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Cited by 163Cardiovascular Syncope and Autonomic DisordersConnective tissue disorders researchHeart Rate Variability and Autonomic Control

Cardiovascular autonomic dysfunction in Ehlers–Danlos syndrome—Hypermobile type

Open access
Hakim, Alan, O'Callaghan, Chris, De Wandele, Inge, Stiles, Lauren, Pocinki, Alan, Rowe, Peter·2017·American Journal of Medical Genetics Part C: Seminars in Medical Genetics
DOI 10.1002/ajmg.c.31543
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Abstract

Autonomic dysfunction contributes to health‐related impairment of quality of life in the hypermobile type of Ehlers–Danlos syndrome (hEDS). Typical signs and symptoms include tachycardia, hypotension, gastrointestinal dysmotility, and disturbed bladder function and sweating regulation. Cardiovascular autonomic dysfunction may present as Orthostatic Intolerance, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, or Neurally Mediated Hypotension. The incidence, prevalence, and natural history of these conditions remain unquantified, but observations from specialist clinics suggest they are frequently seen in hEDS. There is growing understanding of how hEDS‐related physical and physiological pathology contributes to the development of these conditions. Evaluation of cardiovascular symptoms in hEDS should include a careful history and clinical examination. Tests of cardiovascular function range from clinic room observation to tilt‐table assessment to other laboratory investigations such as supine and standing catecholamine levels. Non‐pharmacologic treatments include education, managing the environment to reduce exposure to triggers, improving cardiovascular fitness, and maintaining hydration. Although there are limited clinical trials, the response to drug treatments in hEDS is supported by evidence from case and cohort observational data, and short‐term physiological studies. Pharmacologic therapy is indicated for patients with moderate‐severe impairment of daily function and who have inadequate response or tolerance to conservative treatment. Treatment in hEDS often requires a focus on functional maintenance. Also, the negative impact of cardiovascular symptoms on physical and psycho‐social well‐being may generate a need for a more general evaluation and on‐going management and support. © 2017 Wiley Periodicals, Inc.

Integrity signals

Registry

Crossref · 10.1002/ajmg.c.31543

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 30 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    The incidence, prevalence, and natural history of cardiovascular autonomic dysfunction in hEDS are unquantified.

    “The incidence, prevalence, and natural history of these conditions remain unquantified, but observations from specialist clinics suggest they are frequently seen in hEDS.”
    Quote in the paperNot a substantial claim
  • Premisenone given

    Autonomic dysfunction contributes to impaired quality of life in hEDS.

    “Autonomic dysfunction contributes to health-related impairment of quality of life in the hypermobile type of Ehlers-Danlos syndrome (hEDS).”
    Quote in the paperSubstantial claim
  • Premisecitation

    An association has been reported between multi-systemic pathologies including autonomic disturbances and germline duplications and triplications of the TSPAB1 gene encoding alpha 1 tryptase.

    “and an intriguing association reported between multi-systemic pathologies including autonomic disturbances and germline duplications and triplications of the TSPAB1 gene encoding alpha 1 tryptase [Lyons et al., 2016].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lyons et al., 2016

      Not checked in the free run.

  • Premisecitation

    Symptoms of cardiovascular autonomic dysfunction can be highly debilitating in hEDS.

    “Symptoms can be highly debilitating in hEDS [Rowe et al., 1999;Hakim and Grahame, 2004;Mathias et al., 2011;De Wandele et al., 2014b].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rowe et al., 1999

      Not checked in the free run.

    • cites Hakim and Grahame, 2004

      Not checked in the free run.

    • cites Mathias et al., 2011

      Not checked in the free run.

  • Premisenone given

    Observations from specialist clinics suggest cardiovascular autonomic dysfunction is frequently seen in hEDS.

    “The incidence, prevalence, and natural history of these conditions remain unquantified, but observations from specialist clinics suggest they are frequently seen in hEDS.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 33

  • May combine two claims.

    Findingnone given

    Evidence for management in hEDS is lacking; there are no published clinical trials.

    “Equally the causal relationships in hEDS are unclear though there are plausible mechanisms, and the evidence for the management in hEDS is lacking in that there are no published clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    There are no clinical trials of treatment in hEDS, either in general or in specific subgroups based on pathophysiology.

    “However, there are no clinical trials of treatment in hEDS, either in general or in specific subgroups based on pathophysiology.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    There has been no general hEDS population cohort study of cardiovascular autonomic dysfunction, and only one published case-control study of symptom reporting.

