Category: Pathophysiology

Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance

Abstract:

Background: Orthostatic intolerance (OI) is a core finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Deconditioning is often proposed as an important determinant for OI. Deconditioning can be objectively classified using the predicted peak oxygen consumption (%VO2 peak) values as derived from cardiopulmonary exercise testing (CPET) and OI can be objectively quantified using cerebral blood flow (CBF) changes during tilt testing. Therefore, if deconditioning contributes to OI, a correlation between peak VO2 and the %CBF reduction is expected.

Methods and results: 18 healthy controls (HC) and 122 ME/CFS patients without hypotension or tachycardia on tilt testing were studied. Deconditioning was classified as follows: %VO2 peak ≥85%= no deconditioning, %VO2 peak 65-85%= mild deconditioning, %VO2 peak<65%= severe deconditioning. HC had higher %VO2 peak compared to ME/CFS patients (p<0.0001). ME/CFS patients had significantly larger CBF reduction than HC (p<0.0001). No relation between the degree of deconditioning by the %VO2 peak and the %CBF reduction in ME/CFS patients was found. Moreover, we separately analyzed ME/CFS patients without an abnormal CBF reduction. Despite equal CBF reductions compared to HC and large differences between these patients and the patients with an abnormal CBF reduction, cardiac index (CI) changes (measured by suprasternal Doppler) were significantly less compared to ME/CFS patients with an abnormal CBF reduction (p<0.0001) but larger than in HC (p=0.004). Despite these different hemodynamic findings, %VO2 values were not different between the two patient groups, argumenting again against the causative role of hemodynamic abnormalities in deconditioning.

Conclusion: In ME/CFS patients without hypotension or tachycardia there is no relation between the %VO2 peak during CPET and the %CBF and %CI reduction during tilt testing, whether or not patients have an abnormal CBF reduction during tilt testing. It suggests again that deconditioning does not play an important role in OI.

Source: VAN CAMPEN, C (Linda) M.C.; VISSER, Frans C.. Comparison of the Degree of Deconditioning in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Patients with and without Orthostatic Intolerance. Medical Research Archives, [S.l.], v. 10, n. 6, june 2022. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/2858>. Date accessed: 17 july 2022. doi: https://doi.org/10.18103/mra.v10i6.2858.

Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Abstract:

As inflammation in the brain contributes to several neurological and psychiatric diseases, the cause of neuroinflammation is being widely studied. The causes of neuroinflammation can be roughly divided into the following domains: viral infection, autoimmune disease, inflammation from peripheral organs, mental stress, metabolic disorders, and lifestyle. In particular, the effects of neuroinflammation caused by inflammation of peripheral organs have yet unclear mechanisms.

Many diseases, such as gastrointestinal inflammation, chronic obstructive pulmonary disease, rheumatoid arthritis, dermatitis, chronic fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger neuroinflammation through several pathways. The mechanisms of action for peripheral inflammation-induced neuroinflammation include disruption of the blood-brain barrier, activation of glial cells associated with systemic immune activation, and effects on autonomic nerves via the organ-brain axis. In this review, we consider previous studies on the relationship between systemic inflammation and neuroinflammation, focusing on the brain regions susceptible to inflammation.

Source: Sun Y, Koyama Y, Shimada S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front Aging Neurosci. 2022 Jun 16;14:903455. doi: 10.3389/fnagi.2022.903455. PMID: 35783147; PMCID: PMC9244793. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9244793/ (Full text)

Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Abstract:

In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified, yet, it remains unclear how they are related and which of them may be upstream or downstream.

In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS and suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.

For this “histological” approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit. Through this search we have identified the CNS neuroglia – microglia and astroglia – as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS.

While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

Source: Renz-Polster, H. (2021, August 3). Broken Connections: The Evidence for Neuroglial Failure in ME/CFS. https://doi.org/10.31219/osf.io/ef3n4 https://osf.io/ef3n4/ (Full text)

Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: Several studies have suggested that low levels of omega-3 fatty acids (n-3 PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with cardiovascular risk, major depression, sleep problems, inflammation and other health-related issues. So far, however, erythrocyte PUFA status in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) has not been established. This study aimed to determine whether n-3 PUFA content and omega-3 index are associated with measures in CFS/ME patients.

