The Postural Tachycardia Syndrome A Concise Guide to Diagnosis and Management Blair P. Grubb, M.D., Yousuf Kanjwal, M.D., Daniel J. Kosinski, M.D.
J Cardiovasc Electrophysiol. 2006;17(1):108-112. 2006 Blackwell Publishing During the last 20 years, there has been a tremendous growth in our knowledge of disorders that affect theautonomic nervous system. While at first these investigations centered on neurocardiogenic syncope, a subgroupof patients was identified who suffered from a similar, yet distinct, disorder manifested by postural tachycardia andexercise intolerance. This disorder is now referred to as the postural tachycardia syndrome (POTS) andencompasses a heterogenous group of disorders that share similar clinical characteristics.[1] The aim of this briefreport is to outline the clinical picture, subtypes, diagnosis, and management of POTS.
The hallmark of these disorders is orthostatic intolerance, defined as the provocation of symptoms on standing,which are relieved when becoming supine. Patients often relate complaints of palpitations, exercise intolerance,fatigue, lightheadedness, tremor, headache, nausea, near syncope, and syncope.[2] Patients may be severelylimited as activities such as housework, bathing, and even meals may exacerbate symptoms. Recent studieshave shown that many patients with POTS may suffer the same degree of functional impairment as patients withchronic obstructive pulmonary disease or congestive heart failure, yet these patients are often misdiagnosed ashaving chronic anxiety or panic disorder.[3] A grading system for the severity of orthostatic intolerance (similar tothat for heart failure) has been developed ( ).
The Grading of Orthostatic Intolerance* Normal orthostatic tolerance Orthostatic symptoms are infrequent or occur only under conditions of increased orthostatic stress Subject is able to stand >15 minutes on most occasions Subject typically has unrestricted activities of daily living Orthostatic symptoms are frequent, developing at least once a week Orthostatic symptoms commonly develop with orthostatic stress Subject is able to stand >5 minutes on most occasions Some limitation in activities of daily living is typical Orthostatic symptoms develop on most occasions and are regularly unmasked by orthostatic stresses Subject is able to stand for >1 minute on most occasions Patient is seriously incapacitated, being bed- or wheelchair-bound because of orthostatic intolerance Syncope/presyncope is common if patient attempts to stand *Symptoms may vary with time and state of hydration and circumstances. Orthostatic stresses include prolongedstanding, a meal, exertion, and head stress.
At present POTS is defined as the presence of orthostatic intolerance symptoms associated with a heart rateincrease of 30 beats/minute (or a rate that exceeds 120 beats/minute) within the first 10 minutes of standing orupright tilt, which is seen in the absence of other chronic debilitating disorders, prolonged bed rest, or medicationsthat impair vascular or autonomic tone.[3] It should be noted that many patients with orthostatic intolerance willnot have orthostatic hypotension (a fall of >20/10 mmHg); rather there may be only a small drop in blood pressure,and no change or even a small increase in blood pressure upon assuming an upright posture. It has been pointedout that this focus on heart rate may overlook other autonomic symptoms such as disturbances in bowel function,sweating, and thermoregulatory function.
As was alluded to before, POTS is a group of different disorders associated with similar clinical manifestations.
POTS is classified as being either primary or secondary. The primary forms are idiopathic and not associated withother diseases. The secondary forms occur in association with a known disease or disorder. Proper recognition ofsubtypes is essential in management[4] (Fig. 1).
Subtypes of postural tachycardia syndrome. POTS = postural tachycardia syndrome; JHS = joint hypermobilitysyndrome.
The most common primary form of POTS is called the "partial dysautonomic" (PD) form.[1-3] These patients seemto suffer from a mild type of peripheral autonomic neuropathy characterized by an inability of the peripheralvasculature to constrict in the face of orthostatic stress. This causes a much greater than normal degree of bloodpooling in the dependent areas of the body when upright, which in turn causes a compensatory increase in heartrate and contractility that attempt to maintain cerebral perfusion at constant levels. While this increase in heartrate and contractility may initially be fully compensatory, the degree of peripheral venous pooling may continue toincrease over time and exceed this compensatory effect. These individuals then become increasingly dependenton their skeletal muscle pump to maintain adequate blood pressure until increased venous pooling exceeds itscompensatory effects as well. There is a 5:1 female-to-male ratio. Many patients will report the abrupt onset ofsymptoms after a febrile illness (presumed viral), as well as after pregnancy, immunizations, sepsis, surgery, ortrauma. It is currently felt that this form of POTS has an immune-mediated pathogenesis. Studies havedemonstrated serum autoantibodies to alpha3 acetylcholine receptors of the peripheral autonomic ganglia inpatients with postviral autonomic neuropathy.
