EECs
      are the first line components of the Brain-Gut axis. Multiple peptides, such as incretins
      (GLP-1, GLP-2, GIP), and PYY (peptide YY) are important for the maintenance of glucose
      homeostasis. They are secreted by a different type of EEC in the GI tract. Prior to their
      absorption, nutrients in the GI lumen are important stimuli for peptide secretion in the
      ileum in rats, pigs , and humans. These peptides are secreted before the bulk of ingested
      meal reaches to the ileum, suggesting the presence of a neuronal/endocrine pathway in GI
      tract.

      In summary, the SNS through innervation the gut smooth muscle; ENS (enteric nervous system)
      and EECs negatively regulate the GI motor function and incretins secretion which impact
      glucose homeostasis.

      Evidence from animal models showed that when rats underwent removal of the superior autonomic
      mesenteric ganglia that contains mostly SNS neurons and were challenged with an oral glucose
      gavage; plasma insulin and C-peptide secretion were increased compared with controls
      (non-ganglionectomised rats). Furthermore, glucose levels were much lower in the
      ganglionectomised rats suggesting that the SNS splanchnic innervation plays a critical role
      in the maintenance of glucose homeostasis. The increased secretion of insulin and C-peptide
      levels in this model could be explained by an increase in incretin hormonal release.
      Additional studies using isolated guineas pig ileum (in vitro model) showed that GLP-1
      secretion is inhibited by SNS nerve stimulation which is mediated by α-adrenergic receptors.

      In summary, in the absence of sympathetic tone on ENS and EECs the incretins secretion
      increases which may cause low levels of plasma glucose.

      The focus of the present proposal is to determine glucose homeostasis, GI motility, and their
      association with GI and cardiovascular symptoms in POTS patients versus healthy controls.
      Furthermore, we will determine differences in these outcomes in POTS patients with and
      without evidence of postganglionic sympathetic fiber neuropathy.

      The glucose homeostasis will be evaluated by a modified oral glucose tolerance test (OGTT).
      In addition, we will assess GI symptoms and hemodynamics before and after oral glucose (at
      minute 0, 30, 60, 90, and 120). The plasma levels of GI peptides (GLP-1, GLP-2, PYY,
      glucagon, C-peptide, insulin) will be measured in different time points after oral glucose.
      Gastric emptying will be evaluated by acetaminophen absorption test (AAT). The LPS
      (lipopolysaccharide), LBP (lipopolysaccharid-binding protein), sCD14, and I-FABP (faty
      acid-binding protein) as GUT cells damage markers will be measured at baseline. The following
      technics will be used in this study:

        1. Oral glucose tolerance test (OGTT): In the case of OGTT, subjects will be given a
           ready-to-use test solution (TRUTOL® 75, Thermo Scientific, USA) containing 75 g glucose
           dissolved in 300 mL water, immediately after fasting blood sampling. They will be
           instructed to drink the test solution within 5 mins. Blood samples will be drawn at 5,
           10, 15, 30, 60, 90, and 120 minutes after drinking the ready-to-use test solution.
           Gastric emptying will be measured by acetaminophen absorption test.

        2. Acetaminophen absorption test (AAT): Acetaminophen (20 mg/kg) will be given to patients.
           Serum acetaminophen will be determined by fluorescence polarization immunoassay. This
           assay uses a six-point calibration curve, and the detection limit is 4 µmol/L. The
           coefficient of variation is less than 5%. Estimation of the rate of gastric emptying was
           based on serum concentrations of acetaminophen in the blood samples collected. An
           algorithm that transforms serum concentrations of paracetamol into estimates of gastric
           emptying was applied. This algorithm adjusts for first-pass metabolism, unequal
           distribution and individual rate of elimination, and provides estimates for the
           percentage of meal emptied from the stomach as a function of time.

