Although most research related to the disorder has occurred within the last 25 years, POTS is not a new phenomenon. The previous incidence is impossible to quantify, but similar clinical syndromes have been recognized under different names for more than 150 years.7,8 In 1871, physician Jacob Mendes Da Costa described a disorder similar to POTS that he had observed in soldiers during the American civil war and which he called irritable heart syndrome.9 Researchers now theorize that previous descriptions in the literature of soldier's heart, vasoregulatory asthenia, neurocirculatory asthenia, mitral valve prolapse syndrome, Da Costa syndrome, effort syndrome, anxiety neurosis, and idiopathic tachycardia syndrome were early descriptions of POTS.3,5,10-12 In 1993, the constellation of signs and symptoms associated with many of these syndromes was described under one name: postural orthostatic tachycardia syndrome.13
Patients may be misdiagnosed for a variety of reasons, including variability in causes and presentation of POTS, lack of clinician awareness of the condition, misconceptions about its prevalence, and inconsistency in the nomenclature. Patients with POTS have been misdiagnosed with panic disorder, inappropriate sinus tachycardia, chronic fatigue syndrome, and a variety of other maladies before receiving the correct diagnosis.14-17 The average diagnostic delay is almost 6 years.18 The result is increased healthcare expenditure and inappropriate patient management resulting in prolonged illness and disability. This article describes the pathophysiology, clinical presentation, differential diagnosis, diagnosis, and management of POTS.
A form of dysautonomia, POTS is the result of abnormal sympathetic and parasympathetic activity. However, defining the specific pathophysiology of POTS is difficult because the overall cause remains unclear. In most of the literature, POTS has been classified into subtypes, but these subtypes are not distinct with separate causes; instead they represent the continuum of interrelated autonomic dysfunction typical in most patients.19,20 Although these subtypes are not a comprehensive illustration of the pathophysiology, they are helpful in understanding the clinical manifestations and approach to treatment of POTS.
Most patients with POTS have some degree of hypovolemia.21,22 Studies have found that these patients have a 13% plasma volume deficit as compared with patient controls, a 22.7% deficit from their expected red blood cell (RBC) volume, and an abnormal physiologic response to decreased plasma volume.21-23 This phenomenon is known as the renin-aldosterone paradox.23 In normal, healthy patients, hypovolemia stimulates increased renin, angiotensin, and aldosterone activity, promoting vasoconstriction, renal sodium and water retention, and increased plasma volume.5,21,23 However, in patients with POTS and hypovolemia, plasma renin and aldosterone were found to be paradoxically low.5,21,23 A partial renal sympathetic denervation may be responsible for this phenomenon.21,23
About 50% of POTS patients have a partial sympathetic denervation, typically in the lower limbs.5,10,21 In normal patients, standing causes a fluid shift; the body compensates with smooth muscle contraction to increase venous return to the heart.24 In patients with neuropathic POTS, the physiologic mechanism to combat gravity is impaired due to this sympathetic denervation. The result is venous pooling, decreased venous return to the heart, and tachycardia upon standing.
