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Cited by 62Cardiovascular Syncope and Autonomic DisordersHeart Rate Variability and Autonomic ControlConnective tissue disorders research

Orthostatic intolerance and postural orthostatic tachycardia syndrome in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type: neurovegetative dysregulation or autonomic failure?

Open access
Celletti, Claudia, Camerota, Filippo, Castori, Marco, Censi, Federica, Gioffrè, Laura, Calcagnini, Giovanni, Strano, Stefano·2017·BioMed Research International
DOI 10.1155/2017/9161865PMC PMC5329674
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Abstract

Background. Joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), is a hereditary connective tissue disorder mainly characterized by generalized joint hypermobility, skin texture abnormalities, and visceral and vascular dysfunctions, also comprising symptoms of autonomic dysfunction. This study aims to further evaluate cardiovascular autonomic involvement in JHS/EDS-HT by a battery of functional tests.Methods. The response to cardiovascular reflex tests comprising deep breathing, Valsalva maneuver, 30/15 ratio, handgrip test, and head-up tilt test was studied in 35 JHS/EDS-HT adults. Heart rate and blood pressure variability was also investigated by spectral analysis in comparison to age and sex healthy matched group.Results. Valsalva ratio was normal in all patients, but 37.2% of them were not able to finish the test. At tilt, 48.6% patients showed postural orthostatic tachycardia, 31.4% orthostatic intolerance, 20% normal results. Only one patient had orthostatic hypotension. Spectral analysis showed significant higher baroreflex sensitivity values at rest compared to controls.Conclusions.This study confirms the abnormal cardiovascular autonomic profile in adults with JHS/EDS-HT and found the higher baroreflex sensitivity as a potential disease marker and clue for future research.

AI snapshot

Written from the paper’s full text.

TL;DR

In 35 adults with joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type (JHS/EDS-HT), head-up tilt commonly revealed postural orthostatic tachycardia syndrome (POTS) or orthostatic intolerance, while orthostatic hypotension was rare. Resting baroreflex sensitivity was significantly higher than in healthy controls, especially in the POTS subgroup, suggesting a potential disease marker rather than classic autonomic failure.

Key findings

  • Among 35 JHS/EDS-HT patients (6 men, 29 women; mean age 35 ± 14 years), head-up tilt showed POTS in 17 (48.6%), orthostatic intolerance in 11 (31.4%), normal results in 7 (20%), and orthostatic hypotension in only 1 (3%).
  • Deep breathing and the 30/15 ratio were normal in all patients; Valsalva ratio was normal in all who finished the test (54.3%), but 31.4% could not conclude it due to breathing difficulties and incoordination, and all patients failed sustained handgrip because pain and fatigue occurred at <1 min.
  • Spectral analysis showed comparable heart rate variability between groups, but at rest JHS/EDS-HT patients had significantly higher baroreflex sensitivity than controls; the POTS subgroup had αLF+HF = 68.4 ± 41.3 ms/mmHg versus 35.5 ± 11.0 ms/mmHg in controls (P < 0.005), while non-POTS patients showed a non-significant increase (49.2 ± 29.6 ms/mmHg versus 35.5 ± 11.0 ms/mmHg).
  • Among the 22 patients who completed Valsalva, blood pressure increased between early phase II and late phase II and showed an overshoot in late phase IV; no significant differences were observed between patients with POTS and those without POTS/orthostatic hypotension.

Methods

  • Patients were selected from the Joint Hypermobility Outpatient Service at Umberto I University Hospital in Rome; JHS/EDS-HT diagnosis used Beighton score, Villefranche criteria, and Brighton criteria, with exclusion of diabetes, heart failure, severe arterial hypertension, cardiac arrhythmias, and medications affecting autonomic cardiovascular regulation.
  • Thirty-five JHS/EDS-HT adults underwent cardiovascular reflex tests comprising deep breathing, Valsalva maneuver, 30/15 ratio, sustained handgrip, and head-up tilt at 70° for up to 20 minutes, with continuous noninvasive blood pressure recording and beat-to-beat heart rate/blood pressure variability analysis.
  • Spectral analysis estimated low-frequency and high-frequency heart rate variability, blood pressure variability, and baroreflex sensitivity (α-index) at rest and during tilt; results were compared with 23 age- and sex-matched healthy controls using paired and unpaired t-tests, with P < 0.01 considered significant.

Limitations

  • The paper states that autonomic cardiovascular symptoms were not tested with a specific questionnaire (e.g., Composite Autonomic Scoring Scale), no correlation between clinical and instrumental results is present, the number of patients is reduced, and symptoms/tests were not reevaluated during the natural history of JHS/EDS-HT or after clinical/pharmacological therapies.
  • Evident from the text: all patients failed the sustained handgrip test, preventing collection of valid blood pressure values for that test, and a subset did not complete the Valsalva maneuver (31.4% in Results; the Abstract reports 37.2%), limiting assessment of sympathetic and parasympathetic reflex responses.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1155/2017/9161865

Cites

34 of 34 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 13 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In JHS/EDS-HT adults, POTS was present in 48.6% (17/35) at head-up tilt.

