Printer Friendly

Potential mechanisms of autonomic lnvolvement in subgroups of chronic fatigue syndrome patients.

Chronic fatigue syndrome (CFS) is a debilitating disease whose onset is often triggered by a flu-like illness. Signs and symptoms can include overwhelming fatigue, tremor, palpitations, and resting tachycardia. In some cohorts, there is postural orthostatic tachycardia syndrome (POTS) or orthostatic hypotension (OH), and in addition to autonomic dysfunction, there is also evidence of endocrine or cardiac involvement and possibly a genetic predisposition. In some CFS patients with a particular genetic predisposition, a virus may have triggered the development of autonomic dysfunction. Similar mechanisms to those in other diseases accompanied by autonomic dysfunction may play a role in CFS. Pursuing these could open up new avenues in CFS research.

Often CFS patients and approximately one-third of POTS patients have reported an infectious trigger. (1), (2) In one CFS study, "The onset of autonomic symptoms occurred within 4 weeks of a viral infection in 46% of patients. ... " (1) CFS patients also show evidence of a "heritable" predisposition. (3)

Human leukocyte antigens (HLA) play a role in the response to infection and the development of autoimmune diseases. Viruses can lead to the expression of HLA on tissues that do not normally express them like the thyroid in thyroiditis and the heart in myocarditis. (4), (5) In an animal model of virally induced myocarditis, "The development of inflammation takes place only in mice with a predisposing genetic background." (5)

Among HLA found in CFS, HLA-DR4 has been found in a cohort with evidence of viral reactivation. (6) HLA-DR4 has also been associated with risk of dilated cardiomyopathy (DCM), Hashimoto's thyroiditis (HT), and type 1 diabetes, with HLA-DR4 being "significantly more common" in familial cases of DCM. (5), (7-10)

In some CFS cohorts, endocrine findings include abnormal thyroid biopsies, autoantibodies to thyroid peroxidase (TPO), and genes indicating thyroid involvement. (11-13) Autonomic findings include POTS or OH. (14-18) Cardiac findings include cardiopulmonary exercise (CPX) test results described as similar to those of heart failure (HF) patients, evidence of left ventricle dysfunction and possibly dilation, and heart failure tied for one of the top three causes of death among CFS patients at a mean age of 58.7 years. (19-24)

An increased incidence of endocrine diseases had been found among CFS patients' family members. (25) In an unpublished CFS family medical history survey, patients frequently reported Hashimoto's thyroiditis and/or autonomic dysfunction in themselves and endocrine and/or cardiac involvement in family members. In families where the type of enlargement and failure was known, it was due to DCM.

Up to this point, findings thought to contribute to the POTS or OH in CFS include increases in norepinephrine (NE), decreases in hormones (renin, aldosterone, or antidiuretic hormone [ADI-11, a.k.a. arginine vasopressin) that affect the kidneys, hypovolemia, or an exaggerated response to acetylcholine (ACh) with prolonged vasod ilation. (14), (25-28) "Prolongation of ACh-induced vasodilation is suggestive of a disturbance to cholinergic pathways, perhaps within the vascular endothelium of patients with CFS, and might be related to some of the unusual vascular symptoms, such as hypotension and orthostatic intolerance (01), which are characteristic of the condition." (28)

In a CFS cohort predominantly made up of those with an infectious trigger, gene expression was tested before and after moderate exercise. Most patients had increases in gene expression for some adrenergic receptors and catechol-0-methyltransferase (COMT). (29) In a subgroup, who had decreases in gene expression for a-2A adrenergic receptors, the majority also had 01. (29) In adolescents with CFS, "CFS might be related to polymorphisms of COMT and the beta 2-adrenergic receptor." (30)

Autonomic dysfunction is often seen alongside cardiac and sometimes endocrine diseases. The autonomic dysfunction in CFS and in the diseases that run in CFS patients' families may potentially share some similar mechanisms.