This subtype is characterized by a significant increase in orthostatic plasma norepinephrine levels. Elevated orthostatic norepinephrine and sympathetic outflow is theorized to be a compensatory mechanism in patients with hypovolemia and peripheral denervation.10,21 Although most patients with POTS have elevated plasma norepinephrine on standing, about 29% of patients are hyperadrenergic, defined as an elevation of 600 pg/mL or greater in plasma norepinephrine upon standing.1,23 This is phenotypically manifested as tachycardia, palpitations, anxiety, and tremulousness.5,10 A very rare subset of patients with hyperadrenergic POTS have a genetic deficiency in the norepinephrine reuptake transportery.21,25 This causes the decreased synaptic clearance and increased circulating norepinephrine manifesting clinically as hyperadrenergic POTS.21,25
Autoimmunity appears to have a role in the pathogenesis of POTS. A 2007 study by Thieben and colleagues detected ganglionic acetylcholine receptor antibodies in 14.6% of patients previously diagnosed with POTS.1 Newer research has demonstrated evidence of autoantibodies against cardiac membrane proteins, and adrenergic receptor autoantibodies to alpha and beta receptors in patients with POTS.2,26 The specific mechanism of these autoantibodies and their effect are beyond the scope of this article, but the findings reveal potential causes for the tachycardia and peripheral vasoinsufficiency of POTS.2 Furthermore, the fact that many patients have comorbid autoimmune disease supports the hypothesis of an autoimmune basis for POTS.4,14
Mast cell activation and POTS
A subset of patients with POTS have symptoms of mast cell activation and increased histamine release.21,22 Mast cell degranulation causes histamine-mediated symptoms along with the symptoms of orthostatic intolerance.21,22 Whether the sympathetic activation of POTS triggers mast cell degranulation or if the mast cell activation is the primary event in these patients is unclear. Regardless of the mechanism, the symptoms tend to occur concurrently in patients with this presentation.21,22
Patients with POTS present with orthostatic tachycardia and myriad associated symptoms. Diagnostic criteria for POTS are:
* an increase in heart rate of 30 beats/minute or greater (40 beats/minute or greater in children) within 10 minutes of transitioning from supine to standing.5,21,27
* an absolute heart rate of 120 beats/minute or greater in the absence of orthostatic hypotension.21,22,28
* symptoms of orthostatic intolerance for 6 or more months
* symptoms are exacerbated by standing and improved with recumbence.21,22
* no other overt causes of tachycardia, such as hyperthyroidism, acute dehydration, or anemia.21,22,29
Lightheadedness and dizziness (presyncopal and vertiginous symptoms) are the most common presenting symptoms of POTS, but patients typically will have multiple complaints. Other common presenting symptoms may include weakness, fatigue, palpitations, tremulousness, anxiety, difficulty concentrating, mental clouding, blurred vision, dyspnea, chest pain, anhidrosis, hyperhidrosis, nausea, vomiting, bloating, abdominal pain, constipation, diarrhea, sleep disturbances, muscle aches, and headache.1,21,22,30 Frank syncope occurs in about 30% of patients, but most patients will have episodes of presyncope.22,31 Patients also report specific triggers for their symptoms such as menstruation, weight changes, weather and environmental changes, ingestion of large meals, dietary changes, increased caffeine intake, and alcohol use.10,21,32
The most remarkable physical examination finding in patients with POTS is orthostatic tachycardia. About 50% of patients develop dependent acrocyanosis in their legs and feet (Figure 1).21,22 With prolonged standing, this appears as a reddish-blue discoloration that is cold to the touch.21,22 Another physical examination finding in some patients is “flack sign,” which refers to a difficulty palpating or the disappearance of the radial pulse with Valsalva maneuver or continued standing.10,33
Eighty percent to 85% of the patients diagnosed with POTS are women ages 13 to 50 years (that is, of childbearing age). Patients rarely are diagnosed before age 9 years.8 Patients often report a physiologic stressor or illness before the onset of postural symptoms.1,21 Most commonly, patients report a preceding viral syndrome such as infectious mononucleosis or enterovirus.1,30,34 Other reported precipitating events include pregnancy, trauma, surgery, sepsis, and immunization.1,21,35 Patients may recount that they have never fully recovered from a seemingly innocuous illness or event.
POTS is associated with a number of different disorders (Table 1). A causal relationship between these disorders and POTS has yet to be established. However, the predominance of autoimmune and connective tissue disorders suggests a common pathway of disease. Clinician awareness of these comorbidities is essential to improve management strategies and outcomes for patients with POTS.
The differential diagnosis for a patient presenting with symptoms of POTS is broad. A thorough history and physical examination are essential to rule out other more common disorders or causes of orthostatic intolerance. Table 2 lists some of these potential differential diagnoses. Deconditioning from recent extended bed rest and/or injury, menorrhagia and pallor indicating anemia, and weight loss and thyroid bruit indicating hyperthyroidism should be elicited in the patient's history and physical. Medications such as vasodilators, diuretics, antidepressants, anxiolytics, and certain oral contraceptives can cause orthostatic intolerance.20,21
Along with the thorough history and physical, the diagnostic evaluation must include studies to rule out potential alternative diagnoses. Clinical suspicion is paramount to diagnosis.