    “There has been no general hEDS population cohort study of cardiovascular autonomic dysfunction, and there has been one published case-control study of symptom reporting.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    Causal relationships in hEDS are unclear, though there are plausible mechanisms.

    “Equally the causal relationships in hEDS are unclear though there are plausible mechanisms, and the evidence for the management in hEDS is lacking in that there are no published clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    The causes of cardiovascular autonomic dysfunction in hEDS are unclear.

    “The causes of cardiovascular autonomic dysfunction in hEDS are unclear.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    In the general literature on management of autonomic dysfunction, there is evidence for the effectiveness of treatment strategies.

    “In the general literature on the management of autonomic dysfunction there is evidence for the effectiveness of treatment strategies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Findingreasoning

    Even where evidence exists, it is confounded by imprecision in definitions and diagnostic methods that further confound extrapolation from data to individual patients.

    “Even where evidence exists, it is confounded by imprecision in definitions and diagnostic methods that further confound extrapolation from data to individual patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Findingnone given

    There is no evidence that specific treatments should be targeted at subgroups of patients with hEDS.

    “There is no evidence that specific treatments should be targeted at subgroups of patients with hEDS.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Findingreasoning

    Level IV evidence of the associations with EDS arises from small cohort studies, case reports, and expert opinion.

    “Level IV evidence of the associations with EDS arises from small cohort studies, case reports, and expert opinion.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Findingreasoning

    Guidance is principally based on expert consensus, but draws on Level I to III guidance published by international groups on the assessment and management of POTS and OI per se.

    “As such guidance is principally based on expert consensus, but draws on Level I to III guidance published by international groups on the assessment and management of POTS and OI per se [Grubb et al., 2006;Lahrmann et al., 2006;Sheldon et al., 2015].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Grubb et al., 2006;Lahrmann et al., 2006;Sheldon et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Findingnone given

    The incidence, prevalence, and natural history of cardiovascular autonomic dysfunction in the hEDS population are unknown, as are the distribution and types of co-associated mechanisms.

    “The incidence, prevalence, and natural history of cardiovascular autonomic dysfunction in the hEDS population are unknown, as are the distribution and types of (co-associated) mechanisms that may trigger or influence these phenomena.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Level I to III evidence for the management of cardiovascular autonomic dysfunction in hEDS is lacking; there are no published clinical trials.

    “Using the standard nomenclature for guidelines Level I to III evidence for the management of cardiovascular autonomic dysfunction in hEDS is lacking; there are no published clinical trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Autonomic dysfunction in hEDS commonly includes cardiovascular, pupillary, bladder, sweating, and gastrointestinal symptoms, such as tachycardia and hypotension.

    “Typical signs and symptoms include tachycardia, hypotension, gastrointestinal dysmotility, and disturbed bladder function and sweating regulation.”
    • Also stated in: § INTRODUCTION AND METHODS · plain
      “While many symptoms of autonomic dysfunction have been observed clinically in hEDS, including cardiovascular, pupil, bladder, sweating dysfunction, and gastrointestinal dysmotility (see”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Aziz et al.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Mitral valve prolapse can be associated with excessive catecholamines, orthostatic intolerance, and occasionally dysrhythmias.

    “Mitral valve prolapse (MVP) can be associated with excessive catecholamines, orthostatic intolerance, and occasionally with dysrhythmias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In some cases, OI in hEDS may be attributed to abnormal connective tissue in dependent blood vessels, with veins distending excessively in response to ordinary hydrostatic pressures, leading to increased venous pooling and its hemodynamic and symptomatic consequences.

    “Rowe et al. [1999] suggested that in some cases the association of OI with hEDS could be attributed to abnormal connective tissue in dependent blood vessels with veins distending excessively in response to ordinary hydrostatic pressures.This in turn leads to increased venous pooling and its hemodynamic and symptomatic consequences.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rowe et al. [1999]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    POTS is associated with fatigue.

    “There is recognition of an association of POTS with fatigue [Schondorf et al., 1999], reduced quality of life [Benrud-Larson et al., 2002], and a greater incidence of migraine and syncope with POTS in patients with joint hypermobility syndrome compared to those without [Kanjwal et al., 2010].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schondorf et al., 1999

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    When poorly controlled, cardiovascular symptoms may restrict treatment strategies for other symptomatic management including physical therapies.

    “When poorly controlled, these symptoms may also restrict treatment strategies for other symptomatic management including physical therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Histamine can induce hypotension and tachycardia.

    “Histamine can induce hypotension and tachycardia [Frieri et al., 2013].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Frieri et al., 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    There is growing recognition of an association between autonomic dysfunction and hEDS.

