THE POSTURAL TACHYCARDIA
SYNDROME
Marvin S. Medow, Ph.D. and Julian M. Stewart, M.D., Ph.D.
Departments of Pediatrics and Physiology, New York Medical
College, Valhalla, New York 10595
Address all correspondence to:
Marvin S. Medow, Ph.D.
Associate Professor of Pediatrics and Physiology
Associate Director, Division of Research
The Center for Hypotension
Department of Pediatrics
New York Medical College
Valhalla, New York 10598
914-593-8886 (phone)
914-593-8890 (fax)
Marvin_Medow@nymc.edu
ABSTRACT
Postural tachycardia syndrome (POTS) is a disorder of unknown etiology, and patients with this
condition exhibit orthostatic intolerance (OI) and excessive tachycardia. Excessive tachycardia
with POTS has been defined as a rapid (within 10 minutes) increase in heart rate by more than 30
beats per minute, or to a heart rate that exceeds 120 beats per minute. Patients with POTS can
experience difficulty with daily routines such as housework, shopping, eating and attending work
or school. The possibility exists that all forms of OI, including POTS, result from central
hypovolemia even without tachycardia. The clinical findings of POTS are observed in an
increasing number of patients who are usually female and aged 15-50 years. Adults with POTS
do not have hypotension, while children may exhibit hypotension. Many patients with POTS are
intolerant of exercise. “Idiopathic” POTS must be distinguished from other conditions that can
reduce venous return to the heart and produce similar signs and symptoms, such as dehydration,
anemia or hyperthyroidism. Therapies for POTS are directed at relieving the central
hypovolemia or at compensating for the circulatory dysfunctions that may cause this disorder.
Treatments have resulted in varying degrees of success, and are often used in combination with
each other.
Key Words: Postural tachycardia syndrome; orthostatic intolerance; excessive tachycardia
2
Orthostatic Intolerance (OI) is a constellation of symptoms that are elicited by standing upright
and relieved by becoming supine. As shown in Table 1, symptoms of OI include headache,
nausea, abdominal pain, lightheadedness, diminished concentration, tremulousness, syncope,
near-syncope and hyperpnea. OI is defined by its symptoms and does not require heart rate or
blood pressure abnormalities. In addition, some patients with OI complain of extreme fatigue,
sleep abnormalities and migraine headaches (1). Postural tachycardia syndrome (POTS) can be
defined as a form of OI, but with the clinical findings of excessive upright tachycardia. The
possibility exists that all forms of OI (including POTS) result from central hypovolemia even
without tachycardia.
While patients with POTS, by definition, have OI, excessive tachycardia has been
defined as a rapid (within 10 minutes) increase in heart rate by more than 30 beats per minute, or
a heart rate that exceeds 120 beats per minute (2). OI can occur in the absence of significant
heart rate increases, and patients with OI, similar to those with POTS, can experience difficulty
with daily routines such as housework, shopping, eating and attending work or school.
HISTORY AND BACKGROUND
Although POTS has been the subject of many recent investigations, it may have been described
in the 1870’s at the time of the American Civil War by DaCosta (3), who reported symptoms of
tachycardia and palpitations and classified these as being due to “irritable heart syndrome” and
“Soldier’s heart”. In the early 1900’s patients with “vasoregulatory asthenia” and
“neurocirculatory asthenia” were cited in the literature as exhibiting POTS-like symptoms that
were due to poor neural regulation of peripheral blood flow (4). Some 30 years later, MacLean
described patients who upon standing, exhibited orthostatic tachycardia, a modest decrease in
blood pressure, exercise intolerance, lightheadedness, palpitations and generalized weakness and
3
ascribed these symptoms to defective venous return to the heart (5). Several similar reports were
published in the ensuing decades describing tachycardia upon standing with little or no
hypotension (6).
A more contemporary study by Streeten of patients classified as having “postural
tachycardia” were shown to have marked venous pooling of sodium pertechnetate Tc99 upon
standing, as well as an exaggerated response to the infusion of isoproterenol (7;8). Hoeldtke et al.
then described a cohort of patients, all of whom exhibited symptoms of postural tachycardia
along with exercise intolerance, cognitive impairment, anxiety, and gastrointestinal hypermotility
(9;10). Other names, such as idiopathic orthostatic tachycardia, have been used more recently to
describe patients with POTS-like symptoms (11). The term “postural tachycardia syndrome” was
then operationally defined by Schondorf and Low as an increase in heart rate by more than 30
beats per minute, or an increase to a heart rate exceeding 120 beats per minute within 10 minutes
when changing from supine to an upright position without associated hypotension (12). This
working definition of POTS applies largely to adults, and may not be appropriate for younger
patients who often develop hypotension when maintained upright for long periods of time. Older
subjects may experience an increase in blood pressure with the imposition of an orthostatic
challenge (13-15), thus producing an “orthostatic hypertension”.