Increased sympathetic activity, also known as a hyperadrenergic state, is seen in several CFS cohorts, POTS, many of the cardiac conditions, including DCM, and in some cases of diabetic autonomic neuropathy (DAN). (31-35) One potential mechanism involves changes in the norepinephrine transporter (NET). A decrease in the density or activity of NET has been linked to many of these same conditions. It has been found in some cases of 01, cardiac conditions (DCM, post myocardial infarction [MI], degenerative mitral valve prolapse [MVP], sustained ventricular fibrillation, arrhythmia), and possibly diabetes or DAN. (33-35) In addition, a mutation in NET has been found in a family with 01.(33) When researchers have used pharmaceutical agents to inhibit NET, they have reported results that resemble 01 with signs and symptoms that include fatigue, palpitations, headache, dry mouth, nausea, and urinary urgency. (36)

Another potential mechanism is through autoantibodies. In POTS patients, autoantibodies have been found to "cross-react with a wide range of cardiac proteins and may induce alterations in cardiac function." "Many of the proteins have previously been implicated in cardiac dysfunction or cardiac disease. ..." Of the 10 POTS patients studied, one had CFS plus fibromyalgia (FM), one had FM, and both had some of these autoantibodies.(37)

In OH, most patients had autoantibodies to at least one of the following receptors: beta 1 -adrenoceptors (B1 AR), beta 2-adrenoceptors (B2AR), muscarinic 2-recptors (M2R), or muscarinic 3-receptors (M3R); and 25% had more than one autoantibody. (38), (39) These autoantibodies may act as agonists, "causing or enhancing peripheral vasodi lation (mediated by B2AR and/or M3R activation) or inhibiting compensatory rise in pulse rate (M2R)." "These data support the concept that circulating agonistic autoantibodies serve as vasodilators and may cause or exacerbate orthostatic hypotension." (38) This team noted, in one study, 4/6 patients had other autoimmune diseases, and in another study, diabetics were included because autonomic dysfunction can occur in association with diabetes.(38), (39)

Autoantibodies to beta adrenergic receptors and/or muscarinic receptors have also been linked to some cases of DCM, Chagas, post MI, ischemic HF, atrial fibrillation, ventricular tachycardia, and DAN. (40), (41) In one study, over half the patients with ventricular arrhythmias had autoantibodies to beta 1- and beta 2-adrenoceptors. (41) In HLADR4 positive DCM patients, up to 72% had beta 1-adrenoreceptor autoantibodies. (7) In addition, in one study, 38.8% of DCM patients were found to have M2R autoantibodies.(42) In DCM, "A highly significant correlation was found between the presence of an ti m uscarin ic receptor-2 autoantibodies and anti-beta-adrenoceptor-1 autoantibodies in the patients' sera."(42)

In other diseases with autonomic dysfunction, researchers are looking at autoantibodies and the norepinephrine transporter, and looking into similar mechanisms could open up new research avenues in CFS as well.

(The autonomic nervous system is regulated by adrenergic and cholinergic receptors in the sympathetic and parasympathetic nervous systems respectively. Beta 1 -adrenoceptors and muscarinic 2 receptors primarily affect heart rate, and beta 2-adrenoceptors and muscarinic 3 receptors primarily affect blood pressure. In addition to these receptors, the NET and the enzymes catechol-O-methyltransferase [COMT] and monoamine oxidase [MAO] also influence adrenergic activity. If in the density or activity of the NET is decreased, and allows norepinephrine to stay in the synaptic space longer, or if there are lower levels or activity of the enzymes COMT or MAO, which would allow catecholamines to accumulate rather than be broken down, these could result in a hyperadrenergic state. Hormones [renin, aldosterone, ADH]b that affect the kidneys influence blood pressure through their effect on blood volume.)



(1.) Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am f Med. 1997;102(4):357-364.

(2.) Kimpinski K, Figueroa 1.1, Singer W, et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc. 2012;87(8):746-552. doi:10.1016/j. mayocp.2012.02.020.

(3.) Albright F, Light K, Light A, Bateman L, Cannon. Albright LA. Evidence for a heritable predisposition to chronic fatigue syndrome. BMC Neuro!. 2011;11:62. doi:10.1186/1471-2377-11-62.

(4.) Todd I, Pujol-Borrell R, Hammond LI, Bottazzo GF, Feldmann M. Interferon-gamma induces HLA-DR expression by thyroid epithelium. Clin Exp Immunol. 1985;61(21:265-273.

(5.) Caforio AL, Bonifacio E, Keeling 11, et al. Idiopathic dilated cardiomyopathy: a persistent viral infection or an organ-specific autoimmune disease? The trial of 2 major pathogenic hypotheses. C nal Cardiol. 1992;22(11:6372.

