Giris Jacob, M.D., D.Sc., Fernando Costa, M.D., John R. Shannon, M.D., Rose Marie Robertson, M.D., Mark Wathen, M.D., Michael Stein, M.D., Italo Biaggioni, M.D., Andy Ertl, Ph.D., Bonnie Black, R.N., and David Robertson, M.D.
Background The postural tachycardia syndrome is a common disorderthat is characterized by chronic orthostatic symptoms and adramatic increase in heart rate on standing, but that does notinvolve orthostatic hypotension. Several lines of evidence indicatethat this disorder may result from sympathetic denervation ofthe legs.
Methods We measured norepinephrine spillover (the rate of entryof norepinephrine into the venous circulation) in the arms andlegs both before and in response to exposure to three stimuli(the cold pressor test, sodium nitroprusside infusion, and tyramineinfusion) in 10 patients with the postural tachycardia syndromeand in 8 age- and sex-matched normal subjects.
Results At base line, the mean (±SD) plasma norepinephrineconcentration in the femoral vein was lower in the patientswith the postural tachycardia syndrome than in the normal subjects(135±30 vs. 215±55 pg per milliliter [0.80±0.18vs. 1.27±0.32 nmol per liter], P=0.001). Norepinephrinespillover in the arms increased to a similar extent in the twogroups in response to each of the three stimuli, but the increasesin the legs were smaller in the patients with the postural tachycardiasyndrome than in the normal subjects (0.001±0.09 vs.0.12±0.12 ng per minute per deciliter of tissue [0.006±0.53vs. 0.71±0.71 nmol per minute per deciliter] with thecold pressor test, P=0.02; 0.02±0.07 vs. 0.23±0.17ng per minute per deciliter [0.12±0.41 vs. 1.36±1.00nmol per minute per deciliter] with nitroprusside infusion,P=0.01; and 0.008± 0.09 vs. 0.19±0.25 ng per minuteper deciliter [0.05± 0.53 vs. 1.12±1.47 nmol perminute per deciliter] with tyramine infusion, P=0.04).
Conclusions The neuropathic postural tachycardia syndrome resultsfrom partial sympathetic denervation, especially in the legs.
The postural tachycardia syndrome is a chronic form of orthostaticintolerance that primarily affects young women. This disorderis characterized by symptoms (such as lightheadedness, dimmingof vision, confusion, and anxiety) and signs (such as bluish-redskin in dependent limbs) that occur on standing and that arerelieved by lying down or sitting.1,2 A remarkable physicalfinding is a dramatic increase in the heart rate that occurson standing and that is not associated with a decrease in bloodpressure.3 Patients with this syndrome frequently have highplasma catecholamine concentrations, a finding that suggeststhat the disorder is a primary hyperadrenergic condition.1,4,5,6,7The syndrome, which has also been referred to as idiopathicorthostatic intolerance,8,9,10,11 has features in common withthe mitral-valve prolapse syndrome,12 the hyperdynamic ß-adrenergiccirculatory state,13 and vasoregulatory asthenia.1
Patients with the postural tachycardia syndrome often have highplasma norepinephrine concentrations,14 hypovolemia,4,15 excessivepooling of the blood in the legs while standing,16 and exaggeratedorthostatic hypovolemia.3,17,18 These findings help explainsome of the clinical features of the disorder, but few studieshave examined its pathophysiology. Several lines of evidenceindicate that sympathetic denervation of the legs may be theunderlying mechanism. The results of galvanic skin testing19,20and quantitative testing of the sudomotor axon reflex suggestthat autonomic denervation of the skin is present.21,22 Thefinding of hypersensitivity to infusion of norepinephrine intoveins of the foot, despite high plasma catecholamine concentrations,suggests that denervation hypersensitivity of the veins of thelegs is involved.18 Increased sensitivity to systemically administeredphenylephrine and isoproterenol and resistance to the norepinephrine-releasingeffects of tyramine9 are findings consistent with noradrenergicneuronal dysfunction, as is the short-term improvement in orthostaticsymptoms after the administration of the 1-adrenergic–receptoragonist midodrine.8
To test the hypothesis that the postural tachycardia syndromeis caused by partial dysautonomia resulting in dysregulationof autonomic control of the cardiovascular system, we measuredthe spillover of norepinephrine (the rate of entry of norepinephrineinto the venous circulation) in the arms and legs of patientswith the postural tachycardia syndrome and in the arms and legsof normal subjects before and after exposure to several stimulatorsof sympathetic activation.