POTS is thought to be an acquired disease and the onset of OI symptoms often follow an
infectious disease (2;16). As a result, associations with abnormalities in the inflammatory response
have been proposed. Patients often slowly improve after the initial infectious illness, only to
become ill again spontaneously or during an intercurrent infection (2;17). Symptoms may begin
following pregnancy, major surgery, trauma or a presumed viral illness. There may also be an
association between POTS and joint hypermobility as seen in some patients with Ehlers-Danlos
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syndrome (18-20). Findings of autonomic dysfunction, such as gastrointestinal symptoms and
sudomotor abnormalities, may occur in some POTS patients (21).
EPIDEMIOLOGY
Approximately 75% to 80% of POTS patients are female, ranging in age from 14 to 50 years (22),
and therefore roughly span the ages from menarche to menopause. POTS is relatively uncommon
in preadolescent children and may have a different pathophysiology in the very young. The
reasons for this sex distribution are unclear, although women are known to be more vulnerable to
orthostatic stress (23). Associations with the menstrual cycle or with altered estrogen or progestin
levels s are yet to be established, however some female patients report an increase of symptoms
in the pre-menstrual phase of their ovulatory cycle (24). The illness may follow a remitting and
relapsing clinical course, often enduring for years, but seems in many instances to be selflimited. Pregnancy may resolve abnormalities (25). As currently construed, POTS was first
reported in adults (2;26-29), but pediatric cases have shown that POTS is a common form of OI
during upright tilt in adolescents with chronic fatigue syndrome (CFS) (30;31). In adults with CFS,
approximately 25% of patients have evidence of POTS (32).
CLINICAL FEATURES
POTS findings are exhibited by an increasing number of patients, usually females (5:1 over
males), who are typically aged 15-50 years (33;34). Adults with POTS do not have hypotension,
while children may exhibit hypotension, and many patients with POTS are intolerant of exercise
(35). “Idiopathic” POTS must be distinguished from other conditions that reduce venous return
to the heart and produce similar signs and symptoms, such as prolonged bed rest or drugs that
impair venous return (vasodilators, diuretics, antidepressants and anxiolytics). Our data indicate
5
that central hypovolemia while upright is a constant feature in patients with POTS. Therefore,
any conditions associated with central hypovolemia that may cause tachycardia (dehydration,
anemia or hyperthyroidism) may also mimic POTS.
In addition to the tachycardia and OI that accompany POTS, we and others have
described a subset of patients with peripheral acrocyanosis (36-38) that is associated with
decreased blood flow, especially in cyanotic skin. The distribution of color change does not
mimic that seen in patients with Raynaud’s phenomenon, which is confined to the hands and
feet. Rather there is more widespread extension, especially in dependent extremities, with a
mottled appearance comprising islands of pink skin and normal cutaneous blood flow
interspersed among prevailing cyanosis with decreased cutaneous blood flow. Although this
appearance is often called venous pooling, evidence does not support excessive venous
capacitance nor an enhanced collection of venous blood within the vasculature. Rather, data
indicate decreased overall blood flow in the affected extremity which results in a relative
coolness of the limb and a type of “stagnant hypoxia” (39;40). This may be mediated by a deficit
of locally-produced nitric oxide and is not likely due to increased pooling in venous capacitance
vessels (41).
PATHOPHYSIOLOGY
POTS represents a category of disease rather than a single distinct illness, and common to all of
its variants is a final physiologic pathway involving excessively reduced venous return to the
heart while upright. Current evidence indicates that the related symptoms are due to excessive
central hypovolemia in all patients with POTS. The signature tachycardia may therefore result
from related reflex parasympathetic withdrawal and sympathetic activation. Studies of heart rate
and blood pressure variability indicate vagal withdrawal and at least relative cardiac sympathetic
6
excess (42-44). Decreases in baroreflex gain measured by the Oxford method (45) or by variability
techniques (46) can be replicated by a model of hypovolemia in human beings (47). Cardiac
sympathetic activity may relate to chest pain experienced by some POTS patients and ECG-wave
changes that are sometimes seen (48).
