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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 3 , N O . 1 0 , 2 0 1 9

ª 2 0 1 9 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

JACC FOCUS SEMINAR

Postural OrthostaticTachycardia SyndromeJACC Focus Seminar

Meredith Bryarly, MD,a,* Lauren T. Phillips, MD,a,* Qi Fu, MD, PHD,b,c Steven Vernino, MD, PHD,a

Benjamin D. Levine, MDb,c

ABSTRACT

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Postural orthostatic tachycardia syndrome (POTS), the most common form of orthostatic intolerance in young people,

affects approximately 500,000 people in the United States alone, typically young women at the peak of their education

and the beginning of their working lives. This is a heterogeneous disorder, the pathophysiology and mechanisms of which

are not well understood. There are multiple contributing factors and numerous potential mimics. This review details the

most current views on the potential causes, comorbid conditions, proposed subtypes, differential diagnoses, evaluations,

and treatment of POTS from cardiological and neurological perspectives. (J Am Coll Cardiol 2019;73:1207–28)

© 2019 by the American College of Cardiology Foundation.

P ostural orthostatic tachycardia syndrome(POTS) is the most common form of ortho-static intolerance in young people (predomi-

nantly premenopausal women), with a prevalenceof 0.2% (1) affecting an estimated 500,000 Ameri-cans based on a 1999 report (2). The current epidemi-ology is not known, but due to increased awarenessof the syndrome, the prevalence of POTS may haveincreased over the past 2 decades. By definition,POTS is a clinical syndrome of orthostatic intoler-ance characterized by a heart rate (HR) incrementof 30 beats/min or more, often with standingHRs >120 beats/min, within 10 min of standing orhead-up tilt (HUT), and in the absence of orthostatichypotension (a decrease in systolic blood pressure(BP) of 20 or more mm Hg and/or decrease in dia-stolic BP of 10 or more mm Hg) (1,3) (Figure 1). Thisspecific syndrome should be distinguished from

N 0735-1097/$36.00

m the aDepartment of Neurology and Neurotherapeutics, University of

stitute for Exercise and Environmental Medicine, Texas Health Presbyt

rdiology, University of Texas Southwestern Medical Center, Dallas, Texas.

rk. Dr. Fu was supported by a K23 grant (no. K23HL075283) from the Natio

an advisory board for Biogen. Dr. Phillips has served as a consultant for AC

est/Athena Diagnostics; and on an advisory board and Speakers Bureau f

ard for Lundbeck; and has been a mentor on a K23 grant from the NIH.

nuscript received February 21, 2017; revised manuscript received Novem

isolated orthostatic intolerance, which is a broaderterm encompassing a range of symptoms that maybe attributed to the upright position, including pal-pitations, fatigue, cognitive disturbance, headache,nausea, pre-syncope, and syncope. Not all patientswith orthostatic intolerance have POTS, though allpatients with POTS have symptoms of orthostaticintolerance. In some cases, the palpitations ofupright tachycardia dominate the clinical picture,which is why most patients with POTS are referredat some point to a cardiologist. However, in others,the orthostatic intolerance predominates, and thetachycardia is a sign that leads toward a formal diag-nosis of POTS. Although some patients report thepersistence of symptoms when sitting or supine, ifthe upright posture does not clearly exacerbate thesymptoms (and the HR), then a diagnosis of POTSshould not be made.

https://doi.org/10.1016/j.jacc.2018.11.059

Texas Southwestern Medical Center, Dallas, Texas;

erian Hospital, Dallas, Texas; and the cDivision of

*Drs. Bryarly and Phillips contributed equally to this

nal Institutes of Health (NIH). Dr. Bryarly has served

I Clinical. Dr. Vernino has served as a consultant for

or Lundbeck. Dr. Levine has served on the advisory

ber 1, 2018, accepted November 5, 2018.


http://JACC.org/

http://crossmark.crossref.org/dialog/?doi=10.1016/j.jacc.2018.11.059&domain=pdf

ABBR EV I A T I ON S

AND ACRONYMS

AChR = acetylcholine receptor

AFT = autonomic function

testing

BP = blood pressure

CFS = chronic fatigue

syndrome

ECG = electrocardiogram

EDS = Ehlers-Danlos syndrome

GI = gastrointestinal

HR = heart rate

HUT = head-up tilt

IST = inappropriate sinus

tachycardia

IV = intravenous

MCAD = mast cell activation

disorder

NE = norepinephrine

NET = norepinephrine

transporter

NMS = neurally mediated

syncope

NOH = neurogenic orthostatic

hypotension

POTS = postural orthostatic

tachycardia syndrome

Bryarly et al. J A C C V O L . 7 3 , N O . 1 0 , 2 0 1 9

Postural Orthostatic Tachycardia Syndrome M A R C H 1 9 , 2 0 1 9 : 1 2 0 7 – 2 8

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By contrast, dysautonomia is a nonspecificterm implying abnormal function of theautonomic nervous system. Although POTS isone cause of orthostatic intolerance, andmany consider POTS to be a form of dysau-tonomia (2), direct testing of autonomicfunction in this patient population is oftennormal/appropriate for the hemodynamicstress (4). Although POTS was formallycharacterized as a syndrome in the 1990s,disorders with very similar phenotypes havebeen described in the published reports forover 150 years by various other names,including DaCosta’s syndrome, irritableheart, soldier’s heart, effort syndrome, neu-rocirculatory asthenia, and mitral valve pro-lapse syndrome (5).

The typical demographic is young women(mean age 30.2 � 10.3 years, 86% women),with an average HR increment of 44.2 � 13.2beats/min from supine to upright (6), in theabsence of provocative medications such asnitroglycerin or isoproterenol. According tothe most recent consensus statements, inpatients under 20 years of age, the HRincrement with upright posture shouldexceed 40 beats/min in order to be consid-

ered clinically significant (1,3). Often the standingHR exceeds 120 beats/min in patients with POTS.Symptoms tend to be most bothersome in themorning, but frequently, patients have symptomsthat persist throughout the day. The onset of POTScan be subacute (13.8%), insidious (5.9%), or acute(12.5%). It is frequently preceded by symptoms of aviral illness (in 42%) or may occur post-operatively(in 9.5%) (6).

As designated in its name, POTS is a syndrome, nota disease. A number of other symptoms and comor-bidities are commonly associated with POTS. Theseinclude bloating, nausea, diarrhea, abdominal pain,fatigue, sleep disturbance, headache, and others.Although these symptoms commonly occur in asso-ciation with POTS, they may not be part of a singleunifying, underlying disease process, or linkedclearly by a common pathophysiology. Pre-syncope ismuch more common than syncope in POTS, but it isnot infrequent that POTS coexists with episodes ofneurally mediated (reflex) syncope (1). In many cases,patients relate a healthy and active premorbid state;some are competitive athletes or high-performinghigh school or college students before developingPOTS.

BASIC PHYSIOLOGY OF CARDIOVASCULAR

RESPONSE TO ORTHOSTATIC STRESS

Because POTS is a postural and orthostatic disorder, afine understanding of gravitational physiology andthe physiology of the upright posture is essential tomanaging these patients. When a healthy personassumes the head-up posture, a multitude of hemo-dynamic changes occur, most in the first 30 s. Whenupright, gravity immediately causes blood to descendfrom the chest to the lower abdomen, buttocks, andlegs. More slowly, there is a shift of plasma volumefrom the vasculature into the interstitial space. Thisfluid shift results in a decrease in effective circulatingblood volume. The resulting fall in venous returnreduces stroke volume and unloads the arterialbaroreceptors by reducing their pulsatile distortion,even if mean arterial pressure is unchanged (7,8). Thebaroreflex rapidly produces a compensatory vagalwithdrawal and sympathetic activation, which in turnincreases HR, cardiac contractility, and peripheralvascular resistance. Clinically, this response usuallymanifests as a small (5 to 20 beats/min) increase inHR, a small decrease in systolic BP, and a slight in-crease in diastolic BP (9,10). Figure 2A shows thecritical role that central blood volume plays in theacute regulation of the sympathetic nervous systemwith volume loading inducing virtual sympatheticsilence and volume unloading causing marked sym-pathetic activation (11); Figure 2B shows the tightrelationship between stroke volume and HR in men,healthy women, and women with POTS (4,12). Notethat healthy women have smaller stroke volumes andhigher HRs compared with healthy men, whereaswomen with POTS have both an exaggerated fallin stroke volume and an apparent compensatoryrise in HR.

