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Cited by 151Cardiovascular Syncope and Autonomic DisordersHeart Rate Variability and Autonomic ControlAutoimmune Neurological Disorders and Treatments

Antiadrenergic autoimmunity in postural tachycardia syndrome

Open access
Fedorowski, Artur, Li, Hongliang, Yu, Xichun, Koelsch, Kristi A., Harris, Valerie M., Liles, Campbell, Murphy, Taylor A., Quadri, Syed M. S. +4 more·2017·EP Europace
DOI 10.1093/europace/euw154PMC PMC5834103
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Abstract

AIMS: Postural tachycardia syndrome (POTS), a common and debilitating cardiovascular disorder, is characterized by an exaggerated heart rate increase during orthostasis and a wide spectrum of adrenergic-related symptoms. To determine the aetiology of POTS, we examined a possible pathophysiological role for autoantibodies against α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR). METHODS AND RESULTS: Immunoglobulin G (IgG) derived from 17 POTS patients, 7 with recurrent vasovagal syncope (VVS), and 11 normal controls was analysed for its ability to modulate activity and ligand responsiveness of α1AR and β1/2AR in transfected cells and to alter contractility of isolated rat cremaster arterioles in vitro. Immunoglobulin G activation of α1AR and β1/2AR was significantly higher in POTS compared with VVS and controls in cell-based assays. Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. Eight of 17 POTS IgG decreased the α1AR responsiveness to phenylephrine and 13 of 17 POTS IgG increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. Postural tachycardia syndrome IgG contracted rat cremaster arterioles, which was reversed by α1AR blockade. The upright heart rate correlated with IgG-mediated β1AR and α1AR activity but not with β2AR activity. CONCLUSION: These data confirm a strong relationship between adrenergic autoantibodies and POTS. They support the concept that allosteric-mediated shifts in the α1AR and β1AR responsiveness are important in the pathophysiology of postural tachycardia.

AI snapshot

Written from the paper’s full text.

TL;DR

IgG from patients with postural tachycardia syndrome (POTS) showed higher direct activation of α1-adrenergic and β1/2-adrenergic receptors than IgG from recurrent vasovagal syncope (VVS) patients or healthy controls, and also altered receptor responsiveness to phenylephrine and isoproterenol. These antiadrenergic autoantibody effects correlated with upright heart rate and support an autoimmune contribution to POTS pathophysiology.

Key findings

  • Among 17 POTS patients, direct receptor activation was found in 8/17 for α1AR (47%), 11/17 for β1AR (65%), and 12/17 for β2AR (71%); none of these autoantibodies were found in VVS patients or healthy controls.
  • Mean autoantibody activity was significantly higher in POTS than in VVS and controls for α1AR (0.31 ± 0.07 vs. 0.24 ± 0.04 and 0.23 ± 0.04; P=0.029 and 0.004), β1AR (1840 ± 186 vs. 1578 ± 117 and 1608 ± 127; P=0.002 and 0.001), and β2AR (1104 ± 230 vs. 816 ± 73 and 837 ± 72; P=0.007 and 0.001).
  • POTS IgG decreased phenylephrine-induced α1AR activation in 8/17 patients and increased isoproterenol-induced β1AR activation in 13/17 patients; 13/17 POTS IgG also increased contractility in isolated rat cremaster arterioles, which was reversed by α1AR blockade with phentolamine.
  • Upright heart rate correlated with IgG-mediated β1AR activity (3 min P=0.0009; maximal P=0.0006) and α1AR activity (maximal P=0.039), but not with β2AR activity (P=0.11).

Methods

  • Case-control functional study using serum IgG from 17 POTS patients (16 females; age 26 ± 9 years), 7 recurrent VVS patients (5 females; age 31 ± 9 years), and 11 healthy controls (10 females; age 31 ± 6 years) recruited from the SYSTEMA cohort in Malmö, Sweden.
  • IgG was tested in cell-based assays for α1AR activation (FRET β-lactamase reporter in α1AR-NFAT-bla CHO-K1 cells) and β1AR/β2AR activation (cAMP Hunter eXpress GPCR assay in transfected CHO cells), with blockade by prazosin or propranolol, and in an isolated rat cremaster arteriole contractility assay with phentolamine.
  • Group comparisons used Student’s t-test, one-way ANOVA with Tukey post hoc, Pearson’s χ2, and linear regression; autoantibody positivity was defined as above mean + 2SD or below mean − 2SD of controls.

