Cardiovagal Baroreflex Deficits Impair Neurovascular Coupling and Cognition in POTS
Condition: Postural Orthostatic Tachycardia Syndrome (POTS); POTS; Orthostatic Intolerance
MeSH terms: Orthostatic Intolerance; Postural Orthostatic Tachycardia Syndrome; Tachycardia; Syndrome
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Postural tachycardia syndrome (POTS), is the chronic form of orthostatic intolerance
      associated with excessive upright tachycardia, and occurs predominantly in young females
      (>85%). Among its most troubling symptoms are lightheadedness, fatigue, and decreased memory
      often called "brain fog" by patients. Task-related neurovascular coupling (NVC) links neural
      activity to an increase in CBF known as "functional hyperemia". Although memory task
      performance and NVC deteriorated with angle of tilt in POTS but not healthy controls,
      cerebral blood flow (CBF) remained similar to control. Instead, the investigators observed
      extensive narrow band low frequency (0.07-0.13 Hz) oscillations in BP (OBP) that entrained
      and amplified oscillations in CBF (OCBF). OBP and OCBF increased with tilt angle and caused
      impaired working memory and reduced functional hyperemia. The cardiovagal baroreflex couples
      BP to HR to buffer BP changes. The investigators hypothesize that the cardiovagal baroreflex
      becomes progressively impaired with orthostasis in POTS, but not in healthy volunteers, and
      accounts for OBP, OCBF, and loss of NVC; further, improving the baroreflex reduces OBP, OCBF
      and Brain Fog in POTS.
    

Detailed description: 
      Orthostatic intolerance is defined by debilitating upright symptoms that are relieved by
      sitting or lying. Symptoms include upright lightheadedness, fatigue, confusion, and decreased
      memory called 'Brain Fog' by patients. The most common chronic form is Postural Tachycardia
      Syndrome (POTS), characterized by excessive upright tachycardia without hypotension. Of note,
      >85% of POTS patients are female. The proposal that Brain Fog was caused by reduced cerebral
      blood flow (CBF) has been disproven, because graded incremental upright tilt failed to
      demonstrate difference in mean CBF compared to healthy volunteers. Nevertheless, memory task
      performance deteriorates with angle of tilt as does task-related neurovascular coupling
      (NVC), which links neural activity to an increase in CBF known as "functional hyperemia". The
      investigators have previously observed that large low frequency (0.07-0.13 Hz) oscillations
      in BP (OBP), which entrained and amplified oscillations in CBF (OCBF), increased with tilt
      angle and were associated with impaired working memory and reduced functional hyperemia.

      The sympathetic baroreflex remains intact and HR is excessively increased in the absence of
      parasympathetic counterregulation. The cardiovagal baroreflex couples BP to HR to buffer BP
      changes. Large low frequency BP oscillations, representing a resonance within the sympathetic
      baroreflex loop, occur if there is central hypovolemia, an intact sympathetic baroreflex, and
      reduced parasympathetic buffering of BP by HR; conditions found in upright POTS. This leads
      to the following hypothetical paradigm:

      ↓Cardiovagal Baroreflex → ↑OBP → ↑↑OCBF → ↓NVC → ↓working memory. Therefore, in this
      application, the investigators hypothesize that the cardiovagal baroreflex is impaired in
      POTS while supine, becomes further impaired with orthostasis, and accounts for OBP, OCBF, and
      loss of NVC. Further, the investigators propose that improving the cardiovagal baroreflex
      improves hemodynamics and Brain Fog in POTS patients.
    

Intervention name(s): Pyridostigmine; Digoxin; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 60mg by mouth; 0.5 (500mcg) by mouth; Lactulose 50mg by mouth
Other intervention name(s): Mestinon
Intervention MeSH terms: Digoxin; Pyridostigmine Bromide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: Postural Orthostatic Tachycardia Syndrome (POTS); POTS; Orthostatic Intolerance; Digoxin; Pyridostigmine; Mestinon