In the setting of hypovolemia, reduced circulatingblood volume leads to more profound unloading ofarterial baroreceptors, which leads to greater sympa-thetic activation and an elevated HR even at rest.In severe hypovolemia, sympathetically mediatedsystemic vascular resistance increases; renin secre-tion also increases, with increased conversion ofangiotensin II. This neurohumoral response leads toincreased vasoconstriction of arteriolar smooth mus-cle as well as stimulation of aldosterone secretion,which increases sodium reabsorption. Antidiuretichormone (ADH) release leads to increased reabsorp-tion of water and sodium chloride. When upright inthe setting of hypovolemia, venous return is severelycompromised (13), and the HR is more significantly

FIGURE 1 Definition of POTS

Postural orthostatic tachycardia syndrome (POTS) is definedas a clinical syndrome lasting at least 6 months that ischaracterized by:

Postural Orthostatic Tachycardia Syndrome Definition:

1) an increase in heart rate ≥30 bpm within 5 to 10 min ofquiet standing or upright tilt (or ≥40 bpm in individuals 12 to19 years of age);

2) the absence of orthostatic hypotension (>20 mm Hg dropin systolic blood pressure); and

3) frequent symptoms that occur with standing such aslightheadedness, palpitations, tremulousness, generalizedweakness, blurred vision, exercise intolerance, and fatigue.

Definition of POTS is adapted from the 2011 and 2015 consensus statements

on the diagnosis and treatment of postural tachycardia syndrome (1,3).

bpm ¼ beats/min; POTS ¼ postural orthostatic tachycardia syndrome.

J A C C V O L . 7 3 , N O . 1 0 , 2 0 1 9 Bryarly et al.M A R C H 1 9 , 2 0 1 9 : 1 2 0 7 – 2 8 Postural Orthostatic Tachycardia Syndrome

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elevated (>20 beats/min) often with orthostatichypotension.

Indeed, any physiological stress resulting incentral hypovolemia will be most impactful in theupright position. One common example is heat stress,which causes orthostatic intolerance even in healthyindividuals. Under thermal stress, cutaneous vasodi-lation increases blood flow to the skin and redirectsup to 50% to 70% of resting cardiac output to the skinto maintain core temperature (14). In order to main-tain BP and offset large falls in systemic vascularresistance, HR and cardiac output rise, the latterpotentially to double its resting value. Heat stressdramatically decreases orthostatic tolerance inhealthy humans, and this is why orthostatic intoler-ance of all types (including POTS) is worsened byheat.

PATHOPHYSIOLOGY OF POTS

The pathophysiological mechanisms underlying POTSare thought to be heterogeneous (15). One analog of agravity-dependent phenomenon that may provideinsight into the pathophysiology of POTS is space-flight. Since the inception of space missions, a post-flight orthostatic intolerance on return to Earth hasbeen noted following both short- and long-termflights, especially in women astronauts. Even afterbrief trips, approximately one-fourth to two-thirds ofastronauts cannot stand for even 10 min upon returnto earth (16–18). This orthostatic intolerancefollowing exposure to a microgravity environmenthas been well described and studied (10,17,19–23). Inthese subjects, physiological changes have beenobserved to occur including cardiac atrophy, a largefall in stroke volume, and hemodynamically appro-priate reactive tachycardia and sympatheticactivation (10,16–18,21,22,24,25). These same mecha-nisms described in space flight have also beenseen following prolonged bedrest deconditioning(23,25–27). Though these mechanisms have not spe-cifically been shown to “cause” POTS, there areremarkable similarities between the effects of space-flight/bedrest and POTS, which may be informative inconsidering the potential pathophysiology of POTS.Indeed, a period of enforced bedrest is often a com-mon theme in patients with POTS, even those whohave previously been quite active.

One feature that appears to be universally presentin all POTS is cardiovascular deconditioning, aspecific biological process characterized by cardiacatrophy and hypovolemia (4). Cardiovascular decon-ditioning can occur rapidly, within 20 h of bedrest(27); like with spaceflight, women, the predominant

group afflicted by POTS, appear to be more suscepti-ble (16,28,29). It is important to emphasize thatphysiological cardiac atrophy in response to bedrestdeconditioning, like its converse, physiologicalhypertrophy in response to exercise training, is auniversal response to cardiac unloading, and by itself,is not pathological. However, in susceptible patients,even mild post-bedrest orthostatic intolerance maylead to a “downward spiral” of further bedrestdeconditioning and worsening orthostatic intolerancethat can be quite debilitating.

What exactly determines this susceptibility isuncertain. However, a number of overlapping patho-physiological variants have been described that maycontribute to an individual’s susceptibility to developPOTS. These include peripheral autonomic neuropa-thy, excessive venous pooling, hypovolemia in thesetting of volume dysregulation, hyperadrenergicstates, mast cell activation disorders, and autoim-munity. Ultimately, regardless of the precipitatingcause, the state of cardiovascular deconditioningoften dominates the clinical picture and is a majorcause of functional disability (26).

POTS SUBTYPES

Even though deconditioning seems to be the “finalcommon pathway” that results in orthostatic intol-erance (30), multiple mechanisms have been pro-posed that may precipitate orthostatic intoleranceand compound bedrest deconditioning that oftenculminates in POTS (26) (Figure 3). Although quitevaried and lacking a unifying hypothesis of POTS,these mechanisms include the following.

FIGURE 2 Changes in MSNA and BP, and HR and Stroke Index

BL 30°Tilt

60°Tilt

10min

Group P < 0.001Protocol P < 0.001Interaction P < 0.001

30min 40min50

70

80

90

100

110

120

60

130

A

B

Hear

t Rat

e (b

pm)

BL 30°Tilt

60°Tilt

10min

Group P < 0.001Protocol P < 0.001Interaction P < 0.001

30min 40min10

30

40

50

60

20

70

–30 mm HgLBNP

POTS Patients Healthy Women Healthy Men

MSNA

BP(mm Hg)

PAP(mm Hg)

22

10 sec

0

–15 mm HgLBNP

Baseline 15 ml / kgsaline

30 ml / kgsaline

Stro

ke In

dex

(ml/m

2 )

100

0

(A) Changes in muscle sympathetic nerve activity and blood pressure in response to lower body negative pressure and volume infusion (11).

Central blood volume plays a critical role in the acute regulation of the sympathetic nervous system; volume loading induces virtual

sympathetic silence, and volume unloading causes marked sympathetic activation. (B) Changes in heart rate and stroke index in response to

head-up tilt in POTS patients, healthy women, and healthy men. There is a tight relationship between stroke volume and heart rate in men,

healthy women, and women with POTS (4,12). BL ¼ baseline; BP ¼ blood pressure; HR ¼ heart rate; LBNP ¼ lower body negative pressure;

MSNA ¼ muscle sympathetic nerve activity; PAP ¼ pulmonary arterial pressure; other abbreviations as in Figure 1.



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“HIGH-FLOW,” “LOW-FLOW,” AND “NORMAL-FLOW”.

Over a decade ago, studies looking at blood flowmeasurements in the lower extremities (measured byvenous occlusion strain-gauge plethysmography ofthe forearm and calf) suggested 3 separate types of

POTS patients with characteristic changes in regionalcirculations: those with increased (“high-flow”

POTS), decreased (“low-flow” POTS), and normal(“normal-flow” POTS) blood flow. The mechanismsunderlying these subgroups were postulated to be

FIGURE 3 POTS and Proposed Subtypes

Neuropathic POTS

Autoimmunity

HyperadrenergicPOTS

Mast CellActivationDisorder

VolumeDysregulation

ProposedPOTS

Subtypes

Several subtypes of POTS have been proposed and include neuropathic POTS, autoim-

munity, hyperadrenergic POTS, mast cell activation disorder, and volume dysregulation.

These subtypes are not mutually exclusive or clearly independent. POTS ¼ postural

orthostatic tachycardia syndrome.


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related to enhanced thoracic hypovolemia duringupright tilt, leading to inadequate cardiac venousreturn during orthostasis (31). However, these find-ings have not been demonstrated prospectively, anddifferentiating POTS subgroups based on lower ex-tremity blood flow have not been shown to lead tounique therapies.