A hemoglobin level can rule out anemia and a basic metabolic profile can help rule out dehydration and electrolyte disturbances precipitating a dysrhythmia.21,22 Thyroid studies will rule out hyperthyroidism.8,21 Pheochromocytoma can be ruled out with urine or plasma metanephrines.21
Tilt testing is the most valuable and easy-to-obtain initial study for patients who may have POTS.20 The procedure is performed using a specific tilt table apparatus.36 The patient's BP and heart rate are measured while the patient is supine for 10 minutes.36 The patient is then placed at a 70- to 90-degree tilt, depending on the protocol, and BP and pulse are monitored continuously.17,36 Concurrently, during the tilt test, a continuous ECG is obtained and the patient is assessed for any symptoms of orthostatic intolerance such as lightheadedness or dyspnea.36 Patients with POTS will have a heart rate increase of 30 beats/minute or greater (40 or greater in children) with an absolute heart rate of 120 beats/minute or greater in the absence of orthostatic hypotension.
Tilt testing is one of a group of tests used to measure autonomic function and quantified in a composite autonomic severity score (CASS).1,36 These tests include deep breathing, Valsalva maneuver, and the quantitative sudomotor axon test (QSART), and evaluate the cardiovagal, adrenergic, and sudomotor autonomic domains.1,36 The QSART provokes and measures a sweat response (sudomotor refers to sympathetic innervation that governs sweat gland activity) as an indicator of paraganglionic parasympathetic cholinergic function.36,37 The thermoregulatory sweat test is similar in methodology and also measures sudomotor function.1 Skin biopsy to evaluate intraepidermal nerve fiber density may also be useful in addition to the CASS and thermoregulatory sweat test in identifying sudomotor denervation, which correlates with the sympathetic denervation characteristic of neuropathic POTS.38,39
All patients should have an ECG to establish that their tachycardia is sinus and to evaluate for conduction disturbances.21,22 Continuous cardiac monitoring may be used to document episodes of orthostatic tachycardia and to look for reentry tachydysrhythmias.21,22 An echocardiogram can rule out mitral valve prolapse and left ventricular dysfunction.21,22
Because most patients with POTS have some functional hypovolemia, blood volume assessments are useful.23 A 24-hour urinary sodium excretion may be used to assess plasma volume but its accuracy is controversial.20,40,41 However, one study showed that this test may have some utility in predicting some patients' response to salt supplementation.40
Nuclear medicine tests are an alternative and can provide quantitative RBC and total plasma volume estimates.20,23 The 131I-labeled albumin method is performed by injecting a radioisotope and collecting blood to assess the isotope's dilution, thereby extrapolating the plasma volume.20,23
In patients with suspected hyperadrenergic POTS, plasma norepinephrine levels should be drawn while the patient is supine and again with the patient standing.20-22 The patient should be in each position for at least 10 minutes before the sample is drawn.21 Patients with hyperadrenergic POTS often will have a normal norepinephrine level when supine and an elevated level, typically greater than 600 pg/mL, when standing.21,22
If autoimmune disease is suspected, an erythrocyte sedimentation rate along with general and specific antinuclear antibody testing may be useful. Ganglionic acetylcholine receptor antibody testing is available through some specialized laboratories.8,34,42 Adrenergic autoantibody testing has demonstrated associations in some patients with POTS and is a focus of ongoing research.2
Urine methylhistamine levels, taken for 4 hours after a significant flushing episode, can elucidate mast cell activation disorder.20,21
Most patients will have a combination of subtype characteristics, so treatment must be individualized to the cause and the patient's symptoms. Tell patients that POTS has no cure and the goals of therapy are to manage the symptoms and restore function (see Table 3). In most cases, a combination of interventions must be used. Patients should also recognize and avoid their triggers, such as heat, dehydration, and alcohol.22 Primary care clinicians can diagnose and manage POTS but may consult with specialists such as cardiologists and neurologists to evaluate for other causes of the patient's symptoms and to help manage care.
