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Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1

Open AccessPublished:June 04, 2021DOI:https://doi.org/10.1016/j.autneu.2021.102828

      Abstract

      Postural orthostatic tachycardia syndrome (POTS) is a chronic and often disabling disorder characterized by orthostatic intolerance with excessive heart rate increase without hypotension during upright posture. Patients often experience a constellation of other typical symptoms including fatigue, exercise intolerance and gastrointestinal distress. A typical patient with POTS is a female of child-bearing age, who often first displays symptoms in adolescence. The onset of POTS may be precipitated by immunological stressors such as a viral infection. A variety of pathophysiologies are involved in the abnormal postural tachycardia response; however, the pathophysiology of the syndrome is incompletely understood and undoubtedly multifaceted.
      Clinicians and researchers focused on POTS convened at the National Institutes of Health in July 2019 to discuss the current state of understanding of the pathophysiology of POTS and to identify priorities for POTS research. This article, the first of two articles summarizing the information discussed at this meeting, summarizes the current understanding of this disorder and best practices for clinical care.
      The evaluation of a patient with suspected POTS should seek to establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the syndrome. Once diagnosed, management typically begins with patient education and non-pharmacologic treatment options. Various medications are often used to address specific symptoms, but there are currently no FDA-approved medications for the treatment of POTS, and evidence for many of the medications used to treat POTS is not robust.

      Keywords

      1. Background

      Postural orthostatic tachycardia syndrome (POTS) is common but the exact prevalence has not been determined, and the cause of this condition remains unclear. Since POTS predominantly affects adolescent or young adult women who would typically be in the midst of education or early careers, the condition can be severely debilitating and economically devastating (
      • Bagai K.
      • Song Y.
      • Ling J.F.
      • Malow B.
      • Black B.K.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      Sleep disturbances and diminished quality of life in postural tachycardia syndrome.
      ;
      • Bourne K.M.
      • Chew D.S.
      • Stiles L.E.
      • Shaw B.H.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Peltier A.
      • Diedrich A.
      • Biaggioni I.
      • Sheldon R.S.
      • Robertson D.
      • Raj S.R.
      Postural orthostatic tachycardia syndrome is associated with significant employment and economic loss.
      ). Although there is a consensus clinical definition for POTS, misdiagosis is common. The syndrome is heterogeneous in the sense that the spectrum of clinical features varies among patients, multiple etiologies may produce similar clinical phenotype and there is overlap with other clinically-defined syndromes. The clinical evaluation of patients with suspected POTS is not standardized, nor are treatment approaches. There is a lack of familiarity with POTS in the medical community, and the epidemiology of the disorder and natural history are not known (
      • Raj S.R.
      • Robertson D.
      Moving from the present to the future of postural tachycardia syndrome - what we need.
      ).
      The US Congress directed the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Neurological Disorders and Stroke (NINDS) to provide a forum for leading POTS experts to meet and discuss the current state of POTS research and clinical care (
      • U.S. Senate Committee on Appropriations
      Departments of labor, health and human services, and education, and related agencies appropriation bill, 2019, (to accompany S. 3158).
      ). A workshop including a broad representation of clinicians and researchers took place on July 29, 2019 at the NIH Intramural campus. To supplement the report prepared by NIH, the workshop participants prepared two independent manuscripts to summarize their findings. This manuscript outlines the current state of the science and clinical care for POTS. This is not meant to be a comprehensive review of the literature but rather an overview from the workshop participants. The accompanying manuscript addresses the current knowledge gaps, clinical needs and research priorities for POTS (
      • Raj S.R.
      • Bourne K.M.
      • Stiles L.
      • Miglis M.G.
      • Boris J.
      • Cortez M.
      • Miller A.
      • Vernino S.
      Postural tachycardia syndrome (POTS); advancing POTS care and research from a 2019 national institute of Health Expert Consensus Meeting.
      ). We hope that these manuscripts will raise awareness in the medical community, stimulate research and improve clinical care for POTS.

      2. Clinical description

      POTS is a complex, multi-system, chronic disorder of the autonomic nervous system characterized by orthostatic intolerance with excessive heart rate (HR) increase and symptoms on standing while blood pressure is maintained. Orthostatic symptoms improve rapidly after return to a supine position. Apart from the abnormal circulatory response to standing, patients with POTS may experience a variety of other persistent symptoms such as low energy, headache, cognitive impairment, muscle fatigue, chest pain, non-specific generalized weakness, along with numerous gastrointestinal symptoms (
      • Benarroch E.E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ;
      • Brignole M.
      • Moya A.
      • de Lange F.J.
      • Deharo J.-C.
      • Elliott P.M.
      • Fanciulli A.
      • Fedorowski A.
      • Furlan R.
      • Kenny R.A.
      • Martiın A.
      • Probst V.
      • Reed M.J.
      • Rice C.P.
      • Sutton R.
      • Ungar A.
      • van Dijk J.G.
      2018 ESC guidelines for the diagnosis and management of syncope.
      ;
      • Fedorowski A.
      Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management.
      ;
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • Benditt D.G.
      • Benarroch E.
      • Biaggioni I.
      • Cheshire W.P.
      • Chelimsky T.
      • Cortelli P.
      • Gibbons C.H.
      • Goldstein D.S.
      • Hainsworth R.
      • Hilz M.J.
      • Jacob G.
      • Kaufmann H.
      • Jordan J.
      • Lipsitz L.A.
      • Levine B.D.
      • Low P.A.
      • Mathias C.
      • Raj S.R.
      • Robertson D.
      • Sandroni P.
      • Schatz I.J.
      • Schondorf R.
      • Stewart J.M.
      • van Dijk J.G.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ;
      • Raj R., Satish
      Postural tachycardia syndrome (POTS).
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ).
      POTS has been defined by major international neurologic, autonomic, cardiac and pediatric societies (
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • Benditt D.G.
      • Benarroch E.
      • Biaggioni I.
      • Cheshire W.P.
      • Chelimsky T.
      • Cortelli P.
      • Gibbons C.H.
      • Goldstein D.S.
      • Hainsworth R.
      • Hilz M.J.
      • Jacob G.
      • Kaufmann H.
      • Jordan J.
      • Lipsitz L.A.
      • Levine B.D.
      • Low P.A.
      • Mathias C.
      • Raj S.R.
      • Robertson D.
      • Sandroni P.
      • Schatz I.J.
      • Schondorf R.
      • Stewart J.M.
      • van Dijk J.G.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      ;
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • Richer L.
      • Schondorf R.
      • Seifer C.
      • Thibodeau-Jarry N.
      • Sheldon R.S.
      Canadian cardiovascular society position statement on postural orthostatic tachycardia syndrome (POTS) and related disorders of chronic orthostatic intolerance.
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ) as requiring:
      • 1.
        A sustained HR increment of not less than 30 beats/minute within 10 min of standing or head-up tilt. For individuals who are 12 to 19 years old, the required HR increment is at least 40 beats/minute; and
      • 2.
        An absence of orthostatic hypotension (i.e. no sustained systolic blood pressure [BP] drop of 20 mmHg or more); and
      • 3.
        Frequent symptoms of orthostatic intolerance during standing, with rapid improvement upon return to a supine position. Symptoms may include lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision, and fatigue; and
      • 4.
        Duration of symptoms for at least 3 months; and
      • 5.
        Absence of other conditions explaining sinus tachycardia such as anorexia nervosa, primary anxiety disorders, hyperventilation, anemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (e.g. sympathomimetics, anticholinergics) or severe deconditioning caused by prolonged bed rest.