“NEUROPATHIC” POTS. In one study, >50% of POTSpatients (6) were noted to have loss of sweat functionin distal lower extremities (32), measured as impairedsweat volume on quantitative sudomotor axon reflextesting (32) or reduced intraepidermal C-fiber densityon skin biopsy (33). These observations led to theconcept that peripheral sympathetic denervationmight lead to impaired vasoconstriction andincreased venous pooling in lower extremities (34).To compensate for the inability to increase lowerextremity vascular tone, an exaggerated increase inHR and cardiac output would be required to maintainsystemic mean arterial pressure. It is important toemphasize however that the regulation of skinblood flow is driven primarily by thermoregulation,and is not under baroreflex control. In thermoneutralconditions, skin blood flow has little impact onBP regulation, though, of course, it becomesincreasingly important in the heat. This neuropathicsubgroup may also show distinct patterns on auto-nomic function testing. In addition to reduced distalsudomotor function, they have also been shownto have lower supine and standing HRs, and lessprominent overshoot during release of Valsalvawhen compared with other POTS patients (6,35). Thissubgroup also tends to demonstrate less anxietyand depression, and greater overall self-perceivedhealth-related quality-of-life scores compared withother POTS patients (35).

“HYPERADRENERGIC” POTS. Another large sub-group within the POTS population is the so-calledhyperadrenergic subtype, with features that maycorrespond to 30% to 60% of POTS patients (6,36,37).On standing, these patients may complain of palpi-tations, tremulousness, hyperhidrosis, abdominalpain, and nausea (38). They may also be more proneto exacerbation of symptoms with physical exertionand emotional stress (15,34). With standing or tilttesting, a more dramatic increment in HR (38), a risein BP, or marked fluctuations in BP may be seen (6).These patients have elevated standing plasmanorepinephrine (NE) levels (>600 pg/ml), reflectingan exaggerated sympathetic response (6,36), which isfelt to be the driver of the excessive orthostatictachycardia and a likely mediator of other symptomsof the syndrome.

NE released from sympathetic nerves is largelycleared from the extracellular space by the norepi-nephrine transporter (NET). A single case of POTSwith elevated standing NE levels was found to have amutation in NET, encoded by the SLC6A2 gene,causing loss of function; this observation led tospeculation that impairment of synaptic NE clearanceand excessive sympathetic activation may underliesome forms of hyperadrenergic POTS. More focusedstudies attempting to tie genetic variations in theSLC6A2 gene to elevated NE levels, however, havebeen inconclusive (39,40).

More common than genetic NET deficiency isNET blockade from pharmacological agents, such asNE reuptake inhibitors (e.g., bupropion), tricyclicantidepressants (e.g., nortriptyline), and othersympathomimetic drugs (e.g., methylphenidate)(15). Stimulant-induced tachycardia has beenknown to closely mimic POTS (41), and dispositiveinterpretation of catecholamine results shouldnever be made unless patients are off drugs thataffect the autonomic nervous system for at least 5half-lives.



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VOLUME DYSREGULATION

Some POTS patients have been noted to havepersistently low plasma volumes (32,42–44), whichevidence suggests is perhaps secondary to impairedfunction of the renin-angiotensin-aldosterone sys-tem. Some have inappropriately low plasma reninactivity and aldosterone levels resulting in inade-quate renal sodium retention (42,44). Others haveelevated plasma angiotensin II levels suggestinginadequate angiotensin-converting enzyme 2 activ-ity (42,44). There also appear to be some fluctua-tions in the renin-angiotensin-aldosterone systemduring different phases of the menstrual cycle thataffect the orthostatic hemodynamic response inPOTS (45). When sodium intake is controlled, urinesodium excretion can be used as a surrogate forhypovolemia, and approximately 30% of POTS pa-tients have evidence of hypovolemia based on <100mEq of urinary sodium excretion in 24 h (6). In POTSpatients with comorbid gastrointestinal (GI) dysmo-tility disorders, secondary hypovolemic states canalso occur from excessive fluid loss from diarrhea orfrom poor volume and electrolyte intake due tochronic nausea.

MAST CELL ACTIVATION DISORDER

Although controversial, the role of excessive mast cellactivation in the pathophysiology of POTS has beenproposed. In mast cell activation disorder (MCAD),inappropriate release of histamine and other mast cellmediators in response to physical activity or ortho-static stress may lead to orthostatic tachycardia. Pa-tients have episodes of flushing, shortness of breath,headache, lightheadedness, excessive diuresis, andGI symptoms (including abdominal pain, diarrhea,nausea and vomiting). Episodes are triggered byprolonged standing and exercise but can alsooccur pre-menstrually, with meals, and with sexualintercourse. Affected patients may also exhibit der-matographism and frequent urticaria (hives). Diag-nosis of MCAD hinges on detection of abnormallyincreased levels of histamine metabolites in the urine(N-methylhistamine) or elevated plasma tryptaseduring an acute episode. MCAD patients may havePOTS with hyperadrenergic features (increased HRand BP with standing). Treatment consideration inthis subtype would be avoidance (or cautious use)of beta-blockers as well as treatment with pharma-cological agents directed at blocking the effects ofhistamine on H1 and H2 receptors and stabilizing mastcells (46).

AUTOIMMUNITY

An autoimmune basis for POTS has been suggested onthe basis of some of the clinical associations,including subacute onset in the setting of stress orviral illness, and the occasional association of POTSwith a personal or family history of systemic auto-immune disorders such as Sjogren’s syndrome. Insome of these cases, orthostatic intolerance may be asecondary feature of a systemic autoimmune diseaseor related to the presence of a peripheral autonomicneuropathy (i.e., neuropathic subtype of POTS).

Several studies have found an increased preva-lence of serum autoantibodies directed againstneuronal targets in POTS patients. These include an-tibodies against ganglionic acetylcholine receptors(AChR) and antibodies against alpha-1 adrenergic re-ceptors (6,47). Thus far, however, none of the auto-antibody associations have been convincingly provento be pathophysiologically or diagnostically impor-tant. In a cohort study of unselected POTS patients,the prevalence of ganglionic AChR antibodies (alwaysat low antibody levels) was <5%, and this antibodyfrequency was not statistically different from popu-lation controls (48,49). Antibodies that appear toactivate G-protein–coupled receptors (adrenergic re-ceptor and muscarinic AChR) have been reported insmall cohorts of POTS patients, but the clinical sig-nificance of these antibodies has not been clearlyestablished.

Although autoimmune mechanisms may play a rolein some POTS cases, this concept requires additionalinvestigation. It is reasonable to consider the possi-bility of autoimmunity in POTS patients, but at thistime, immunomodulatory therapies are not recom-mended unless definitive evidence of a systemicautoimmune disorder is found.

EFFECT OF SEX AND MENSTRUAL CYCLE

Intolerance to orthostasis tends to be more significantin young women compared with their male counter-parts (29). Although the underlying mechanisms arenot completely understood, sex-specific differencesin hemodynamics and hormonal levels may in partcontribute to this difference (50). Women with POTSoften report fluctuations in the severity of POTSsymptoms throughout their menstrual cycle, withworsening during either the pre-menstrual or earlyfollicular phase when both estrogen and progesteronelevels are dropping or low (6,9,45,51). The etiology ofthis subjective variation in symptoms through themenstrual cycle is yet to be delineated, though


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multiple mechanisms have been proposed. In healthywomen, renin activity and aldosterone levels fluc-tuate through the menstrual cycle; however, hemo-dynamic parameters in response to orthostasis arenot noted to change (52). When plasma volume, bloodvolume, and supine hemodynamics were measured ina cohort of POTS patients and controls, no variationswere noted while comparing the mid-luteal phase tothe early-follicular phase (45). No variations in BP orHR response during standing were noted during themenstrual cycle in this study. However, in POTSpatients, cardiac output and stroke volume werelower, and total peripheral vascular resistance higher,during the early-follicular phase. Similarly, the men-strual cycle has not been shown to affect musclesympathetic nerve activity; however, it may play amodest role in modulation of BP and vasoconstrictionin women with POTS during orthostatic stress (53). Inaddition to differences in hormonal levels, physicalcharacteristics of women including a smaller strokevolume and smaller, less distensible hearts (evenwhen normalized to body mass), may also contributeto why women may be more prone to orthostaticintolerance (29,50,54). It is our experience that POTSis quite rare after menopause, though explanationsfor this age specificity are unsatisfying. The under-lying hormonal changes, presumably relating to thebalance between testosterone and estrogen, must beplaying a role.

DIURNAL VARIABILITY

Many patients report worsening of their symptoms inthe morning and improvement through the course ofthe day, which is often reflected in their hemody-namic parameters. Orthostatic HR increments havebeen shown to be larger in the morning than in theafternoon (55). Some patients who fulfill criteria forPOTS when tested in morning do not always fulfillcriteria in the afternoon. This difference is likely areflection of the physiological changes that occurduring sleep, from being supine for a prolongedperiod in the absence of any fluid intake.