The symptoms associated with POTS can best be understood by reviewing the normal
physiological response of accommodation to positional changes. When changing from supine to
standing, gravity produces a rapid downward shift in thoracic blood such that about 600 ml of
blood moves into the lower body (49;50). When standing, about 70% of our blood volume is
located below the heart. This displacement of blood may occur within seconds to minutes of
standing and may affect up to 25% of total blood volume. This results in decreased venous
return to the heart and decreased stroke volume by as much as 40%. Inadequate systemic venous
return to the right heart, or thoracic hypovolemia, is thought to be the precipitating phenomenon
in the genesis of POTS-like symptoms (51-53). Reduction in venous return can be related to flowdependent changes that occur both peripherally and centrally.
Compensation for these dynamic changes occurs rapidly in healthy individuals through
the actions of many integrated mechanisms (54-60). These are initiated by the time-dependent
decrease in arterial pressure and cardiac filling that occurs soon after standing. Decreases in
pressure and filling alter the activity of the high-pressure baroreceptor in the aortic arch and
carotid sinus, and low pressure baroreceptors and stretch receptors located in the heart and lungs.
The net result of standing, therefore, in healthy individuals, is a modest increase in heart rate (1015 beats/min), and an increase in diastolic pressure (about 10 mmHg) with little or no increase in
systolic pressure. Re-attainment of a stable heart rate and blood pressure is achieved by
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maintaining adequate venous blood return through various mechanisms related to physical forces
(e.g. the skeletal muscle pump) and neurovascular control.
Postural changes in blood distribution affect various vascular beds, including those in the
abdominal and pelvic region. This fluid translocation initiates a host of compensatory responses
outlined in Table 2, without which humans could not maintain adequate blood pressure or
essential regional blood flow while upright. Failure of any of these compensatory mechanisms
aggravates thoracic hypovolemia and can result in POTS. While autonomic regulation is among
the neurovascular control mechanisms that compensate for orthostatic vascular changes, other
mechanisms, including local forms of vascular regulation and neurohumoral factors, are also
involved. Humoral vasoregulation is often thought to relate to longstanding alterations in
orthostatic stress and likely plays a small role in the early responses seen upon standing in
otherwise normal individuals.
Factors that Reduce Compensatory Responses to Decreased Blood Volume
Since thoracic hypovolemia can cause POTS, it can be simulated by or its symptoms exacerbated
by dehydration or hemorrhage. Systemic hypovolemia has been demonstrated in some patients
with POTS (5) and may be related to defective denervation of the kidneys and associated
hyporeninemic hypoaldosteronism (61;62). A reflex response to fluid shifts results in the
circulatory insufficiency observed in patients (63). More recent data indicate that hypovolemia
tends to be modest and may not be sufficient to explain OI in orthostatically-challenged patients
with POTS (64). Despite these findings, decreased blood volume impairs venous return and is a
common contributing factor in the genesis of POTS symptoms. All compensatory mechanisms
for orthostasis depend on adequate circulatory volume and all will ultimately fail during
sufficiently severe hypovolemia. Conversely, repletion of blood volume is often helpful in OI,
8
whatever the cause, because it invariably enhances postural venous return (5;65;66), and volume
loading may improve patient well-being nonspecifically as well.
Regional Blood Volume and Vascular Properties
The distribution and disposition of gravitationally displaced blood is controlled by many
factors, chief among them are regional blood flow and vascular compliance, and peripheral
arterial and peripheral venous resistance (Pv). These characteristics can provide a useful and
physiologically important means by which to further categorize POTS patients. Our laboratory
(67-69) has described three groups of POTS patients distinguished by differences in peripheral
blood flow and peripheral arterial resistance with:
1) A low-blood flow, high-arterial resistance, high-Pv group, denoted “low-flow” POTS
is characterized by pallor, generally decreased blood flow, most notable in the dependent parts of
the body. This low-flow condition is related to defects in local blood flow regulation and mild
absolute hypovolemia.
2) A normal-blood flow, normal-arterial resistance group with normal Pv, denoted
“normal flow” POTS is characterized by a normal supine phenotype, with normal peripheral
resistance supine but enhanced peripheral resistance upright. There is specific venous pooling
within the splanchnic vascular bed, making this a redistributive form of hypovolemia.