(6.) Keller RH, Lane JU, Klimas N, Reiter WM, Fletcher MA, van Riel F, Morgan R. Association between HLA class II antigens and the chronic fatigue immune dysfunction syndrome. Clin Infect Dis. 1994;18 Suppl 1:S154-S156.

(7.) Limas CI, Limas C, Kubo SH, Olivari MT. Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens. Am I Cardiol. 1990;65(7):483-487.

(8.) Baretic M. 100 years of Hashimoto thyroiditis, still an intriguing disease. Acta Med Croatica. 2011;65(5):453457.

(9.) MacDonald MJ, Gottschall J, Hunter J B, Winter KL. HLA-DR4 in insulin-dependent diabetic parents and their diabetic offspring: a clue to dominant inheritance. Proc Nati Acad Sci USA. 1986;83(18):7049-7053.

(10.) McKenna CJ, Codd MB, McCann HA, Sugrue DD. Idiopathic dilated cardiomyopathy: familial prevalence and HLA distribution. Heart. 1997;77(6):549-552.

(11.) Wikland B, Lowhagen T, Sandberg PO. Fine-needle aspiration cytology of the thyroid in chronic fatigue. Lancet. 2001;357(9260):956-957.

(12.) Hilgers A, Frank J. Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardiac changes. Wien Med Wochenschr. 1994;144(16):399-406.

(13.) Fuite J, Vernon SD, Broderick G. Neuroendocrine and immune network re-modeling in chronic fatigue syndrome: an exploratory analysis. Genomics. 2008;92(6):393-399.

(14.) Boneva RS, Decker MJ, Maloney EM, et al. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: a population-based study. Auto[much greater than] Neurosci. 2007;137(1-2):94-101.

(15.) Streeten DHP, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am I Med Sci. 2000;320(1):18.

(16.) Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. OJM. 2008;101(12):961-965.

(17.) Reynolds GK, Lewis DP, Richardson AM, Lidbury BA. Comorbidity of postural orthostatic tachycardia syndrome and chronic fatigue syndrome in an Australian cohort. Intern Med. 2013 doi:10.1111/j joim.12161.

(18.) Schondorf R, Benoit J, Wein T, Phaneuf, D. Orthostatic intolerance in the chronic fatigue syndrome. I Auton Nem Syst. 1999;75(2-3):192-201.

(19.) DeBecker P, Roeykens I, Reynders M, McGregor N, DeMeirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 2000;160(21):3270-3277.

(20.) Vanness JM, Snell CR, Strayer DR, Dempsey L IV, Stevens SR. Subclassifying chronic fatigue syndrome through exercise testing. Med Sci Sports &etc. 2003;35(6):908913.

(21.) Dworkin 1-1J, Lawrie C, Bohdiewicz P, Lemer AM. Abnormal left ventricular myocardial dynamics in eleven patients with chronic fatigue syndrome. Clin NIICI Med. 1994;19(8):675-677.

(22). Lerner AM, Zervos M, Dworkin FIL et al. New cardiomyopathy: pilot study of intravenous ganciclorvir in a subset of chronic fatigue syndrome. Infect Dis Clin Pract. 1997;6:1 10-117.

(23.) Jason LA, Corradi K, Gress S. Williams S, Torres-Harding S. Causes of death among patients with chronic fatigue syndrome. Health Care Women lot. 2006;27(7):615626.

(24.) Torres-Harding SR, Jason LA, Turkoglu OD. 'Family medical history of persons with chronic fatigue syndrome. / Chronic Fatigue Syndr. 2005;12(4):25-35.

(25.) De Lorenzo F, Hargreaves J, Kakkar W. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res. 1997;7(4)0 85-190.

(26.) Bakheit AM, Behan PO, Watson WS, Morton JJ. Abnormal arginine-vasopressin secretion and water metabolism in patients with postviral fatigue syndrome. Acta Neural Scand. 1993;87(3):234-238.

(27.) Farquhar WB, Hunt BE, Taylor IA, Darling SE, Freeman R. Blood volume and its relation to peak 02 consumption and physical activity in patients with chronic fatigue. Am Physiol Heart Circ Physiol. 2002;282;H66-H71.

(28.) Khan F, Spence V, Kennedy G, Belch JJ. Prolonged acetylcholine-induced vasodilation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Funct Imaging. 2003;23(5):282285.