Furthermore, some patients with POTS are foundto have lost the physiological drop in BP that typicallyoccurs nocturnally (defined as a <10% day–night dropin systolic BP), termed nondipping. These patientsalso demonstrate significantly greater orthostatic HRincrement and a significantly greater orthostaticplasma NE rise compared with matched dippingcontrols (56), suggesting that the observation may notnecessarily imply a failure to dip, but rather reflectsan exaggerated BP response to the upright postureduring the day (reduced systolic/increased diastolic)

with its resolution in the supine position. This findinghas not yet been reproduced, however, and its sig-nificance is currently unclear.

BEDREST AND

CARDIOVASCULAR DECONDITIONING

Although there is much debate regarding the initialinsult, the role of cardiovascular deconditioning inPOTS has been well-defined. Common to all forms ofPOTS, and a key source of morbidity regardless ofetiology, is a state of physical deconditioning. Manystudies have demonstrated that prolonged bedrest ormicrogravity exposure can result in a POTS-like syn-drome characterized by a tachycardic orthostaticintolerance even in previously healthy and activeindividuals (17,18,25,27,57–60). Multiple parametersassociated with deconditioning have also beendemonstrated in POTS patients, including reducedcardiac size and mass (by 16%), reduced blood volume(by 20%), reduced stroke volume, and reduced peakoxygen uptake (VO2 peak) when compared withmatched sedentary controls (4). These findings sug-gest that the orthostatic tachycardia in POTS is aphysiological compensatory response to the smallerstroke volume (61,62) in the setting of cardiac atrophyand reduced blood volume (Figure 2B). Furtheremphasizing the role of deconditioning in POTS is thepositive response these patients have to exercisetraining, which has been demonstrated to expandblood volume and increase cardiac size and mass inPOTS patients and result in a prominent decrease insymptoms (4,63,64). (Central Illustration).

DIFFERENTIAL DIAGNOSES

Orthostatic tachycardia alone is not sufficient todiagnose POTS; other diagnostic criteria apply, andother syndromes and intrinsic cardiac abnormalitiesmust be excluded.

Neurally mediated syncope (NMS) (“vasovagal” orreflex) syncope is not synonymous with POTS and is aseparate problem, but NMS can lead to similarsymptoms of orthostatic intolerance particularly inthe immediately pre-syncopal phase. In NMS, thepatient’s BP and HR are maintained during head-upposture until a precipitous drop in BP and often HRleads to pre-syncope and syncope. In POTS, the pa-tient’s BP should be maintained throughout HUT.Although many POTS patients report pre-syncopalsymptoms, the majority do not lose consciousness.However, up to 30% of POTS patients may experiencesyncope, and these patients may have both NMSand POTS, because these disorders can occur together(9,65).

CENTRAL ILLUSTRATION Postural Orthostatic Tachycardia Syndrome: Downward Spiral

DEVELOPSSYMPTOMS:

• Orthostatic intolerance(occurs early evenafter brief bedrest)

• Exercise intolerance• Dizziness

CARDIOVASCULARDECONDITIONING:• Decreased blood

volume• Decreased stroke

volume• Cardiac atrophy

SYMPATHETICACTIVATION(in uprightposition):

• Increased heart rate• Decreased GI motility

• Headaches

WORSENINGSYMPTOMS:

• Orthostatic intolerance• Exercise intolerance

• Further bedrest

Susceptible individual• Unknown genetic predisposition• Highly active person

Inciting event:• Infection• Surgery• Concussion• Pain/headache• Enforced bedrest

DIMINISHEDACTIVITY +/-

FURTHERBEDREST

Bryarly, M. et al. J Am Coll Cardiol. 2019;73(10):1207–28.

Postural orthostatic tachycardia syndrome (POTS) has been described as a “downward spiral.” Often, several factors culminate, leading to diminished activity and

bedrest; in a susceptible individual, significant deconditioning and debility can eventually develop. This often dominates the clinical picture, and the cycle can continue

unabated until it is broken. GI ¼ gastrointestinal.



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Similarly to patients with POTS, patients withneurogenic orthostatic hypotension (NOH) can alsocomplain of orthostatic intolerance. It is important todifferentiate these because the treatment approach toeach is distinct. Orthostatic hypotension can occur indisorders such as multiple system atrophy, Parkinsondisease, Lewy body dementia, pure autonomic fail-ure, autoimmune autonomic ganglionopathy, andother autonomic neuropathies. These disorders canbe easily differentiated by checking orthostatic vitals(and/or tilt test). With orthostatic hypotension, thereshould be at least a 20-point drop in systolic BP by3 min of tilt and typically the HR increment isminimal.

Other cardiac causes of sinus tachycardia can bemistaken for POTS, and appropriate evaluationsshould be pursued as guided by clinical judgment.Inappropriate sinus tachycardia (IST) is sometimesconfused with POTS, but occurs independent of bodyposition (66). By contrast, the tachycardia in POTS istriggered by orthostatic stress, and POTS patientsusually have a normal resting supine HR. IST and POTSdo have overlapping features, and similar to POTS, thepathophysiology of IST is not well understood and islikely multifactorial. Patients with IST and POTS sharea common demographic, with both predominatelyaffecting youngwomen. The key tomaking a diagnosisof IST is ambulatory monitoring; IST patients, unlikepatients with POTS, demonstrate relative night-timesupine tachycardia. Of course, other common supra-ventricular tachycardias may need to be excluded,though these generally have a distinct onset and offsetof symptoms and are not primarily postural in pre-sentation. Correlation with symptoms during ambu-latory electrocardiogram (ECG) monitoring or the useof vagal maneuvers can help distinguish theserhythms from a sinus mechanism.

Pheochromocytoma is a rare neuroendocrine tu-mor that can present with paroxysmal hyper-adrenergic symptoms. However, unlike in POTS,these paroxysmal symptoms are not positional.Evaluation for pheochromocytoma is best made bymeasuring plasma metanephrines (67).

The tachycardia of POTS is a sinus tachycardia.Sinus tachycardia is usually a normal physiologicalresponse to conditions in which the sympatheticnervous system is activated and the parasympatheticnervous system is inhibited, such as exercise, fever/infection, anemia, anxiety, and pain. These commoncauses of appropriate sinus tachycardia will not bediscussed in detail, but they should always beconsidered in the differential for a sinus tachycardia.The cardiologist who first evaluates a patient forPOTS must also exclude structural cardiac disease

that would reduce upright stroke volume, includingvalvular heart disease, cardiac tumors or other causesof right or left ventricular outflow tract obstruction,pulmonary hypertension, undiagnosed congenitalheart disease, or acquired myocardial diseases.

Acute or chronic hypovolemia may be associatedwith orthostatic sinus tachycardia, with or withoutaccompanying orthostatic hypotension, as strokevolume falls and HR increases to maintain cardiacoutput and oxygen delivery to tissue. Serum andurine studies and review of medications (diuretics)can be helpful in evaluating for potential causes.

Other conditions that can lead to tachycardiashould also be considered. These include pulmonaryembolism, acute coronary syndrome, hypothyroid-ism, ventricular arrhythmias, and heritable or ac-quired cardiomyopathic or arrhythmic disorders.These can be differentiated by the clinical context.

As previously discussed, exposure to stimulants(sympathomimetic drugs such as amphetamines) andother medications (such as tricyclic antidepressants)can lead to tachycardia. Abrupt withdrawal of certainmedications such as beta-blockers or central sympa-tholytic agents such as clonidine, may also causerebound tachycardia.

COMMONLY ASSOCIATED CONDITIONS

Although the cardinal symptoms of POTS occur withstanding and improve with sitting or lying, patientsoften relate other chronic symptoms and comorbid-ities that cannot physiologically be explained byorthostatic intolerance or tachycardia. These arenumerous and include chronic fatigue, dizziness,syncope, migraines, functional GI disorders, chronicnausea, fibromyalgia, and joint hypermobility amongothers (68). Many symptoms occur independently ofPOTS, and others persist even after the resolution ofpostural intolerance. The connection among many ofthese symptoms and POTS remains unclear. Manyhave speculated that the same pathophysiologicalmechanisms that lead to POTS cause these other co-morbid disorders, and some of these symptoms couldbe attributed to an increased sympathetic activationassociated with POTS. Several recent studies haveshown that these comorbidities occur in increasedfrequency with each other regardless of whether apatient has POTS, suggesting that POTS is simplyanother comorbid condition rather than the cause ofthese other conditions (69). Specifically, the followingdescribed conditions are not core features of, nor arethey synonymous with, POTS. Rather, these aresyndromes that may occur together with POTS(Figure 4).