Methods
Study Population
Between February 1995 and September 1996, we studied 18 patients(16 women and 2 men) who had been referred to the AutonomicDysfunction Center at Vanderbilt University (Nashville) forthe evaluation and treatment of debilitating symptoms consistentwith the postural tachycardia syndrome. Most of these patientsunderwent extensive testing, some of the results of which havebeen reported previously.8,9 Patients with systemic illnessesthat might affect the autonomic nervous system were excluded.
All potentially eligible patients underwent a physical examinationand were interviewed with use of a questionnaire to determinethe type and extent of their symptoms. Patients were enrolledif they met the following criteria: an increase in the heartrate of at least 30 beats per minute (without a concomitantdecrease in systolic blood pressure of more than 20 mm Hg orin diastolic pressure of more than 10 mm Hg) within five minutesafter assuming a standing position on at least three separateoccasions; a plasma norepinephrine concentration of at least600 pg per milliliter (3.5 nmol per liter) on standing; andthe presence of characteristic symptoms of the postural tachycardiasyndrome for at least six months. The last 10 patients enrolledalso underwent testing to assess norepinephrine spillover. Wealso studied 10 normal subjects (8 women and 2 men) matchedfor age and sex with the patients; 8 of the 10 normal subjectsunderwent norepinephrine-spillover testing. All the investigationalprocedures were approved by the Vanderbilt University institutionalreview board, and all the patients and normal subjects gavewritten informed consent before entering the study.
Experimental Design
All the patients and normal subjects were admitted to the GeneralClinical Research Center at Vanderbilt University and givena diet that contained 150 mmol of sodium and 70 mmol of potassiumper day, no caffeine, and low levels of monoamines. All currentmedications were discontinued at least two weeks before admission,and smoking was not permitted during the study. After threedays of this diet and an overnight rest in the supine position,blood was obtained for blood-volume measurements. Blood pressure,heart rate, and plasma catecholamine concentrations were measuredwith the subjects in the supine and upright positions. Bloodvolume was measured by a modification15 of the technique ofCampbell et al.23 Plasma catecholamine concentrations were measuredby high-performance liquid chromatography with electrochemicaldetection.24 Testing of autonomic function (the change in theheart rate in response to controlled ventilation and in responseto hyperventilation, the change in the heart rate in responseto the Valsalva maneuver, and the change in blood pressure inresponse to sustained handgrip exercise) was performed as previouslydescribed.25
On the following day, sympathetic-nerve function was tested(in 10 of the patients and in 8 of the normal subjects) by measuringthe rate of entry of norepinephrine into the systemic circulation(systemic spillover) or into the local venous drainage (localspillover). Subjects were studied after an overnight rest inthe supine position and an overnight fast. After catheterizationof the brachial artery (for blood-pressure monitoring and bloodsampling), the ipsilateral femoral vein (for blood sampling),and two large antecubital veins (one ipsilateral to the arterialline for blood sampling and one contralateral to the arterialcatheter for the infusion of tritiated norepinephrine), thesubjects rested for 30 minutes. Tritiated norepinephrine (sterile,pyrogen-free levo-[ring-2,5,6-3H]-norepinephrine [Dupont–NewEngland Nuclear, Boston]) was then administered intravenously,first as a 25-µCi loading dose over a two-minute periodand then at an infusion rate of 0.9 µCi per milliliterper minute.9 After 30 minutes, when a steady state had beenattained, blood samples for the measurement of norepinephrinespillover were simultaneously obtained from the brachial artery,the femoral vein, and an antecubital vein. Blood flow in a forearmand leg was then measured by venous-occlusion air plethysmography.26,27
Norepinephrine spillover and other variables were measured duringstimulation by three methods: immersion of the contralateralhand in ice water for at least one minute (the cold pressortest), infusion of sodium nitroprusside (at an initial rateof 0.1 µg per kilogram of body weight per minute in thearm contralateral to that in which blood flow was measured,with the rate increased until systolic blood pressure had decreasedby approximately 20 mm Hg), and infusion of tyramine (0.25 mgper minute until systolic blood pressure had increased by approximately25 mm Hg). Values for norepinephrine spillover were determinedbefore and during exposure to each of these stimuli, and atleast 20 minutes was allowed after each stimulus for recovery.The concentrations of 3H-norepinephrine in plasma were measuredas previously described.9
