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      Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome

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          Abstract

          Background

          Both the adrenergic and renin‐angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome ( POTS). Activating autoantibodies to the α1‐adrenergic and β1/2‐adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor ( AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS.

          Methods and Results

          Serum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and α1‐adrenergic receptor.

          Conclusions

          Most patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS.

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          Most cited references22

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          2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.

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            Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.

            Postural tachycardia syndrome (POTS) is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. POTS manifests with symptoms of cerebral hypoperfusion and excessive sympathoexcitation. The pathophysiology of POTS is heterogeneous and includes impaired sympathetically mediated vasoconstriction, excessive sympathetic drive, volume dysregulation, and deconditioning. POTS is frequently included in the differential diagnosis of chronic unexplained symptoms, such as inappropriate sinus tachycardia, chronic fatigue, chronic dizziness, or unexplained spells in otherwise healthy young individuals. Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity. The aims of evaluation in patients with POTS are to exclude cardiac causes of inappropriate tachycardia; elucidate, if possible, the most likely pathophysiologic basis of postural intolerance; assess for the presence of treatable autonomic neuropathies; exclude endocrine causes of a hyperadrenergic state; evaluate for cardiovascular deconditioning; and determine the contribution of emotional and behavioral factors to the patient's symptoms. Management of POTS includes avoidance of precipitating factors, volume expansion, physical countermaneuvers, exercise training, pharmacotherapy (fludrocortisone, midodrine, β-blockers, and/or pyridostigmine), and behavioral-cognitive therapy. A literature search of PubMed for articles published from January 1, 1990, to June 15, 2012, was performed using the following terms (or combination of terms): POTS; postural tachycardia syndrome, orthostatic; orthostatic; syncope; sympathetic; baroreceptors; vestibulosympathetic; hypovolemia; visceral pain; chronic fatigue; deconditioning; headache; Chiari malformation; Ehlers-Danlos; emotion; amygdala; insula; anterior cingulate; periaqueductal gray; fludrocortisone; midodrine; propranolol; β-adrenergic; and pyridostigmine. Studies were limited to those published in English. Other articles were identified from bibliographies of the retrieved articles. Copyright © 2012 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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              Autoimmune Basis for Postural Tachycardia Syndrome

              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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                Author and article information

                Contributors
                david-kem@ouhsc.edu
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                04 April 2018
                17 April 2018
                : 7
                : 8 ( doiID: 10.1002/jah3.2018.7.issue-8 )
                : e008351
                Affiliations
                [ 1 ] Department of Medicine University of Oklahoma Health Sciences Center and VA Medical Center Oklahoma City OK
                [ 2 ] Department of Pediatrics University of Oklahoma Health Sciences Center Oklahoma City OK
                [ 3 ] Department of Cardiac Sciences Libin Cardiovascular Institute of Alberta University of Calgary Alberta Canada
                [ 4 ] Department of Medicine Autonomic Dysfunction Center Vanderbilt University Nashville TN
                [ 5 ] Department of Clinical Sciences Lund University Lund Sweden
                [ 6 ] Department of Cardiology Skåne University Hospital Malmö Sweden
                Author notes
                [*] [* ] Correspondence to: David C. Kem, MD, 1000 N Lincoln Blvd, Ste 2900, Oklahoma City, OK 73104. E‐mail: david-kem@ 123456ouhsc.edu
                [†]

                Dr Yu, Dr Fedorowski, and Dr Kem are co–senior authors.

                Article
                JAH33118
                10.1161/JAHA.117.008351
                6015435
                29618472
                2564b3a5-9363-441c-a7c7-62755f7d1541
                © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 14 December 2017
                : 27 February 2018
                Page count
                Figures: 4, Tables: 1, Pages: 7, Words: 4962
                Funding
                Funded by: National Institutes of Health
                Award ID: R01HL128393
                Funded by: Dysautonomia International
                Funded by: American Heart Association
                Funded by: Will and Helen Webster
                Funded by: Swedish Heart and Lung Foundation
                Funded by: Medical Faculty of Lund University, Region Skåne
                Funded by: Crafoord Foundation
                Funded by: Eva and Carl‐Eric Larsson Foundation
                Categories
                Original Research
                Original Research
                Arrhythmia and Electrophysiology
                Custom metadata
                2.0
                jah33118
                17 April 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.4 mode:remove_FC converted:17.04.2018

                Cardiovascular Medicine
                angiotensin ii type 1 receptor,autoimmunity,autonomic nervous system,postural orthostatic tachycardia syndrome,vasoconstriction,arrhythmias,ace/angiotension receptors/renin angiotensin system,translational studies

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