A second type of partial dysautonomic POTS (which we term "developmental") seems to afflict adolescents.[5]Onset is usually around 14 years, often following a period of very rapid growth. Symptoms progressively worsenand frequently reach their peak around age 16. Symptoms of orthostatic intolerance (and often severe headaches)may be of such intensity that the patient may be functionally disabled. Symptoms will then slowly start to fadeover the ensuing years such that by young adulthood (19–24 years old) roughly 80% are asymptomatic. The etiology is unclear but appears to reflect a transient period of autonomic imbalance that occurs in rapidly growingadolescents.
The second (and less common) form of primary POTS is referred to as the "hyperadrenergic" form. These patientstend to report a gradual and progressive onset of symptoms as opposed to an abrupt onset. HyperadrenergicPOTS patients report significant tremor, anxiety, and cold sweaty extremities when upright. Many will report asignificant increase in urinary output after being upright for even a short period of time, and over half suffer fromtrue migraine headaches. The hallmark of this form of POTS is that in addition to orthostatic tachycardia they willoften display orthostatic hypertension, as well as exaggerated response to isoproterenol infusions. As opposed tothe PD POTS patients, the hyperadrenergic patients have significantly elevated serum catecholamine levels withserum norepinephrine levels >600 ng/mL. There is often a family history of this disorder. Currently,hyperadrenergic POTS is felt to be a genetic disorder, in which a single point mutation produces a dysfunction ofthe re uptake transporter protein that clears norepinephrine from the intrasynaptic cleft. This in turn leads toexcessive degree of norepinephrine serum spillover in response to a variety of sympathetic stimuli therebyproducing a "hyperadrenergic" state that appears similar to a pheochromocytoma.
The term secondary POTS is used to describe various conditions that produce peripheral autonomic deinnervationbut with sparing of cardiac innervation. The most common form of secondary POTS is chronic diabetes mellitus;however, it also occurs in conjunction with amyloidosis, sarcoidosis, alcoholism, Lupus, Sjogren's Syndrome,heavy metal intoxication, and following chemotherapy (especially from the vinca alkaloids).
A recently recognized and important cause of secondary POTS is due to the connective tissue disorder known asthe joint hypermobility syndrome (JHS). An inherited condition, it is characterized by joint hypermobility,connective tissue fragility, and soft "velvety" skin with variable amounts of hyperextensibility. The condition is alsoassociated with easy bruising, premature varicose veins, diffuse muscle and joint pain, and orthostaticacrocyanosis. Orthostatic intolerance develops in these patients due to the presence of abnormally elasticconnective tissue in the vasculature, which results in an increase in vessel distensibility in response to theaugmented hydrostatic pressure that occurs during orthostatic stress. This leads to excessive peripheral venouspooling with a resultant compensatory tachycardia. Recent studies have suggested that up to 70% of patientswith hypermobility syndrome may suffer from some form of orthostatic intolerance. Adolescents with thedevelopmental form of POTS frequently have been noted to have features of JHS. Studies are currently under wayto better elucidate this potential relationship.
POTS may also be the presenting form of more severe autonomic nervous system disorders such as pureautonomic failure or multiple system atrophy. POTS may also present as a paraneoplastic syndrome seen inassociation with adenocarcinomas of the lung, breast, ovary, and pancreas. Current investigations have shownthat these tumors produce autoantibodies against acetylcholine receptors in the autonomic ganglia similar tothose seen in the postviral syndromes.