Determination of Norepinephrine Kinetics
Norepinephrine kinetics were calculated by the one-compartmentmodel of Esler et al.28 Systemic norepinephrine clearance (inliters per minute) was defined as the rate of infusion of [3H]norepinephrine(in disintegrations per minute [dpm]) divided by the arterialconcentration of [3H]norepinephrine (in dpm per liter). Systemicnorepinephrine spillover (in nanograms per minute) was calculatedas systemic norepinephrine clearance multiplied by the arterialplasma concentration of norepinephrine (in nanograms per liter).The fractional extraction of [3H]norepinephrine (a unitlessmeasure) in the arm or leg was calculated as (A*–V*)÷A*,where A* and V* are the arterial and venous concentrations of[3H]norepinephrine (in dpm per liter), respectively. Local norepinephrinespillover (in nanograms per minute per deciliter of tissue)in the arm or leg was calculated as ([V – A] + A[EF])x PF, where V is the local venous plasma norepinephrine concentration(in nanograms per liter), A the arterial norepinephrine concentration(in nanograms per liter), EF the fractional extraction of norepinephrine,and PF the local plasma flow (calculated as the blood flow x[1 – hematocrit], expressed in milliliters per minuteper deciliter of tissue). Local norepinephrine clearance (inliters per minute) was calculated as EF x PF. The term "spillover"is used, rather than "release," because what was measured wasnot the norepinephrine released from the sympathetic neuronsbut, more accurately, the norepinephrine that escaped from thesynaptic and neuronal pools into the circulation.
Statistical Analysis
The results are expressed as means ±SD. Paired and unpairedt-tests were used for comparisons between groups and withineach group before and after exposure to the various stimuli.One-way analysis of variance for repeated measures was usedto assess the effect of time on each of the variables. Datawere analyzed with Quattro Pro software, version 7 (Corel, Jericho,N.Y.) and GraphPad Prism software, version 2.0 (GraphPad Software,San Diego, Calif.). All P values are two-sided.
Results
Characteristics of the Study Population
The blood pressure in the supine and upright positions and theheart rate in the supine position were similar in the patientswith the postural tachycardia syndrome and the normal subjects(Table 1). The mean heart rate in the upright position was 113±13beats per minute in the patients and 82±7 beats per minutein the normal subjects. In the supine position, the mean plasmanorepinephrine and epinephrine concentrations were similar inthe two groups, but in the upright position, the plasma norepinephrineconcentration was substantially higher in the patients thanin the normal subjects (840±500 vs. 430±80 pgper milliliter [5.0±3.0 vs. 2.5±0.5 nmol per liter],P=0.02), as was the plasma epinephrine concentration (80±42vs. 47±30 pg per milliliter [0.44±0.23 vs. 0.26±0.16nmol per liter], P=0.04). Lightheadedness or dizziness and exerciseintolerance were the symptoms most frequently reported by thepatients (Table 1). Most of the patients could not preciselyidentify the point in time at which their symptoms had begun,but the mean estimated time of onset was about 2.5 years (range,8 months to 7 years) before the beginning of the study.
Table 1. Characteristics of the Patients with the Postural Tachycardia Syndrome and the Normal Subjects.
The autonomic-function tests revealed normal parasympatheticcontrol of the heart rate in both the patients and the normalsubjects (sinus arrhythmia ratio, 1.5±0.2 and 1.4±0.1,respectively; Valsalva ratio, 2.0±0.3 and 1.9±0.4,respectively). The increase in blood pressure during sustainedhandgrip exercise was higher in the patients than in the normalsubjects (15±7 vs. 9±5 mm Hg, P=0.02). The increasein heart rate with hyperventilation was also greater in thepatients than in the normal subjects (21±5 vs. 4±1beats per minute, P=0.01).
Local and Systemic Spillover and Clearance of Norepinephrine
Local and systemic norepinephrine spillover was measured in10 of the 18 patients (8 women and 2 men) and in 8 of the 10normal subjects (6 women and 2 men). At base line, the meannorepinephrine concentration in the femoral vein was significantlylower in the patients than in the normal subjects (Table 2).Systolic blood pressure increased by a similar amount in thetwo groups during the cold pressor test and decreased by a similaramount during nitroprusside infusion. During nitroprusside infusion,the heart rate increased in both groups, but the increase wasgreater in the patients than in the normal subjects (27±6vs. 12±5 beats per minute, P<0.001).
Table 2. Effects of Exposure to Three Stimuli of the Sympathetic Nervous System in 10 Patients with the Postural Tachycardia Syndrome and 8 Normal Subjects.