PATIENTS AND METHODS: PUFA levels and omega-3 index were measured in 31 Spanish CFS/ME patients using the HS-Omega-3 Index method. Demographic and clinical characteristics and self-reported outcome measures were also recorded.

RESULTS: A low mean omega-3 index (5.75%) was observed in 92.6% of the sample. Omega-3 index was inversely correlated with the AA/EPA ratio (p = 0.00002) and the BMI (p = 0.0106). In contrast, the AA/EPA ratio was positively associated with the BMI (p = 0.0038). No association for FIS-40 and PSQI measures was found (p > 0.05).

CONCLUSION: The low omega-3 index found in our CFS/ME patients may indicate increased risks for cardiovascular health, which should be further investigated. A low omega-3 index also suggests a pro-inflammatory state in these patients. Attempts should be made to increase the omega-3 index in CFS/ME patients, based on intervention trials assessing a potential therapeutic value.

Source: Castro-Marrero J, Zaragozá MC, Domingo JC, Martinez-Martinez A, Alegre J, von Schacky C. Low omega-3 index and polyunsaturated fatty acid status in patients with chronic fatigue syndrome/myalgic encephalomyelitis. Prostaglandins Leukot Essent Fatty Acids. 2018 Dec;139:20-24. doi: 10.1016/j.plefa.2018.11.006. Epub 2018 Nov 9. https://www.ncbi.nlm.nih.gov/pubmed/30471769

Mechanistic factors contributing to pain and fatigue in fibromyalgia and ME/CFS: autonomic and inflammatory insights from an experimental medicine study

Abstract:

Background: Fibromyalgia and ME/CFS are multifaceted conditions with overlapping symptoms(1); the pathoaetiological mechanisms are complex and debated(2), however there is a strong association with features of hereditary disorders of connective tissue (hypermobility) and autonomic and inflammatory abnormalities (1,2).

Objectives: To determine potential autonomic and inflammatory mechanisms of pain and fatigue in fibromyalgia and ME/CFS

Methods: After excluding participants with WCC higher than 10 (suggesting acute infection) baseline markers of inflammation (CRP and ESR) were available for 60 patients with confirmed diagnoses of Fibromyalgia and/ or ME/CFS and 23 matched controls. Participants then underwent full research diagnostic evaluation including a hypermobility assessment(1) and autonomic challenge (60 degree head up tilt, ISRCTN78820481). Subjective pain and fatigue were assessed before and after challenge (VAS). Linear regression models were used to explore predictors, with adjustment for confounders as appropriate. Mediation analyses (looking for mechanistic effects) were conducted according to the method of Hayes (3) and mediation considered significant if bootstrapped confidence intervals of the estimated indirect effect did not cross zero. In these mediation analyses predictor variable was group membership (patient or control), outcome variable was change in 1)pain and 2)fatigue induced by challenge and mediatiors 1)no of connective tissue features in hypermobility diagnostic criteria endorsed by participant; 2)baseline inflammatory markers.

Results: ESR and CRP were significantly higher in patients rather than controls, even after correcting for BMI, age and sex (B=5.15, t=2.05, p=0.044; B=1.77, t=2.15, p=0.044 respectively). Adjusted ESR and CRP correlated with both subjective fatigue (B=0.44, t=2.09, p=0.04; B=1.63, t=2.60, p=0.011) and pain severity (B=0.13, t=2.51, p=0.014; B=0.45, t=3.01, p=0.004) at baseline. Autonomic challenge amplified pain (B=14.20, t=2.87, p=0.005) and fatigue (B=31.48, t=5.95, p=<0.001) in patients to a significantly greater degree than controls, controlling for baseline levels. Baseline ESR and CRP also predicted challenge-induced increase in fatigue (B=0.78, t=370, p=<0.001; B=1.91, t=3.36, p=<0.001) and ESR challenge-induced increases in pain (B=0.46, t=2.35, p=0.021).