      3. Epidemiology & natural history

      The prevalence of POTS has not been properly studied. Estimates, based largely on clinical experience, range from 0.2% and 1% of the US population, which would suggest approximately 1–3 million affected persons (
      • Arnold A.C.
      • Ng J.
      • Raj S.R.
      Postural tachycardia syndrome – diagnosis, physiology, and prognosis.
      ;
      • Low P.A.
      • Sandroni P.
      • Joyner M.
      • Shen W.-K.
      Postural tachycardia syndrome (POTS).
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ). A typical patient with POTS is a 12 to 50 years old female (F:M ratio > 4:1) (
      • Arnold A.C.
      • Ng J.
      • Raj S.R.
      Postural tachycardia syndrome – diagnosis, physiology, and prognosis.
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ). Similarly, our current understanding of the natural history of POTS is derived from incomplete data from clinical experience, small case series or uncontrolled patient-reported data. In a large survey of over 4800 patients with a self-reported POTS diagnosis, the most common age at onset was 14 years (
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ). The onset of POTS may be precipitated by a typical immunological stressor such as viral syndrome (often upper respiratory or gastrointestinal), physical trauma (such as concussion), menarche, pregnancy, or surgery (
      • Boris J.R.
      • Bernadzikowski T.
      Demographics of a large paediatric postural orthostatic tachycardia syndrome program.
      ;
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Textor S.C.
      • Benarroch E.E.
      • Shen W.K.
      • Schondorf R.
      • Suarez G.A.
      • Rummans T.A.
      Postural tachycardia syndrome (POTS).
      ;
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome--current experience and concepts.
      ;
      • Sandroni P.
      • Opfer-Gehrking T.L.
      • McPhee B.R.
      • Low P.A.
      Postural tachycardia syndrome: clinical features and follow-up study.
      ;
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • Fealey R.D.
      • Vernino S.
      • Lennon V.A.
      • Shen W.K.
      • Low P.A.
      Postural orthostatic tachycardia syndrome: the Mayo Clinic experience.
      ;
      • Watari M.
      • Nakane S.
      • Mukaino A.
      • Nakajima M.
      • Mori Y.
      • Maeda Y.
      • Masuda T.
      • Takamatsu K.
      • Kouzaki Y.
      • Higuchi O.
      • Matsuo H.
      • Ando Y.
      Autoimmune postural orthostatic tachycardia syndrome.
      ). An antecedent history of suspected viral infection is reported in 20–50% of patients (
      • Sandroni P.
      • Opfer-Gehrking T.L.
      • McPhee B.R.
      • Low P.A.
      Postural tachycardia syndrome: clinical features and follow-up study.
      ;
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ;
      • Watari M.
      • Nakane S.
      • Mukaino A.
      • Nakajima M.
      • Mori Y.
      • Maeda Y.
      • Masuda T.
      • Takamatsu K.
      • Kouzaki Y.
      • Higuchi O.
      • Matsuo H.
      • Ando Y.
      Autoimmune postural orthostatic tachycardia syndrome.
      ). The presentation seems to have two patterns – acute onset after one of the above triggers or with slowly progressive symptoms over a longer period of time (
      • Thieben M.J.
      • Sandroni P.
      • Sletten D.M.
      • Benrud-Larson L.M.
      • Fealey R.D.
      • Vernino S.
      • Lennon V.A.
      • Shen W.K.
      • Low P.A.
      Postural orthostatic tachycardia syndrome: the Mayo Clinic experience.
      ). Significant symptomatic recovery has been reported by a subset of patients, but a majority report chronic symptoms with recurrent exacerbations. The natural history of POTS over the later decades of life has not been studied.

      4. Clinical associations & co-morbidities

      A variety of other clinical diagnoses may coexist with POTS, but it is largely unclear whether the presence of one of these other diagnoses defines a unique pathophysiological subset of POTS. Patients with POTS may simultaneously meet the diagnostic criteria for migraine, hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS) or chronic fatigue syndrome (CFS) (
      • Kavi L.
      • Nuttall M.
      • Low D.A.
      • Opie M.
      • Nicholson L.M.
      • Caldow E.
      • N.J
      A profile of patients with postural tachycardia syndrome and their experience of healthcare in the UK.
      ;
      • McDonald C.
      • Koshi S.
      • Busner L.
      • Kavi L.
      • Newton J.L.
      Postural tachycardia syndrome is associated with significant symptoms and functional impairment predominantly affecting young women: a UK perspective.
      ;
      • Okamoto L.E.
      • Raj S.R.
      • Peltier A.
      • Gamboa A.
      • Shibao C.
      • Diedrich A.
      • Black B.K.
      • Robertson D.
      • Biaggioni I.
      Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes.
      ;
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ). The estimated frequencies of these clinical associations vary, and careful systematic assessments to identify these other disorders have not been done in a large POTS population. Current estimates derived from small samples or uncontrolled survey data suggest that approximately 40% of POTS patients experience migraine, 20–30% meet the diagnostic criteria for hypermobile Ehlers-Danlos syndrome (
      • Miller A.J.
      • Stiles L.E.
      • Sheehan T.
      • Bascom R.
      • Levy H.P.
      • Francomano C.A.
      • Arnold A.C.
      Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome.
      ;
      • Roma M.
      • Marden C.L.
      • De Wandele I.
      • Francomano C.A.
      • Rowe P.C.
      Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome.
      ), and about 15% carry a diagnosis of a co-morbid autoimmune disease. Some POTS patients endorse symptoms suggestive of abnormal mast cell activation but again accurate data on the frequency of MCAS in POTS is not available (
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ). This subset of POTS patients commonly report episodes of flushing, urticaria, dyspnea, headache, excessive diuresis, and gastrointestinal symptoms such as diarrhea, nausea, and vomiting, which may be accompanied by elevated urine methylhistamine or 11-ß-Prostaglandin F2 excretion or elevation of other mast cell mediators (
      • Shibao C.
      • Arzubiaga C.
      • Roberts I.I.L.J.
      • Raj S.
      • Black B.
      • Harris P.
      • Biaggioni I.
      Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
      ;
      • Weinstock L.B.
      • Pace L.A.
      • Rezaie A.
      • Afrin L.B.
      • Molderings G.J.
      Mast cell activation syndrome: a primer for the gastroenterologist.
      ). Conversely, orthostatic intolerance and tachycardia can be found in up to 40% of patients with hypermobility spectrum disorder or hypermobile Ehlers-Danlos Syndrome (
      • Miller A.J.
      • Stiles L.E.
      • Sheehan T.
      • Bascom R.
      • Levy H.P.
      • Francomano C.A.
      • Arnold A.C.
      Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome.
      ;
      • Roma M.
      • Marden C.L.
      • De Wandele I.
      • Francomano C.A.
      • Rowe P.C.
      Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome.
      ).
      A summary of comorbid conditions identified in the large survey of self-identified POTS patients16 is shown in Table 1.
      Table 1Co-morbidities in patients diagnosed with Postural Orthostatic Tachycardia Syndrome.
      ComorbidityNumber (%)

      (of 3933 respondents)
      Migraine headaches1557 (40%)
      Irritable bowel syndrome1192 (30%)
      Ehlers-Danlos syndrome994 (25%)
      Chronic Fatigue Syndrome809 (21%)
      Asthma798 (20%)
      Fibromyalgia786 (20%)
      Raynaud's phenomena610 (16%)
      Iron deficiency anemia628 (16%)
      Gastroparesis548 (14%)
      Vasovagal syncope499 (13%)
      Inappropriate sinus tachycardia448 (11%)
      Mast cell activation disorder353 (9%)
      Autoimmune disease616 (16%)
       Hashimoto's thyroiditis228 (6%)
       Celiac Disease133 (3%)
       Sjogren's Syndrome112 (3%)
       Rheumatoid Arthritis93 (2%)
       Lupus81 (2%)
       Other160 (4%)
      Other autoimmune conditions included the following: idiopathic thrombocytopenic purpura, Addison's Disease, Grave's disease, Behcet's disease, autoimmune pancreatitis, autoimmune hepatitis, vasculitis, multiple sclerosis, myasthenia gravis and type 1 diabetes mellitus. Reproduced with permission from BH
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      .

      5. Gastrointestinal dysfunction in POTS

      Gastrointestinal functions are intricately controlled and regulated by the autonomic nervous system and its specialized gastrointestinal specific subsystem, the enteric nervous system (ENS) (
      • Furness J.B.
      The enteric nervous system and neurogastroenterology.
      ). Gastrointestinal symptoms are commonly reported by individuals with autonomic disorders, including POTS (
      • Sullivan S.D.
      • Hanauer J.
      • Rowe P.C.
      • Barron D.F.
      • Darbari A.
      • Oliva-Hemker M.
      Gastrointestinal symptoms associated with orthostatic intolerance.
      ). Clinical diagnostic studies to identify gastrointestinal dysfunction are limited; however, gastrointestinal dysmotility is frequently diagnosed in POTS (
      • DiBaise J.K.
      • Harris L.A.
      • Goodman B.
      Postural tachycardia syndrome (POTS) and the GI tract: A primer for the gastroenterologist.
      ;
      • Zhang L.N.
      • Moak J.P.
      • Desbiens J.
      • Hanumanthaiah S.
      • Fabian R.R.
      • Clarke L.
      • Sahay R.D.
      • Darbari A.
      Utility of diagnostic studies for upper gastrointestinal symptoms in children with orthostatic intolerance.
      ). Patients with mild dysmotility as well as those with complete intestinal failure requiring total parental nutrition or surgery have been observed. The pathophysiology and natural history of gastrointestinal dysfunction in POTS has not been studied. It is intuitive to speculate that dysautonomia may disrupt the intricate neuroimmunophysiology of the gastrointestinal system and gastrointestinal dysfunction may ensue. Further research is needed about how the autonomic, ENS and immune systems interact with each other and with the host microbiota, in order to develop better diagnostic tests and potential new treatments.