There was no effect of time on any of the measured or calculatedvalues (i.e., no significant change in base-line values). Thefractional extraction of [3H]- norepinephrine before exposureto each of the three stimuli was similar in the patients andthe normal subjects, both in the arms (55±13 and 56±14percent in the two groups, respectively) and in the legs (56±10and 55±9 percent, respectively).
Norepinephrine spillover before exposure to each of the threestimuli was lower in the patients than in the normal subjects,both in the arms and in the legs (Figure 1). In the arms, beforeexposure to each of the stimuli, norepinephrine clearance wassimilar in the two groups, but in the legs it was lower in thepatients than in the normal subjects (Figure 2). During exposureto each of the three stimuli, norepinephrine spillover in thearms increased by a similar amount in the two groups, but inthe legs the increases were significantly smaller in the patientsthan in the normal subjects (0.001±0.09 vs. 0.12±0.12ng per minute per deciliter [0.006±0.53 vs. 0.71±0.71nmol per minute per deciliter] with the cold pressor test, P=0.02;0.02±0.07 vs. 0.23±0.17 ng per minute per deciliter[0.12±0.41 vs. 1.36±1.00 nmol per minute per deciliter]with nitroprusside infusion, P=0.01; and 0.008±0.09 vs.0.19±0.25 ng per minute per deciliter [0.05±0.53vs. 1.12±1.47 nmol per minute per deciliter] with tyramineinfusion, P=0.04) (Figure 3). The increase in norepinephrineclearance in the arms was similar in the patients and the normalsubjects, but in the legs the norepinephrine clearance tendedto increase less in the patients than in the normal subjects(data not shown). During cold pressor testing and nitroprussideinfusion, the fractional extraction of norepinephrine in thelegs did not change significantly in either group. With tyramineinfusion, the fractional extraction of norepinephrine decreasedto 46±3 percent in the normal subjects but did not changein the patients (P=0.04).
Figure 1. Mean (+SD) Norepinephrine Spillover in the Arms and Legs in 10 Patients with the Postural Tachycardia Syndrome (Solid Bars) and 8 Normal Subjects (Hatched Bars) before the Cold Pressor Test, Nitroprusside Infusion, and Tyramine Infusion.
P values were calculated by the unpaired two-tailed t-test. To convert the values for norepinephrine spillover to nanomoles per minute per deciliter, multiply by 5.9.
Figure 2. Mean (+SD) Norepinephrine Clearance in the Arms and Legs in 10 Patients with the Postural Tachycardia Syndrome (Solid Bars) and 8 Normal Subjects (Hatched Bars) before the Cold Pressor Test, Nitroprusside Infusion, and Tyramine Infusion.
P values were calculated by the unpaired two-tailed t-test.
Figure 3. Mean (+SD) Increase in Norepinephrine Spillover in the Arms and Legs in 10 Patients with the Postural Tachycardia Syndrome (Solid Bars) and 8 Normal Subjects (Hatched Bars) during the Cold Pressor Test, Nitroprusside Infusion, and Tyramine Infusion.
P values were calculated by the unpaired two-tailed t-test. To convert the values for norepinephrine spillover to nanomoles per minute per deciliter, multiply by 5.9.
Discussion
The postural tachycardia syndrome is characterized by orthostaticsymptoms and tachycardia without orthostatic hypotension. Thenonspecific nature of the symptoms and the absence of orthostatichypotension have probably resulted in a lack of recognitionof this syndrome by both clinicians and investigators. Poorlydefined diagnostic criteria and the likelihood of multiple causeshave made it difficult to clarify the underlying pathophysiology.In the current study, we used stringent criteria to obtain ashomogeneous a study group as possible. Only patients with anincrease in the heart rate of at least 30 beats per minute onstanding and a plasma norepinephrine concentration of at least600 pg per milliliter on standing were included in the study.
Several previous investigations have provided clues that patientswith the postural tachycardia syndrome have peripheral autonomicdysfunction. Streeten et al. found that patients with orthostatictachycardia had excessive venous pooling in the legs while standingand suggested that denervation of the legs was a mechanism ofthe syndrome.16 This hypothesis was supported by the findingof hypersensitivity to infusion of norepinephrine into the veinsof the foot, despite high plasma catecholamine concentrations.18Other investigators studying patients with a similar syndromeobserved prolonged latency of plantar autonomic surface potentialsduring galvanic skin testing,19,20 as well as greater impairmentof sweating in the legs than in the arms.21 Previously, we foundthat patients with the postural tachycardia syndrome were twiceas sensitive as normal subjects to the hypertensive effect ofthe 1-adrenergic–receptor agonist phenylephrine9 and hadshort-term improvement in orthostatic tachycardia and orthostaticsymptoms with the administration of the oral 1-adrenergic–receptoragonist midodrine8; these findings suggest that dysfunctionof the peripheral autonomic neurons of the cardiovascular systemmay contribute to the pathophysiology of the postural tachycardiasyndrome. Dysfunction of these nerves, if present, should becomeapparent when they are activated.