        3. Gastrointestinal symptoms scoring: The 2-page questionnaire is based on elements from a
           questionnaire that have been validated with some modifications. The questionnaire
           contains 17 questions on the frequency of GI symptoms that have been troublesome in the
           preceding 6 months. The frequency of each symptom is rated on seven-point Likert scale
           from no discomfort to very severe discomfort.

        4. Hemodynamic symptoms scoring: Hemodynamic symptoms will be measured by using the
           Vanderbilt POTS Symptom Score. The patients will be asked to rate the severity of 9
           symptoms on a 0-10 scale (with 0 reflecting an absence of symptoms). The sum of the
           scores at each time point will be used as a measure of symptom burden. The 9 symptoms
           are: mental clouding, blurred vision, shortness of breath, rapid heartbeat,
           tremulousness, chest discomfort, headache, lightheadedness, and nausea. This symptom
           score has been previously used by our center, and the symptoms were chosen as they
           reflect common complaints of patients with POTS.

        5. Glucose and insulin levels: Glucose levels will be measured with a glucose analyzer (YSI
           Life Sciences, Yellow Springs, OH).

        6. GI peptides measurements: The plasma designated for GLP-1 measurement will be
           supplemented with aprotinin (1,000 kallikrein inactivation unit (KIU)/ml) and dipeptidyl
           peptidase-4 inhibitor (20 μl/ml plasma; Millipore, St. Charles, MO). Plasma insulin,
           c-peptide, glucagon, GIP, active GLP-1 (7-37 and 7-36 amide), peptide YY, pancreatic
           polypeptide, and leptin were measured by multiplex immunoassays (Luminex, Millipore).
observational model: Case-Control
time perspective: Prospective
measure: Gastrointestinal hormones plasma levels after oral glucose tolerance test
time frame: 0-120 minutes.
description: The plasma levels of GI peptides (GLP-1, GLP-2, PPY, glucagon, C-peptide, insulin) and their pattern of secretion after ingestion of 75 g glucose.
measure: Gastric emptying after oral glucose
time frame: 0-120 minutes.
description: Gastric emptying time will be measured by acetaminophen absorption test after ingestion of 75 grams glucose.
measure: Gastrointestinal symptoms
time frame: 0-120 minutes
description: The gastrointestinal symptoms will be evaluated by questionnaire after ingestion of 75 grams glucose.
measure: POTS related symptoms
time frame: 0-120 minutes.
description: Symptoms related to postural orthostatic tachycardia symptoms will be evaluated by specific questionnaire after ingestion of 75 grams glucose.
arm group label: POTS
description: patients with postural orthostatic tachycardia syndrome diagnosis.
arm group label: Healthy controls
description: Patients with Postural orthostatic tachycardia syndrome who has peripheral neuropathy
intervention type: Diagnostic Test
intervention name: Oral glucose tolerance test
description: 75 grams of glucose
arm group label: Healthy controls
arm group label: POTS
Whole blood will be retain for DNA extraction.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 60 Years
last name: cyndya shibao
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
facility: 
country: United States
citation: Agarwal AK, Garg R, Ritch A, Sarkar P. Postural orthostatic tachycardia syndrome. Postgrad Med J. 2007 Jul;83(981):478-80. doi: 10.1136/pgmj.2006.055046.
PMID: 17621618
citation: Postural Tachycardia Syndrome Information Page: National Institute of Neurological Disorders and Stroke (NINDS) [Internet]. [cited 2016 Aug 15]. Available from: http://www.ninds.nih.gov/disorders/postural_tachycardia_syndrome/postural_tachycardia_syndrome.htm