Limitations

  • The paper states that parasympathetic tonus was not assessed during head-up tilt and that possible autoantibodies against muscarinic receptors and/or the acetylcholine system were not investigated.
  • The paper states that study groups were not strictly age matched, although the age difference was not significant.
  • Evident from the text: the study has small group sizes (17 POTS, 7 VVS, 11 controls), and the authors note that the cremaster arteriolar bioassay is not suitable for large numbers of samples.

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

Integrity signals

Registry

Crossref · 10.1093/europace/euw154

Cites

21 of 21 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Eight of 17 POTS patients possessed autoantibodies that activated α1AR.

    “Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively.”
    • Also stated in: § Autoantibody activity · plain
      “Among the 17 patients with POTS, 8, 11, and 12 showed direct activation of α1AR (47%), β1AR (65%), and β2AR (71%), respectively”
    Quote in the paperSubstantial claim
  • Findingown data

    Twelve of 17 POTS patients possessed autoantibodies that activated β2AR.

    “Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively.”
    • Also stated in: § Autoantibody activity · plain
      “Among the 17 patients with POTS, 8, 11, and 12 showed direct activation of α1AR (47%), β1AR (65%), and β2AR (71%), respectively”
    Quote in the paperSubstantial claim
  • Findingown data

    In POTS patients, IgG activation of β2AR was significantly higher than in VVS patients and healthy controls in cell-based assays.

    “β2AR: POTS 1104 ± 230 vs. VVS 816 ± 73 and control 837 ± 72, P= 0.007 and 0.001, respectively”
    Quote in the paperSubstantial claim
  • Findingown data

    In POTS patients, IgG activation of β1AR was significantly higher than in VVS patients and healthy controls in cell-based assays.

    “β1AR: POTS 1840 ± 186 vs. VVS 1578 ± 117 and control 1608 ± 127, P= 0.002 and 0.001, respectively”
    Quote in the paperSubstantial claim
  • Findingown data

    Eleven of 17 POTS patients possessed autoantibodies that activated β1AR.

    “Eight, 11, and 12 of the 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively.”
    • Also stated in: § Autoantibody activity · plain
      “Among the 17 patients with POTS, 8, 11, and 12 showed direct activation of α1AR (47%), β1AR (65%), and β2AR (71%), respectively”
    Quote in the paperSubstantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    β1/2AR autoantibody activity was increased in POTS but not in VVS.

    “β1/2AR autoantibody activity was increased in POTS but not in VVS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IgG-mediated β1AR activity was strongly correlated with both 3 min upright heart rate (P=0.0009) and maximal upright heart rate (P=0.0006).

    “In the linear regression analysis, IgG-mediated β1AR activity was strongly correlated with both 3 min (P= 0.0009) and maximal upright heart rate (P= 0.0006), whereas the latter was also correlated with α1AR activity (P= 0.039) but not with β2AR activity (P= 0.11).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither the phenylephrine nor the isoproterenol response curve shift was observed using control IgG.

    “Neither shift was observed using control IgG.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Serum from subjects with POTS contains circulating autoantibodies, some with a direct stimulatory effect on adrenergic receptors.

    “We have demonstrated that serum from subjects with POTS contains circulating autoantibodies, some with a direct stimulatory effect on adrenergic receptors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no significant difference in mean α1AR, β1AR, and β2AR autoantibody activities between VVS and control groups.

    “There was no significant difference between the latter two groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    POTS IgG significantly decreased phenylephrine-induced α1AR activation (0.13 ± 0.02) compared with phenylephrine alone (0.18 ± 0.03, P<0.0036) and compared with IgG from normal controls (0.17 ± 0.02, P<0.0005).