    “There is growing recognition of an association between autonomic dys-function and Ehlers-Danlos syndrome -hypermobile type (hEDS).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuropathy, connective tissue laxity, and vasoactive medication play a role in the development of cardiovascular dysfunction in hEDS.

    “Studies by Mathias et al. [2011] and De Wandele et al. [2014a] suggest that neuropathy, connective tissue laxity, and vasoactive medication play a role in development of cardiovascular dysfunction in hEDS.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Mathias et al. [2011]

      Not checked in the free run.

    • cites De Wandele et al. [2014a]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Potentially pathogenic adrenergic, muscarinic, and other neural autoantibodies have been identified in a significant percentage of POTS cases and a subset of OH cases in the general literature.

    “Also in the general literature, research has identified potentially pathogenic adrenergic [Fedorowski et al., 2016], muscarinic [Yu et al., 2012;Dubey et al., 2016], and other neural autoantibodies [Thieben et al., 2007;Li et al., 2014;Singer et al., 2016] in a significant percentage of cases with POTS and a subset of those with OH.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Fedorowski et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Yu et al., 2012;Dubey et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Thieben et al., 2007;Li et al., 2014;Singer et al., 2016

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In patients with joint hypermobility syndrome, POTS is associated with a greater incidence of migraine and syncope compared to those without POTS.

    “There is recognition of an association of POTS with fatigue [Schondorf et al., 1999], reduced quality of life [Benrud-Larson et al., 2002], and a greater incidence of migraine and syncope with POTS in patients with joint hypermobility syndrome compared to those without [Kanjwal et al., 2010].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kanjwal et al., 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    POTS is associated with reduced quality of life.

    “There is recognition of an association of POTS with fatigue [Schondorf et al., 1999], reduced quality of life [Benrud-Larson et al., 2002], and a greater incidence of migraine and syncope with POTS in patients with joint hypermobility syndrome compared to those without [Kanjwal et al., 2010].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Benrud-Larson et al., 2002

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A hyperadrenergic state was identified in 29% of POTS cases from a general cohort, though hEDS cases were not specifically identified.

    “In support of the hypothesis that this is one mechanism in hEDS, a study by Thieben et al. [2007] identified a hyperadrenergic state in 29% of cases of POTS from a general cohort though cases of hEDS were not specifically identified.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Thieben et al. [2007] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Normal cardiac anatomy does not rule out cardiovascular dysfunction.

    “Also, normal cardiac anatomy does not rule out cardiovascular dysfunction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Suggested mechanisms for cardiovascular autonomic dysfunction in hEDS include low blood pressure, increased peripheral venous dilation and blood pooling, low circulating blood volume, medications with autonomic side effects, elevated circulating catecholamines, autoimmunity, excess systemic histamine, and rarely brainstem or cervical cord impingement.

    “Suggested mechanisms include (listed based on clinical experience and in order of most common occurrence): Low blood pressure, increased peripheral venous dilation and blood pooling, low circulating blood volume, medications with side effects that trigger or impair autonomic responses, for example tricyclics, elevated circulating catecholamines, auto-immunity, particularly auto-antibodies directed”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Many common symptoms of cardiovascular dysfunction in hEDS relate to changes in posture.

    “Many of the common symptoms relate to changes in posture.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The prognosis remains uncertain with outcomes ranging from virtually complete resolution of symptoms to long-term disability, which may be so severe as to affect education, employment, or socialization.

    “The prognosis remains uncertain with the outcomes ranging from virtually complete resolution of symptoms to long-term disability, which may be so severe as to affect education, employment, or socialization.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A 3-month moderate gradual endurance and strength training programme can decrease upright heart rate, improve baroreflex sensitivity and heart rate variability, and improve quality of life.

    “Fu et al. [2011] and George et al. [2016] have shown that after a 3-month training programme, moderate gradual endurance and strength training can decrease upright heart rate, improve baroreflex sensitivity and heart rate variability, and improve quality of life.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Fu et al., 2011

      Not checked in the free run.

    • cites George et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Physical deconditioning and poor aerobic fitness are common findings in patients chronically unwell with hEDS.

    “Physical deconditioning and poor aerobic fitness are common findings in patients chronically unwell with hEDS.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Symptoms of OI can overlap with some features of cardiac dysrhythmias.

    “Symptoms of OI can overlap with some features of cardiac dysrhythmias.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Fludrocortisone is a first-line drug therapy for OI at doses of 100-200 mg daily (Level III evidence).

