Autoimmune Basis for Postural Tachycardia Syndrome
Open accessAbstract
BACKGROUND: Patients with postural tachycardia syndrome (POTS) have exaggerated orthostatic tachycardia often following a viral illness, suggesting autoimmunity may play a pathophysiological role in POTS. We tested the hypothesis that they harbor functional autoantibodies to adrenergic receptors (AR). METHODS AND RESULTS: Fourteen POTS patients (7 each from 2 institutions) and 10 healthy subjects were examined for α1AR autoantibody-mediated contractility using a perfused rat cremaster arteriole assay. A receptor-transfected cell-based assay was used to detect the presence of β1AR and β2AR autoantibodies. Data were normalized and expressed as a percentage of baseline. The sera of all 14 POTS patients demonstrated significant arteriolar contractile activity (69±3% compared to 91±1% of baseline for healthy controls, P<0.001) when coexisting β2AR dilative activity was blocked; and this was suppressed by α1AR blockade with prazosin. POTS sera acted as a partial α1AR antagonist significantly shifting phenylephrine contractility curves to the right. All POTS sera increased β1AR activation (130±3% of baseline, P<0.01) and a subset had increased β2AR activity versus healthy subjects. POTS sera shifted isoproterenol cAMP response curves to the left, consistent with enhanced β1AR and β2AR agonist activity. Autoantibody-positive POTS sera demonstrated specific binding to β1AR, β2AR, and α1AR in transfected cells. CONCLUSIONS: POTS patients have elevated α1AR autoantibodies exerting a partial peripheral antagonist effect resulting in a compensatory sympathoneural activation of α1AR for vasoconstriction and concurrent βAR-mediated tachycardia. Coexisting β1AR and β2AR agonistic autoantibodies facilitate this tachycardia. These findings may explain the increased standing plasma norepinephrine and excessive tachycardia observed in many POTS patients.
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Autoantibodies to cardiovascular G protein-coupled membrane receptors are a particular focus of research, but their role in the pathophysiology of POTS is still unclear.
“Autoantibodies to cardiovascular G protein–coupled membrane receptors is a particular focus of research, but their role in the pathophysiology of POTS is still unclear.35”
From Diagnosis and management of postural orthostatic tachycardia syndrome (2022) · cites this paper as [35]
The Results and Discussion examine autoantibodies to cardiovascular G protein–coupled receptors in POTS and propose how they could contribute to tachycardia. The Discussion calls the pathophysiological mechanism a hypothesis, but also says the data support an autoimmune pathophysiology; it does not characterize the autoantibodies’ role as simply unclear. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCompensatory sympathetic activation to maintain adequate vasoconstriction could induce tachycardia via β-ARs, and β1-AR- and β2-AR-activating autoantibodies could also contribute to tachycardia.
“Compensatory sympathetic activation to maintain adequate vasoconstriction could then induce tachycardia via β-ARs. β1-AR- and β2-AR-activating autoantibodies could also contribute to the tachycardia.”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [57]
Li et al. presented evidence from two cohorts of POTS patients for α1 adrenergic receptor autoantibodies acting as partial peripheral receptor antagonists.
“Recently, Li et al. [57] presented evidence from two cohorts of POTS patients for α1 adrenergic receptor (AR) autoantibodies acting as partial peripheral receptor antagonists.”
From Postural tachycardia syndrome: beyond orthostatic intolerance (2015) · cites this paper as [57]
Evidence of autoantibodies that act as partial alpha-1 antagonists has been found in POTS patients.
“Evidence of autoantibodies that act as partial alpha-1 antagonists have also been found in POTS patients (32).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [32]
These autoantibodies could have an effect similar to a partial autonomic neuropathy due to inadequate vasoconstriction in response to alpha-adrenergic stimulation.
“These could have an effect similar to a partial autonomic neuropathy due to inadequate vasoconstriction in response to alpha-adrenergic stimulation ( Figure 1 ).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [32]
The binding of these autoantibodies to the adrenergic receptors is postulated to drive the tachycardia in some POTS patients.
“The binding of these autoantibodies to the adrenergic receptors is postulated to drive the tachycardia in some POTS patients (32).”
From Postural orthostatic tachycardia syndrome: mechanisms and new therapies (2020) · cites this paper as [32]
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 [32]
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”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
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.”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
The α1AR activity in the previous study was assayed using IgG in an arteriolar assay and not the present cell-based assay.
“The α1AR activity in our previous study was assayed using IgG in an arteriolar assay and not the present cell-based assay.”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
Nearly half of the POTS subjects had direct activation of the α1AR autoantibody activity.
“In contrast to our initial publication,8 nearly half of the POTS subjects had direct activation of the α1AR autoantibody activity.”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
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”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
These contrasting effects provide an appealing explanation for the cardiovascular effects associated with upright posture in those so afflicted.
“These contrasting effects provide an appealing explanation for the cardiovascular effects associated with upright posture in those so afflicted.1,8”
From Antiadrenergic autoimmunity in postural tachycardia syndrome (2017) · cites this paper as [8]
A specific focus has been on cardiovascular G-protein-coupled membrane complexes, including adrenergic, muscarinic, and angiotensin II type-1 receptors.
“A specific focus was given cardiovascular G-protein-coupled membrane complexes, such as adrenergic, muscarinic and angiotensin II type-1 receptors The symptoms of POTS, especially [43,45] (Fig. 1).”
From Postural orthostatic tachycardia syndrome: clinical presentation, aetiology and management (2019) · cites this paper as [43]
Emerging evidence suggests that some patients with IST have circulating autoantibodies to the beta-adrenergic receptor.
“Emerging evidence suggests that some patients with IST have circulating autoantibodies to the beta-adrenergic receptor.101”
From Sinus Tachycardia: a Multidisciplinary Expert Focused Review (2022) · cites this paper as [101]
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- Authors
- 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.
- Affiliations
- University of Oklahoma Health Sciences Center (US)
- University of Missouri (US)
- Vanderbilt University (US)
- ORCID
- Venue
- Journal of the American Heart Association
- Published
- 2014-01-27
- Volume
- 3
- Issue
- 1
- Pages
- e000755-e000755
- ISSN
- 2047-9980 (ISSN-L)
- PMC
- PMC3959717
- OpenAlex
- W2100637118
- Cited by
- 255
- References
- 28
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 23 · 2023: 20 · 2022: 38 · 2021: 28 · 2020: 36 · 2019: 15 · 2018: 25 · 2017: 18 · 2016: 14 · 2015: 11 · 2014: 4
- FWCI
- 15.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Journal of the American Heart Association (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR000445)
- U.S. Public Health Service (U26IHS300412)
- National Heart, Lung, and Blood Institute (R56HL056267, R01HL056267, R01HL102387)
- National Institute of General Medical Sciences (GM092238)
- National Institute of Neurological Disorders and Stroke (U54NS065736)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Cardiovascular Syncope and Autonomic Disorders
- Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- postural orthostatic tachycardia syndrome, autoantibodies, adrenergic receptors, beta1-adrenergic receptor, beta2-adrenergic receptor, orthostatic tachycardia, norepinephrine, viral illness
- MeSH terms
- Adrenergic Agonists, Adult, Animals, Autoantibodies, Autoimmune Diseases, Biological Assay, Cricetulus, Dose-Response Relationship, Drug, Female, Cricetinae, Heart Rate, Hemodynamics, Humans, Male, Middle Aged, Oklahoma, Receptors, Adrenergic, Tennessee, Transfection, Vasoconstriction, Vasodilation, Biomarkers, 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
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