FIGURE 4 Coexisting Conditions in POTS

ChronicFatigue

Syndrome

Functional GIdisorders

Anxiety &Hypervigilance

Autoimmunity

JointHypermobility

& EDS

Fibromyalgia

Migraine

Concussion

POTS &CoexistingConditions

Patients often relate many other symptoms and comorbidities that are not

physiologically explained by orthostatic tachycardia. Some of these persist

even with resolution of orthostatic intolerance. These include chronic fatigue

syndrome, joint hypermobility and EDS, autoimmune diseases, anxiety and

hypervigilance, functional gastrointestinal disorders, fibromyalgia,

migraine, and concussion. EDS ¼ Ehlers-Danlos syndrome;

GI ¼ gastrointestinal; POTS ¼ postural orthostatic tachycardia syndrome.



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EHLERS-DANLOS SYNDROME AND JOINT HYPERMOBILITY.

Ehlers-Danlos syndrome (EDS) is a connective tissuedisorder characterized by joint hypermobility; thereare several types, depending on the phenotype andgenetic defect. Type III (hypermobility type) is theleast severe type and causes joint hypermobility witha propensity for joint dislocations. Unlike other formsof EDS, type III has no defined genetic mutation andis diagnosed on the basis of clinical criteria alone.Previous retrospective reviews suggest that EDS mayoccur more frequently in association with POTS (70).It has been proposed that the impairment in connec-tive tissue leads to abnormalities in vascular compli-ance, increased leg blood pooling, and poor venousreturn that may all predispose patients to orthostatictachycardia and intolerance; however, attemptsto substantiate these hypotheses have not beenconvincing (15). In fact, there is no apparent differ-ence in prevalence between the incidence of jointhypermobility in POTS patients and patients withother underlying chronic functional conditions. Thissuggests that joint hypermobility may not be patho-physiologically important for the development of

orthostatic intolerance in POTS patients; rather it maybe another comorbid condition that occurs in patientswith chronic functional disorders (71).

MIGRAINE AND CONCUSSION. A frequentlydescribed comorbidity in POTS patients is migraine,as well as other chronic headache types (6,65,72,73).Intractable migraines often lead to physical inac-tivity, which may exacerbate orthostatic intolerance,and conversely, the increased sympathetic activityassociated with POTS may contribute to increasedfrequency of headaches. Sport-related concussion hasbeen reported to affect postural stability as well asneurocognitive function (74). Concussion has alsobeen associated with development of POTS, and thereis a relatively high rate of POTS in patients withpersistent post-concussive syndrome. As with otherPOTS triggers, this may in part be related to decon-ditioning, because a period of physical activitywithdrawal and increased bedrest is typically rec-ommended following a concussion. The resolution ofPOTS often runs parallel with the resolution of post-concussive syndrome (75) likely reflecting thepatient’s return to physical activity.

HYPERVIGILANCE AND ANXIETY. Perceptual ampli-fication and hypervigilance are phenomena describedin chronic pain conditions, like fibromyalgia. Theyare associated with an increased sensitivity andaversion toward somatic signals, tactile stimuli, andpain, with an increased propensity to report sensa-tions that others might ignore (76–78). This has morerecently been expanded to explain some of thesymptoms and comorbid conditions associated withPOTS (79). Although anxiety is a commonly describedin POTS, the excessive tachycardia is not simply aphysiological manifestation of anxiety (80). Pediatricpatients with chronic pain and POTS have beenshown to demonstrate reduction in depression,anxiety, and overall functionality followingtreatment with a comprehensive pain rehabilitationprogram (68).

CHRONIC FATIGUE AND FIBROMYALGIA. Chronicfatigue syndrome (CFS) and fibromyalgia are comor-bidities frequently associated with POTS. Chronic fa-tigue has been cited in up to 48% of POTS patients (6),and patients with CFS often have POTS as well (81).Not surprisingly, both POTS and CFS patients sharemany of the same characteristics including smallhearts (81) and lab markers of excessive sympatheticactivation; as such, they may exist along the sameclinical spectrum (82). Furthermore, chronic fatigueand fibromyalgia often lead to a reduction in physicalactivity, subsequent deconditioning, and exacerba-tion of orthostatic intolerance.

FIGURE 5 Diagnostic Algorithm for Suspected POTS

Complains of Orthostatic Symptoms

Physical Exam

Tachycardia withstable BP?

Tachycardia unrelatedto rest or position?

Fall in BP with rise inHR?

Fall in BP with stableHR?

Orthostatic Vitals (see text)Patient must stand quietly for a minimum of 3-5 minutes.

POTS IST NOH/AFPrimary OH

(amyloid infiltration,systemic inflammation)

Careful medication review(i.e. diuretics, birth control with antimineralocorticoid action

(drospirenone), vasodilators, antipsychotics, stimulants/ADHDmedications, anticholinergics)

MEDICATION HISTORY

Symptom onset?

Do symptoms go away or improve with sitting or supine position?Any exacerbating factors?

(i.e. waiting in line, shopping, cooking)

Any precipitating factors?(i.e. viral illness, injury, enforced bedrest, marked change in social situation, other chronic illness)

Are symptoms exclusively or primarily in upright position?

MEDICAL HISTORY

(i.e. heat, menstrual cycle, circadian rhythm)

Consider hyperthyroidism

Consider anemia

Warm, moist skin, tremor,pretibial myxedema?

Pale skin with history ofheavy menstrual periods,

vegetarianism?

ADHD ¼ attention deficit/hyperactivity disorder; AF ¼ autonomic failure; HR ¼ heart rate; IST ¼ inappropriate sinus tachycardia syndrome; NOH ¼ neurogenic

orthostatic hypotension; OH ¼ orthostatic hypotension; other abbreviations as in Figures 1 and 2.


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“BRAIN FOG”. “Brain fog” is a commonly described,but imprecise, symptom in patients with POTS andsimilar conditions. When this symptom was studiedin detail, it was more consistently described as beinga cognitive complaint similar to mental fatigue;additionally, brain fog was not limited to the uprightposture and was made worse by poor sleep (83). Itsunderlying mechanism is unclear and is likelymultifactorial with contributions from diminishedrestfulness during sleep and diminished cerebralperfusion in the upright position either from hy-perventilation, sympathetic activation, or endothe-lial mechanisms.

INCREASED DAYTIME SLEEPINESS AND SLEEP

DISTURBANCE. POTS patients often complain ofdaytime sleepiness and insomnia (63%). In POTSpatients who do get overnight polysomnography, noobjective sleep parameter abnormalities are typicallyidentified, and findings are comparable to those ofhealthy controls (84,85). A negative correlation be-tween supine HR and sleep efficiency has been noted;a potential etiology for this link is less refreshingsleep due to increased sympathetic activation (84).When asked to quantify and qualify their symptoms,POTS patients score higher on fatigue scales than theydo sleepiness scales, which suggests the underlying



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factor may not be a primary sleep disorder, but ratherbody fatigue, chronic pain, and other somatic symp-toms (86).

GI DYSMOTILITY. The co-occurrence of GI symptomsand POTS has been well-described, but the extent ofthis connection is still not well understood. Common,but nonspecific, GI complaints reported by somePOTS patients include bloating, nausea, vomiting,abdominal pain, constipation, and diarrhea. In aretrospective study looking at GI transit in patientswith POTS, two-thirds had abnormal gastricemptying. The majority of these patients had rapidgastric emptying, but a smaller subset had delayedgastric emptying (87); these findings may have beenconfounded by medication effects, however. Severalother studies have implicated dysmotility atdifferent levels of the GI tract (duodenal, gastric) inPOTS (87–89). Some theorize that the same sympa-thetic activation and vagal withdrawal leading toPOTS may result in abnormal gut motility and GIdiscomfort (88), and in fact, some patients reportworsening of GI symptoms with orthostatic stress.Whether the GI dysfunction that may occur withPOTS stems from autonomic imbalance, medicationeffects, a dysfunction at higher central nervous sys-tem centers of control, or some combination of thesefactors has yet to be determined.

CHRONIC PELVIC PAIN AND OVERACTIVE

BLADDER. Lower urinary tract symptoms, includingincreased daytime frequency, urgency, and nocturiahave been reported at higher frequencies in POTS(90). Only a single case report has been described of awoman with POTS who had both symptoms andurodynamic evidence of detrusor hyperreflexia (91);other data providing objective evidence of urinarydysfunction in POTS patients are lacking. Urinaryfrequency and urgency may in part be related toincreased fluid intake because POTS patients oftenhave been told to drink more water or intuitively doso to combat orthostatic symptoms. Orthostaticintolerance has been reported to occur morefrequently in patients with chronic pelvic pain,including interstitial cystitis, bladder pain syndrome,and myofascial pelvic pain (92). This higher incidenceof orthostatic intolerance may be related to percep-tual amplification and hypervigilance, which havebeen well-described in pain conditions (77).