3) A high-blood flow, low-arterial resistance group with normal to decreased Pv,
denoted “high-flow” POTS is related to a long tract neuropathy and is characterized by high
cardiac output caused by inadequate peripheral vasoconstriction supine and upright. Patients
typically are acyanotic, warm to touch, with extensive filtration, resulting in dependent edema.
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The changes in regional blood flow with upright tilt, comparing control subjects to those
with low, normal and high-flow POTS are shown in Figure 1. This illustrates the differences in
regional blood flow exhibited by each of these subgroups of POTS, and in aggregate, may
explain the wide variation of symptoms exhibited by these patients.
In low-flow POTS there appears to be a general deficit in blood flow regulation that is
most notable in the dependent parts of the body. Prior work suggests that there are defects in
local blood flow regulation in these patients (70). Absolute hypovolemia is also present and
further contributes to the OI response. Decreased peripheral venous capacitance provides
evidence for either venous remodeling or persistent peripheral leg venoconstriction, which
allows for cephalad redistribution of blood under resting conditions. Normal-flow POTS is
characterized by normal peripheral resistance in the supine and upright positions and specific
venous pooling within the splanchnic vascular bed. The specific mechanism or mechanisms that
result in such pooling remains undetermined. Lastly, high-flow POTS is characterized by
inadequate peripheral vasoconstriction in both the supine and upright positions. This enhances
cardiac output as in other high-output conditions.
This 3 group classification scheme incorporates various physiological parameters such as
blood flow, blood distribution and venous compliance to construct a dynamic model of human
vascular dysfunction in POTS. It provides a framework to test hypotheses used to explain the
findings of POTS and will likely evolve as more information is accumulated. Although this
physiologic classification scheme has the potential to refine treatment approaches, this
classification of 3 groups of POTS patients is not easily made in most clinical laboratories.
Therefore, further research will be needed to translate these research findings into clinical
practice.
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Low Flow POTS: Contributions to the compensatory response to orthostasis arising from
local vasoactive products are often less well appreciated than classic myogenic, metabolic, and
venoarteriolar flow control (71-73) . Often, local factors interact extensively with the autonomic
nervous system (ANS). The ANS may provide a systemic framework modulated by local
biochemical and metabolic requirements. Local responses may be important compensatory
mechanisms during orthostasis and arise from vasoactive endothelial-derived products (i.e., nitric
oxide [NO], prostacyclin/prostaglandin I2 [PGI-2], endothelin, endothelium-derived
hyperpolarizing factor [EDHF] (74;75), metabolites (adenosine,Ca2+ , CO2, H+ ions, lactate) (7678
), autacoids (histamine, bradykinin, serotonin/5-hydroxytryptamine [5-HT], platelet-activating
factor [PAF], prostaglandins) (79), local neurogenic mechanisms such as the axon reflex (80),
and neurogenic inflammation (calcitonin-gene related protein [CGRP], substance-P) (81;82),
especially within the cutaneous and enteric circulations. A defect in local vascular compensation
to orthostatic stress is demonstrable in a subgroup of patients with POTS (83).
These patients are intensely peripherally vasoconstricted while supine and have decreased
blood volume, increased total peripheral resistance, and low resting cardiac output. They have a
characteristic phenotype of pallor, extensive supine and upright acrocyanosis, cool skin and
extremities, and defective skeletal muscle pump (84;85). They are usually tachycardic while
supine, more so during orthostasis, and give the appearance of early circulatory insufficiency.
Although blood volume is, on average, decreased compared with control subjects, individual
values often fall within the normal range and fail to correlate with the degree of supine
vasoconstriction (86). Hyperemic blood flow, a measure of endothelial cell function, is abnormal
compared with either control patients or other patients with POTS, indicating abnormal local
blood flow regulation in these patients.
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We have recently shown that abnormalities in the regulation of blood flow in patients
with low-flow POTS are related to bioavailable NO release (87), as illustrated by the results
shown in Figure 2 (A & B). In these studies, we used skin as a surrogate for the peripheral
circulation, and administered the nitric oxide synthase (NOS) inhibitor, Nω-Nitro-L-arginine
methyl ester hydrochloride (L-NAME) by iontophoresis during heating. Local heating followed
by saline or L-NAME in a low-flow POTS patient results in an initial peak, but there is marked
attenuation of the NO-dependent plateau, even after saline administration. This resembles
blunting by the NOS inhibitor L-NAME. Iontophoretic administration of L-NAME minimally
blunts the initial peak, but has no additional effect on the plateau phase because of preexistent
impairment of NO release.