    “Fludrocortisone is a first line drug therapy for OI at doses of 100-200 mg daily (Level III evidence).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Dihydroxyphenylserine titrated 100-200 mg three times daily reduces OH (Level I evidence).

    “Dihydroxyphenylserine titrated 100-200 mg three times daily reduces OH (Level I evidence).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    A simple clinic room standing test can help assess whether a brief period of standing can provoke orthostatic symptoms in those with NMH, but provocation of hypotension usually requires more prolonged tilt table testing.

    “A simple clinic room standing test can help assess whether a brief period of standing can provoke orthostatic symptoms in those with NMH, but provocation of hypotension usually requires more prolonged tilt table testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Individuals with hEDS can develop cardiovascular autonomic dysfunction.

    “Individuals with hEDS can develop cardiovascular autonomic dysfunction.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    These symptoms occur when changing from lying or sitting to standing, or with maintaining upright posture, and are improved but not always completely relieved by sitting or lying down.

    “They occur when changing from a lying or sitting to a standing position, or with maintaining upright posture, and are improved but not always completely relieved by sitting or lying down.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pyridostigmine can be effective for neurally mediated syncope and for POTS (Level I evidence).

    “Pyridostigmine is a peripheral acetylcholinesterase inhibitor that increases synaptic acetylcholine in the autonomic ganglia and at peripheral muscarinic receptors [Raj et al., 2005].The drug can be effective for neurally mediated syncope and for POTS (Level I evidence).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Raj et al., 2005

      Not checked in the free run.

    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The diagnosis of NMH associated with recurrent syncope can be made clinically, and in most cases does not require formal tilt table testing.

    “The diagnosis of NMH that is associated with recurrent syncope can be made clinically, and in most cases does not require formal tilt table testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The diagnosis is predominantly based upon taking a detailed personal and family history of symptoms, provoking circumstances, and accompanying complaints.

    “The diagnosis is predominantly based upon taking a detailed personal and family history of symptoms, provoking circumstances, and accompanying complaints.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Simple clinic room tests can provide support for the diagnosis and other tests may be useful to exclude other diseases that can present in a similar manner.

    “Simple clinic room tests can provide support for the diagnosis and other tests may be useful to exclude other diseases that can present in a similar manner.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Specific conditions include POTS and NMH.

    “Specific conditions include POTS and NMH.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    None of the treatments available for cardiovascular autonomic dysfunction in hEDS is universally effective, and several treatments used together are likely to be needed.

    “None of the treatments available is universally effective, and several treatments, used together, are likely to be needed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    POTS, OH, and some forms of OI can be diagnosed in clinic without the need for complex tests.

    “POTS, OH, and some forms of OI can be diagnosed in clinic without the need for complex tests.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Midodrine significantly reduces POTS symptoms and reduces the frequency of neurally mediated syncope (Level I evidence).

    “Midodrine significantly reduces POTS symptoms and reduces the frequency of neurally mediated syncope (Level I evidence).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

  • May combine two claims.

    Premisenone given

    Ivabradine slows sinus heart rate without affecting blood pressure, and has been reported to be helpful in those with POTS (Level III evidence).

    “Ivabradine slows sinus heart rate without affecting blood pressure, and has been reported to be helpful in those with POTS (Level III evidence).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

  • May combine two claims.

    Premisenone given

    Manifestations of cardiovascular autonomic dysfunction in hEDS include symptoms related to inadequate cerebral perfusion and symptoms of heightened adrenergic tone.

    “Its manifestations include symptoms related to inadequate cerebral perfusion and symptoms of heightened adrenergic tone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Beta blockers can help with management of recurrent syncope, NMH, POTS, and OI (Level I evidence).

    “Beta blockers can help with management of recurrent syncope, NMH, POTS, and OI (Level I evidence).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.
47 of 47

  • The paper relies on this without support.

    Treatments shown to be effective for POTS and OI in the general population are also effective for cardiovascular autonomic dysfunction in hEDS.

    “Such treatments have been applied to individual cases of hEDS, based on physiological findings.However, there are no clinical trials of treatment in hEDS, either in general or in specific subgroups based on pathophysiology.”
    “As such guidance is principally based on expert consensus, but draws on Level I to III guidance published by international groups on the assessment and management of POTS and OI per se [Grubb et al., 2006;Lahrmann et al., 2006;Sheldon et al., 2015].”

  • The paper relies on this without support.

    The consensus definitions of POTS, OH, NMH, and OI developed for general populations are valid for diagnosing these conditions in hEDS.