      6. Potential pathophysiological mechanisms

      Clinical observations may show a post-viral onset (
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Textor S.C.
      • Benarroch E.E.
      • Shen W.K.
      • Schondorf R.
      • Suarez G.A.
      • Rummans T.A.
      Postural tachycardia syndrome (POTS).
      ;
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?.
      ) suggesting the possibility of an immunological cause. Positive (though often non-specific) autoantibody tests are frequently seen among POTS patients, and about 20% report a history of an autoimmune disorder such as Hashimoto's thyroiditis, rheumatoid arthritis or Sjögren syndrome (
      • Blitshteyn S.
      Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS).
      ;
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ). In recent years, a focus of POTS research has been on autoantibodies to cardiovascular G-protein coupled membrane receptors (see below) (
      • Blitshteyn S.
      Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS).
      ;
      • Dahan S.
      • Tomljenovic L.
      • Shoenfeld Y.
      Postural orthostatic tachycardia syndrome (POTS)--A novel member of the autoimmune family.
      ;
      • Fedorowski A.
      • Li H.
      • Yu X.
      • Koelsch K.A.
      • Harris V.M.
      • Liles C.
      • Murphy T.A.
      • Quadri S.M.S.
      • Scofield R.H.
      • Sutton R.
      • Melander O.
      • Kem D.C.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ;
      • Gunning W.T.
      • Kvale H.
      • Kramer P.M.
      • Karabin B.L.
      • Grubb B.P.
      Postural orthostatic tachycardia syndrome is associated with elevated G-protein coupled receptor autoantibodies.
      ;
      • Li H.
      • Yu X.
      • Liles C.
      • Khan M.
      • Vanderlinde-Wood M.
      • Galloway A.
      • Zillner C.
      • Benbrook A.
      • Reim S.
      • Collier D.
      • Hill M.A.
      • Raj S.R.
      • Okamoto L.E.
      • Cunningham M.W.
      • Aston C.E.
      • Kem D.C.
      Autoimmune basis for postural tachycardia syndrome.
      ;
      • Ruzieh M.
      • Batizy L.
      • Dasa O.
      • Oostra C.
      • Grubb B.
      The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review.
      ;
      • Schofield J.R.
      • Chemali K.R.
      Intravenous immunoglobulin therapy in refractory autoimmune dysautonomias: a retrospective analysis of 38 patients.
      ;
      • Vernino S.
      • Stiles L.E.
      Autoimmunity in postural orthostatic tachycardia syndrome: current understanding.
      ;
      • Wang X.-L.
      • Ling T.-Y.
      • Charlesworth M.C.
      • Figueroa J.J.
      • Low P.
      • Shen W.-K.
      • Lee H.-C.
      Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome.
      ;
      • Watari M.
      • Nakane S.
      • Mukaino A.
      • Nakajima M.
      • Mori Y.
      • Maeda Y.
      • Masuda T.
      • Takamatsu K.
      • Kouzaki Y.
      • Higuchi O.
      • Matsuo H.
      • Ando Y.
      Autoimmune postural orthostatic tachycardia syndrome.
      ;
      • Xichun Y.
      • Hongliang L.
      • A. M.T.
      • Zachary N.
      • Jonathan L.
      • Campbell L.
      • E. A.C.
      • R. R.S.
      • Artur F.
      • C. K.D.
      Angiotensin II type 1 receptor autoantibodies in postural tachycardia syndrome.
      ).
      Other proposed pathophysiological mechanisms include abnormally increased sympathetic activity and circulating catecholamine excess (“hyperadrenergic POTS”) (
      • Jacob G.
      • Biaggioni I.
      Idiopathic orthostatic intolerance and postural tachycardia syndromes.
      ;
      • Schondorf R.
      • Low P.A.
      Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia?.
      ), peripheral sympathetic noradrenergic denervation leading to venous pooling and relative central hypovolemia (“neuropathic POTS”) (
      • Istvan B.
      • Roy F.
      Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome.
      ;
      • Jacob G.
      • Costa F.
      • Shannon J.R.
      • Robertson R.M.
      • Wathen M.
      • Stein M.
      • Biaggioni I.
      • Ertl A.
      • Black B.
      • Robertson D.
      The neuropathic postural tachycardia syndrome.
      ;
      • Peltier A.C.
      • Garland E.
      • Raj S.R.
      • Sato K.
      • Black B.
      • Song Y.
      • Wang L.
      • Biaggioni I.
      • Diedrich A.
      • Robertson D.
      Distal sudomotor findings in postural tachycardia syndrome.
      ), and low blood volume (absolute hypovolemia). In the “hyperadrenergic” subtype, patients often complain of tremor, anxiety, migraine and angina-like chest pain (
      • Grubb B.P.
      Postural tachycardia syndrome.
      ). In the “neuropathic” subtype, clinical features of small fiber neuropathy may be present while reduced cardiac preload may lead to a compensatory HR increase during orthostatic challenge. Many POTS patients have a blood volume that is lower than expected for their size and sex, suggesting that hypovolemia may underlie some of the hemodynamic findings of POTS (
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • Shibata S.
      • Jain M.
      • Hastings J.L.
      • Bhella P.S.
      • Levine B.D.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ;
      • Mar P.L.
      • Raj S.R.
      Neuronal and hormonal perturbations in postural tachycardia syndrome.
      ;
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ).
      Cardiovascular deconditioning (objectively demonstrated by low cardiac stroke volume and reduced cardiac mass) may also contribute in a significant way to the pathophysiology of POTS and exacerbate the symptomatology (
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • Shibata S.
      • Jain M.
      • Hastings J.L.
      • Bhella P.S.
      • Levine B.D.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ). Prolonged bed rest from any cause can itself result in cardiovascular deconditioning and orthostatic intolerance, and should be considered before making a diagnosis of POTS.
      These pathophysiological mechanisms are neither fully inclusive, nor completely exclusive. Fig. 1 summarizes the heterogenous and overlapping potential pathophysiological mechanisms in POTS. Many patients have features indicative of more than one mechanism. At this time, there are no data that long-term prognosis or response to therapies differ based on specific pathophysiological features.
      Fig. 1
      Fig. 1Schematic of possible mechanisms leading to orthostatic intolerance and tachycardia in POTS. During upright posture, there is a gravitational shift of plasma volume toward the lower parts of the body which if unopposed would result in reduced cardiac preload and a fall in blood pressure. The autonomic baroreflex serves to prevent orthostatic hypotension and preserve cardiac output through sympathetic activation (peripheral vasoconstriction and increased heart rate). In POTS, excessive orthostatic tachycardia may result from a combination of appropriate autonomic responses to various physiological changes (shown in blue) or an inappropriate exaggeration of the sympathetic response to orthostatic stress (shown in red).
      Abnormal cardiovascular physiology could include (1) absolute hypovolemia due to impaired regulation of plasma volume or (2) cardiovascular deconditioning resulting in reduced cardiac mass and low stroke volume. Excessive sympathetic activation may occur in the context of (3) a systemic inflammatory state with increased inflammatory mediators (for example, increased histamine in conditions of mast cell overactivity) or (4) increased sympathetic tone driven by central nervous system (e.g. anxiety or chronic pain). Autoantibodies targeting G-protein coupled autonomic receptors (5) could produce mixed effects by acting as partial agonists that both augment cardiac sympathetic signals and reduce the efficacy of norepinephrine-induced peripheral vasocontriction. Finally, abnormal peripheral vascular function may result from (6) peripheral small fiber neuropathy causing partial denervation in the lower extremities or (7) tissue laxity resulting in increased dependent venous pooling (which might explain an association of POTS with hEDS).
      RAAS = renin-angiotensin-aldosterone system; MCAS = mast cell activation syndrome; AAbs = autoantibodies; hEDS = hypermobile form of Ehlers-Danlos syndrome. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