    “There was a significant decrease in phenylephrine-induced α1AR activation with POTS IgG (0.13 ± 0.02) compared with phenylephrine alone (0.18 ± 0.03, P< 0.0036) or IgG from normal controls (0.17 ± 0.02, P< 0.0005) (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither systolic nor diastolic blood pressure was correlated with adrenergic receptor stimulation.

    “Neither SBP nor DBP were correlated with adrenergic receptor stimulation.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Number of syncope episodes did not differ between POTS and VVS patients.

    “The VVS group reported a longer history of syncopal symptoms (P= 0.017), but the number of syncope episodes, proportions of characteristic precipitating symptoms, and self-reported dizziness on standing did not differ between POTS and VVS patients.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    POTS IgG significantly increased isoproterenol-stimulated β1AR activation (1835 ± 309) compared with isoproterenol alone (1479 ± 86, P<0.037) and compared with IgG from normal controls (1508 ± 80, P<0.032).

    “The isoproterenol-stimulated β1AR activation, on the other hand, was significantly increased with POTS IgG (1835 ± 309) compared with isoproterenol alone (1479 ± 86, P< 0.037) or IgG from normal controls (1508 ± 80, P< 0.032) (Figure 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was some overlap for the α1AR and considerable overlap for the β1AR with the other tests.

    “There was some overlap for the α1AR and considerable overlap for the β1AR with the other tests (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For the primary objective, antiadrenergic α1AR autoantibody activity was evident in POTS, while VVS subjects were not different from normal subjects.

    “For the primary objective, we found that antiadrenergic α1AR autoantibody activity was evident in POTS, while the VVS subjects were not different from normal subjects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the presence of POTS IgG, the phenylephrine response curve was shifted to the right, indicating a decreased α1AR response.

    “In the presence of POTS IgG, the phenylephrine response curve was shifted to the right, demonstrating a decreased α1AR response (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A majority of POTS IgG exerted an allosterically mediated positive modulatory effect upon β1AR and a negative modulatory effect on α1AR activity.

    “A majority also exerted an allosterically mediated positive modulatory effect upon β1AR and a negative modulatory effect on α1AR activity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The active α1AR autoantibodies inhibited the phenylephrine response and shifted the phenylephrine dosage response curve to the right.

    “As previously reported,8 these data confirmed the active α1AR autoantibodies inhibited the phenylephrine response and shifted the phenylephrine dosage response curve to the right.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Li, 2014, Autoimmune basis for postural tachycardia syndrome, J Am Heart Assoc source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    β1AR autoantibodies enhanced the isoproterenol response and shifted the isoproterenol dosage response curves to the left.

    “Moreover, β1AR autoantibodies enhanced the isoproterenol response and most importantly shifted the isoproterenol dosage response curves to the left, confirming our previous observations.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Li, 2014, Autoimmune basis for postural tachycardia syndrome, J Am Heart Assoc source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The β1AR effect was opposite to the α1AR effect and shifted the β1AR agonist dosage response curve to the left.

    “In contrast, the β1AR effect was just the opposite and shifted the β1AR agonist dosage response curve to the left.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Since the pathophysiological basis for POTS is unclear, therapeutic interventions are empirical.

    “Since the pathophysiological basis for POTS is unclear, therapeutic interventions are empirical.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The cremaster arteriole procedure was approved by the Oklahoma University Health Sciences Center Institutional Animal Care and Use Committee.

    “This procedure was approved by the Oklahoma University Health Sciences Center Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Treatment options for POTS have limited efficacy in the more severe forms and are often questioned.

    “A number of treatment options have been proposed in POTS but their efficacy in the more severe forms is limited and often questioned.2,7”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Sheldon, 2015, 2015 Heart Rhythm Society Expert Consensus Statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope, Heart Rhythm source

      Not checked in the free run.

    • cites [7] Fedorowski, 2013, Syndromes of orthostatic intolerance: a hidden danger, J Intern Med source

      Not checked in the free run.