BASIC EVALUATIONS

In a standard primary care, clinical cardiology, orneurology practice, the majority of POTS patients canbe easily diagnosed with few tools (Figure 5).

� History� Review of medications� Physical examination� Active stand test� Labs or cardiovascular testing as clinically

indicated

ACTIVE STAND TEST

An active stand test is a simple evaluation for POTS(and orthostatic hypotension) that can be done at thebedside or in the clinic with only an automated ormanual BP cuff. The patient lies quietly in a supineposition for at least 10 min before baseline supine BPand HR are measured. The patient then stands andremains standing unassisted for 10 min. BP and HRare measured at regular intervals (such as 1 min,3 min, 5 min, and 10 min) in the standing position.The accepted clinical criteria for POTS may be appliedto these data (Figure 1). Orthostatic tachycardia ismore pronounced in the morning, and the activestand test (or HUT) should be performed in themorning when possible (93).

It is the opinion of the authors that this type oftesting should be considered the standard of care forassessing patients with orthostatic complaints. If theymeet criteria for POTS, then it is well within thepurview of the primary care physician to evaluatecarefully the use of medications that can compromiseorthostatic BP control, check for common conditionssuch as anemia, or thyroid disease that could causesecondary upright tachycardia, and determinewhether precipitating factors for POTS exist. Referralto cardiology should be considered to exclude struc-tural cardiac disease, or to evaluate for a possiblearrhythmia if such a concern arises after a carefulhistory and physical examination. If not, PCPs caneasily implement the exercise-based intervention forPOTS described here without fear of adverse out-comes, with referral only if no response to this first-line treatment.

LABS AND OTHER

CARDIOLOGICAL EVALUATIONS

Depending on the presentation, additional laboratoryevaluations may include a complete metabolic pro-file, complete blood count (to evaluate for anemia),thyroid function testing, or more specialized testing(discussed later in the text) (Figure 6). Additionalcardiac evaluations may be considered as clinicallyindicated. A 12-lead ECG may capture cardiac con-duction abnormalities and is reasonable to obtain.Holter monitoring is useful to evaluate paroxysmal

FIGURE 6 Other Conditions That Can Cause Tachycardia

AnemiaHypovolemia

Other medical problems that can cause orcontribute to tachycardia:

HyperthyroidismPulmonary EmbolismPheochromocytoma

Medications

There are other etiologies that can cause tachycardia, and these

must be excluded in order to diagnose postural orthostatic

tachycardia syndrome. This is a list of some common etiologies

that can contribute to tachycardia.


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symptoms as well as characterize patterns of HRvariability during daily activities. Because Holtermonitoring is routinely only performed for 24 h, moreprolonged ambulatory monitoring is necessary toevaluate syncope or other intermittent symptoms.Many cardiovascular conditions can impair uprighthemodynamics and should be excluded with anechocardiogram if suspected. An ambulatory BPmonitor or wrist BP monitor are convenient ways totrack BP changes throughout the day or duringevents. As the technology for wearable devices im-proves, many of these can be used to track at least HRchanges, and for some devices, spot ECG checks overprolonged periods of time. These devices may beparticularly useful when arrhythmias are not highlysuspected.

SUPPLEMENTAL EVALUATIONS

With unusual presentations, cases suggestive of amore diffuse autonomic disorder, or patients who arenot responding to treatment, referral for formalautonomic evaluation might be considered.

AUTONOMIC FUNCTION TESTING. Formal auto-nomic function testing (AFT), which includes HUT, ishelpful to evaluate for other types of autonomicimpairment and differentiate among POTS subtypes.Ti l t tab le test ing . Formal tilt table testing is notroutinely needed to diagnose POTS; an active standtest is sufficient in most circumstances, especiallybecause it reproduces the circumstances in whichpatients are most symptomatic. Active standing doesenable patients to use the “skeletal muscle pump,” inwhich skeletal muscle contraction in the legs in-creases venous return to the heart (94). Unless thetest is conducted carefully and patients are instructed

to stand quietly, active standing can lead to poten-tially hemodynamically significant differences whencompared with more passive HUT in which thepatients are typically restrained on a tilt bed.

The clinical criteria for POTS do not specify themethod of achieving the upright posture. When theactive stand test was compared with passive HUT,orthostatic tachycardia was noted to be greater withHUT than with the active stand test in both POTSpatients and healthy controls. Both HUT and theactive stand test were sensitive for the diagnosis ofPOTS, but the stand test was more specific (79% vs.23% for HUT). When the 10-min criterion for uprightposition was applied to these data, HUT and theactive stand test were comparable (95).

The HR after the use of nitroglycerin or isoproter-enol should never be used to achieve clinical criteriafor POTS. In the past, administration of medicationsuch as isoproterenol, nitrates, or clomipramine wereused to provoke vasovagal responses during HUT. Itwas believed that these medications would blunt theadaptive response of the autonomic nervous systemand unmask NMS. A positive response is defined asdemonstration of pre-syncope or syncope withhypotension and bradycardia. In actuality, these testsunmask NMS in addition to evoking syncope inseveral other conditions, including many normalindividuals, and recent studies have shown thesetests to be very nonspecific. Furthermore, cardiacarrhythmias following isoproterenol administrationhave been reported (96). Thus, administration ofmedications to provoke NMS is no longer recom-mended, and they should never be used to enhancecriteria for POTS.

If a tilt table test is performed in the evaluation of aPOTS patient, then special care should be taken toreassure the patient and limit the anxiety that oftencompounds the orthostatic stress under these artifi-cial conditions. Patients should be tilted at 70�, andthis position should be maintained for 10 min withmonitoring of HR and BP at the same time periodsnoted earlier in the text (1, 3, 5, and 10 min).

HR var iab i l i ty . Most academic autonomic labsperform HR variability measured during paceddeep breathing (measure of cardiovagal function),evaluation of BP and HR changes during a Valsalvamaneuver (measure of both HR and vasoconstrictorbaroreflex function), and some form of controlledorthostatic testing; some also perform thequantitative sudomotor axon reflex test (a test ofpostganglionic sudomotor function) and/or thermo-regulatory sweat test. It is crucial to take a detailedmedication history at the time of AFT because many

FIGURE 7 Treatment Algorithm for POTS

(if possible, avoid mineralocorticoidsdue to hypokalemia & theoretical

risk of myocardial fibrosis)

Consider midodrine

POTS Treatment Algorithm

(raise HOB, liberal hydration, graded exerciseprogram for 3 months, compression garments, etc.)

Try nonpharmacologic measures first

In severe cases, can consider addingmedication while initiating exercise

program

If symptoms aredominated bypalpitations

If background low BP &symptoms dominatedby lightheadedness

If symptomsdominated by standing brainfog with low catecholamines

Consider ivabradine ornonselective beta-

blocker

If co-existingconstipation, consider

mestinon

Consider NE reuptakeinhibitor

HOB ¼ head of bed; NE ¼ norepinephrine; other abbreviations as in Figures 1 and 2.



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medications can significantly alter the results ofthese tests.

Subtle clues in AFT findings may help differentiateamong different POTS subtypes. For example, ina patient who otherwise meets accepted clinicalcriteria for POTS, impaired quantitative sudomotoraxon reflex test or thermoregulatory sweat testresponses may be suggestive of neuropathic POTS.An exaggerated sympathetic vasoconstrictorresponse during the Valsalva maneuver or the pres-ence of orthostatic hypertension may suggesthyperadrenergic POTS (46).

Addi t iona l tests . Handgrip exercise (assessment ofexercise pressor reflex) and cold pressor test (assess-ment of central integration of vasomotor processesand their efferent pathways) are other evaluationsthat may provide supplemental information insome cases. A few academic labs additionallyperform pupillometry and/or microneurographic

measurement of muscle sympathetic nerve activity,which have various other clinical implications.

PLASMA CATECHOLAMINES. Though not routinelynecessary, plasma catecholamines may be helpful indifferentiating hyperadrenergic POTS from othersubtypes. This is best accomplished in a controlledclinic setting because it requires placement of a pe-ripheral intravenous (IV) line, and the blood samplesmust be immediately placed on ice and processedappropriately. To correctly measure plasma cate-cholamines, an IV line must be placed first. The pa-tient then rests quietly in the supine position for atleast 10 min. Although supine, a plasma sample iscollected for determination of supine plasma cate-cholamine levels (dopamine, NE, and epinephrine).The patient is subsequently asked to stand, andplasma catecholamines are again measured after5 min of standing. A normal response is an approxi-mate doubling of the NE level from a supine to a


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standing position. Patients with hyperadrenergicPOTS may have elevated NE levels (typically >600 to1,000 pg/ml). This is felt to be a reflection of exag-gerated sympathetic neuronal activation (97).