      7. Cardiovascular pathophysiology

      A wide variety of cardiovascular pathophysiological mechanisms may lead to an abnormal postural tachycardia response. Importantly, these mechanisms may not be mutually exclusive. The hemodynamic properties of POTS identify closely with those seen in moderate hemorrhage in that central hypovolemia, reduced cardiac output, and increased adrenergic-mediated vasoconstriction occur (
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • Shibata S.
      • Jain M.
      • Hastings J.L.
      • Bhella P.S.
      • Levine B.D.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ;
      • Stewart J.M.
      Mechanisms of sympathetic regulation in orthostatic intolerance.
      ), while BP is maintained and may even increase (orthostatic hypertension) (
      • Grubb B.P.
      • Kosinski D.J.
      • Boehm K.
      • Kip K.
      The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing.
      ). Reduced systemic venous return and reduced cardiac output contribute to reduced central blood volume when upright,(
      • Barcroft H.
      • Edholm O.G.
      • McMichael J.
      • Sharpey-Shafer E.P.
      Posthaemorrhagic fainting: study by cardiac output and forearm flow.
      ) and absolute hypovolemia can be found (
      • Fouad F.M.
      • Tadena-Thome L.
      • Bravo E.L.
      • Tarazi R.C.
      Idiopathic hypovolemia.
      ;
      • Raj R.S.
      • Robertson R.D.
      Blood volume perturbations in the postural tachycardia syndrome.
      ;
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ) similar to bed-rested patients or astronauts with gravitational deconditioning (
      • Montgomery L.D.
      • Parmet A.J.
      • Booher C.R.
      Body volume changes during simulated microgravity: auditory changes, segmental fluid redistribution, and regional hemodynamics.
      ). In others, redistributive central hypovolemia when upright occurs due to decreased lower extremity venous tone (
      • Stewart J.M.
      • Montgomery L.D.
      Regional blood volume and peripheral blood flow in postural tachycardia syndrome.
      ), or splanchnic pooling (
      • Stewart J.M.
      • Glover J.L.
      • Medow M.S.
      Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume.
      ). These cases may correlate with “neuropathic POTS”(
      • Stewart J.M.
      • Medow M.S.
      • Glover J.L.
      • Montgomery L.D.
      Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome.
      ;
      • Tani H.
      • Singer W.
      • McPhee B.R.
      • Opfer-Gehrking T.L.
      • Haruma K.
      • Kajiyama G.
      • Low P.A.
      Splanchnic-mesenteric capacitance bed in the postural tachycardia syndrome (POTS).
      ), in which local sympathetic noradrenergically-mediated vasoconstriction is impaired because of autonomic denervation or a biochemical milieu that locally reduces vasoconstriction, causing baroreflex unloading, decreased baroreflex-cardiovagal function, increased reflexive sympathetic noradrenergic excitation at other sites (
      • Istvan B.
      • Roy F.
      Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome.
      ), and augmented reflex tachycardia (
      • Stewart J.M.
      • Weldon A.
      Reflex vascular defects in the orthostatic tachycardia syndrome of adolescents.
      ).
      While a “hyperadrenergic” state with orthostatic hypertension is defined in some cases, there is scant evidence for enhanced sympathetic outflow from the central nervous system as a primary cause. Most investigations show exaggerated skeletal muscle sympathetic nerve activity while upright (
      • Muenter Swift N.
      • Charkoudian N.
      • Dotson R.M.
      • Suarez G.A.
      • Low P.A.
      Baroreflex control of muscle sympathetic nerve activity in postural orthostatic tachycardia syndrome.
      ), consistent with reflexive activation. In addition, cardiac parasympathetic deficits (
      • Jacob G.
      • Diedrich L.
      • Kyoko S.
      • J. B.R.
      • R. R.S.
      • David R.
      • Italo B.
      • André D.
      Vagal and sympathetic function in neuropathic postural tachycardia syndrome.
      ;
      • Stewart J.M.
      Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion.
      ) may be found in many individuals with POTS leading to relative excess of “sympatho-vagal balance” based on various measures including power spectral analysis of heart rate variability.

      8. Pathophysiology of plasma volume and renin-angiotensin system

      Absolute hypovolemia is commonly observed in POTS, with up to 70% of patients exhibiting deficits in plasma volume and red blood cell volume (
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • Shibata S.
      • Jain M.
      • Hastings J.L.
      • Bhella P.S.
      • Levine B.D.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ;
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ;
      • Stewart J.M.
      • Glover J.L.
      • Medow M.S.
      Increased plasma angiotensin II in postural tachycardia syndrome (POTS) is related to reduced blood flow and blood volume.
      ). This hypovolemia can reduce stroke volume and lead to compensatory tachycardia to maintain cardiac output and BP. The importance of hypovolemia in POTS pathophysiology is illustrated by the finding that some patients have reduced orthostatic tachycardia and improved symptoms after acute plasma volume expansion (e.g. intravenous saline, the vasopressin analog desmopressin, exercise training) (
      • Coffin S.T.
      • Black B.K.
      • Biaggioni I.
      • Paranjape S.Y.
      • Orozco C.
      • Black P.W.
      • Dupont W.D.
      • Robertson D.
      • Raj S.R.
      Desmopressin acutely decreases tachycardia and improves symptoms in the postural tachycardia syndrome.
      ;
      • Fu Q.
      • Vangundy T.B.
      • Galbreath M.M.
      • Shibata S.
      • Jain M.
      • Hastings J.L.
      • Bhella P.S.
      • Levine B.D.
      Cardiac origins of the postural orthostatic tachycardia syndrome.
      ;
      • Jacob G.
      • Shannon J.R.
      • Black B.
      • Biaggioni I.
      • Mosqueda-Garcia R.
      • Robertson R.M.
      • Robertson D.
      Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia.
      ;
      • Ruzieh M.
      • Baugh A.
      • Dasa O.
      • Parker R.L.
      • Perrault J.T.
      • Renno A.
      • Karabin B.L.
      • Grubb B.
      Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome.
      ). Ongoing studies are examining the impact of increasing plasma volume with dietary sodium, chronic intravenous saline, or albumin infusions in POTS. While useful as rescue therapy in clinically decompensated patients, long-term intravenous saline infusions are not currently recommended for routine care due to complications associated with chronic venous catheterization (
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ).
      A normal compensatory response to hypovolemia includes activation of the renin-angiotensin aldosterone system (RAAS) to increase angiotensin II, which stimulates aldosterone release to promote renal sodium and water reabsorption and restore blood volume. While circulating angiotensin II levels are high, POTS patients have impaired ability of the RAAS to expand blood volume (
      • Li J.
      • Liao Y.
      • Du J.
      • Zhang Q.
      Relationship between 24-hour urinary sodium and renin-angiotensin-aldosterone system in children with postural tachycardia syndrome.
      ;
      • Mustafa H.I.
      • Garland E.M.
      • Biaggioni I.
      • Black B.K.
      • Dupont W.D.
      • Robertson D.
      • Raj S.R.
      Abnormalities of angiotensin regulation in postural tachycardia syndrome.
      ;
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ;
      • Stewart J.M.
      • Medow M.S.
      • Glover J.L.
      • Montgomery L.D.
      Persistent splanchnic hyperemia during upright tilt in postural tachycardia syndrome.
      ). Some POTS patients have reduced plasma renin activity, reduced aldosterone and normal BP, suggesting a primary abnormality of the RAAS or of renal sodium and water homeostasis (
      • Garland E.M.
      • Raj S.R.
      • Black B.K.
      • Harris P.A.
      • Robertson D.
      The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome.
      ;
      • Mustafa H.I.
      • Raj S.R.
      • Diedrich A.
      • Black B.K.
      • Paranjape S.Y.
      • Dupont W.D.
      • Williams G.H.
      • Biaggioni I.
      • Robertson D.
      Altered systemic hemodynamic and baroreflex response to angiotensin II in postural tachycardia syndrome.
      ,
      • Mustafa H.I.
      • Garland E.M.
      • Biaggioni I.
      • Black B.K.
      • Dupont W.D.
      • Robertson D.
      • Raj S.R.
      Abnormalities of angiotensin regulation in postural tachycardia syndrome.
      ;
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ). Initial studies also show reduced levels and actions of angiotensin converting enzyme 2 (ACE2) and angiotensin-(1–7) in POTS, components of the RAAS that oppose deleterious cardiovascular actions of angiotensin II (
      • Raj S.R.
      • Biaggioni I.
      • Yamhure P.C.
      • Black B.K.
      • Paranjape S.Y.
      • Byrne D.W.
      • Robertson D.
      Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome.
      ;
      • Stewart J.M.
      • Ocon A.J.
      • Clarke D.
      • Taneja I.
      • Medow M.S.
      Defects in cutaneous angiotensin-converting enzyme 2 and angiotensin-(1-7) production in postural tachycardia syndrome.
      ). While these findings suggest RAAS perturbations contribute to underlying POTS pathophysiology, it remains unknown whether targeting this hormone system restores blood volume and improves orthostatic tolerance in patients with hypovolemia in the setting of POTS.

