Project Summary/Abstract
Postural tachycardia syndrome (POTS) is chronic orthostatic intolerance with excessive upright
tachycardia without hypotension and occurs mostly in young females (>85%). Symptoms are lightheadedness,
fatigue, cognitive loss, and dyspnea with hyperpneic hypocapnia and ventilatory instability in approximately
50% of our new POTS patients. Our recent studies support an increased hypoxic ventilatory response,
sympathoexcitation with sensitization of the carotid body peripheral chemoreflex. Hypocapnia alone produces
tachycardia and reduces cerebral blood flow (CBF) engendering many POTS symptoms. Unlike voluntary
hyperventilation, hyperpneic POTS is related to decreased central blood volume and cardiac output, increased
systemic vascular resistance and BP, splanchnic blood pooling, and a shift in the sigmoidal baroreflex relation
that favors tachycardia even while supine. Carotid body sensitivity is highly plastic and can be rapidly
conditioned by chronic intermittent hypoxia or by “stagnant hypoxia” - recurrent ischemia of the carotid body.
Stagnant hypoxia can be produced by “initial orthostatic hypotension” (IOH) comprising a transient fall in BP
and CBF on standing. IOH is abnormal in POTS with a paradoxical decrease in cerebral conductance
indicating impaired cerebral autoregulation.
We hypothesize that a mechanism for the genesis of POTS involves carotid body sensitization initiated
by recurrent IOH results in hyperpneic hypocapnia driving tachycardia directly and indirectly by resetting
arterial baroreflexes. We will compare female POTS patients aged 15 to 39 years with (N=40) and without
(N=40) orthostatic hyperpnea, to healthy volunteers (N=40) with the following aims:
1. To test orthostatic cardiorespiratory responses to determine whether prolonged IOH precedes upright
hypocapnia in hyperpneic POTS but not in controls or non-hyperpneic POTS. Cerebral blood flow, respiratory
and hemodynamic measurements, investigating splanchnic blood flow and measuring changes of CBV,
regional blood volumes, and cardiac output during a 10 min stand to quantify IOH, and a 10 min tilt test to 70°
to quantitate cardiorespiratory changes will allow us to stratify hyperpneic and non-hyperpneic POTS patients.
2.To test if chemoreflex sensitization of ventilation and sympathetic activity are abnormal when supine and
upright (at 45o) and how that interacts with Oxford measured cardiovagal and sympathetic baroreflexes under
controlled gas conditions: isocapnic hypoxia and isocapnic hyperoxia to measure carotid body reflex; hyperoxic
isocapnia and hyperoxic hypercapnia to measure central chemoreflexes. Hyperoxia silences peripheral
chemoreceptors and will normalize baroreflex and tilt responses.
3. To employ pharmaceutical modulation of the chemoreflex to elucidate mechanisms of hyperpneic POTS,
with the potential of determining treatment modalities to reduce chemoreflex sensitivity and hyperpnea – using
an angiotensin type 1 receptor blocker, dietary nitrate to donate NO, and an adenosine receptor antagonist.
