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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.)

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Notes

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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.
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Author:Dennison, Laurie
Publication:Townsend Letter
Article Type:Disease/Disorder overview
Date:Nov 1, 2014
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