      9. Antibodies and immunology of POTS

      Associations between immune dysfunction and POTS remains poorly understood. Both pediatric and adult POTS patients may report an infectious prodrome before the emergence of orthostatic symptoms (
      • Boris J.R.
      • Bernadzikowski T.
      Demographics of a large paediatric postural orthostatic tachycardia syndrome program.
      ;
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ). A variety of infectious pathogens have been proposed to be linked to POTS, including Epstein Barr virus (
      • Pohlgeers K.M.
      • Stumbo J.R.
      Syncope in an athlete: a case of infectious mononucleosis-induced postural tachycardia syndrome.
      ;
      • Yaxley K.L.
      Infectious mononucleosis complicated by peritonsillar abscess and postural orthostatic tachycardia syndrome: a case report.
      ), Mycoplasma pneumoniae (
      • Kasmani R.
      • Elkambergy H.
      • Okoli K.
      Postural orthostatic tachycardia syndrome associated with mycoplasma pneumoniae.
      ), and recently SARS-CoV2 (
      • Goldstein D.S.
      The possible association between COVID-19 and postural orthostatic tachycardia syndrome.
      ;
      • Kanjwal K.
      • Jamal S.
      • Kichloo A.
      • Grubb B.P.
      New-onset postural orthostatic tachycardia syndrome following coronavirus disease 2019 infection.
      ;
      • Miglis M.G.
      • Prieto T.
      • Shaik R.
      • Muppidi S.
      • Sinn D.-I.
      • Jaradeh S.
      A case report of postural tachycardia syndrome after COVID-19.
      ).
      POTS patients (
      • Vernino S.
      • Stiles L.E.
      Autoimmunity in postural orthostatic tachycardia syndrome: current understanding.
      ) and their close relatives (
      • Boris J.R.
      • Huang J.
      • Shuey T.
      • Bernadzikowski T.
      Family history of associated disorders in patients with postural tachycardia syndrome.
      ;
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • Green E.A.
      • Shibao C.A.
      • Okamoto L.E.
      • Garland E.M.
      • Gamboa A.
      • Diedrich A.
      • Raj V.
      • Sheldon R.S.
      • Biaggioni I.
      • Robertson D.
      • Raj S.R.
      The face of postural tachycardia syndrome – insights from a large cross-sectional online community-based survey.
      ) have a higher than expected prevalence of autoimmune disorders including celiac disease (
      • Penny H.A.
      • Aziz I.
      • Ferrar M.
      • Atkinson J.
      • Hoggard N.
      • Hadjivassiliou M.
      • West J.N.
      • Sanders D.S.
      Is there a relationship between gluten sensitivity and postural tachycardia syndrome?.
      ), Hashimoto's thyroiditis (
      • Blitshteyn S.
      Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS).
      ), Sjögren's syndrome (
      • Goodman B.P.
      • Crepeau A.
      • Dhawan P.S.
      • Khoury J.A.
      • Harris L.A.
      Spectrum of autonomic nervous system impairment in Sjögren syndrome.
      ), and systemic lupus erythematosus (SLE) (
      • Tang S.
      • Calkins H.
      • Petri M.
      Neurally mediated hypotension in systemic lupus erythematosus patients with fibromyalgia.
      ). Anecdotal reports and small open-label clinical studies (
      • Weinstock L.B.
      • Brook J.B.
      • Myers T.L.
      • Goodman B.
      Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment.
      ) suggest a beneficial effect of intravenous immunoglobulin (IVIG) therapy in POTS, suggesting that immunomodulatory therapy can play a role in treatment, but there have been no controlled clinical trial data published to date.
      Serum immunoglobulins isolated from POTS patients have been reported to act as partial agonists to both α- and β-adrenergic receptors in vitro (
      • Fedorowski A.
      • Li H.
      • Yu X.
      • Koelsch K.A.
      • Harris V.M.
      • Liles C.
      • Murphy T.A.
      • Quadri S.M.S.
      • Scofield R.H.
      • Sutton R.
      • Melander O.
      • Kem D.C.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ;
      • Li H.
      • Yu X.
      • Liles C.
      • Khan M.
      • Vanderlinde-Wood M.
      • Galloway A.
      • Zillner C.
      • Benbrook A.
      • Reim S.
      • Collier D.
      • Hill M.A.
      • Raj S.R.
      • Okamoto L.E.
      • Cunningham M.W.
      • Aston C.E.
      • Kem D.C.
      Autoimmune basis for postural tachycardia syndrome.
      ), a finding independently confirmed by several other groups (
      • Vernino S.
      • Stiles L.E.
      Autoimmunity in postural orthostatic tachycardia syndrome: current understanding.
      ) and expanded to include a wider range of G-protein coupled receptors (GPCRs) as targets (
      • Kharraziha I.
      • Axelsson J.
      • Ricci F.
      • Di Martino G.
      • Persson M.
      • Sutton R.
      • Fedorowski A.
      • Hamrefors V.
      Serum activity against G protein-coupled receptors and severity of orthostatic symptoms in postural orthostatic tachycardia syndrome.
      ). These reports have employed transfected cell assays and enzyme-linked immunoassays, as well as functional tests utilizing rat cardiomyocytes and smooth muscle, to detect antibodies that target cellular receptors for norepinephrine (
      • Fedorowski A.
      • Li H.
      • Yu X.
      • Koelsch K.A.
      • Harris V.M.
      • Liles C.
      • Murphy T.A.
      • Quadri S.M.S.
      • Scofield R.H.
      • Sutton R.
      • Melander O.
      • Kem D.C.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ;
      • Gunning W.T.
      • Kvale H.
      • Kramer P.M.
      • Karabin B.L.
      • Grubb B.P.
      Postural orthostatic tachycardia syndrome is associated with elevated G-protein coupled receptor autoantibodies.
      ;
      • Li H.
      • Yu X.
      • Liles C.
      • Khan M.
      • Vanderlinde-Wood M.
      • Galloway A.
      • Zillner C.
      • Benbrook A.
      • Reim S.
      • Collier D.
      • Hill M.A.
      • Raj S.R.
      • Okamoto L.E.
      • Cunningham M.W.
      • Aston C.E.
      • Kem D.C.
      Autoimmune basis for postural tachycardia syndrome.
      ;
      • Watari M.
      • Nakane S.
      • Mukaino A.
      • Nakajima M.
      • Mori Y.
      • Maeda Y.
      • Masuda T.
      • Takamatsu K.
      • Kouzaki Y.
      • Higuchi O.
      • Matsuo H.
      • Ando Y.
      Autoimmune postural orthostatic tachycardia syndrome.
      ), acetylcholine (
      • Fedorowski A.
      • Li H.
      • Yu X.
      • Koelsch K.A.
      • Harris V.M.
      • Liles C.
      • Murphy T.A.
      • Quadri S.M.S.
      • Scofield R.H.
      • Sutton R.
      • Melander O.
      • Kem D.C.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ;
      • Gunning W.T.
      • Kvale H.
      • Kramer P.M.
      • Karabin B.L.
      • Grubb B.P.
      Postural orthostatic tachycardia syndrome is associated with elevated G-protein coupled receptor autoantibodies.
      ;
      • Li J.
      • Zhang Q.
      • Liao Y.
      • Zhang C.
      • Hao H.
      • Du J.
      The value of acetylcholine receptor antibody in children with postural tachycardia syndrome.
      ;
      • Watari M.
      • Nakane S.
      • Mukaino A.
      • Nakajima M.
      • Mori Y.
      • Maeda Y.
      • Masuda T.
      • Takamatsu K.
      • Kouzaki Y.
      • Higuchi O.
      • Matsuo H.
      • Ando Y.
      Autoimmune postural orthostatic tachycardia syndrome.
      ), and angiotensin II (
      • Xichun Y.
      • Hongliang L.
      • A. M.T.
      • Zachary N.
      • Jonathan L.
      • Campbell L.
      • E. A.C.
      • R. R.S.
      • Artur F.
      • C. K.D.
      Angiotensin II type 1 receptor autoantibodies in postural tachycardia syndrome.
      ). In most of these studies, similarly reactive antibodies have been found in healthy control groups, although less frequently or at lower levels than in POTS patients. Preliminary studies using active immunization animal models have supported a potential role of the adrenergic autoantibodies in the pathophysiology of POTS (
      • Li H.
      • Zhang G.
      • Zhou L.
      • Nuss Z.
      • Beel M.
      • Hines B.
      • Murphy T.
      • Liles J.
      • Zhang L.
      • Kem D.C.
      • Yu X.
      Adrenergic autoantibody-induced postural tachycardia syndrome in rabbits.
      ). Despite these observations, a causal role of these autoantibodies in POTS is not established.