    “Seventeen (48.6%) met the criteria of POTS”
    • Also stated in: § 4. Discussion · hedged
      “we found POTS in ~50% JHS/EDS-HT patients”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.
  • Findingown data

    In JHS/EDS-HT adults, the Valsalva ratio was normal in all patients who completed the test.

    “Valsalva ratio was also normal in all patients who finished the test (54.3%)”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.
  • Findingown data

    Non-POTS JHS/EDS-HT patients showed a slight but not statistically significant increase in baroreflex sensitivity compared to controls.

    “non-POTS patients showed a slight but not statistically significant increase of the BRS compared to controls (αLF + HF = 49.2 ± 29.6 ms/mmHg versus 35.5 ± 11.0 ms/mmHg in controls).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The age- and sex-matched healthy control subjects are free of autonomic dysfunction.
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.
  • Findingown data

    The higher baroreflex sensitivity at rest in JHS/EDS-HT is more marked in the subgroup of patients with POTS.

    “we observed a significant higher BRS in the JHS/EDS-HT group with POTS versus controls (αLF + HF = 68.4 ± 41.3 ms/mmHg in POTS versus 35.5 ± 11.0 ms/mmHg in controls, P < 0.005)”
    • Also stated in: § 4. Discussion · plain
      “this difference is more marked in the subgroup of patients with POTS”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The age- and sex-matched healthy control subjects are free of autonomic dysfunction.
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.
  • Findingown data

    In JHS/EDS-HT adults, orthostatic hypotension was rare, present in only one patient (3%).

    “Only one (3%) had OH while a normal pressure response was observed in the other 34 (97%).”
    • Also stated in: § 4. Discussion · plain
      “OH, as a genuine form of autonomic failure, was rare in our sample.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.
  • May combine two claims. 5
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    All JHS/EDS-HT adults failed to complete the sustained handgrip test because pain and fatigue occurred in the early stage (<1 min), preventing valid BP values.

    “All patients failed to complete the sustained handgrip test, because pain and fatigue occurred in the early stage of the text (<1 min), and this did not allow the collection of valid BP values.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.

  • May combine two claims.

    Findingown data

    Among JHS/EDS-HT patients who completed the Valsalva maneuver, the increase of BP between early phase II and late phase II and the overshoot in late phase IV were observed.

    “Among the 22 patients that completed the Valsalva maneuver, the increase of BP between early phase II and late phase II and the overshoot in late phase IV were observed (Table 2).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Potentially overlapping disorders were excluded on clinical and, if needed, molecular grounds.

    “partially overlapping disorders were excluded on clinical and, if needed, molecular grounds as detailed elsewhere [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] source

      Not checked in the free run.

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

    Premisecitation

    Resting heart rate is influenced by exercise.

    “The resting HR seems to be influenced by exercise.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] 1982, Journal of Applied Physiology Respiratory Environmental and Exercise Physiology

      Not checked in the free run.

    • cites [33] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductnone given

    None of the patients had diabetes, heart failure, severe arterial hypertension, or cardiac arrhythmias, nor had any medications that might influence autonomic cardiovascular regulation.

    “None of the patients had diabetes, heart failure, severe arterial hypertension, or cardiac arrhythmias, nor had any medications that might influence autonomic cardiovascular regulation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cardiac remodeling and blood volume expansion associated with exercise training increase physical fitness and improve performance in POTS patients.

    “cardiac remodeling and blood volume expansion associated with exercise training increase physical fitness and improve performance in these patients [31]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Spectral analysis is a noninvasive tool for evaluating the neural mechanisms controlling HR and BP.

    “Spectral analysis is a noninvasive tool for evaluating the neural mechanisms controlling HR and BP [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 1996, Circulation source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    All patients underwent a full cardiovascular evaluation to exclude preexisting cardiovascular disease not linked to the underlying genetic disorder.

    “To exclude potentially preexisting cardiovascular disease not linked to the underlying genetic disorder, all patients underwent a full cardiovascular evaluation comprising complete history and physical examination, 12-lead electrocardiogram (ECG), 24 H Holter, hematocrit, and echocardiogram.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Autonomic cardiovascular symptoms were not tested using a specific questionnaire (e.g., the Composite Autonomic Scoring Scale).

    “autonomic cardiovascular symptoms are not tested using specific questionnaire (e.g., the Composite Autonomic Scoring Scale)”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Symptoms and tests have not been reevaluated during the natural history of JHS/EDS-HT to analyze possible variations or response to therapies.