Mediation analysis demonstrated that number of connective tissue features expressed in hypermobility criteria mediated the degree to which subjective pain was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero, 0.1572 – 6.8171). ESR mediated the degree to which subjective fatigue was increased by the autonomic challenge (Bootstraped 95% CI of indirect effect do not cross zero,0.7541 – 7.3888).

Conclusion: To our knowledge this is the first study to directly explore autonomic and inflammatory mechanisms of pain and fatigue in a combined population of Fibromyalgia and ME/CFS. This study this adds to the evidence-base of baseline inflammatory abnormalities in fibromyalgia and ME/CFS. It highlights their potential role in predicting symptom severity and their potential mechanistic role in autonomic induced pain and fatigue, suggesting future treatment strategies.

Source: Eccles J, Thompson C, Thompson B, et al. AB1209 MECHANISTIC FACTORS CONTRIBUTING TO PAIN AND FATIGUE IN FIBROMYALGIA AND ME/CFS: AUTONOMIC AND INFLAMMATORY INSIGHTS FROM AN EXPERIMENTAL MEDICINE STUDY. Annals of the Rheumatic Diseases 2022;81:1719 https://ard.bmj.com/content/annrheumdis/81/Suppl_1/1719.2.full.pdf (Full text available as PDF file)

The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

We have previously demonstrated that platelet poor plasma (PPP) obtained from patients with LongCovid/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state reflected in hyperactivated platelets and the presence of considerable numbers of fibrin(ogen) amyloid microclots or fibrinaloid microclots. Due to substantial overlap in symptoms and aetiology between PASC and ME/CFS, we investigated whether coagulopathies, platelet hyperactivation and/or fibrin amyloid formation differed between individuals exhibiting ME/CFS and gender- and age-matched healthy controls.

ME/CFS patients were statistically far more hypercoagulable as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated platelet-poor plasma from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed massive hyperactivation and spreading of platelets in samples from individuals with ME/CFS. Using a quantitative scoring system, this was found to have a score of 2.72 ± 1.24 vs 1.00 (activation with pseudopodia formation) for healthy controls.

We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, fibrinaloid microclot load was not as prevalent as was previously noted in PASC. Fibrinaloid microclots, in particular can provide a ready explanation, via (temporary) blockage of microcapillaries and hence ischaemia, for many of the symptoms, such as fatigue, seen in patients with ME/CFS. The discovery of these biomarkers pointing to significant and systemic endothelial inflammation, represents an important development in ME/CFS research. It also points at novel treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation.

Source: Massimo Nunes, Arneaux Kruger, Amy Proal et al. The occurrence of hyperactivated platelets and fibrinaloid microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 08 June 2022, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-1727226/v1 (Full text)

Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome

Abstract:

There is evidence that chronic fatigue spectrum disorders (CFAS-D) including Myalgic Encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue with physiosomatic symptoms including when due to comorbid medical disease are characterized by neuroimmune and neuro-oxidative biomarkers.

The present study was performed to delineate the protein-protein interaction (PPI) network of CFAS-D and to discover the pathways, molecular patterns and domains enriched in their PPI network.

We performed network, enrichment and annotation analysis using differentially expressed proteins and metabolics, which were established in CFAS-D patients.

PPI network analysis revealed that the backbone of the highly connective CFAS-D network comprises NFKB1, CTNNB1, ALB, peroxides, NOS2, TNF, and IL6, and that the network comprises interconnected immune-oxidative-nitrosative and Wnt/catenin subnetworks.

MultiOmics enrichment analysis shows that the CFAS-D network is highly significantly associated with cellular (antioxidant) detoxification, hydrogen peroxide metabolic process, peroxidase and oxidoreductase activity, IL10 anti-inflammatory signaling, and neurodegenerative, canonical Wnt, the catenin complex, cadherin domains, cell-cell junctions and TLR2/4 pathways; and the transcription factors NF-κB and RELA.

The top-10 DOID annotations of the CFAS-D network include four intestinal, three immune system disorders, cancer and infectious disease.

Custom GO term annotation analysis revealed that the CFAS-D network is associated with a response to a toxic substance, lipopolysaccharides, bacterium or virus.