    “The following consensus definitions 1 [Freeman et al., 2011;Sheldon et al., 2015] are applied:”
    “This document uses definitions already proposed by international consensus and published in the general literature.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Clinical features of HSD and hEDS include associations with cardiovascular autonomic dysfunction, gastrointestinal difficulties, fatigue, pain syndromes, gynecological and obstetric problems, and mental health concerns.

    “Clinical features of HSD and hEDS are not limited to musculoskeletal and cutaneous symptoms (9). Associations exist with cardiovascular autonomic dysfunction (12), gastrointestinal difficulties (13), fatigue (12) and pain syndromes (14), gynecological and obstetric problems (15, 16), and mental health concerns (17–19).”

    From Joint Hypermobility Links Neurodivergence to Dysautonomia and Pain (2022) · cites this paper as [12]

    The Introduction and Methods and Literature Review describe cardiovascular autonomic dysfunction in hEDS, and the Literature Review reports an association between POTS and fatigue. The cited passages do not establish those associations for HSD specifically; the fatigue statement concerns POTS rather than fatigue across all people with hEDS. The other listed problems have separate citations in the citing sentence and are not attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Symptoms of orthostatic intolerance can be debilitating.

    “Symptoms of orthostatic intolerance can be debilitating (12).”

    From Joint Hypermobility Links Neurodivergence to Dysautonomia and Pain (2022) · cites this paper as [12]

  • Cardiovascular autonomic dysfunction can include orthostatic hypotension, orthostatic intolerance, neurally-mediated hypotension and postural orthostatic tachycardia syndrome (PoTS), the latter of which is commonly associated with HSD/hEDS.

    “Cardiovascular autonomic dysfunction can include orthostatic hypotension, orthostatic intolerance, neurally‐mediated hypotension and postural orthostatic tachycardia syndrome (PoTS), the latter of which is commonly associated with HSD/hEDS. 66”

    From Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know (2022) · cites this paper as [66]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The cited gene has two different identifiers

    Minor

    The discussion names the gene TSPAB1, whereas the title of the cited Lyons et al. reference names it TPSAB1. The identifiers differ despite referring to the same reported copy-number finding.

  • A 20 mm Hg pressure drop falls on both sides of the stated definitions

    Minor

    The POTS definition excludes orthostatic hypotension only when the systolic pressure drop is greater than 20 mm Hg, but the OH definition includes a drop of at least 20 mm Hg. At exactly 20 mm Hg, the stated criteria therefore overlap.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. Cheung I, 2015, A new disease cluster: Mast Cell Activation syndrome, Postural Orthostatic Tachycardia syndrome, & Ehlers‐Danlos syndrome, J Allergy Clin lmmunol, 35, AB 209
  2. Dubey D, 2016, M1 and M2 muscarinic receptor antibodies among patients with postural orthostatic tachycardia syndrome: Potential disease biomarker, J Clin Neuromuscul Dis, 17, 179
  3. Louisias M, 2013, Prevalence of allergic disorders and mast cell activation syndrome in patients with Ehlers Danlos syndrome, Ann Allergy Asthma lmmunol, 111, A12
  4. Singer W, 2016, Autoantibodies in the postural tachycardia syndrome, Clin Auton Res, 24, 214

Cited by

Sorted by citations

Related

Authors
Hakim, A., O'Callaghan, C., De Wandele, I., Stiles, L., Pocinki, A., & Rowe, P.
Affiliations
National Institutes of Health (US)
Corresponding author
Hakim, Alan
ORCID
Venue
American Journal of Medical Genetics Part C: Seminars in Medical Genetics
Publisher
Wiley
Published
2017-02-04
Volume
175
Issue
1
Pages
168-174
ISSN
  • 1552-4868 (ISSN-L)
  • 1552-4876
DOI
10.1002/ajmg.c.31543
OpenAlex
W2586005000
Cited by
163
References
45
Citations by year
2026: 14 · 2025: 20 · 2024: 17 · 2023: 14 · 2022: 19 · 2021: 40 · 2020: 15 · 2019: 11 · 2018: 5 · 2017: 7
FWCI
2.20
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • American Journal of Medical Genetics Part C Seminars in Medical Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
Keywords
cardiac autonomic dysfunction, orthostatic intolerance, orthostatic hypotension, postural orthostatic tachycardia syndrome, gastrointestinal motility disorders, bladder dysfunction, tilt table test, catecholamine levels, non-pharmacological treatment, pharmacotherapy, quality of life
MeSH terms
Cardiovascular Diseases, Ehlers-Danlos Syndrome, Humans, Disease Management

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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