Support for differences in NO production is provided for by recent findings that showed
the frequencies for two polymorphisms that encode for endothelial NOS (eNOS) were
significantly lower in patients with POTS, compared to controls (88). These polymorphisms were
also associated with the largest changes in heart rate and plasma norepinephrine levels with
standing and this genotype may influence the development of POTS and the severity of POTS
symptoms.
We also showed that in low-flow POTS patients, thoracic hypovolemia may be a result of
increased angiotensin-II, decreased renin and relative hypovolemia (89). These results are shown
in Figure 3. Although the precise cause of flow abnormalities is currently uncertain, it is clear
that treatments that increase blood volume may help to alleviate signs and symptoms. Data from
our laboratory showed no improvement in response to an acute infusion of a β-blocker in this
subset, although we have not studied the use of β-blockers as part of combination therapy (90).
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Normal Flow POTS: Some patients with POTS have neither increased nor decreased
recumbent blood flow compared with control subjects. These patients with so-called ‘‘normal
flow POTS’’ appear perfectly well when supine and make up an increasing subset of patients
identified in our practice. When upright, they have excessive tachycardia, greatly enhanced
peripheral vasoconstriction, and often acrocyanosis. There are no findings suggesting a local
peripheral defect. Instead, their excessive vasoconstriction appears to be related to thoracic
hypovolemia and reciprocal splanchnic pooling (91).
High Flow POTS: Our data indicate that patients designated “high flow POTS” are
peripherally vasodilated and mildly tachycardic when supine and have relatively increased blood
volume, reduced total peripheral resistance, and high resting cardiac output compared with
healthy control subjects (92;93). Support for a ‘‘long tract neuropathy’’ with a neuropathic
adrenergic vasoconstrictive defect comes from Jacob et al.(94). These patients exhibit defective
peripheral vasoconstriction during orthostasis that leads to excess blood delivery to the lower
limbs, enhanced microvascular filtration and edema formation (95). Acrocyanosis does not
generally occur in these types of POTS patients. Persistent upright vasodilation responds to
vasoconstrictor therapy with midodrine or similar agents. Patients are extremely likely to have
illness after a viral infection. A peripheral autoimmune neuropathy may be suspect, and if
present, is self-limiting, although the clinical course could extend for months to 1 year or more
(96).
Additional Pathophysiological and Etiologic Mechanisms in POTS
Muscle Pump Defects: Physical forces comprise a primary defense against the pooling
of blood in the dependent lower extremities in human beings. This occurs through the activity of
the ‘‘skeletal muscle pump’’ in which contractions of leg and gluteal muscles increase interstitial
13
pressure and propel sequestered venous blood back to the heart (97). The effectiveness of this
pumping action is facilitated by the presence of one-way venous valves. Patients whose venous
valves are incompetent or congenitally absent suffer from severe OI (98). Skeletal muscle may
also be involved in neurogenic compensation through chemoreceptors and through local control
mechanisms (99). Recent data indicate that while the muscle pump is normal in most patients
with POTS, the muscle pump is defective in low flow POTS patients who also have decreased
resting peripheral blood flow unrelated to exercise capability but exacerbated by bed rest (100).
Ambulation is therefore essential for the reduction of POTS symptoms. Lower body exercise
may be very helpful, but its utility has not yet been examined in a systematic way.
Autonomic Autoimmune Neuropathy: The largest proportion of POTS patients are said
to have a mild form of peripheral autonomic autoimmune neuropathy manifested by a
dysfunctional peripheral vasculature. They demonstrate findings of increased adrenergic tone at
rest and enhanced postganglionic sympathetic response to upright posture (101). However, serum
catecholamine levels are normal or only slightly elevated when upright. This is currently
attributed to an immune-mediated process as autoantibodies to the peripheral nervous system
have been identified (102). This mechanism as the cause of POTS is further supported by the
frequent reports of antecedent illnesses preceding the onset of symptoms.
Histamine Related: Other patients with POTS have episodic flushing and increased
urinary levels of methylhistamine, a primary urinary metabolite of histamine. These patients are
thought to have a co-existing mast cell activation disorder that is associated with shortness of
breath, headache, lightheadedness, diarrhea nausea and vomiting (103). Patients can have a
hyperadrenergic response resulting in orthostatic tachycardia and hypertension. At the present
time, it is unclear whether mast cell activation associated release of vasoactive mediators is the
14
primary event, or if sympathetic activation results in mast cell activation (104). In these patients,
while β-adrenergic antagonists may exacerbate symptoms, treatment with antihistamines (H1 and
H2 antagonists) in combination with non-steroidal anti-inflammatory drugs may be beneficial.