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

    Study design and conductnone given

    All samples were assayed in triplicate.

    “All samples were assayed in triplicate.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Receipt and assay of de-identified samples was approved by the University of Oklahoma Health Sciences Center Institutional Review Board.

    “Receipt and assay of these de-identified samples was approved by the University of Oklahoma Health Sciences Center Institutional Review Board.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Mean age for POTS patients was not significantly different from VVS and control subjects.

    “The mean age for the POTS patients was not significantly different from those with VVS and control subjects.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Digital test records were inspected off-line to ascertain the accuracy of diagnoses.

    “In order to ascertain the accuracy of diagnoses, the digital test records were subsequently inspected off-line using Nexfin@PC (BMEYE, Amsterdam, the Netherlands), dedicated software provided by the manufacturer.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Li et al. reported that activating autoantibodies to α1AR and β1/2AR might play a pathophysiological role in POTS.

    “Li et al. recently reported that activating autoantibodies (AAb) to the α1-adrenergic (α1AR) and β1/2-adrenergic receptors (β1/2AR) might play a pathophysiological role in POTS.8”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Li, 2014, Autoimmune basis for postural tachycardia syndrome, J Am Heart Assoc source

      Not checked in the free run.

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

    Study design and conductown data

    Negative and positive controls were included in each assay.

    “Negative (buffer) and positive (phenylephrine) controls were included in each assay.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    POTS onset may follow an acute infection or vaccination but more commonly appears without antecedent causative events.

    “Its onset may follow an acute infection or vaccination but more commonly appears without antecedent causative events.2,6”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Sheldon, 2015, 2015 Heart Rhythm Society Expert Consensus Statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope, Heart Rhythm source

      Not checked in the free run.

    • cites [6] Brinth, 2015, Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus, Vaccine source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    POTS and VVS diagnoses were confirmed by clinical history and tilt testing.

    “Within the SYSTEMA cohort, we randomly selected 17 patients with a confirmed diagnosis, by clinical history and tilt testing, of POTS (16 females; age, 26 ± 9 years), and 7 with recurrent VVS (5 females; age: 31 ± 9 years).”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study protocol was approved by the Regional Ethical Review Board in Lund, Sweden, and all participants gave written informed consent.

    “The Regional Ethical Review Board in Lund, Sweden approved the study protocol (ref no 82/2008), and all study participants gave their written informed consent including serum analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    These and possibly other yet-to-be identified immunoglobulins with different target epitopes may exert varying biological effects in particular patients, which may explain different constellations of symptoms in POTS.

    “These and possibly other yet-to-be identified immunoglobulins with different target epitopes may exert varying biological effects in particular patients, which may explain different constellations of symptoms in POTS.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Patients were randomly selected from the SYSTEMA cohort.

    “Within the SYSTEMA cohort, we randomly selected 17 patients with a confirmed diagnosis, by clinical history and tilt testing, of POTS (16 females; age, 26 ± 9 years), and 7 with recurrent VVS (5 females; age: 31 ± 9 years).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study groups were not strictly age matched, although the age difference was not significant.

    “Finally, the study groups were not strictly age matched, although the age difference was not significant.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The catecholamine surge may be seen as a compensatory mechanism to override the α1AR malfunction associated with the proposed autoimmune blockade as present in POTS patients, but this explanation is unlikely in those with recurrent VVS.

    “The catecholamine surge may be seen as a compensatory mechanism to override the α1AR malfunction associated with the proposed autoimmune blockade as present in POTS patients but this explanation is unlikely in those with recurrent VVS.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    This report more than doubles the number of the group's previous observations and focuses on a tightly characterized group of patients and controls.

    “This report more than doubles the number of our previous observations, and focuses on a tightly characterized group of patients and controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationnone given

    Diagnostic criteria based on measuring the autoantibodies' impact on an allosteric-mediated receptor response to the natural ligand may provide a more favourable estimate of autoantibody involvement in the complex pathophysiology of POTS.