      10. Genetics

      Although there is no evidence for a monogenetic cause of POTS, increased POTS prevalence in family members suggests the presence of genetic predisposition. Case series have identified both familial cases (
      • Shannon J.R.
      • Flattem N.L.
      • Jordan J.
      • Jacob G.
      • Black B.K.
      • Biaggioni I.
      • Blakely R.D.
      • Robertson D.
      Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
      ) and associated polymorphisms in several candidate genes (
      • Garland E.M.
      • Winker R.
      • Williams S.M.
      • Jiang L.
      • Stanton K.
      • Byrne D.W.
      • Biaggioni I.
      • Cascorbi I.
      • Phillips 3rd, J.A.
      • Harris P.A.
      • Rüdiger H.
      • Robertson D.
      Endothelial NO synthase polymorphisms and postural tachycardia syndrome.
      ;
      • Jacob G.
      • Garland E.M.
      • Costa F.
      • Stein C.M.
      • Xie H.-G.
      • Robertson R.M.
      • Biaggioni I.
      • Robertson D.
      Beta2-adrenoceptor genotype and function affect hemodynamic profile heterogeneity in postural tachycardia syndrome.
      ). As many as 14% of POTS patients have a family member with POTS, 31% have a family member with orthostatic intolerance, 20% have a family member with joint hypermobility, and 45% have a family member with autoimmune disease (
      • Boris J.R.
      • Huang J.
      • Shuey T.
      • Bernadzikowski T.
      Family history of associated disorders in patients with postural tachycardia syndrome.
      ). Genome-wide association studies in POTS have not been reported. In one family, a rare mutation of norepinephrine-transporter gene was found, resulting in reduced synaptic norepinephrine reuptake and excessive sympathetic activation (
      • Shannon J.R.
      • Flattem N.L.
      • Jordan J.
      • Jacob G.
      • Black B.K.
      • Biaggioni I.
      • Blakely R.D.
      • Robertson D.
      Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.
      ). In a small study, a single-nucleotide polymorphism of the G-protein β3 subunit C825T was more frequently found in POTS (45.8%) than in controls (20.0%) and was associated with a greater increase in HR on standing.(
      • Nakao R.
      • Tanaka H.
      • Takitani K.
      • Kajiura M.
      • Okamoto N.
      • Kanbara Y.
      • Tamai H.
      GNB3 C825T polymorphism is associated with postural tachycardia syndrome in children.
      ) Human-leukocyte antigen variants associated with autoimmune diseases have been overrepresented in POTS (
      • Orban Z.
      • Miller A.
      • Bourne K.
      • Nitis J.
      • Hu W.
      • Reinsel R.A.
      • Stiles L.E.
      • Fedorowski A.
      • Axelsson J.
      Immunogenetic risk markers in postural orthostatic tachycardia syndrome [abstract]. Clin. Auton.
      ;
      • Shin Y.-W.
      • Moon J.
      • Kim T.-J.
      • Kim D.-Y.
      • Chang H.
      • Jun J.-S.
      • Lee S.-T.
      • Jung K.-H.
      • Park K.-I.
      • Jung K.-Y.
      • Kim M.
      • Lee S.K.
      • Chu K.
      Human leukocyte antigen associations in postural tachycardia syndrome.
      ). Some POTS patients have a single nucleotide polymorphism in the endothelial nitric oxide synthase gene (
      • Garland E.M.
      • Winker R.
      • Williams S.M.
      • Jiang L.
      • Stanton K.
      • Byrne D.W.
      • Biaggioni I.
      • Cascorbi I.
      • Phillips 3rd, J.A.
      • Harris P.A.
      • Rüdiger H.
      • Robertson D.
      Endothelial NO synthase polymorphisms and postural tachycardia syndrome.
      ).

      11. Pediatric considerations

      Although clinical manifestations of POTS are similar in children compared to adults, there are a few important differences. The sensitivity and specificity of the pediatric heart rate criteria are not established, and POTS remains undefined under age 12 years despite patients under 12 presenting with similar syndromic findings, particularly in the setting of a familial predisposition. Some patients anecdotally report chronic symptoms since infancy or toddlerhood, raising the question of additional genetic factors. A unique factor of all chronic medical illnesses in childhood is parental involvement (
      • Padilla-Walker L.M.
      • Nelson L.J.
      Black Hawk down? Establishing helicopter parenting as a distinct construct from other forms of parental control during emerging adulthood.
      ). Parents of these patients can be strong advocates but may also may have their own medical and/or psychosocial issues that impact the treatment of their child (
      • Boris J.R.
      Postural orthostatic tachycardia syndrome in children and adolescents.
      ).

      12. Clinical evaluation of POTS

      The evaluation of a patient with suspected POTS should establish the diagnosis, identify co-morbid conditions, and exclude conditions that could cause or mimic the autonomic syndrome. Detailed clinical history must establish the symptoms of orthostatic intolerance, the severity and extent of other autonomic issues, other possible arrhythmia, possible contributory effects of drugs or dietary supplement, and associated comorbid disorders (
      • Goodman B.P.
      Evaluation of postural tachycardia syndrome (POTS).
      ). The physical examination should include postural vital signs in order to confirm exaggerated orthostatic tachycardia (and absence of orthostatic hypotension), careful cardiac examination to exclude gross structural heart disease, neurological examination to identify any features of peripheral neuropathy, and an assessment for clinical features of hypermobile Ehlers-Danlos syndrome. Laboratory studies should, at a minimum, include a complete blood count, electrolytes, thyroid function tests, and an electrocardiogram. Other laboratory tests will often be required, but this should be driven by the patient's clinical presentation.
      While POTS can usually be identified by recording HR and BP while supine and during a 10-minute standing test (with minimal stimulation), more detailed autonomic function testing including tilt table testing can be useful, particularly when other conditions such as neurocardiogenic syncope or peripheral autonomic neuropathy are suspected, or when a patient is unable to perform a 10-minute standing test. Tests that measure the integrity of the cardiovagal and peripheral vasomotor adrenergic responses will be normal in most, but not all, POTS patients (
      • Goodman B.P.
      Evaluation of postural tachycardia syndrome (POTS).
      ). Abnormal sudomotor tests, such as the quantitative sudomotor axon reflex test (QSART) or abnormal intraepidermal nerve fiber density on skin biopsy may be seen in patients with underlying small fiber neuropathy (“neuropathic POTS”). The significance of these findings in terms of prognosis and treatment merits further research.