Exercise training is recommended for most patients with POTS and has shown efficacy in some studies.43,44 Encourage patients to start a graded exercise program over a period of months.20,43 The program should begin with semirecumbent exercises such as swimming, rowing, or recumbent cycling and progress to upright exercise.20,43 Lower extremity strength is emphasized later in the exercise program to promote smooth muscle contraction and augment peripheral venous return.43,45 Using similar principles to increase venous return, waist-high compression hose have also been beneficial as an adjunctive treatment in patients with POTS.21,22
Oral fluid replacement is recommended for most patients. Between 2 L and 2.5 L of hydrating fluids per day is ideal.20,22 Salt supplementation, in the form of dietary modification or salt tablets, has also been successful in these patients; 8 to 10 g/day appears to be optimal.20,22,40 IV 0.9% sodium chloride solution is useful for managing acute symptomatic hypovolemia and associated symptoms, but is impractical as a regular therapy because of infection risk, phlebitis, and other complications.20,46
No medications are approved by the FDA for the treatment of POTS; all medication use is off-label.20,21 Fludrocortisone, an aldosterone analog, typically is used when hypovolemia is suspected. Fludrocortisone promotes the renal retention of sodium and water and expands plasma volume.21 The primary adverse reaction to fludrocortisone is hypokalemia, which can be managed with potassium supplementation.21 Desmopressin causes retention of free water in the kidney and may be useful in some situations.21,47 However, continual use of desmopressin may cause hyponatremia, so this drug is not a first-line therapy and close sodium monitoring is imperative.21,47
Beta-blockers have been proven to reduce heart rate and alleviate symptoms in some patients.21,48 Lower-dose beta-blockade, such as 10 to 20 mg of propranolol, seems to be more effective than high-dose.48 One study showed that patients had worse symptom scores when taking higher doses of propranolol compared with the group taking a lower dose.48 Perhaps this is because tachycardia is a compensatory mechanism for the lower stroke volume in these patients and excessive beta-blockade may actually be counterproductive.20,48 Fatigue and postural hypotension are commonly reported with the use of beta-blockers in patients with POTS.5,21
Midodrine, an alpha-1 agonist, augments peripheral vasoconstriction and has shown some efficacy in suppressing orthostatic tachycardia.21,49 This drug appears to work best in patients with neuropathic POTS.50 The primary adverse reactions to midodrine are headache, scalp tingling, and piloerection.21 Pyridostigmine, an acetylcholinesterase inhibitor, also can increase peripheral vasoconstriction and improve tachycardia but may cause diarrhea, limiting patient compliance.20,51 Clonidine, an alpha-2 agonist, decreases central sympathetic outflow and is effective at stabilizing the heart rate in patients with POTS, especially those with hyperadrenergic POTS.5,21 However, it may worsen peripheral vasodilation, fatigue, and mental clouding in some patients.5,21
Ivabradine is a selective sinoatrial node blocker with proven efficacy in treating patients with significant tachycardia and improving fatigue in limited trials.3,52,53 Anecdotally, ivabradine has been most effective as an adjunctive medication rather than as first-line monotherapy.53
Patients with mast cell activation have been treated successfully with histamine1 and histamine2 blockers, mast cell stabilizers such as cromolyn sodium, and high-dose aspirin.20
Table 3 describes nonpharmacologic and pharmacologic management options.
POTS is a dysautonomia with many causes and presentations, making it difficult to diagnose. Clinician awareness is the key to more expedient diagnosis and more effective treatment. Tilt testing is the most valuable tool that is widely available for the diagnosis. Once the diagnosis is established, providing patient education is an important part of management. Although POTS has no cure, most patients will see improvement in symptoms and function when treated with a multidisciplinary tailored approach.
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Keywords:Copyright © 2016 American Academy of Physician Assistants
postural orthostatic tachycardia syndrome; cardiac; idiopathic; dysautonomia; hypovolemia; renal sympathetic denervation