    “Diagnostic criteria based on measuring the autoantibodies' impact on an allosteric-mediated receptor response to the natural ligand may provide a more favourable estimate of autoantibody involvement in the complex pathophysiology of POTS.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The cremaster arteriolar bioassay is not suitable for use in large numbers of samples, and the specific cell-based assays are an improvement with regard to numbers.

    “This cremaster arteriolar bioassay is not suitable for use in large numbers of samples and the specific cell-based assays are an improvement with regard to numbers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The high percentage of POTS subjects examined by the group present with an apparent autoimmune diathesis that supports the concept that these autoantibodies play an important role in the pathophysiology of POTS.

    “It seems apparent that the high percentage of POTS subjects examined by our group present with an apparent autoimmune diathesis that supports the concept that these autoantibodies play important role in the pathophysiology of this entity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: There is a paucity of concrete evidence for other pathophysiological bases for POTS for the vast majority of patients.

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

    Interpretationcitation

    Vagal drive may have an important implication in related POTS symptomatology.

    “The vagal drive may have an important implication in related POTS symptomatology.20”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Yoshida, 2014, Variant cardiovascular regulation in children with postural tachycardia syndrome, Pediatr Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both POTS and IST share an abnormal sinus tachycardia tendency, and differ in regard to resting heart rate control that is usually preserved in POTS but not in IST.

    “Both POTS and IST share abnormal sinus tachycardia tendency, and differ in regard to resting heart rate control that is usually preserved in POTS but not in IST.2”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Sheldon, 2015, 2015 Heart Rhythm Society Expert Consensus Statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope, Heart Rhythm source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This spectrum would range from subclinical to overt expressions that may overlap with other entities such as inappropriate sinus tachycardia (IST), where circulating antibodies against cardiac β-receptors have been previously reported.

    “This spectrum would certainly range from subclinical to overt expressions that may overlap with other entities such as inappropriate sinus tachycardia (IST), where circulating antibodies against cardiac β-receptors have been previously reported.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Chiale, 2006, Inappropriate sinus tachycardia may be related to an immunologic disorder involving cardiac beta andrenergic receptors, Heart Rhythm source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    The POTS patients selected from the SYSTEMA cohort are representative of POTS patients generally.

    “we planned to examine the AAb profile of a larger, well-characterized, and representative cohort of patients with POTS from an independent European institution whose selection was completely separate from the originating laboratory.”

  • The paper relies on this without support.

    There is a paucity of concrete evidence for other pathophysiological bases for POTS for the vast majority of patients.

    “Although it is likely that POTS has multiple causes, there has been a paucity of concrete evidence for other pathophysiological bases for an underlying pathophysiology to date for the vast majority of patients.”

  • The paper relies on this without support.

    The isolated rat cremaster arteriole assay is a valid measure of α1AR autoantibody-mediated contractile activity in POTS.

    “Immunoglobulin G (0.05 mg/mL) from each subject with POTS and 8 controls were tested for α1AR autoantibody-mediated contractile activity using an isolated rat cremaster arteriole assay.”
3 of 3

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?

  • Altered GPCR activity in people with POTS has been observed.

    “Although altered GPCR activity in people with POTS has been observed (Fedorowski et al., 2017”

    From Self-reported symptom burden in postural orthostatic tachycardia syndrome (POTS): A narrative review of observational and interventional studies (2023) · cites this paper as Fedorowski et al., 2017

  • Serum immunoglobulins isolated from POTS patients act as partial agonists to both α- and β-adrenergic receptors in vitro, a finding independently confirmed and expanded to a wider range of G-protein coupled receptors.

    “Serum immunoglobulins isolated from POTS patients have been reported to act as partial agonists to both α- and β-adrenergic receptors in vitro (Fedorowski et al., 2017; Li et al., 2014), a finding independently confirmed by several other groups (Vernino and Stiles, 2018) and expanded to include a wider range of G-protein coupled receptors (GPCRs) as targets (Kharraziha et al., 2020).”