Hyperadrenergic Neuropathy: Measurements of plasma norepinephrine in POTS
patients show that supine levels are often “high-normal” while values obtained when POTS
patients are upright can be elevated above 600 ng/ml (105). Accordingly, they show intact or
exaggerated autonomic reflex responses. This is manifested in vigorous pressor response to the
Valsalva maneuver with preservation of vagal function (106). These patients often complain
about extreme anxiety when upright and having cold, sweaty extremities. The majority also have
true migraine headaches that include prodromes of photophobia and nausea (107).
There have been several reports of POTS patients who have a form of partial autonomic
neuropathy with regional denervation of sympathetic nerves that may be autonomic autoimmune
neuropathy. This appears to be somewhat paradoxical in view of the description of POTS
patients with elevated plasma norepinephrine levels (108-110). Jacob et al, reported patients with
neuropathic POTS that had normal sympathetic neuronal norepinephrine release in their arms,
but impaired release in their lower body (111).
Norepinephrine Transporter Protein Deficiency: Another recent autonomic condition
producing a complex form of POTS is norepinephrine transporter (NET) protein deficiency. This
has been reported in only a single family. Investigators have identified a single point mutation in
the NET protein (112) that exerts both central and peripheral effects on vascular regulation (113).
Despite its rarity, the illness has furnished an ideal monogenetic model for autonomic illness, and
appropriate animal knock-out models have been constructed and investigated (114). A NETdeficient mouse was recently shown to have near normal resting arterial pressure and heart rate,
15
likely due to increased sympatho-inhibition. When engaged in awake activities, however, these
mice exhibited excessive tachycardia and elevated blood pressure (115).
TREATMENT OF POTS
The treatment of POTS is difficult because no single therapy has been shown to be effective and
large-scale, blinded studies have not yet been performed. This is due, in part, to the wide range
of symptoms exhibited by most patients and the finding that most patients exhibit signs of
cardiovascular and gravitational deconditioning as a result of chronic sedentary state. This may
include prolonged immobilization, significant weight loss, chronic debilitating diseases, diabetes
and dehydration, to name a few. Initial treatment should therefore be directed towards correcting
any chronic disease or condition that may presently exist, and in mobilizing and reconditioning
patients. Initial therapy should also include increasing fluid and salt intake. Patients should be
required to drink 8-10, 16 ounce glasses of water each day, and to increase their sodium intake to
200 mEq/day. A review of some of the major treatment modalities is shown in Table 3.
Aerobic exercise and resistance training have also been shown to be beneficial (116).
POTS patients should therefore be encouraged to slowly work up to doing 20 minutes of aerobic
exercise 3 times per week (117). Patients who exhibit signs of deconditioning may benefit from
initial exercise training in a swimming pool. This confers the benefits of both buoyant support
and hydrostatic pressure-enhanced venous return. Exercise has the added benefit of increasing
blood volume, thereby diminishing hypovolemia-related symptoms. Elastic support garments,
such as pantyhose and lycra bicycle shorts and leggings, can also minimize venous pooling and
enhance venous return. These are most useful if they can provide 30-40 mmHg counterpressure.
16
To obviate the effects of hypovolemia, blood volume expansion can be achieved rapidly
by infusing saline in these patients. Jacob et al has shown that infusing 1L saline over 1 hour
significantly reduced the tachycardia in subjects with POTS (118). Sometimes the beneficial
effects of such infusions are delayed by a day or more. While volume expansion is effective and
provides relatively rapid relief from symptoms, it is seldom a practical option to employ on a
regular, prolonged basis due to the associated risks of vascular access and infection.
The management of POTS using pharmacological agents is accomplished through the use
of “off-label” medications, because there are no FDA-approved regimens for this condition.
Heart rate control can be accomplished through the use of low-dose β-antagonists, such as
propranolol or labetalol, or through the use of digoxin. -blockers however, can potentially
cause hypotension or increasing fatigue. Inappropriate control of peripheral vascular resistance
has been postulated as a cause of POTS (119), and as a result, the use of α-agonists (α-1,
midodrine hydrochloride, pseudoephedrine α-2, clonidine) can improve orthostatic tolerance and
suppress the related tachycardia (120). Side effects are prominent and may include
“goosebumps”, scalp-tingling and supine hypertension with midodrine, and dry mouth and
constipation with clonidine. An association with hypermobility syndromes may exist (121) and
serves as a bridge to the recent findings by Rowe et al in CFS (122). Therapies that result in
vasoconstriction, such as midodrine, are sometimes helpful.
