Tag: sympathetic nervous system

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01).

Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Source: Hendrix J, Fanning L, Wyns A, Ahmed I, Patil MS, Richter E, Van Campenhout J, Ickmans K, Mertens R, Nijs J, Godderis L, Polli A. Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Sep 25:e14318. doi: 10.1111/eci.14318. Epub ahead of print. PMID: 39319943. https://pubmed.ncbi.nlm.nih.gov/39319943/

Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients

Abstract:

An overactive sympathetic nervous system (SNS) may cause one subtype of Long COVID. People who are genetically at risk for noradrenergic nerve problems may develop an overactive SNS after an infection. Alternatively, genetic or virus-induced dysregulation of astrocytes could lead to overactivation of the SNS. An overactive SNS could disrupt regulation of immune cells, energy metabolism, sleep homeostasis, respiratory rate, gastrointestinal function, and systemic and cerebral blood pressure, causing fatigue and cognitive dysfunction.

Hypothesis: Long COVID refers to symptoms that continue for more than four weeks after onset of acute COVID-19 illness. This umbrella term includes a wide variety of symptoms and presentations. Long COVID patients may have different types of biological dysfunction, meaning that there may be distinct subtypes of Long COVID. One possible subtype is sympathetic nervous system (SNS) over-activation. This subtype may exist in both Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)1.

Underlying mechanisms of the SNS overactivation subtype: Theoretically, patients with this subtype already have a genetic dysregulation of neuronal norepinephrine (NE) release/clearance or noradrenergic receptor sensitivity2. This latent genetic dysfunction of NE signaling may not cause significant problems unless there is a trigger that causes excess NE release.

As NE affects immune cell signaling, this could result in an over-activation or prolonged activation of the immune system in response to infection with SARS-CoV-2, the virus that causes COVID-193 . This subtype could explain why ME/CFS is often triggered by a virus or brain injury, as these occurrences can trigger noradrenergic signaling3.

Possible mechanisms for the SNS overactivation subtype include viral reservoirs, antibody reaction, and dysregulation of noradrenergic receptor expression. In Long COVID patients, viral antigens and reservoirs that remain in the body long after the initial infection may keep the overactive immune system in an inflammatory state4,5. A healthy person may not react to these SARS-CoV-2 reservoirs, as their functional immune cells should develop immune tolerance. Another possibility is that the immune system is reacting to SARS-CoV-2 antibodies.

Finally, it is possible that excess extracellular NE could keep the SNS and noradrenergic systems in the brain stuck in an overactive state. A prolonged period of increased levels of extracellular NE could lead to dysregulation of noradrenergic receptor expression. The excess extracellular NE may be due to a prolonged release of excess NE during the initial infection, or a failure of the negative feedback mechanisms that should reduce NE release.

Symptoms of an overactive SNS: An overactive SNS explains many of the symptoms found in Long COVID patients, such as IBS/gastrointestinal symptoms6, heart palpitations7, and sleep disturbance8. Additionally, in orthostatic intolerance, which is common in Long COVID and ME/CFS, the release of NE causes pronounced tachycardia. This rapid heart rate may cause palpitations, breathlessness, and chest pain.

Dysfunctional energy metabolism causes fatigue and cognitive dysfunction: An important piece of the puzzle is to explain how a dysregulated SNS could lead to chronic fatigue and brain fog (cognitive dysfunction). The most likely explanation is a dysregulation of metabolic function. There are many ways excess NE could affect metabolism, including enhancing aerobic glycolysis and depleting glycogen stores.