citation: Dysautonomia International: Postural Orthostatic Tachycardia Syndrome [Internet]. [cited 2016 Aug 15]. Available from: http://www.dysautonomiainternational.org/page.php?ID=30
citation: Zhang Q, Chen X, Li J, Du J. Clinical features of hyperadrenergic postural tachycardia syndrome in children. Pediatr Int. 2014 Dec;56(6):813-816. doi: 10.1111/ped.12392. Epub 2014 Oct 15.
PMID: 24862636
citation: Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis M, Grahame R. Postural tachycardia syndrome--current experience and concepts. Nat Rev Neurol. 2011 Dec 6;8(1):22-34. doi: 10.1038/nrneurol.2011.187.
PMID: 22143364
citation: Lawal A, Barboi A, Krasnow A, Hellman R, Jaradeh S, Massey BT. Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol. 2007 Mar;102(3):618-23. doi: 10.1111/j.1572-0241.2006.00946.x.
PMID: 17100966
citation: Antiel RM, Risma JM, Grothe RM, Brands CK, Fischer PR. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):285-8. doi: 10.1097/MPG.0b013e318145a70c.
PMID: 18376245
citation: Wang LB, Culbertson CJ, Deb A, Morgenshtern K, Huang H, Hohler AD. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci. 2015 Dec 15;359(1-2):193-6. doi: 10.1016/j.jns.2015.10.052. Epub 2015 Oct 30.
PMID: 26671111
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PMID: 25483980
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PMID: 23708963
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PMID: 16527847
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PMID: 7729267
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PMID: 12462361
citation: Orskov C, Rabenhoj L, Wettergren A, Kofod H, Holst JJ. Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes. 1994 Apr;43(4):535-9. doi: 10.2337/diab.43.4.535.
PMID: 8138058
citation: Kumakura A, Shikuma J, Ogihara N, Eiki J, Kanazawa M, Notoya Y, Kikuchi M, Odawara M. Effects of celiac superior mesenteric ganglionectomy on glucose homeostasis and hormonal changes during oral glucose tolerance testing in rats. Endocr J. 2013;60(4):525-31. Epub 2013 Jan 11.
PMID: 23318598
citation: Hansen L, Lampert S, Mineo H, Holst JJ. Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004 Nov;287(5):E939-47. doi: 10.1152/ajpendo.00197.2004.
PMID: 15475512
citation: Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000 Oct 5;343(14):1008-14. doi: 10.1056/NEJM200010053431404.
PMID: 11018167
citation: Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993 Jan;43(1):132-7. doi: 10.1212/wnl.43.1_part_1.132.
PMID: 8423877
citation: Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One. 2013 Dec 27;8(12):e84716. doi: 10.1371/journal.pone.0084716. eCollection 2013.
PMID: 24386408
citation: Fujimura J, Camilleri M, Low PA, Novak V, Novak P, Opfer-Gehrking TL. Effect of perturbations and a meal on superior mesenteric artery flow in patients with orthostatic hypotension. J Auton Nerv Syst. 1997 Dec 3;67(1-2):15-23. doi: 10.1016/s0165-1838(97)00087-8.
PMID: 9470140
citation: Chaudhuri KR, Thomaides T, Mathias CJ. Abnormality of superior mesenteric artery blood flow responses in human sympathetic failure. J Physiol. 1992 Nov;457:477-89. doi: 10.1113/jphysiol.1992.sp019388.
PMID: 1297840
citation: Tani H, Singer W, McPhee BR, Opfer-Gehrking TL, Haruma K, Kajiyama G, Low PA. Splanchnic-mesenteric capacitance bed in the postural tachycardia syndrome (POTS). Auton Neurosci. 2000 Dec 28;86(1-2):107-13. doi: 10.1016/S1566-0702(00)00205-8.
PMID: 11269915
citation: Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res. 1998 Jan;7(1):75-83. doi: 10.1023/a:1008841022998.
PMID: 9481153
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Cyndya Shibao
investigator title: Assistant Professor
mesh term: Postural Orthostatic Tachycardia Syndrome
mesh term: Tachycardia
mesh term: Syndrome
sharing ipd: No
submitted: April 19, 2022
returned: January 18, 2023
submitted: January 25, 2023