    From Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health Expert Consensus Meeting - Part 1 (2021) · cites this paper as Fedorowski et al., 2017

  • Higher levels of autoantibodies against beta-1 and beta-2 adrenoreceptors have been detected in POTS patients versus healthy controls in serologic studies.

    “Higher levels of autoantibodies against beta-1 and beta-2 adrenoreceptors have been detected in POTS patients versus healthy controls in serologic studies (32, 44).”

    From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [44]

  • Autoantibody affinity toward beta-receptors positively correlated with a greater degree of orthostatic tachycardia.

    “This group also demonstrated that autoantibody affinity toward beta-receptors positively correlated with a greater degree of orthostatic tachycardia (44).”

    From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [44]

  • Fedorowski et al. demonstrated that these autoantibodies, in addition to acting like a direct beta-agonist, can also upregulate sympathetic nervous activity through allosteric interactions with the beta-receptors.

    “Fedorowski et al. (44) demonstrated that these autoantibodies, in addition to acting like a direct beta-agonist, can also upregulate sympathetic nervous activity through allosteric interactions with the beta-receptors.”

    From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [44]

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.

  • POTS sex counts disagree

    Minor

    The Methods describe 16 female POTS patients among 17, whereas Table 1 lists 15 females and 2 males among 17.

  • Fewer than half showed the stated α1AR modulation

    Minor

    The Discussion says a majority exerted a negative modulatory effect on α1AR activity, but Table 2 reports that effect in only 8 of 17 POTS patients.

  • POTS age summary disagrees with Table 1

    Minor

    The Methods give the POTS group's age as 26 ± 9 years, but Table 1 gives 25 ± 7.

3 of 3

Cites

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1 of the 22 references couldn’t be matched to a known paper.

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Related

Authors
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.
Affiliations
  • Lund University (SE)
  • University of Oklahoma Health Sciences Center (US)
  • Oklahoma Medical Research Foundation (US)
  • Imperial College London (GB)
Corresponding author
Fedorowski, Artur
ORCID
Venue
EP Europace
Publisher
Oxford University Press (OUP)
Published
2016-10-04
Volume
19
Issue
7
Pages
1211-1219
ISSN
  • 1099-5129 (ISSN-L)
  • 1532-2092
DOI
10.1093/europace/euw154
PMC
PMC5834103
OpenAlex
W2528071726
Semantic Scholar
31fdba9a6b101b72fdc3c4780b2b82249e111255
Cited by
151
References
22
Citations by year
2026: 7 · 2025: 8 · 2024: 16 · 2023: 23 · 2022: 24 · 2021: 18 · 2020: 21 · 2019: 11 · 2018: 14 · 2017: 8
FWCI
12.18
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • EP Europace (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
Funders
  • U.S. Department of Veterans Affairs
  • American Heart Association
  • European Society of Cardiology
  • Lunds Universitet
  • Medical Research Council
  • National Heart, Lung, and Blood Institute (R01HL128393, R56HL128393)
  • National Institute of General Medical Sciences (U54GM104938)
Topics
  • Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
Keywords
postural orthostatic tachycardia syndrome, autoantibodies, adrenergic receptors, alpha1-adrenoceptors, beta1-adrenergic receptor, beta2-adrenergic receptor, vasovagal syncope, orthostatic intolerance, autonomic dysfunction
MeSH terms
Abdominal Muscles, Adolescent, Adult, Animals, Arterioles, Autoantibodies, Cricetulus, Dose-Response Relationship, Drug, Female, Humans, Immunoglobulin G, Male, Transfection, Vasoconstriction, Autoimmunity, Case-Control Studies, CHO Cells, Receptors, Adrenergic, alpha-1, Receptors, Adrenergic, beta-1, Receptors, Adrenergic, beta-2, Rats, Postural Orthostatic Tachycardia Syndrome, Young Adult, Adrenergic alpha-1 Receptor Agonists, Adrenergic beta-1 Receptor Agonists, Adrenergic beta-2 Receptor Agonists, In Vitro Techniques

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