In conclusion, CFAS-D may be triggered by a variety of stimuli and their effects are mediated by aberrations in the cross-talks between redox, NF-κB, and Wnt/catenin signaling pathways leading to dysfunctions in multicellular organismal homeostatic processes.

Source: Michael Maes, Marta Kubera and Magdalena Kotańska. Aberrations in the Cross-Talks Among Redox, Nuclear Factor-κB, and Wnt/β-Catenin Pathway Signaling Underpin Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Frontiers in Psychiatry 13: 822382. https://www.frontiersin.org/articles/10.3389/fpsyt.2022.822382/full  (Full text)

Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by intractable fatigue, post-exertional malaise, and orthostatic intolerance, but its pathophysiology is poorly understood. Pharmacologic cholinergic stimulation was used to test the hypothesis that neurovascular dysregulation underlies exercise intolerance in ME/CFS.

Research Question: Does neurovascular dysregulation contribute to exercise intolerance in ME/CFS and can its treatment improve exercise capacity?

Methods: Forty-five subjects with ME/CFS were enrolled in a single-center, randomized, double-blind, placebo-controlled trial. Subjects were assigned in a 1:1 ratio to receive a 60 mg dose of oral pyridostigmine or placebo after an invasive cardiopulmonary exercise test (iCPET). A second iCPET was performed 50 minutes later. The primary end point was the difference in peak exercise oxygen uptake (VO2). Secondary end points included exercise pulmonary and systemic hemodynamics and gas exchange.

Results: Twenty-three subjects were assigned to pyridostigmine and 22 to placebo. The peak VO2 increased after pyridostigmine but decreased after placebo (13.3 ± 13.4 mL/min vs. -40.2 ± 21.3 mL/min, P<0.05). The treatment effect of pyridostigmine was 53.6 mL/min (95% CI, -105.2 to -2.0). Peak versus rest VO2 (25.9 ± 15.3 mL/min vs. -60.8 ± 25.6 mL/min, P<0.01), cardiac output (-0.2 ± 0.6 L/min vs. -1.9 ± 0.6 L/min, P<0.05), and RAP (1.0 ± 0.5 mm Hg vs. -0.6 ± 0.5 mm Hg, P<0.05) were greater in the pyridostigmine group compared to placebo.

Interpretation: Pyridostigmine improves peak VO2 in ME/CFS by increasing cardiac output and right ventricular filling pressures. Worsening peak exercise VO2, Qc, and RAP after placebo may signal the onset of post-exertional malaise. We suggest treatable neurovascular dysregulation underlies acute exercise intolerance in ME/CFS.

Abbreviations List: Ca-vO2 (arterial-venous oxygen content difference), iCPET (Invasive cardiopulmonary exercise test), MAP (Mean arterial pressure), mPAP (Mean pulmonary artery pressure), ME/CFS (Myalgic encephalomyelitis/chronic fatigue syndrome), PASC (Post-acute sequelae of SARS-CoV-2 infection), PAWP (Pulmonary arterial wedge pressure), POTS (Postural orthostatic tachycardia syndrome), Qc (Cardiac output), RAP (Right atrial pressure), SE (Standard error), SFN (Small fiber neuropathy), VE/VCO2 (Ventilatory efficiency), VO2 (Oxygen uptake)

Source: Phillip Joseph, MD, Rosa Pari, MD, Sarah Miller, BS, Arabella Warren, BS, Mary Catherine Stovall, BS, Johanna Squires, MSc, Chia-Jung Chang, PhD, Wenzhong Xiao, PhD, Aaron B. Waxman, MD, PhD, David M. Systrom, MD. Neurovascular Dysregulation and Acute Exercise Intolerance in ME/CFS: A Randomized, Placebo-Controlled Trial of Pyridostigmine. Chest, Published: May 05, 2022. DOI: https://doi.org/10.1016/j.chest.2022.04.146

Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial

Rationale: One third of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have evidence of small fiber neuropathy (SFN). Neurovascular dysregulation during upright exercise may be associated with impaired venoconstriction resulting in low biventricular filling pressures and impaired arteriolar constriction resulting in a mismatch between perfusion and skeletal muscle metabolism. We hypothesize that pyridostigmine, a reversible acetylcholinesterase inhibitor, may improve vascular regulation and exercise tolerance in ME/CFS by increasing sympathetic outflow.