Source: Carnac, T. (2023). Hypothesis: Astrocyte dysregulation of sympathetic nervous system causes metabolic dysfunction in subset of Long COVID and ME/CFS patients. Patient-Generated Hypotheses Journal for Long COVID & Associated Conditions, Vol. 1, 36-43 https://patientresearchcovid19.com/hypothesis-astrocyte-dysregulation-of-sympathetic-nervous-system-causes-metabolic-dysfunction-in-subset-of-long-covid-and-me-cfs-patients-pghj-issue1-may2023/ (Full text)

Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients

Abstract:

Several disabling symptoms potentially related to dysautonomia have been reported in “long-COVID” patients. Unfortunately, these symptoms are often nonspecific, and autonomic nervous system explorations are rarely performed in these patients. This study aimed to evaluate prospectively a cohort of long-COVID patients presenting severe disabling and non-relapsing symptoms of potential dysautonomia and to identify sensitive tests.

Autonomic function was assessed by clinical examination, the Schirmer test; sudomotor evaluation, orthostatic blood pressure (BP) variation, 24-h ambulatory BP monitoring for sympathetic evaluation, and heart rate variation during orthostatism, deep breathing and Valsalva maneuvers for parasympathetic evaluation. Test results were considered abnormal if they reached the lower thresholds defined in publications and in our department. We also compared mean values for autonomic function tests between patients and age-matched controls.

Sixteen patients (median age 37 years [31–43 years], 15 women) were included in this study and referred 14.5 months (median) [12.0–16.5 months] after initial infection. Nine had at least one positive SARS-CoV-2 RT-PCR or serology result. Symptoms after SARS-CoV-2 infection were severe, fluctuating and disabling with effort intolerance. Six patients (37.5%) had one or several abnormal test results, affecting the parasympathetic cardiac function in five of them (31%). Mean Valsalva score was significantly lower in patients than in controls.

In this cohort of severely disabled long-COVID patients, 37.5% of them had at least one abnormal test result showing a possible contribution of dysautonomia to these nonspecific symptoms. Interestingly, mean values of the Valsalva test were significantly lower in patients than in control subjects, suggesting that normal values thresholds might not be appropriate in this population.

Source: Zanin, A., Amah, G., Chakroun, S. et al. Parasympathetic autonomic dysfunction is more often evidenced than sympathetic autonomic dysfunction in fluctuating and polymorphic symptoms of “long-COVID” patients. Sci Rep 13, 8251 (2023). https://doi.org/10.1038/s41598-023-35086-8 https://www.nature.com/articles/s41598-023-35086-8 (Full text)

Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome

Abstract:

Background: Orthostatic intolerance markedly affects the day-to-day activities of patients with myalgic encephalomyelitis (ME) or chronic fatigue syndrome. Chronotropic incompetence (CI), defined as an impaired chronotropic response or reduced increases in heart rate during exercise and resulting in lower exercise capacity, may also be observed during orthostasis in patients with ME.

Methods and Results: In this study, the recordings of 101 adult patients with ME (36 men, 65 women; mean [±SD] age 37±12 years) who underwent conventional active 10-min standing tests at least 3 times to determine the presence of CI were analyzed. Recordings were selected for 13 patients who experienced tests both with and without exhibiting postural orthostatic tachycardia syndrome (POTS; an increase in heart rate of ≥30 beats/min or an actual heart rate of ≥120 beats/min) while also both successfully completing and failing to complete 10-min standing on different occasions. Subjects in whom failure without POTS was observed in any test(s) while success was associated with POTS on other occasions were considered positive for CI during orthostasis. Of the 13 patients, 12 (92%) were CI positive, 5 (38%) of whom exclusively failed the tests without experiencing POTS.

Conclusions: Some patients with ME were CI positive during standing tests, suggesting impaired sympathetic activation. The presence of POTS appears to be essential for maintaining orthostasis in these patients.

Source: Kunihisa Miwa. Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Circulation Reports, Article ID CR-22-0114. https://www.jstage.jst.go.jp/article/circrep/advpub/0/advpub_CR-22-0114/_html/-char/en (Full text)

Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients

Abstract:

Purpose: The purpose of this study was to assess differences in the physiological profiles of completers vs. non-completers following a structured exercise programme (SEP) and the ability to predict non-completers, which is currently unknown in this group.