The most critical aspect of evaluation is the history. Elicit information about the onset of symptoms. Were theysudden or gradual? Were there any events associated with onset? What makes symptoms worse or better? Areother family members affected? Does the patient have gastrointestinal, sudomotor, or thermoregulatory problems?Are migraines also a problem? A careful physical exam is also critical. Blood pressure and heart rate need to be taken in the supine, sitting,immediate standing, and at 2-, 5-, and 10-minute intervals. Ideally, the lower extremities should be watched for thedevelopment of a mottled bluish discoloration (acral cyanosis) that suggests peripheral venous pooling. Becausethe results obtained during standing are quite variable, we usually perform tilt table testing on most patients, asthis setting is more controlled with fewer variables and with more reproducible results (in our experience betterthan that seen with neurocardiogenic syncope). Other tests of autonomic nervous system function may be usefulin select POTS patients as a way of measuring the degree of systemic autonomic involvement. Sudomotorfunction can be determined by thermoregulatory sweat testing or by assessment of skin conductance, skinresistance, or sympathetic skin potentials. Serum catecholamine levels, both in the supine and upright positions,should be obtained in patients suspected of having the hyperadrenergic form of POTS. Bowel motility studies areuseful in ascertaining the degree of gastrointestinal involvement present. More detailed descriptions of autonomic testing can be found elsewhere.[1] Treatment is based upon subtype but must be individualized to the needs of each patient. Any drug the patient istaking that could contribute to the condition should be stopped if possible ( ). Any underlying condition that maybe causing POTS should be identified and treated (i.e., sarcoidosis). All patients should be encouraged to begin aprogram of reconditioning working toward a goal of performing at least 20–30 minutes of aerobic activity threetimes a week. In addition, we encourage resistance training of the lower extremities to augment the effectivenessof the skeletal muscle pumps. Fluid intake of 2 L a day of water and 3–5 grams of salt per day are encouraged inall but the patients with the hyperadrenergic form of POTS. Compression hose can be helpful but must provide 30mmHg pressure and be waist high to be effective.
Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance Angiotensin-converting enzyme inhibitors Alpha receptor blockers Calcium channel blockers Sildenafil citrate MAO, monoamine oxidase.
Pharmacotherapy is initiated with the goal of getting patients well enough to pursue reconditioning. No drug iscurrently approved by the US FDA for the treatment of POTS; therefore, any use of pharmacotherapy is done "offlabel." Knowing the subtype is important in choosing appropriate pharmacotherapy ( ).
Therapeutic Options in POTS Aerobic exercise 20 min 3 If too vigorously done may worsen 0.1-0.2 mg po q day Nausea, scalp itching, supinehypertension Methylphenidate 5-10 mg po tid Anorexia, insomnia, dependency 150-300 mg XL/q day Tremor, agitation, insomnia Tremor, agitation, sexual problems 10,000-20,000 i.v. sq q week Pain at injection site, expensive 50-200 micrograms sq tid Nausea, diarrhea, gallstones 0.1-0.3 mg po bid 0.1-0.3 mg patch Dry mouth, blurred vision 100-200 mg po bid PD = partial dysautonomic; H = hyperadrenergic; POTS = postural tachycardia syndrome.
In the partial dysautonomic POTS, patient therapy is directed at augmenting fluid volume and increasing vascularresistance. We often begin with fludrocortisone, a mineral corticoid that promotes sodium and fluid retention, andalso sensitizes peripheral alpha adrenergic receptors. The drug appears to be most helpful in younger patients.
Usually, 0.1–0.2 mg daily is employed (never exceed 0.4 mg orally each day as adrenal suppression may occur).
Next, we add a vasoconstrictor such as midodrine, starting at 5 mg orally three times a day. Dosages can betitrated up to 15–20 mg orally four times a day, if necessary. Since patients are most symptomatic early in themorning, we often advise patients to take their midodrine dose approximately 15 minutes prior to getting out ofbed. We also advise patients that they can take an extra 5 mg dose as needed if severe breakthrough symptomsoccur. The most common problems encountered with midodrine are nausea, "goose bumps," and scalp itching. Ifmidodrine is not tolerated methylphenidate can be an effective alternative, especially because it comes in severallong-acting preparations. Some investigators have also advocated the use of yohimbine.