PLASMA TRYPTASE. If flushing accompanies thesymptoms of tachycardia, evaluation for a MCAD maybe appropriate. Plasma tryptase may be elevated inthese individuals during symptomatic episodes.N-methylhistamine >230 mg/g creatinine in a 4-hurine collection immediately following a sponta-neous event would also be suggestive of this disorder.Patients with MCAD may also demonstrate hyper-adrenergic POTS features with testing, such as anexaggerated BP overshoot during recovery after theValsalva maneuver (46).

MANAGEMENT

In the majority of cases, POTS can be diagnosed andmanaged by primary care physicians. Patients withatypical signs or symptoms may be referred to acardiologist or neurologist with expertise in this areafor additional testing and guidance with respect tomanagement recommendations as well as to excludetrue cardiac disorders as discussed earlier.

The approach to the management of POTS isgenerally pragmatic (Figure 7). It includes a combi-nation of exercise, nonpharmacological measures,and only in select cases, the use of medications.Exercise is the key treatment approach for mostpatients and is universally recommended (barringany unrelated contraindications).

EXERCISE. Research has demonstrated thatphysical reconditioning with a short-term (3 month)progressive exercise training program leads toimprovement or remission of POTS in the majority ofpatients (4,64).

An exercise training regimen consists of regular“base training” using a recumbent bike, rowingmachine, or swimming. This approach allows patientsto exercise while avoiding the upright position andimproves tolerance of the program. As the patientsbecome more fit, the duration and intensity of exer-cise sessions is increased, and upright exercise can begradually added as tolerated in the second or thirdmonth. Resistance training with weight lifting is alsoimportant to improve cardiac and skeletal musclemass (4). Exercise therapy is most successful whenthe program is supervised by experienced trainers orphysical therapists that understand the pathophysi-ology of POTS, though it has also been demonstratedto be highly effective when administered in a com-munity setting (64).

This exercise regimen has been demonstrated toincrease physical fitness (measured as increasedVO2 max), left ventricular mass, end-diastolic volume,stroke volume, and blood volume (4,98,99), andimprove autonomic circulatory control and arterial-cardiac baroreflex function (100). Even in caseswhere deconditioning does not seem to be a largefactor in the development of POTS, it can still beuseful in its treatment by improving fitness, andreducing pain and hypervigilance through well-defined neural mechanisms. The majority of pa-tients who complete the exercise training program nolonger meet criteria for POTS, and the vast majority, ifnot all patients, report improved quality of life usinga reliable and valid questionnaire (4,101).

This exercise training program was compared withpropranolol in a double-blind drug trial. Even thoughpropranolol was also effective at reducing standingHR, exercise training was found to be superior topropranolol at restoring upright hemodynamics andnormalizing renal-adrenal responsiveness. Patientquality of life also improved after exercise training,but not with propranolol treatment (98).

In a follow-up of a small number of patients whoparticipated in the exercise program in a communitysetting, the effectiveness persisted for at least 1 year(64). A regular, structured, and progressive exerciseprogram is a Heart Rhythm Society (HRS) Class IIarecommendation for the treatment of POTS, and it mayreceive enhanced recommendation based on recentdata and lack of other proven effective therapies (1).

The major challenge with implementing exercisetherapy is achieving regular and consistent patientcompliance with the program for at least 3 months.Patients often complain that they feel more fatiguedin the first few weeks of exercise and may abandonthe program before any benefits are realized; thispossibility must be anticipated, and patients must beencouraged to persevere with the program, becausetolerance does improve as patients become more fit.In order to preserve symptomatic improvement,patients are encouraged to sustain a lifelong habit ofregular exercise.

Please see the Online Appendix for relevant infor-mation that is useful in implementing this exerciseregimen for POTS patients.

Reconditioning via exercise may not improve allsymptoms (101). If symptoms of comorbid conditionsare intrusive and limiting participation with treat-ment recommendations, referrals to the appropriatesubspecialists (such as headache, sleep, gastroenter-ology) may be indicated. Additionally, cognitivebehavioral therapy and biobehavioral treatment can


FIGURE 8 Nonpharmacological Interventions for Minimizing Orthostatic Intolerance Symptoms

POTS often can be managed by nonpharmacological measures alone. These strategies can help increase blood volume and minimize orthostatic symptoms. In addition

to boosting blood volume, an exercise regimen geared toward POTS can also increase stroke volume, increase left ventricular mass, and lead to longer lasting reduction

in orthostatic symptoms. POTS ¼ postural orthostatic tachycardia syndrome.



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be useful in mitigating some of the complicatingfactors.

In young patients with normal cardiac and renalfunction (which constitutes the majority of POTS

patients), increasing blood volume can be accom-plished by drinking 3 l of water per day and liberal-izing salt intake by ingesting 5 to 10 g of sodium perday, if tolerated. This is a HRS Class IIb


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recommendation in POTS (1). Salt tablets should beavoided as they are very concentrated, actuallyinduce an osmotic load into the stomach, and maycause nausea, vomiting, and paradoxically, reducedplasma volume.

OTHER NONPHARMACOLOGICAL

TREATMENTS

Other nonpharmacological treatments can also bevery effective in managing symptoms of orthostaticintolerance and are less likely than medications toproduce undesirable side effects (Figure 8). Environ-mental heat, prolonged upright posture, prolongedfasting, excessive alcohol intake, straining (such asduring urination or bowel movements), or vaso-dilatory medications will exacerbate orthostaticintolerance and should be avoided when possible.Keeping the skin cool with iced mist can be helpful inhot environments. Large meals should be avoided,especially those high in fat and complex carbohy-drates, because these can lead to postprandialaggravation of symptoms due to increased blood flowto the gut. Small, frequent meals are recommended,and a high-fiber diet can help normalize GIsymptoms.

Physical maneuvers such as leg crossing, muscletensing, and squatting have been shown to be effec-tive in postponing and in some subjects preventingvasovagal syncope if used at the onset of prodromalsymptoms (102,103). Intravenous saline can be usedfor acute clinical decompensation attributable tohypovolemia from vomiting, etc., but should bereserved for severe and incapacitating symptomsassociated with an acute volume-depleting stimulus.Long-term repeated saline infusions are not recom-mended (1). Patients often report symptomaticbenefit from saline infusions, and they can effectivelyexpand intravascular volume and consequentlyreduce orthostatic tachycardia for a brief period oftime. This effect, however, is transient, and ulti-mately results in a net loss of plasma volumefollowing the infusion (104). Although IV fluids can bebeneficial in the acute setting, there are no datasuggesting that saline infusions are an effective long-term solution. Furthermore, repeated IV access, orworse, central venous port placement, is invasive andcan increase risk of infection and other serious con-sequences such as endocarditis or upper extremitythrombophlebitis.

All individuals, including patients with POTS,experience hemodynamically significant venouspooling from gravitational gradients in the uprightposition, and compression stockings for the lower

extremities may be effective in treating this symp-tom. However, to be of any benefit, they must extendat least to the top of the thighs and preferably tothe abdomen. Abdominal binders can decreasesplanchnic–mesenteric venous pooling and may beeasier to use, particularly in combination with thigh-high compression stockings. These measures increasevenous return and lessen orthostatic tachycardia(105).

Sleeping with the head of bed elevated by 4 to 6inches (reverse Trendelenburg position) is commonlyrecommended in the setting of a separate disorder,NOH (106); the supine hypertension that accompaniesNOH leads to increased nocturnal diuresis, which inturn worsens orthostatic intolerance, particularly inthe morning. The reverse Trendelenburg position re-duces supine hypertension and thereby reducesnocturnal diuresis, which preserves plasma volume.This position also minimizes suppression of ADH andrenin-angiotensin-aldosterone system. Though thereare no specific data in POTS, the benefits related toreduction in nocturnal diuresis and subsequent in-crease in plasma volume are theoretically applicableto POTS patients as well and may improve symptomsin the early morning.

PHARMACOLOGICAL TREATMENT

Due to potential side effects and absence of clinicaltrials supporting efficacy, medications should beavoided in POTS if possible. Medications can beconsidered in patients with severe symptoms who arehaving difficulty initiating an exercise program as abridge to help minimize some symptoms and allowthem to initiate the exercise program. Pharmacolog-ical treatment for POTS often requires serial trials tofind a treatment or combination of treatments thatprovides the best symptomatic benefit with the few-est side effects. No medication is Food and DrugAdministration approved to treat POTS; all use is off-label. As such, many commonly used medications willbe discussed here, but this list is likely not exhaustiveof all those used in clinical practice.