Methods: Sixty-nine patients met the Fukuda criteria. Patients completed baseline measures assessing fatigue, autonomic nervous system (ANS), cognitive, and cardiovascular function. Thirty-four patients completed a home-based SEP consisting of 10-40 min per day at between 30 and 80% actual HR max. Exercise intensity and time was increased gradually across the 16 weeks and baseline measures were repeated following the SEP.

Results: Thirty-five patients discontinued, while 34 completed SEP. For every increase in sympathetic drive for blood pressure control as measured by the taskforce, completion of SEP decreased by a multiple of 0.1. For a 1 millisecond increase in reaction time for the simple reaction time (SRT), the probability for completion of SEP also decreases by a multiple of 0.01. For a one beat HRmax increase, there is a 4% increase in the odds of completing SEP.

Conclusion: The more sympathetic drive in the control of blood vessels, the longer the reaction time on simple visual stimuli and the lower the HRmax during physical exercise, then the lower the chance of SEP completion in ME/CFS.

Source: Kujawski S, Cossington J, Słomko J, Dawes H, Strong JW, Estevez-Lopez F, Murovska M, Newton JL, Hodges L, Zalewski P. Prediction of Discontinuation of Structured Exercise Programme in Chronic Fatigue Syndrome Patients. J Clin Med. 2020 Oct 26;9(11):E3436. doi: 10.3390/jcm9113436. PMID: 33114704. https://www.mdpi.com/2077-0383/9/11/3436 (Full text)

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

Abstract:

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function.

A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2500 fewer steps compared with placebo (Pinteraction=0.04).

There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions

 

Source: Hall KT, Kossowsky J, Oberlander TF, Kaptchuk TJ, Saul JP, Wyller VB, Fagermoen E, Sulheim D, Gjerstad J, Winger A, Mukamal KJ. Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome. Pharmacogenomics J. 2016 Oct;16(5):454-60. doi: 10.1038/tpj.2016.53. Epub 2016 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5028250/ (Full article)

 

Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a common and disabling disorder, and a major threat against adolescent health. The pathophysiology is unknown, but alteration of neuroendocrine control systems might be a central element, resulting in attenuation of the hypothalamus-pituitary-adrenalin (HPA) axis and enhancement of the sympathetic/adrenal medulla (SAM) system. This study explored differences in neuroendocrine control mechanisms between adolescent CFS patients and healthy controls, and whether characteristics of the control mechanisms are associated with important clinical variables within the CFS group.

METHODS: CFS patients 12-18 years of age were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied. A comparable group of healthy controls were recruited from local schools. A total of nine hormones were assayed and subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and daily physical activity was recorded by an accelerometer.

RESULTS: A total of 120 CFS patients and 68 healthy controls were included. CFS patients had significantly higher levels of plasma norepinephrine, plasma epinephrine and plasma FT4, and significantly lower levels of urine cortisol/creatinine ratio. Subgrouping according to other case definitions as well as adjusting for confounding factors did not alter the results. Multivariate linear regression models as well as network analyses revealed different interrelations between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls. Also, single hormone degree centrality was associated with clinical markers within the CFS group.

CONCLUSION: This study reveals different interrelation between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls, and an association between hormone control characteristics and important clinical variables in the CFS group. These results add to the growing insight of CFS disease mechanisms.

Trial registration Clinical Trials NCT010404

 

Source: Wyller VB, Vitelli V, Sulheim D, Fagermoen E, Winger A, Godang K, Bollerslev J. Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study. J Transl Med. 2016 May 5;14(1):121. doi: 10.1186/s12967-016-0873-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858924/ (Full article)

 

Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies

Abstract:

BACKGROUND: Fibromyalgia often coexists and overlaps with other syndromes such as chronic fatigue, irritable bowel syndrome, and interstitial cystitis. Chronic stress has been implicated in the pathogenesis of these illnesses. The sympathetic nervous system is a key element of the stress response system. Sympathetic dysfunction has been reported in these syndromes, raising the possibility that such dysautonomia could be their common clustering underlying pathogenesis.