Methods: 45 subjects (39 women, 6 men) with ME/CFS were assessed. A baseline invasive cardiopulmonary exercise test (iCPET) was performed to confirm presence of low peak exercise RAP (<6.5mmHg). Eligible subjects were blindly administered placebo (n=22) or 60mg pyridostigmine (n=23) at a 1:1 ratio. A second iCPET was performed following a 50 minute combined rest and dosing period. Serial iCPET results were compared to assess changes in oxygen uptake at peak exercise (VO2 max). Secondary outcomes included subject ventilatory efficiency (VE/VCO2), peak hemodynamic response (RAP, PCWP, SV, Qt), systemic gas exchange (Ca-vO2/Hgb), and subjective reporting of dyspnea and fatigue. Results: 39 subjects (all women) were considered in data analysis. There was a significant increase in VO2 max between iCPET 1 and iCPET 2 in the treatment group when compared with the placebo group (p = 0.043).

There was a significant decrease in the placebo group and a significant increase in the treatment group in VO2 (p = 0.008), Qt (p = 0.039), and RAP (p = 0.045) when comparing iCPET 1 peak – rest and iCPET 2 peak – rest between groups. There were no significant differences in peak arteriovenous oxygen content difference (Ca-vO2/Hgb). 38% of subjects had objective evidence of SFN with no statistically significant difference between groups.

Conclusion: Using pyridostigmine as an investigative tool, this study suggests that neurovascular dysregulation underlies acute exercise intolerance in ME/CFS. Additionally, we have new evidence that worsening vascular dysregulation results from prior exercise, which sheds insight into the post exertional malaise that is a hallmark of this syndrome.

Source: M. Stovall, P. Joseph, R. Pari, A. Warren, S. Miller, J. Squires, W. Xiao, A.B. Waxman, D.M. Systrom. Acute effect of pyridostigmine in exertional intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A randomized placebo-controlled clinical trial. American Journal of Respiratory and Clinical Care Medicine, Vol 205, p A2063, May 2022. https://www.atsjournals.org/doi/pdf/10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2063

Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE)

Abstract:

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS), is a multisystem illness characterized by extreme muscle fatigue associated with pain, neurocognitive impairment, and chronic inflammation. Despite intense investigation, the molecular mechanism of this disease is still unknown. Here we demonstrate that autophagy-related protein ATG13 is strongly upregulated in the serum of ME/CFS patients, indicative of impairment in the metabolic events of autophagy.

A Thioflavin T-based protein aggregation assay, array screening for autophagy-related factors, densitometric analyses, and confirmation with ELISA revealed that the level of ATG13 was strongly elevated in serum samples of ME/CFS patients compared to age-matched controls. Moreover, our microglia-based oxidative stress response experiments indicated that serum samples of ME/CFS patients evoke the production of reactive oxygen species (ROS) and nitric oxide in human HMC3 microglial cells, whereas neutralization of ATG13 strongly diminishes the production of ROS and NO, suggesting that ATG13 plays a role in the observed stress response in microglial cells. Finally, an in vitro ligand binding assay provided evidence that ATG13 employs the Receptor for Advanced Glycation End-products (RAGE) to stimulate ROS in microglial cells.

Collectively, our results suggest that an impairment of autophagy following the release of ATG13 into serum could be a pathological signal in ME/CFS.

Source: Gottschalk G, Peterson D, Knox K, Maynard M, Whelan RJ, Roy A. Elevated ATG13 in serum of patients with ME/CFS stimulates oxidative stress response in microglial cells via activation of receptor for advanced glycation end products (RAGE). Mol Cell Neurosci. 2022 Apr 26:103731. doi: 10.1016/j.mcn.2022.103731. Epub ahead of print. PMID: 35487443. https://www.sciencedirect.com/science/article/abs/pii/S1044743122000379?via%3Dihub (Full text)