Category: Pathophysiology

Comparison of the finger plethysmography derived stroke volumes by Nexfin CO Trek and suprasternal aortic Doppler derived stroke volume measurements in adults with myalgic encephalomyelitis/chronic fatigue syndrome and in healthy controls

Abstract:

Background: Finger plethysmography derived stroke volumes are frequently measured during tilt table testing. There are two algorithms to determine stroke volumes: Modelflow and NexfinCO Trek. Most tilt studies used Modelflow, while there are differences between the two algorithms.

Objective: To compare stroke volume indices by Nexfin CO Trek (SVINexfinCOTrek) with suprasternal Doppler derived SVI (SVIDoppler) in healthy controls (HC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients during tilt testing. These patients may have a large SVI decrease during the tilt enabling a large range of SVI to be studied.

Methods: One hundred and fifty-four patients and 39 HC with a normal tilt test were included. Supine and end-tilt SVIDoppler and SVINexfinCOTrek were compared using the Bland-Altman analysis. Also, the effect of calibrating supine SVINexfinCOTrek to SVIDoppler was studiedRESULTS: Supine and end-tilt SVINexfinCOTrek were significantly higher than SVIDoppler: both P< 0.005. Bias, limits of agreement, and percent error (PE) were high with PE’s between 37 and 43%. The calibration procedure resulted in an acceptable variance with a PE of 29%.

Conclusions: SVINexfinCOTrek overestimates stroke volumes compared to SVIDoppler, leading to high PE’s. Calibration reduced variance to an acceptable level, allowing SVINexfinCOTrek to be used for assessment of SVI changes during tilt testing.

Source: van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. Comparison of the finger plethysmography derived stroke volumes by Nexfin CO Trek and suprasternal aortic Doppler derived stroke volume measurements in adults with myalgic encephalomyelitis/chronic fatigue syndrome and in healthy controls. Technol Health Care. 2021 Apr 25. doi: 10.3233/THC-202669. Epub ahead of print. PMID: 33998565. https://pubmed.ncbi.nlm.nih.gov/33998565/

Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS)

Abstract:

Background: Patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) sometimes present with stiffness of the cervical muscles. To investigate the pathophysiology of ME/CFS, this observational study compared patients with versus without recovery from ME/CFS through local modulation of the cervical muscles.

Methods: Over a period of 11 years, a total of 1226 inpatients with ME/CFS who did not respond to outpatient care were enrolled in this study. All patients received daily cervical muscle physical therapy during hospitalization. Self-rated records documenting the presence or absence of ME/CFS, as well as the representative eight symptoms that frequently accompany it at admission and discharge, were compared. Pupil diameter was also measured to examine autonomic nervous system function involvement.

Results: The recovery rate of ME/CFS after local therapy was 55.5%, and did not differ significantly by sex, age strata, and hospitalization period. The recovery rates of the eight symptoms were variable (36.6-86.9%); however, those of ME/CFS in the symptom subpopulations were similar (52.3-55.8%). The recovery rates of all symptoms showed strong associations with that of ME/CFS (p < 0.001). The pupil diameter was more constricted in the ME/CFS-recovered patients than in the ME/CFS-unrecovered patients in the total population and the subpopulations stratified by sex, age, and hospitalization period.

Conclusions: There was a strong association between the recovery of ME/CFS and other related whole-body symptoms. The recovery of ME/CFS may be partly linked to amelioration of the autonomic nervous system in the cervical muscles.

Source: Matsui T, Hara K, Iwata M, Hojo S, Shitara N, Endo Y, Fukuoka H, Matsui M, Kawaguchi H. Possible involvement of the autonomic nervous system in cervical muscles of patients with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS). BMC Musculoskelet Disord. 2021 May 5;22(1):419. doi: 10.1186/s12891-021-04293-7. PMID: 33952227. https://pubmed.ncbi.nlm.nih.gov/33952227/

Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome)

Abstract:

Background: Orthostatic intolerance (OI) is a frequent finding in individuals with myalgic encephalomyelitis /chronic fatigue syndrome (ME/CFS). Published studies have proposed that deconditioning is an important pathophysiological mechanism in various forms of OI, including postural orthostatic tachycardia syndrome (POTS), however conflicting opinions exist. Deconditioning can be classified objectively using the predicted peak oxygen consumption (VO2) values from cardiopulmonary exercise testing (CPET). Therefore, if deconditioning is an important contributor to OI symptomatology, one would expect a relation between the degree of reduction in peak VO2during CPET and the degree of reduction in CBF during head-up tilt testing (HUT).