(29.) Light AR, Bateman L, Jo D, et al. Gene expression alterations at baseline and following exercise in patients with chronic fatigue syndrome and fibromyalgia syndrome. I Intern Med. 2012;271(1):64-81. doi:10.1111/j.1365-2796.2011.02405.x.

(30.) Sommerfeldt L, Portilla H, Jacobsen L, Gjerstad J, Wyller VB. Polymorphisms of adrenergic cardiovascular control genes are associated with adolescent chronic fatigue syndrome. Acta Paediatr. 2011;100(2):293-298, doi:10.1111/0 651-2227.2010.02072.x.

(31.) Pagani M, Lucini D, Mela GS, Langewitz W, Malliani A. Sympathetic overactivity in subjects complaining of unexplained fatigue. Clin Sci (Lona 1994;87(6):655661.

(32.) Wyller VP, Saul JP, Amile JR, Thaulow E. Sympathetic predominance of cardiovascular regulation during mild orthostatic stress in adolescents with chronic fatigue. Clin Physiol Fund Imaging. 2007;27:231-238.

(33.) Robertson D, Flattem N, Tellioglu T, et al. Familial orthostatic tachycardia due to norepinephrine transporter deficiency. Ann N Y Acad Sci. 2001;940:527-543.

(34.) Bohm M, La Rosee K, Schwinger RH, Erdmann E. Evidence for reduction of norepinephrine uptake sites in the failing human heart. / Am Coll Cardiol. 1995;25(1):146-153.

(35.) Thackeray JT, Radziuk J, Harper ME, et al. Sympathetic nervous dysregulation in the absence of systolic left ventricular dysfunction in a rat model of insulin resistance with hyperglycemia. Cardiovasc Diabetol. 2011;10:75. doi:10.1186/1475-2840-10-75.

(36.) Schroeder C, Tank J, Boschmann M, et al. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation. 2002;105:347-353.

(37.) Wang XL, Chai Q, Charlesworth MC, et al. Autoimmunoreactive IgGs from patients with postural orthostatic tachycardia syndrome. Proteomic-s Clin App/. 2012;6(11-121:615-625. doi:10.1002/prca.201200049.

(38.) Li H, Kern DC, Reim 5, et al. Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Hypertension. 2012;59(2):402-408. doi:10.1161/HYPERTENSIONAHA.111.184937.

(39.) Yu X, Stavrakis S, Hill MA, et al. Autoantibody activation of beta-adrenergic and muscarinic receptors contributes to an "autoimmune" orthostatic hypotension: Receptor autoantibodies in orthostatic hypotension. I Am Soc Hypertens. 2012;6(11:40-47. doi:10.1016/j. jash.2011.10.003.

(40.) Herda LR, Felix SB, Boege F. Drug-like actions of autoantibodies against receptors of the autonomous nervous system and their impact on human heart function. Br I Pharrnacol. 2012;166(3):847-857. doi:10.1111/0 476-5381.2012.01828.x.

(41.) Chiale PA, Rosenbaum MB, Elizari MV, et al. High prevalence of antibodies against beta 1- and beta 2-adrenoceptors in patients with primary electrical cardiac abnormalities. I Am Coll Cardiol. 1995;26(4):864-869.

(42.) Fu XL, Magnusson V. Bergh OH, et al. Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathy. I Clin Invest. 1993;91(51:19641968.

by Laurie Dennison Busby, BEd

Laurie Busby received a BEd from the University of Missouri. At age 30, she developed chronic fatigue syndrome and the hypersensitivities that sometimes accompany it. Shortly thereafter, her aunt, a nurse anesthetist, handed her a huge medical dictionary and some studies, insisting that Laurie learn how to read them because she had something with no answers. Since that time, Laurie has asked for several tests that have given her incredible clues about her illness, conducted a family medical health survey among patients, testified before the CFS Advisory Committee to the US Department of Health and Human Services, and started a chronic illness blog, cfsfmmcsandrelatedstudies.tumblr. corn, in an attempt to share what she has learned.
COPYRIGHT 2014 The Townsend Letter Group
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2014 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Dennison, Laurie
Publication:Townsend Letter
Article Type:Disease/Disorder overview
Date:Nov 1, 2014
Previous Article:The Doctor-Patient Agrees.
Next Article:Update: injection therapies for chronic fatigue and fibromyalgia.

Terms of use | Copyright © 2017 Farlex, Inc. | Feedback | For webmasters