If patients continue to be symptomatic, we add either a serotonin reuptake inhibitor (SSRI) or a norepinephrinereuptake inhibitor. While the SSRIs are very useful in the prevention of neurocardiogenic syncope, thenorepinephrine reuptake inhibitors are somewhat more helpful in POTS patients. We usually employ bupropion inthe XL form starting at 150 mg orally each day and titrating to 300 mg XL daily, if necessary.
Of all the currently available SSRIs, we have noted that those with combined serotonin and norepinephrinereuptake inhibition (such as venlafaxine and duloxetine) are often the most effective. Tolerance for these agents isusually good (approximately 80%) with the most common side effects being gastrointestinal upset, tremor, andsleep disturbance. Less common side effects include agitation and sexual dysfunction. We will on occasioncombine an SSRI with bupropion to achieve the same type of combination effect. A very promising new therapy ispyridostigmine, an acetylcholinesterase inhibitor that facilitates neural transmission at the ganglionic level of bothsympathetic and parasympathetic nerves. The drug is particularly useful in postviral POTS patients as well aspatients with POTS secondary to a primary autoimmune disorder (such as Sjogren's syndrome or Lupus). Thestarting dose is 30 mg orally twice a day, titrating to 60 mg orally twice daily, if necessary.
In severely affected patients, where other forms of therapy have either been poorly tolerated or ineffectual, weemploy the drug erythropoietin. Originally developed for the treatment of anemia, it is also a potent vasoconstrictorthat is quite useful in the treatment of orthostatic disorders.
Due to the fact that erythropoietin (EPO) has to be administered by subcutaneous injection and because of itsconsiderable expense, we normally reserve its use to patients who have proven refractory to or intolerant of otherforms of therapy. Prior to starting EPO, a complete serum blood count (CBC) as well as a serum iron, total ironbinding capacity, and ferritin level should be obtained. EPO can be employed as long as the hematocrit (HCT) isless than 50. The usual starting dose is 10,000 units injected subcutaneously once weekly. It usually takes 4–6 weeks to see the full effect of a particular dose amount. While the red cell augmentation effect and thehemodynamic effect are independent, they tend to rise in parallel. Patients appear to achieve the besthemodynamic effect when the HCT is in the low to mid-40 range. Once EPO therapy is initiated, a CBC should bechecked monthly to assure that the HCT does not exceed 50. If the HCT on EPO therapy goes over this amount,we usually have the patient skip doses until it drops below 50, and then restart EPO at a lower dose (in a mannernot dissimilar to the way warfarin is managed with respect to the international normalized ratio [INR]). The mostcommon complaint of patients on EPO therapy is pain at the injection site. This can be minimized by allowing theEPO (which is kept refrigerated) to warm prior to injection. One way to do this is to roll the vial between the handsuntil it becomes warm. An additional way to minimize injection discomfort is to place an ice cube on the injectionsite 3–5 minutes before use; alternatively, a lidocaine patch or cream can be applied 15–30 minutes before use.
Many patients will require supplemental oral iron for EPO to have its best effect. If no clinical improvement is seenfrom the starting EPO dose after 4–6 weeks, the weekly dose can be increased to 20,000 units. We have rarelyhad to exceed this dose in POTS patients. A rare complication of EPO therapy is that the patient can develop a"serum sickness" like reaction to EPO, characterized by fever, chills, nausea, and a general sense of malaise.
We have only seen this occur in a handful of patients over the last 12 years; it resolves promptly after the agent isdiscontinued.
Another potential therapy is the somatostatin analog octreotide, which has potent vasoconstrictive effects. It isadministered by subcutaneous injection starting at 50 μg subcutaneously 2–3 times a day; dosages may betitrated up to 100–200 μg three times a day. A long-acting injectable form (lasting weeks) has also beendeveloped. While some PD POTS patients may benefit from small doses of beta blockers (i.e., metoprolol 25 mgorally once or twice daily), the majority tend to feel worse on these agents.
The hyperadrenergic form of POTS is best treated by agents that block the release of norepinephrine or block itseffects. Clonidine is often useful in these patients, starting at 0.1 mg a day and titrating upward. The patch form ofthe agent is particularly useful as it provides a steady level of the drug for up to a week at a time. Labetalol isoften effective, due to its alpha and beta blocking effects. Dosages of 100–400 mg orally twice a day may beemployed. Methyldopa is also helpful in select patients. Both the SSRIs and the norepinephrine reuptakeinhibitors have been helpful in controlling patients' symptoms.
