Postural Orthostatic Tachycardia Syndrome



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

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 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 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 self-limited. 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 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 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 flow-dependent 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 (10-15 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 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, 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.

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.

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) (76-78), 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.

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).

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 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 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 NET-deficient mouse was recently shown to have near normal resting arterial pressure and heart rate, 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.

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 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.

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.

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).

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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 |

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.

TABLE III – TREATMENT of POTS

THERAPY USUAL DOSAGE MECHANISM of ACTION DISADVANTAGES

Non-Pharmacological

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 Difficult, Nausea, Peripheral edema

Exercise 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 Increase Venous Return Hot, Uncomfortable

Pressure

Standing Exercises Squat while crossing legs, Increase Venous Return Transient symptom relief

Contract gluteal muscles

Acute IV Saline 1 L infused 1-3 hrs. Blood Volume Expansion Inconvenient, Medical facilities required

Chronic IV Saline 1 L infused every 1-2 days Blood Volume Expansion Inconvenient, Requires central

access, Risk of infection

Pharmacological

Fludrocortisone 0.05-0.1 mg PO Blood Volume Expansion Edema, Fluid Retention,

OD or BID Hypokalemia, Headache,

Hypertension

Desmopressin 0.1-0.2 mg PO Blood Volume Expansion Hyponatremia, Headache, Edema

(DDAVP) OD or BID

Erythropoietin 2000-3000 IU SQ Blood Volume Expansion Expense, Requires injections,

1 to 3 times/week Vasoconstriction 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 β-adrenergic Antagonist Hypotension, Fatigue, Wheezing

BID

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

[pic]

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 (136).

[pic]

[pic]

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).

[pic]

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