      13. Non-pharmacologic management of POTS

      Patient education is a key aspect of the management of POTS. Acute worsening of symptoms may be avoided by appropriate attention to environmental temperature, excessive exercise, or in the post-prandial period after eating. Medications that can worsen sinus tachycardia and orthostatic tachycardia should be withdrawn when possible. These include stimulant medications (
      • Fedorowski A.
      • Li H.
      • Yu X.
      • Koelsch K.A.
      • Harris V.M.
      • Liles C.
      • Murphy T.A.
      • Quadri S.M.S.
      • Scofield R.H.
      • Sutton R.
      • Melander O.
      • Kem D.C.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ), and norepinephrine reuptake inhibitors (
      • Green E.A.
      • Raj V.
      • Shibao C.A.
      • Biaggioni I.
      • Black B.K.
      • Dupont W.D.
      • Robertson D.
      • Raj S.R.
      Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome.
      ), among others. Measures to increase effective blood volume and exercise to increase cardiovascular conditioning are very important (
      • Miller A.J.
      • Raj S.R.
      Pharmacotherapy for postural tachycardia syndrome.
      ). In some cases, non-pharmacological interventions (Table 2) are sufficiently effective (
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • Richer L.
      • Schondorf R.
      • Seifer C.
      • Thibodeau-Jarry N.
      • Sheldon R.S.
      Canadian cardiovascular society position statement on postural orthostatic tachycardia syndrome (POTS) and related disorders of chronic orthostatic intolerance.
      ).
      Table 2Treatments for postural tachycardia syndrome.
      DrugDosing informationSide effectsPrecautions
      Non-pharmacological treatments
      Withdraw exacerbating medicationsStop drugs that decrease blood volume or directly increase heart rate
      Increased oral water intakeTarget 2–3 L/dayFrequent urination
      Increased oral NaCl intakeTarget 8–10 g/dayHypertension, peripheral edemaBuffered NaCl tablets/solutions if cannot be done with diet alone
      Lower body compression garments20–40 mmHg compression; focus on abdomen +/− legsCan be hot, tight, and itchy
      Exercise trainingAerobic: 30+ min 4 days/week with some leg resistance trainingWill initially feel poorly/worse for up to 6 weeksInitial recumbent exercise (rowing, recumbent cycle or swimming)
      Pharmacological treatments
      Blood volume expanders
       Fludrocortisone0.1 to 0.2 mg dailyHypokalemia, edema, headacheElectrolytes must be monitored
       Desmopressin (DDAVP)0.1 to 0.2 mg as neededHyponatremia, edemaMonitor electrolytes
       Acute IV saline2 L Intravenous over 2–3 hVenous thrombosis, infection
       Chronic IV saline2 L given intravenously once weeklyInfection/thrombosis risk of central venous cathetersAvoid long-term use; avoid placement of central catheters
       Erythropoietin10,000 IU weeklyIncreased risk of cardiovascular deathMonitor Hematocrit
      Heart rate inhibitors
       Propranolol10–20 mg orally up to 4 times dailyHypotension, bradycardia, bronchospasmCan worsen asthma or exercise tolerance
       Ivabradine2.5–7.5 mg orally twice dailyheadaches, palpitations, hypertension, visual disturbances
       Pyridostigmine30–60 mg orally up to 3 times dailyAbdominal cramps, diarrheaCan worsen asthma
      Vasoconstrictors
       Midodrine2.5–15 mg orally 3 times dailyHeadache, scalp tingling, hypertension
       OctreotideLong-acting intramuscular injection 10–30 mgNausea, stomach cramps, diarrhea
       Methylphenidate10 mg orally 2–3 times a day. Last dose should be avoided before bed.Tachycardia, insomnia, nausea, headache, dizziness
      Sympatholytic drugs
       Alpha-2 adrenergic agonists, such as clonidine0.1–0.2 mg orally 2–3 times daily or long acting patchHypotension, fatigue, brain fog
       Methyldopa125–250 mg orally twice dailyHypotension, fatigue, brain fog
      Other
       Modafinil50–200 mg orally 1–2 times dailyTachycardia
      Modified with permission from
      • Miller A.J.
      • Raj S.R.
      Pharmacotherapy for postural tachycardia syndrome.
      .
      To expand blood volume, patients should have a minimum intake of 2 to 3 L of water per day along with increased sodium intake (
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • Richer L.
      • Schondorf R.
      • Seifer C.
      • Thibodeau-Jarry N.
      • Sheldon R.S.
      Canadian cardiovascular society position statement on postural orthostatic tachycardia syndrome (POTS) and related disorders of chronic orthostatic intolerance.
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ). Most clinicians recommend oral sodium intake to avoid potential complications of intravenous access. Sodium intake can be increased to 3 to 10 g daily using ordinary table salt (1 tsp. is approximately 2.3 g sodium), salt tablets or electrolyte solutions (
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • Richer L.
      • Schondorf R.
      • Seifer C.
      • Thibodeau-Jarry N.
      • Sheldon R.S.
      Canadian cardiovascular society position statement on postural orthostatic tachycardia syndrome (POTS) and related disorders of chronic orthostatic intolerance.
      ). Further research is needed to establish the true therapeutic benefit of salt loading and the optimal sodium intake. In addition to increased water and sodium intake, measures to reduce venous pooling in the lower limbs or splanchnic circulation can be accomplished using waist-high compression stockings with or without abdominal compression (
      • Bourne K.M.
      • Sheldon R.S.
      • Hall J.
      • Lloyd M.
      • Kogut K.
      • Sheikh N.
      • Jorge J.
      • Ng J.
      • Exner D.V.
      • Tyberg J.V.
      • Raj S.R.
      Compression garment reduces orthostatic tachycardia and symptoms in patients with postural orthostatic tachycardia syndrome.
      ), or with an abdominal binder alone (
      • Smith E.C.
      • Diedrich A.
      • Raj S.R.
      • Gamboa A.
      • Shibao C.A.
      • Black B.K.
      • Peltier A.
      • Paranjape S.Y.
      • Biaggioni I.
      • Okamoto L.E.
      Splanchnic venous compression enhances the effects of ß-blockade in the treatment of postural tachycardia syndrome.
      ).
      Exercise training should be a component of any POTS treatment plan. Along with increased water and salt intake, a progressive exercise program with recumbent aerobic exercise and leg resistance training transitioning to upright exercise has been shown to improve quality of life and reduce orthostatic HR in many patients (
      • Fu Q.
      • Levine B.D.
      Exercise and non-pharmacological treatment of POTS.
      ,
      • Fu Q.
      • Levine B.D.
      Exercise in the postural orthostatic tachycardia syndrome.
      ;
      • George S.A.
      • Bivens T.B.
      • Howden E.J.
      • Saleem Y.
      • Galbreath M.M.
      • Hendrickson D.
      • Fu Q.
      • Levine B.D.
      The international POTS registry: evaluating the efficacy of an exercise training intervention in a community setting.
      ;
      • Sheldon R.S.
      • Grubb B.P.
      • Olshansky B.
      • Shen W.-K.
      • Calkins H.
      • Brignole M.
      • Raj S.R.
      • Krahn A.D.
      • Morillo C.A.
      • Stewart J.M.
      • Sutton R.
      • Sandroni P.
      • Friday K.J.
      • Hachul D.T.
      • Cohen M.I.
      • Lau D.H.
      • Mayuga K.A.
      • Moak J.P.
      • Sandhu R.K.
      • Kanjwal K.
      2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.
      ;
      • Shibata S.
      • Fu Q.
      • Bivens T.B.
      • Hastings J.L.
      • Wang W.
      • Levine B.D.
      Short-term exercise training improves the cardiovascular response to exercise in the postural orthostatic tachycardia syndrome.
      ). Best practices for long-term management of POTS patients after improvement have not been determined.