Methods and results: In 22 healthy controls and 199 ME/CFS patients were included. Deconditioning was classified by the CPET response as follows: %peak VO2 ≥ 85% no deconditioning, %peak VO2 65–85% = mild deconditioning, and %peak VO2 < 65% = severe deconditioning. HC had higher oxygen consumption at the ventilatory threshold and at peak exercise as compared to ME/CFS patients (p ranging between 0.001 and < 0.0001). Although ME/CFS patients had significantly greater CBF reduction than HC (p < 0.0001), there were no differences in CBF reduction among ME/CFS patients with no, mild, or severe deconditioning. We classified the hemodynamic response to HUT into three categories: those with a normal heart rate and blood pressure response, postural orthostatic tachycardia syndrome, or orthostatic hypotension. No difference in the degree of CBF reduction was shown in those three groups.

Conclusion: This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.

Source: van Campen, C.(.M.C., Rowe, P.C. & Visser, F.C. Deconditioning does not explain orthostatic intolerance in ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome). J Transl Med 19, 193 (2021). https://doi.org/10.1186/s12967-021-02819-0 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-021-02819-0 (Full study)

Delineating the Association Between Soluble CD26 and Autoantibodies Against G-Protein Coupled Receptors, Immunological and Cardiovascular Parameters Identifies Distinct Patterns in Post-Infectious vs. Non-Infection-Triggered Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Soluble cluster of differentiation 26 (sCD26) has a wide range of enzymatic functions affecting immunological, metabolic and vascular regulation. Diminished sCD26 concentrations have been reported in various autoimmune diseases and also in Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). Here we re-evaluate sCD26 as a diagnostic marker and perform a comprehensive correlation analysis of sCD26 concentrations with clinical and paraclinical parameters in ME/CFS patients. Though this study did find significantly lower concentrations of sCD26 only in the female cohort and could not confirm diagnostic suitability, results from correlation analyses provide striking pathomechanistic insights.

In patients with infection-triggered onset, the associations of low sCD26 with elevated autoantibodies (AAB) against alpha1 adrenergic (AR) and M3 muscarinic acetylcholine receptors (mAChR) point to a pathomechanism of infection-triggered autoimmune-mediated vascular and immunological dysregulation. sCD26 concentrations in infection-triggered ME/CFS were found to be associated with activated T cells, liver enzymes, creatin kinase (CK) and lactate dehydrogenase (LDH) and inversely with Interleukin-1 beta (IL-1b). Most associations are in line with the known effects of sCD26/DPP-4 inhibition.

Remarkably, in non-infection-triggered ME/CFS lower sCD26 in patients with higher heart rate after orthostatic challenge and postural orthostatic tachycardia syndrome (POTS) suggest an association with orthostatic regulation. These findings provide evidence that the key enzyme sCD26 is linked to immunological alterations in infection-triggered ME/CFS and delineate a different pathomechanism in the non-infectious ME/CFS subset.

Source: Szklarski M, Freitag H, Lorenz S, Becker SC, Sotzny F, Bauer S, Hartwig J, Heidecke H, Wittke K, Kedor C, Hanitsch LG, Grabowski P, Sepúlveda N, Scheibenbogen C. Delineating the Association Between Soluble CD26 and Autoantibodies Against G-Protein Coupled Receptors, Immunological and Cardiovascular Parameters Identifies Distinct Patterns in Post-Infectious vs. Non-Infection-Triggered Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Immunol. 2021 Apr 6;12:644548. doi: 10.3389/fimmu.2021.644548. PMID: 33889154; PMCID: PMC8056217. https://www.frontiersin.org/articles/10.3389/fimmu.2021.644548/full  (Full text)

Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Chronic Fatigue Syndrome or Myalgic Encephaloymelitis (ME/CFS) is a frequent debilitating disease with an enigmatic etiology. The finding of autoantibodies against ß2-adrenergic receptors (ß2AdR) prompted us to hypothesize that ß2AdR dysfunction is of critical importance in the pathophysiology of ME/CFS.