In the current study, we measured the responses to three distinctstimuli of the sympathetic nervous system. The cold pressortest — a nonspecific, painful stimulus — activatesthe sympathetic nervous system centrally, increasing blood pressureand muscle sympathetic-nerve activity.29 Nitroprusside induceshypotension, which in turn causes baroreflex-mediated increasesin plasma catecholamine concentrations and muscle sympathetic-nerveactivity.30 Tyramine is taken up into the sympathetic neuronsand causes the release of norepinephrine.31,32 These stimuli,each of which causes sympathetic activation by a different mechanism,increased norepinephrine spillover in the arms of both the patientswith the postural tachycardia syndrome and the normal subjects,with similar increases in the two groups, but failed to increasenorepinephrine spillover in the legs of the patients. Moreover,approximately 35 percent more tyramine was required in the patientsthan in the normal subjects to achieve similar pressor responses.These findings suggest that in the legs of patients with thepostural tachycardia syndrome, neuronal stores of norepi-nephrineare low, norepinephrine release is impaired, or the uptake oftyramine is impaired.33 The results of the current study supportthe hypothesis that partial autonomic dysfunction that is morepronounced in the legs than in the arms can cause the posturaltachycardia syndrome.
In the absence of stimulation, systemic norepinephrine spilloverin these patients was normal despite the impaired spilloverin the legs. This finding may be explained by the activationof intact sympathetic neurons in other organs (such as the mesentery),a process that contributes more than one third of the systemicspillover in normal subjects.34 The reduced clearance of norepinephrinein the legs, without a similar reduction in the arms, may resultfrom impairment of norepinephrine-reuptake mechanisms due toisolated damage to nerve terminals in the legs. Hypovolemia,shown previously to be present in patients with this syndrome,4may result in a reduction in local blood flow and a subsequentreduction in norepinephrine spillover.35 Changes in capillarypermeability in the limbs,36 the possibility of which is notaddressed by assessments of spillover, may also contribute tothe observed alterations in norepinephrine spillover and clearance.However, our data strongly implicate impaired noradrenergicfunction in the legs as the cause of a neuropathic form of thepostural tachycardia syndrome.
The dysautonomia associated with the neuropathic postural tachycardiasyndrome suggests that its treatment should be similar to thatof pure autonomic failure, which results from nearly completeperipheral autonomic neuropathy.37,38 Autonomic failure is treatedby increasing blood volume through greater intake of fluidsand salt and administration of the mineralocorticoid agonistfludrocortisone39 and by minimizing orthostatic pooling of theblood in the lower body with compression garments to increaseextravascular hydrostatic pressure40 or with short-acting vasoconstrictorsto increase intravascular pressure.41,42,43 Indeed, volume loading,8administration of an 1-adrenergic–receptor agonist,8 andcompression of the legs16 in patients with the postural tachycardiasyndrome have been shown to decrease the severity of orthostatictachycardia. Regular exercise, by increasing intravascular volume,44would probably also be beneficial. However, the long-term effectsof these measures have not been determined.
References
Supported in part by grants (HL-56693 and RR-00095) from theNational Institutes of Health, by a grant (NAS 9-19483) fromthe National Aeronautics and Space Administration, and by theNathan Blaser Shy–Drager Research Program of VanderbiltUniversity.
Source Information
From the Jacob Recanati Autonomic Dysfunction Center and the Department of Internal Medicine C, Rambam Medical Center, Haifa, Israel (G.J.); and the Autonomic Dysfunction Center and the Departments of Medicine (F.C., J.R.S., R.M.R., M.W., M.S., I.B., A.E., B.B., D.R.), Pharmacology (D.R.), and Neurology (D.R.), Vanderbilt University, Nashville.
Address reprint requests to Dr. David Robertson at the Autonomic Dysfunction Center, AA3228 MCN, Vanderbilt University, Nashville, TN 37232-2195, or at david.robertson{at}mcmail.vanderbilt.edu.
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1-adrenergic–receptor agonist midodrine.8 
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