It is important to differentiate between patients with POTS and those suffering from inappropriate sinustachycardia (IST). There are similarities between the hyperadrenergic form of POTS and IST. Clinicalpresentations are similar and IST appears to be more common in women. Both conditions display an exaggeratedresponse to isoproterenol infusion and some investigators have suggested that they may represent differentaspects of the same disease process. POTS patients, however, display a greater degree of postural change inheart rate and the supine (resting) heart rate rarely exceeds 100 beats/minute (as opposed to IST where theresting heart rate is often more than 100 beats/minute). In addition, IST patients tend not to display the samedegree of postural change in serum norepinephrine levels as those seen in hyperadrenergic POTS patients. Thedifferentiation between POTS and IST is important as radiofrequency catheter ablation of the sinus node can makePD POTS patients markedly worse, and rarely seems to benefit patients with hyperadrenergic POTS.
In the secondary forms of POTS, therapy is first directed at correcting the underlying disorder to as great anextent possible. Patients with diabetes mellitus or JHS-related POTS are treated as peripheral dysautonomicPOTS. Patients with POTS secondary to sarcoidosis or amyloidosis may also benefit from steroid therapy.
Paraneoplastic POTS patients often respond well to pyridostigmine, and symptoms often resolve with treatment ofthe malignancy.
It should be remembered that patients suffering from POTS may experience an inability to pursue normalemployment or educational opportunities and often suffer significant psychosocial disruption. Patients frequentlyrequire the services of psychologists, social workers, and lawyers to address these aspects of their illness. Theattitude of the treating physician is crucial. Hope is a powerful medicine that should be encouraged by all.
There is only limited data available at present on the prognosis of POTS patients. We are still in the process offollowing patients and analyzing their outcomes. Nonetheless some general trends have been noted. In patientssuffering from postviral onset POTS, roughly one-half will make a good practical recovery over a 2–5 year period.
Here, we define recovery as the relative absence of orthostatic symptoms with the ability to perform the normalactivities of daily living with little or no restriction. However there are some patients that will not enjoy this degreeof recovery and occasionally patients experience a progressive decline in functional status over time. In general,the younger the patient the better the prognosis. In adolescents with the "developmental" form of POTS,approximately 75% will experience a significant recovery by the time they are in their early to mid-twenties. Thevast majority of patients ( 90%) will respond to a combination of physical therapy and pharmacotherapy. Patientswith the hyperadrenergic form of POTS usually require treatment indefinitely. The prognosis of patients with thesecondary POTS syndromes is usually determined by the prognosis of the underlying causative disorder.
The postural tachycardia syndrome is a heterogenous group of disorders that disturb normal autonomic control.
Successful treatment is often dependent on identifying the subtype and pursuing a comprehensive treatmentprogram.
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1. Grubb BP, Kosinski D, Boehm K, Kip K: The postural tachycardia syndrome: A neurocardiogenic variant identified during head up tilt table testing. Pacing Clin Electrophysiol 1997;20: 2205-2212.
2. Karas B, Grubb BP, Boehm K, Kip K: The postural tachycardia syndrome: A potentially treatable cause of chronic fatigue, exercise intolerance, and cognitive impairment. Pacing Clin Electrophysiol 2000;23: 344-351.
3. Kanjwal Y, Kosinski D, Grubb BP: The postural tachycardia syndrome: Definition, diagnosis and management. Pacing Clin Electrophysiol 2003;26: 1747-1757.
4. Kanjwal Y, Kosinski D, Grubb BP: Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. Curr Cardiol Rep 2003;5: 402-406.
5. Grubb BP, Rowe P, Calkins H: Postural tachycardia, orthostatic intolerance and the chronic fatigue syndrome. In: Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management, Second Edition.
Malden, MA: Blackwell/Futura Press, 2005, pp. 225-244.
Blair P. Grubb, M.D., Division of Cardiology, Medical University of Ohio, 3000 Arlington Ave., Toledo, OH 43614.
Fax: 419-383-3041; E-mail: J Cardiovasc Electrophysiol. 2006;17(1):108-112. 2006 Blackwell Publishing


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