Local Vasoconstriction in Postural Tachycardia Syndrome
Condition: Postural Tachycardia Syndrome
MeSH terms: Postural Orthostatic Tachycardia Syndrome; Tachycardia; Syndrome
Study type: Interventional
Phase: Early Phase 1

Summary: 
      The investigators study will determine how often blood flow regulation abnormalities and
      abnormalities of sympathetic regulation produced by nitric oxide, angiotensin-II, and
      oxidative stress occur in POTS and the mechanism(s) of POTS in individual patients. Specific
      causes for POTS may vary from patient to patient. Patients will be compared to healthy
      control subjects. There is a treatment arm with a medication (losartan) that reduces the
      binding of angiotensin and increases NO. If the investigators know the specific biochemical
      mechanism the investigators may be able to offer further specific treatments to specific
      patients.
    

Detailed description: 
      Chronic orthostatic intolerance due to the postural tachycardia syndrome (POTS) severely
      impairs daily life in over a million Americans, mostly young women. POTS is defined by
      symptoms of orthostatic intolerance associated with excessive upright heart rate. While there
      is general agreement that abnormalities in vascular regulation and autonomic activity account
      for the tachycardia and symptoms of POTS, its pathophysiology is heterogeneous and only
      partially characterized.

      The key feature of POTS is symptoms which are most prominent when standing. However, in some,
      findings are present supine (lying down) but worsened standing. Symptoms of POTS include
      dizziness in all patients, exercise provoked symptoms and thus exercise intolerance,
      excessive fatigue, nausea and abdominal pain, headache, shortness of breath and deep
      breathing, weakness, shakiness and postural anxiety, pallor, and neurocognitive loss
      (difficulty thinking). These occur on a day-to-day basis. The symptoms overlap with the case
      definition of chronic fatigue syndrome (CFS) and POTS is often found in CFS in the young.
      Fainting is relatively uncommon during daily life.

      A major subset of POTS has increased peripheral resistance and low blood flow(LFP) related to
      increased angiotensin-II (Ang-II), and decreased nitric oxide (NO). NO deficits are reversed
      by Ang-II type-1 receptor (AT1R) blockade, ascorbic acid (AA) and tetrahydrobiopterin in skin
      suggesting the importance of oxidative stress. Preliminary data also suggest that the
      coupling of sympathetic nerve activity to blood vessel contraction is enhanced via ↑Ang-II
      and ↓NO. We hypothesize that this is due to activation of reactive oxygen species (ROS)
      including superoxide, which scavenges NO to generate peroxynitrite, and hydrogen peroxide.
      Combined measurements in the skin and the systemic circulation will be combined with local
      measurement of ROS production and sympathetic nerve activity will enable us to determine
      precisely how the autonomic nervous system is affected by the illness. Methods include
      cutaneous microdialysis to measure ROS, skin biopsy and blood tests to measure gene
      expression of nitric oxide synthase and Ang-II receptors, and peroneal microneurography to
      measure muscle sympathetic nerve activity (MSNA). Combined with ultrasonic femoral artery
      blood flow this will yield assessment of the interactions of nerves with the blood vessels
      that they control.

      If we discover specific biochemical mechanisms of POTS in patients, then we may be able to
      specifically treat the defect.
    

Intervention name(s): Losartan; Ascorbic Acid (Vitamin C); Normal Saline
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Subjects will receive placebo or losartan for 4 weeks. Days 1-7, subjects will receive 12.5mg of Losartan or placebo. Days 7-14, subjects will receive 25mg of Losartan or placebo. Days 14-28, subjects will receive 50mg of Losartan or placebo.; Subjects will receive 60mg/kg of Ascorbic Acid over 20 minutes followed by a maintenance infusion of 20mg/kg.; Subjects will receive 60mg/kg of normal saline over 20 minutes followed by a maintenance infusion of 20mg/kg of normal saline.
Other intervention name(s): Vitamin C
Intervention MeSH terms: Vitamins; Ascorbic Acid; Losartan
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Diagnostic
Keywords: Postural Tachycardia Syndrome; Orthostatic Intolerance; Reactive Oxygen Species; Oxidative Stress; Angiotensin II; Nitric Oxide; Blood Flow; POTS; Ascorbic Acid; Vitamin C; Losartan