Several studies have described the use of octreotide, a somatostatin analogue that
produces systemic vasoconstriction as well as selective splanchnic vasoconstriction, for the
treatment of POTS, postprandial hypotension and hypotension associated with diabetic
neuropathies (123;124). Its use is unfortunately limited by side effects that include abdominal pain
and diarrhea, and the inconvenience of having to administer the drug subcutaneously. It has also
17
been used successfully in combination with midodrine hydrochloride which seems to potentiate
its effects (125). A sustained-release formulation of octreotide is currently available.
Long-term treatment of patients for hypovolemia can be accomplished with the use of the
aldosterone analogue, fludrocortisone, that results in salt retention and volume expansion. The
vasopressin analogue, [deamino-Cys1, Val4, D-Arg8]-Vasopressin (DDAVP) can also be used,
however hyponatremia due to free-water retention, may result. Erythropoietin has been used
effectively to treat POTS and is proposed to work by both increasing vascular volume (126;127)
and by exerting a direct, vasoconstrictive effect (128).
The acetylcholinesterase inhibitor pyridostigmine (mestinon) has also been used
successfully to treat POTS (129;130). It achieves this effect by increasing the availability of
acetylcholine at both ganglionic nicotinic acetylcholine receptors and postganglionic muscarinic
acetylcholine receptors. This results in increased parasympathetic tone, increased cardiovagal
tone and a decreased heart rate. Orthostatic heart rate increases were attenuated with this drug in
a group of patients with neurogenic orthostatic hypotension (131).
SUMMARY
POTS is a disorder of unknown etiology and patients with POTS exhibit OI and excessive
tachycardia. Excessive tachycardia has been defined as a rapid (within 10 minutes) increase in
heart rate by more than 30 beats per minute, or to a heart rate that exceeds 120 beats per minute.
Reports of patients with “POTS-like symptoms” have been reported for over 100 years. POTS
represents a category of disease rather than a single distinct illness, and common to all of its
variants is a final physiologic pathway involving excessively reduced venous return to the heart
while upright.
18
Symptoms may begin following pregnancy, major surgery, trauma or a presumed viral illness.
Patients with POTS can experience difficulties with daily routines such as housework, shopping,
eating and attending work or school. It is likely that all forms of OI (including POTS) result from
central hypovolemia even without tachycardia.
POTS findings are exhibited by an increasing number of patients who are usually female
and aged 15-50 years. Adults with POTS do not have hypotension while children may exhibit
hypotension. Many patients with POTS are intolerant of exercise. “Idiopathic” POTS must be
distinguished from other conditions that reduce venous return to the heart and that also produce
similar signs and symptoms. Conditions associated with central hypovolemia (dehydration,
anemia or hyperthyroidism) may cause tachycardia and mimic POTS.
Therapies are directed at relieving the central hypovolemia or at compensating for the
circulatory dysfunctions that may cause this disorder. Treatments include the use of water, saline
infusions, β-antagonists, α-agonists and other agents that may correct the central hypovolemia.
These have resulted in varying degrees of success, and they are often used in combination.
Continued research is necessary to help fully understand the pathogenesis of POTS and
its symptoms, as well as to validate the efficacy of various therapies.
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Figure 1. Changes in thoracic, splanchnic, pelvic, and leg percent volume changes during
upright tilt averaged over subject groups. Splanchnic changes dominate normal (Nl)-flow POTS.
Low-flow POTS patients have widespread blood collection. High-flow POTS patients have
blood pooling in the dependent body parts (132).
Figure 2A - Top, Saline or L-NAME administered to a representative reference subject by
iontophoresis followed by local heating to 43°C. An initial peak occurs and is followed by a higher
plateau. Iontophoretic administration of L-NAME slightly blunts the initial peak and markedly
decreases the plateau phase. Figure 2B - Bottom, Local heating followed by saline or L-NAME in a
representative low-flow POTS patient. The initial peak is present, but there is marked attenuation of
the NO-dependent plateau, even after saline administration, which resembles blunting by the NO
inhibitor L-NAME. Iontophoretic administration of L-NAME minimally blunts the initial peak but has
no additional effect on the plateau phase because of preexistent impairment of NO release (133).