      14. Pharmacologic management of POTS

      Pharmacologic therapy (Table 2) has largely been directed toward improving orthostatic tolerance in POTS. Therapies may also be directed at disabling autonomic and non-autonomic symptoms as well as comorbid conditions such as gastrointestinal dysmotility, immune disorders, sleep, pain, cognitive dysfunction (“brain fog”) and headache. Therapies directed at improving orthostatic tolerance can be broadly characterized as targeting blood volume expansion, HR modulation, and BP stabilization. At this point, there are no FDA-approved medications for the treatment of POTS, and more importantly evidence of efficacy for many of the medications used to treat POTS is not robust.
      Fludrocortisone is frequently used in the treatment of POTS patients for the purposes of volume expansion, though evidence supporting its use is quite limited (
      • Fortunato J.E.
      • Wagoner A.L.
      • Harbinson R.L.
      • D’Agostino R.B.J.
      • Shaltout H.A.
      • Diz D.I.
      Effect of fludrocortisone acetate on chronic unexplained nausea and abdominal pain in children with orthostatic intolerance.
      ). There is no evidence that POTS patients who are hypovolemic respond better to fludorocortisone than do POTS patients who are normovolemic. There is also no evidence that fludrocortisone actually increases blood volume. For fludrocortisone to work, the patient must be on a high sodium diet, with appropriate monitoring of serum potassium. Beta-adrenoreceptor antagonists have often been used to treat POTS, with propranolol (
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • Paranjape S.Y.
      • Ramirez M.
      • Dupont W.D.
      • Robertson D.
      Propranolol decreases tachycardia and improves symptoms in the postural tachycardia syndrome: less is more.
      ), metoprolol, bisoprolol, and atenolol used most commonly (
      • Abe H.
      • Nagatomo T.
      • Kohshi K.
      • Numata T.
      • Kikuchi K.
      • Sonoda S.
      • Mizuki T.
      • Kuroiwa A.
      • Nakashima Y.
      Heart rate and plasma cyclic AMP responses to isoproterenol infusion and effect of beta-adrenergic blockade in patients with postural orthostatic tachycardia syndrome.
      ;
      • Chen L.
      • Wang L.
      • Sun J.
      • Qin J.
      • Tang C.
      • Jin H.
      • Du J.
      Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.
      ;
      • Freitas J.
      • Santos R.
      • Azevedo E.
      • Costa O.
      • Carvalho M.
      • de Freitas A.F.
      Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone.
      ;
      • Lai C.C.
      • Fischer P.R.
      • Brands C.K.
      • Fisher J.L.
      • Porter C.-B.J.
      • Driscoll S.W.
      • Graner K.K.
      Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers.
      ;
      • Lin J.
      • Han Z.
      • Li H.
      • Chen S.Y.
      • Li X.
      • Liu P.
      • Wang Y.
      • Tang C.
      • Du J.
      • Jin H.
      Plasma C-type natriuretic peptide as a predictor for therapeutic response to metoprolol in children with postural tachycardia syndrome.
      ;
      • Zhang Q.
      • Chen X.
      • Li J.
      • Du J.
      Orthostatic plasma norepinephrine level as a predictor for therapeutic response to metoprolol in children with postural tachycardia syndrome.
      ;
      • Zhao J.
      • Du S.
      • Yang J.
      • Lin J.
      • Tang C.
      • Du J.
      • Jin H.
      Usefulness of plasma copeptin as a biomarker to predict the therapeutic effectiveness of metoprolol for postural tachycardia syndrome in children.
      ). A recent clinical trial found propranolol and bisoprolol to have equal efficacy, with no significant benefit of pyridostigmine added to the beta-blocker (
      • Moon J.
      • Kim D.-Y.
      • Lee W.-J.
      • Lee H.S.
      • Lim J.-A.
      • Kim T.-J.
      • Jun J.-S.
      • Park B.
      • Byun J.-I.
      • Sunwoo J.-S.
      • Lee S.-T.
      • Jung K.-H.
      • Park K.-I.
      • Jung K.-Y.
      • Kim M.
      • Lee S.K.
      • Chu K.
      Efficacy of propranolol, bisoprolol, and pyridostigmine for postural tachycardia syndrome: a randomized clinical trial.
      ). A recent meta-analysis of ivabradine, a “funny channel” blocker that modulates cardiac sinus node activity, suggested benefit in lowering HR and providing symptomatic relief in POTS patients (
      • Gee M.E.
      • Watkins A.K.
      • Brown J.N.
      • Young E.J.A.
      Ivabradine for the treatment of postural orthostatic tachycardia syndrome: A systematic review.
      ). Midodrine, an oral alpha-adrenoceptor agonist prodrug, is used to promote venoconstriction and vasoconstriction in POTS patients and has shown benefit in small studies (
      • Lai C.C.
      • Fischer P.R.
      • Brands C.K.
      • Fisher J.L.
      • Porter C.-B.J.
      • Driscoll S.W.
      • Graner K.K.
      Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers.
      ;
      • Zhang F.
      • Li X.
      • Ochs T.
      • Chen L.
      • Liao Y.
      • Tang C.
      • Jin H.
      • Du J.
      Midregional pro-adrenomedullin as a predictor for therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome.
      ). Additional studies are necessary to provide better evidence of the efficacy of these medications in the treatment of POTS and whether particular clinical phenotypes favor certain therapies. Further research is needed to explore novel pharmacological interventions that have not yet been studied in POTS, and to explore treatments for the non-cardiovascular symptoms seen in POTS.

      15. Role of immunotherapy

      Several lines of evidence point to an autoimmune mechanism in at least some POTS patients as outlined above. Further, a number of case reports, and retrospective case series have provided anecdotal evidence suggesting efficacy of IVIG in the treatment of refractory POTS and other forms of suspected autoimmune dysautonomia (
      • Goodman B.P.
      Immunoresponsive Postinfectious autonomic neuropathy.
      ;
      • Schofield J.R.
      • Chemali K.R.
      Intravenous immunoglobulin therapy in refractory autoimmune dysautonomias: a retrospective analysis of 38 patients.
      ;
      • Weinstock L.B.
      • Brook J.B.
      • Myers T.L.
      • Goodman B.
      Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment.
      ). These observations are not sufficient however. Beyond the expected placebo effects, intravenous infusion might provide a temporary increase in plasma volume independent of immunomodulatory effects. A small, randomized, double blind clinical trial is now underway to evaluate this treatment (NCT03919773). At this point, the clinical, laboratory, or autonomic features that should prompt consideration of immunotherapy are unknown.

      16. Summary

      POTS is a chronic multi-system disorder involving the autonomic nervous system that is characterized by an exaggerated sinus tachycardia, and symptoms upon standing. POTS primarily affects females starting around puberty and through their child-bearing age and is associated with significant functional disability, such as decreased ability to participate in education, limited ability to work and generate an income, and decreased quality of life. The pathophysiology is incompletely understood, which is likely responsible for limited data on effective treatments. Focused research studies on the pathophysiology and treatment of POTS have the potential to improve the lives of patients with POTS.

      Funding

      This NIH 2019 POTS Conference was supported by the US National Institutes of Health (NIH), Bethesda MD, USA.
      Dr. Goldstein's research is supported by the Division of Intramural Research, NINDS, NIH, Bethesda, MD, USA. The views expressed are the author's own and do not necessarily reflect those of the National Institutes of Health, the Department of Health and Human Services, or the United States Government.

      Declaration of competing interest

      SV – Consultant (topics unrelated to POTS) for Sage Therapeutics, Alterity, Catalyst Pharmaceuticals. Research Support from Dysautonomia International, Grifols, Genentech, BioHaven Pharmaceuticals.
      KMB – Vanier Scholar, Canadian Institutes of Health Research (CIHR; Ottawa, Canada).
      LES – None.
      BPGr – None.
      AF – Personal fees from Medtronic Inc. and Biotronik SE & Co AG, both unrelated to POTS.
      JMS – Research grant from the National, Heart, Lung, and Blood institute (NHLBI) of the National Institutes of Health (NIH; Bethesda, MD, USA); Research grant from Lundbeck NA Ltd.
      ACA – Consultant for National Vaccine Injury Compensation Program, U.S. Department of Health and Human Services; Research grant from Dysautonomia International.
      LAP – Research grants from the National Institutes of Health (NIH); Research grants from Dysautonomia International.
      JA – Founder and financial beneficiary of Ameliekliniken in Stockholm AB, a provider of outpatient healthcare (including to patients with POTS).
      JRB – Consultant for National Vaccine Injury Compensation Program, U.S. Department of Health and Human Services.
      JPM - None.
      BPGo – None.
      KRC – Research Grants from Dysautonomia International.
      THC – None.
      DSG – None.
      ADi - None.
      MGM – Consultant for Med-IQ CME and Infinite MD, Royalties from Elsevier, Expert Witness in POTS-related cases.
      MMC – None.
      AJM – None.
      RF – None.
      IB - Consultant for Theravance Biopharma and Takeda Pharmaceutical. Patent holder, Automated binder for treatment of Orthostatic Hypotension.
      PCR – None.
      RSS - None.
      CAS - Consultant for Theravance Biopharma.
      DMS – None.
      GAC – None.
      TAD - Research support from Equillium Inc.
      HIA - None.
      ADa – None.
      SRR - Consultant for Lundbeck NA Ltd. and Theravance Biopharma; Chair, Data Safety and Monitoring Board for Arena Pharmaceuticals; Research Grant from Canadian Institutes of Health Research (CIHR; Ottawa, Canada); Research Grants from Dysautonomia International; Cardiac Arrhythmia Network of Canada (CANet; London, Ontario, Canada) Network Investigator.

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