OBJECTIVE: The objective of this study was to carry out a review of all published comparative case-control studies investigating sympathetic nervous system performance in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis.

METHODS: Online databases PubMed and EMBASE were accessed using the following key words: autonomic (OR) sympathetic (AND) fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. All entries up to December 10th 2012 were reviewed by 2 independent investigators searching for case-control studies in humans. The Method for Evaluating Research and Guidelines Evidence adapted to the Scottish Intercollegiate Guidelines Network was used to rank the level of evidence contained in the selected articles.

RESULTS: A total of 196 articles are included in this review. The most often used methods to assess sympathetic functionality were heart rate variability analysis, sympathetic skin response, tilt table testing, and genetic studies. The majority of studies (65%) described sympathetic nervous system predominance in these overlapping syndromes. In contrast, 7% of the studies found parasympathetic predominance.

CONCLUSIONS: This review demonstrates that sympathetic nervous system predominance is common in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis. This concordance raises the possibility that sympathetic dysfunction could be their common underlying pathogenesis that brings on overlapping clinical features. The recognition of sympathetic predominance in these 4 syndromes may have potential clinical implications. It may be worth exploring the use of nonpharmacological measures as well as drug therapies aimed to regain autonomic balance.

 

Source: Martínez-Martínez LA, Mora T, Vargas A, Fuentes-Iniestra M, Martínez-Lavín M. Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of case-control studies. J Clin Rheumatol. 2014 Apr;20(3):146-50. doi: 10.1097/RHU.0000000000000089. https://www.ncbi.nlm.nih.gov/pubmed/24662556

 

Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress

Abstract:

Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation.

The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12-18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution.

Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of -20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.50 Hz), using an autoregressive algorithm.

Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.

 

Source: Wyller VB, Barbieri R, Saul JP. Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress. Eur J Appl Physiol. 2011 Mar;111(3):497-507. doi: 10.1007/s00421-010-1670-9. Epub 2010 Oct 2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037975/ (Full article)

 

Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome (CFS) has been shown to be associated with orthostatic intolerance and cardiovascular dysregulation. We investigated the cardiovascular responses to combined orthostatic stress and isometric exercise in adolescents with CFS.

We included a consecutive sample of 15 adolescents 12-18 years old with CFS diagnosed according to a thorough and standardized set of investigations, and a volunteer sample of 56 healthy control subjects of equal sex and age distribution. Heart rate, systolic, mean and diastolic blood pressure, stroke index, and total peripheral resistance index were non-invasively recorded during lower body negative pressure (LBNP) combined with two consecutive periods of handgrip. In addition, we measured baseline plasma catecholamines, and recorded symptoms. At rest, CFS patients had higher heart rate, diastolic blood pressure, plasma norepinephrine (P < 0.01), mean blood pressure and plasma epinephrine (P < 0.05) than controls.

During LBNP, CFS patients had a greater increase in heart rate, diastolic blood pressure, mean blood pressure (P < 0.05) and total peripheral resistance index (n.s.) than controls. During handgrip, CFS patients had a smaller increase in heart rate, diastolic blood pressure (P < 0.05), mean blood pressure and total peripheral resistance index (n.s.) than controls.

Our results indicate that adolescents with CFS have increased sympathetic activity at rest with exaggerated cardiovascular response to orthostatic stress, but attenuated cardiovascular response when performing isometric exercise during orthostatic stress. This suggests that CFS might be causally related to sympathetic dysfunction.

 

Source: Wyller VB, Saul JP, Walløe L, Thaulow E. Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome. Eur J Appl Physiol. 2008 Apr;102(6):623-32. Epub 2007 Dec 8. https://www.ncbi.nlm.nih.gov/pubmed/18066580