Midodrine (an alpha1-adrenergic agonist) 2.5 to10 mg 3 times daily in a front-loaded regimen can betried in patients with low or low-normal BP at rest.The first dose should be given 15 to 30 min beforegetting out of bed in the morning. The last doseshould not be taken later than 4 PM because supinehypertension is a major potential side effect of vaso-active medications such as midodrine (though morefrequently seen in patients with autonomic failure).Patients should take care not to lie flat for severalhours after using the drug. Other reported adverse or



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bothersome side effects include urinary retention,scalp tingling, and piloerection (“goose bumps”).These are direct effects of the drug and should beexpected. Midodrine is a HRS Class IIb recommen-dation in POTS (1).

Fludrocortisone (a synthetic corticosteroid, aldo-sterone analog) starting at 0.1 mg daily and increasingup to 0.2 mg daily can be used to increase bloodvolume. In order to be maximally effective, thismedication should be taken with a high salt diet, andis best taken at night. Patients on fludrocortisoneshould increase potassium intake because hypokale-mia is a potential medication side effect, and potas-sium must be checked after initiation becausehypokalemia can be profound. Fluid retention andworsened migraines are other side effects. Prolongeduse should be avoided because of concern for devel-opment of myocardial fibrosis from chronic elevationin aldosterone activity. Fludrocortisone is a HRS ClassIIb recommendation in POTS (1).

Pyridostigmine (a cholinergic agonist that works byinhibiting acetylcholinesterase) 30 to 60 mg 3 times aday can increase parasympathetic autonomic tone(107,108) and has a lower risk of hypertensioncompared with other medications. Potential side ef-fects include abdominal cramping, diarrhea, andmuscle cramps, which can be limiting in some pa-tients but might be a beneficial effect in others,particularly those with constipation. Pyridostigmineis a HRS Class IIb recommendation in POTS (1).

In patients with evidence of symptomatic adren-ergic hyperactivity (hyperadrenergic POTS), a nonse-lective beta-blocker may be beneficial. Long-actingpropranolol starting at 10 mg and increasing to 60 mgmay be used to limit the HR increment and reducesymptoms. However, although long-acting propran-olol has been demonstrated to reduce standing HR inPOTS, this medication did not improve quality of life(98). Hypotension, fatigue, and reduced exercise ca-pacity are potential side effects of beta-blockers,which may limit their use. Propranolol is a HRSClass IIb recommendation in POTS (1). Atenolol 25 mgor metoprolol 25 mg daily are alternatives forpatients with a history of bronchospasm, althoughnonselective beta-blockers are preferable becausethey additionally block epinephrine-mediatedb-2-vasodilation.

Patients with hyperadrenergic POTS or significanthypertensive responses during tilt may respond tophenobarbital 15 mg in the morning and 60 mg atnight (36). Clonidine (a central sympatholytic) 0.1 mgtwice daily can be used to reduce autonomic insta-bility in similar patients (36). Potential side effectsinclude sedation and cognitive slowing, which can be

minimized by taking the medication just once a day atnight (109).

Selective serotonin reuptake inhibitors may treatsome of the psychological manifestations of POTS.They have not been shown to reduce tachycardia inPOTS (110).

Droxidopa is a synthetic amino acid analog that ismetabolized to NE, by which peripheral arterial andvenous vasoconstriction increases BP. It is approvedonly for the treatment of NOH, which is not present inPOTS. Droxidopa has been studied in a small numberof POTS patients; although it may have helped toimprove some symptoms of orthostatic intolerance, itdid not significantly improve quality of life (111).

Ivabradine is a unique medication that reducesintrinsic HR by specifically blocking the cardiac“funny” channel, the If current that controls thepacemaker activity of the sinus node. It is approvedfor use in heart failure patients with restingHR $70 beats/min not controlled with beta-blockers.In limited studies, ivabradine has also been shownto reduce HR in POTS (112,113). It is generally well-tolerated but has not been well-studied in this con-dition, and therefore, should not be used routinely.

Some patients with MCAD and associatedPOTS anecdotally responded to H1 and H2 histaminereceptor blockers, the sympatholytic alpha-methyldopa, or both (46). Of note, in the sameseries, beta-blockers triggered episodes of worseningsymptoms in several patients and should be used withcaution if MCAD is suspected.

Sympathomimetic drugs, such as droxidopa, se-lective serotonin reuptake inhibitors (SSRIs), combi-nation serotonin and NE reuptake inhibitors (SNRIs)(114), or amphetamines, may lead to exaggeratedsympathetic activity and thereby worsen tachycardiaand the symptoms of POTS. In general, sympathomi-metic drugs should be avoided, particularly if plasmacatecholamine levels are elevated at baseline.Depending on the indication (i.e., to treat psycholog-ical symptoms, fatigue, or brain fog), their use may beconsidered if plasma catecholamines are in the lowerrange of normal. Additionally, medication effects ofstimulant medications such as amphetamines havebeen reported as mimicking the tachycardia of POTS(41). Modafinil is a stimulant that does not appear toalter the release of NE, and subsequently, it may bebetter tolerated for treatment of fatigue and cognitiveimpairment. A small study evaluating this showedthat modafinil did not significantly worsen standingHR or orthostatic symptoms in POTS (115). However, asmall percentage of the general population do reportpalpitations and tachycardia with modafinil, and costmay be prohibitive when used off-label.


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As noted previously, the use of medications inPOTS should be minimized or avoided, and anemphasis should be placed on exercise and non-pharmacological interventions if possible; however,transient use of medications individually or some incombination may be helpful in allowing patients tobecome more active and mobile as they embark upontheir path to recovery.

BEHAVIORAL AND COGNITIVE THERAPY

Frequently, symptoms of anxiety, functional GIdisturbance, headaches, and fatigue persist evenwhen the tachycardia is treated. The mechanisms arelikely multifactorial and may include anxiety, so-matic hypervigilance, and behavioral amplification.Behavioral and cognitive therapy has been used toobtain long-term control of symptoms, particularlywhen anxiety, hypervigilance, or catastrophizing be-haviors are present (15). Specific data supportingpsychological therapy in POTS are lacking, but thereis a 2016 case report demonstrating significantdecrease in POTS-related functional impairment in awoman treated with cognitive behavioral therapy(116). Additionally, there are data that support theefficacy of biobehavioral treatments to reduce head-ache, abdominal pain, and fibromyalgia in the childand adolescent populations (117); clinical impressionssuggest that a similar application may yield similarresults in POTS patients (68).

CONCLUSIONS

POTS is a heterogeneous disorder with manyoverlapping symptoms and pathophysiologicalmechanisms. The unifying characteristics are exces-sive tachycardia in the upright position, without

orthostatic hypotension, and with associated pre-syncopal symptoms and orthostatic intolerance. Themost common demographic is young, previouslyactive women, and frequently, there is an identifiableevent (such as illness, pregnancy, or surgery) thatprecedes symptom onset and precipitates withdrawalof activity or frank bedrest. Standard evaluationsinclude laboratory, physical examination, and simplestand test. The most effective treatment is a regular,structured, progressive exercise regimen, enhancedby volume expansion with ingested salt and fluids.Other nonpharmacological and pharmacologicalinterventions may be supplemental. Nonorthostaticcomorbid symptoms and conditions may persist evenafter the orthostatic tachycardia is treated. Thesesymptoms can be challenging to treat, and behavioraland cognitive therapy may help patients with signif-icant associated symptoms such as anxiety, hyper-vigilance, and brain fog.

Future studies are needed to better define thediversity of mechanisms leading to POTS and,hopefully, to more patient-specific therapies atdifferent points in their natural history. The role ofmedications needs to be studied in well-controlled,randomized studies and compared with exercisetraining, which should be considered the standardof care. Long-term follow-up studies are alsoneeded to quantify the natural course of thissyndrome.

ADDRESS FOR CORRESPONDENCE: Dr. Benjamin D.Levine, Institute for Exercise and EnvironmentalMedicine, Texas Health Presbyterian Hospital Dallas,7232 Greenville Avenue, Suite 435, Dallas, Texas 75231.E-mail: [email protected]. Twitter:@texashealth.

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KEY WORDS orthostatic intolerance,postural orthostatic tachycardia syndrome,POTS, syncope, tachycardia

APPENDIX For supplemental informationon the POTS training program, please see theonline version of this paper.














































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