    “symptoms and tests have not been reevaluated during the natural history of the JHS/EDS-HT in order to analyze possible variations or the response to clinical and pharmacological therapies.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Heart rate and blood pressure variability series were calculated according to the HR variability guidelines.

    “The HR and BP beat-to-beat variability series were calculated according to the HR variability (HRV) guidelines [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] 1996, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During acute exercise, POTS patients have excessive increases in BP and reduced stroke volume at absolute workload compared to sedentary controls without intrinsic abnormality of HR regulation.

    “it has been demonstrated that, during acute exercise, POTS patients have excessive increases in BP and reduced stroke volume at absolute workload compared to sedentary controls without intrinsic abnormality of HR regulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Stiffness of the large elastic arteries with baroreceptors could be associated with a decrease in baroreflex sensitivity.

    “stiffness of the large elastic arteries with baroreceptors (i.e., carotid artery, the aortic arch) could be associated with a decrease in BRS [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] source

      Not checked in the free run.

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

    Study design and conductnone given

    No correlation between clinical and instrumental results is present.

    “no correlation between clinical and instrumental results is present”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The number of patients is reduced.

    “the number of patients is reduced”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    In neuropathic POTS, the phase IV overshoot of the Valsalva maneuver is lower than in controls.

    “In this category of POTS the phase IV overshoot of the Valsalva maneuver is lower than controls”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

      Not checked in the free run.

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

    Premisecitation

    The presence of small fiber neuropathy could identify a clinical subgroup of POTS (neuropathic POTS).

    “the presence of small fiber neuropathy could identify a clinical subgroup of POTS (a.k.a. “neuropathic” POTS) [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

      Not checked in the free run.

17 of 17

  • The paper relies on this without support.

    The age- and sex-matched healthy control subjects are free of autonomic dysfunction.

    “Results were compared with those obtained in a group of 23 age- and sex-matched healthy subjects who underwent the same HUT-test protocol.”

  • The paper relies on this without support.

    The JHS/EDS-HT patients included are representative of the broader JHS/EDS-HT adult population.

    “Thirty-five patients (6 men and 29 women, mean age of 35 ± 14 years) with JHS/EDS-HT were included.”
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?

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.

  • Conflicting Valsalva noncompletion rates

    Major

    The abstract reports that 37.2% could not finish the Valsalva test, while the results section reports 31.4% for the same outcome.

  • Valsalva completion percentage does not match the count

    Minor

    The paper reports 35 patients and says 22 completed the Valsalva maneuver. That is 62.9%, not the reported 54.3%.

    Reported 54.3 · recomputed 62.857143

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. 2000, Journal of Rheumatology, 27, 1777
  2. 2011, Clinical and Experimental Rheumatology, 29, 998
  3. 10.1007/s11910-015-0583-8 · DOI · Paper page
  4. 1988, Recent advances in the non invasive investigation of diabetic autonomic neuropathy, 667
  5. 1982, Journal of Applied Physiology Respiratory Environmental and Exercise Physiology, 52, 1652

Cited by

Sorted by citations

Related

Authors
Celletti, C., Camerota, F., Castori, M., Censi, F., Gioffrè, L., Calcagnini, G., & Strano, S.
Affiliations
  • Policlinico Umberto I (IT)
  • Azienda Ospedaliera San Camillo-Forlanini (IT)
  • Istituto Superiore di Sanità (IT)
  • Sapienza University of Rome (IT)
Corresponding author
Celletti, Claudia
ORCID
Venue
BioMed Research International
Publisher
Wiley
Published
2017
Volume
2017
Pages
1-7
ISSN
  • 1110-7243 (ISSN-L)
  • 2314-6133
  • 2314-6141
DOI
10.1155/2017/9161865
PMC
PMC5329674
OpenAlex
W2587456375
Semantic Scholar
8d020d93d83405bbb44063390d1eae61f945f655
Cited by
62
References
34
Citations by year
2026: 9 · 2025: 11 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 9 · 2020: 13 · 2019: 4 · 2018: 6
FWCI
6.45
Type
journal article
Language
en
Open access
Licence
Locations
  • BioMed Research International (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Topics
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords
joint hypermobility syndrome, Ehlers-Danlos syndrome hypermobility type, postural orthostatic tachycardia syndrome, orthostatic intolerance, autonomic dysfunction, cardiac autonomic function, baroreflex sensitivity, heart rate variability, blood pressure variability, Valsalva maneuver, head-up tilt, connective tissue diseases
MeSH terms
Adult, Autonomic Nervous System Diseases, Ehlers-Danlos Syndrome, Female, Humans, Joint Instability, Male, Middle Aged, Baroreflex, Hand Strength, Neurodegenerative Diseases, Postural Orthostatic Tachycardia Syndrome

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