Figure 3. Plasma Renin Activity (PRA) and serum aldosterone and plasma angiotensin II
concentrations in study subjects. PRA was significantly decreased and angiotensin II was
increased in low-flow POTS patients compared with control subjects. Angiotensin II
concentrations appeared to follow a bimodal distribution (134).
20
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30
TABLE I
Table I. Symptoms of orthostatic intolerance
Lightheadedness
Headache
Fatigue
Neurocognitive/sleep disorders
Exercise intolerance
Weakness
Hyperpnea/dyspnea
Tremulousness
Nausea/abdominal pain
Sweating
Anxiety/palpitations
31
TABLE II
Table II. Compensatory response to orthostasis
Blood volume
Physical forces,
eg, interstitial compression
Neurovascular control
Long distance control
Autonomic nervous system
Neurohumoral: Adrenal, RAS, AVP, ANP
Local control
Autacoids, inflammatory mediators
Neurogenic inflammation
RAS, Renin-Angiotensin System; AVP, Arginine Vasopressin; ANP, Atrial Natriuretic Factor.
32
TABLE III – TREATMENT of POTS
THERAPY
USUAL DOSAGE
MECHANISM of ACTION
DISADVANTAGES
Drinking Water
At least 2L/day
Blood Volume Expansion
Difficult, Possible hyponatremia,
Peripheral edema
Supplemental Salt
up to 150-200 mEq/day
Blood Volume Expansion
edema
Non-Pharmacological
Exercise
Difficult, Nausea, Peripheral
30 minutes, 3X/week
Blood Volume Expansion,
Difficult, Too vigorous exercise
Aerobic and resistance
reversal of deconditioning
may worsen symptoms
Elastic Support Hose
Must provide 30-40 mmHg
Pressure
Increase Venous Return
Hot, Uncomfortable
Standing Exercises
Squat while crossing legs,
Contract gluteal muscles
Increase Venous Return
Transient symptom relief
Acute IV Saline
1 L infused 1-3 hrs.
Blood Volume Expansion
required
Inconvenient, Medical facilities
Chronic IV Saline
1 L infused every 1-2 days
Blood Volume Expansion
Inconvenient, Requires central
access, Risk of infection
Fludrocortisone
0.05-0.1 mg PO
OD or BID
Blood Volume Expansion
Edema, Fluid Retention,
Hypokalemia, Headache,
Hypertension
Desmopressin
(DDAVP)
0.1-0.2 mg PO
OD or BID
Blood Volume Expansion
Hyponatremia, Headache, Edema
Erythropoietin
2000-3000 IU SQ
1 to 3 times/week
Blood Volume Expansion
Vasoconstriction
Expense, Requires injections,
Hypertension
Midodrine Hydrochloride
2.5-10 mg PO BID
α-1 Adrenergic Agonist
Hypertension, Goose-bumps,
Scalp Tingling, Urinary retention
Propranolol
10-20 mg PO OD or
BID
β-adrenergic Antagonist
Hypotension, Fatigue, Wheezing
Octreotide
0.9 mg/kg SQ BID
Splanchnic Vasoconstriction
Abdominal cramping, Diarrhea,
Nausea
Pyridostigmine
30-60 mg PO TID
Splanchnic Vasoconstriction
Abdominal cramping, Diarrhea,
Increased sweating
Pharmacological
33
Figure 2A - Top, Saline or L-NAME administered to a representative reference subject by
iontophoresis followed by local heating to 43°C. An initial peak occurs and is followed by a higher
plateau. Iontophoretic administration of L-NAME slightly blunts the initial peak and markedly
decreases the plateau phase. Figure 2B - Bottom, Local heating followed by saline or L-NAME in a
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representative low-flow POTS patient. The initial peak is present, but there is marked attenuation of
the NO-dependent plateau, even after saline administration, which resembles blunting by the NO
inhibitor L-NAME. Iontophoretic administration of L-NAME minimally blunts the initial peak but has
no additional effect on the plateau phase because of preexistent impairment of NO release (136).
Figure 3. Plasma Renin Activity (PRA) and serum aldosterone and plasma angiotensin II
concentrations in study subjects. PRA was significantly decreased and angiotensin II was
increased in low-flow POTS patients compared with control subjects. Angiotensin II
concentrations appeared to follow a bimodal distribution (137).
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