Our hypothesis published previously considers ME/CFS as a disease caused by a dysfunctional autonomic nervous system (ANS) system: sympathetic overactivity in the presence of vascular dysregulation by ß2AdR dysfunction causes predominance of vasoconstrictor influences in brain and skeletal muscles, which in the latter is opposed by the metabolically stimulated release of endogenous vasodilators (functional sympatholysis). An enigmatic bioenergetic disturbance in skeletal muscle strongly contributes to this release. Excessive generation of these vasodilators with algesic properties and spillover into the systemic circulation could explain hypovolemia, suppression of renin (paradoxon) and the enigmatic symptoms. In this hypothesis paper the mechanisms underlying the energetic disturbance in muscles will be explained and merged with the first hypothesis.

The key information is that ß2AdR also stimulates the Na+/K+-ATPase in skeletal muscles. Appropriate muscular perfusion as well as function of the Na+/K+-ATPase determine muscle fatigability. We presume that dysfunction of the ß2AdR also leads to an insufficient stimulation of the Na+/K+-ATPase causing sodium overload which reverses the transport direction of the sodium-calcium exchanger (NCX) to import calcium instead of exporting it as is also known from the ischemia-reperfusion paradigm. The ensuing calcium overload affects the mitochondria, cytoplasmatic metabolism and the endothelium which further worsens the energetic situation (vicious circle) to explain postexertional malaise, exercise intolerance and chronification.

Reduced Na+/K+-ATPase activity is not the only cause for cellular sodium loading. In poor energetic situations increased proton production raises intracellular sodium via sodium-proton-exchanger subtype-1 (NHE1), the most important proton-extruder in skeletal muscle. Finally, sodium overload is due to diminished sodium outward transport and enhanced cellular sodium loading. As soon as this disturbance would have occurred in a severe manner the threshold for re-induction would be strongly lowered, mainly due to an upregulated NHE1, so that it could repeat at low levels of exercise, even by activities of everyday life, re-inducing mitochondrial, metabolic and vascular dysfunction to perpetuate the disease.

Source: Wirth KJ, Scheibenbogen C. Pathophysiology of skeletal muscle disturbances in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). J Transl Med. 2021 Apr 21;19(1):162. doi: 10.1186/s12967-021-02833-2. PMID: 33882940.  https://pubmed.ncbi.nlm.nih.gov/33882940/

Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study

Abstract:

Introduction: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with a range of symptoms including post-exertional malaise (PEM), orthostatic intolerance, and autonomic dysfunction. Dysfunction of the blood vessel endothelium could be an underlying biological mechanism, resulting in inability to fine-tune regulation of blood flow according to the metabolic demands of tissues. The objectives of the present study were to investigate endothelial function in ME/CFS patients compared to healthy individuals, and assess possible changes in endothelial function after intervention with IV cyclophosphamide.

Methods: This substudy to the open-label phase II trial “Cyclophosphamide in ME/CFS” included 40 patients with mild-moderate to severe ME/CFS according to Canadian consensus criteria, aged 18-65 years. Endothelial function was measured by Flow-mediated dilation (FMD) and Post-occlusive reactive hyperemia (PORH) at baseline and repeated after 12 months. Endothelial function at baseline was compared with two cohorts of healthy controls (N = 66 and N = 30) from previous studies. Changes in endothelial function after 12 months were assessed and correlated with clinical response to cyclophosphamide. Biological markers for endothelial function were measured in serum at baseline and compared with healthy controls (N = 30).

Results: Baseline FMD was significantly reduced in patients (median FMD 5.9%, range 0.5-13.1, n = 35) compared to healthy individuals (median FMD 7.7%, range 0.7-21, n = 66) (p = 0.005), as was PORH with patient score median 1,331 p.u. (range 343-4,334) vs. healthy individuals 1,886 p.u. (range 808-8,158) (p = 0.003). No significant associations were found between clinical response to cyclophosphamide intervention (reported in 55% of patients) and changes in FMD/PORH from baseline to 12 months. Serum levels of metabolites associated with endothelial dysfunction showed no significant differences between ME/CFS patients and healthy controls.

Conclusions: Patients with ME/CFS had reduced endothelial function affecting both large and small vessels compared to healthy controls. Changes in endothelial function did not follow clinical responses during follow-up after cyclophosphamide IV intervention.

Source: Sørland K, Sandvik MK, Rekeland IG, Ribu L, Småstuen MC, Mella O, Fluge Ø. Reduced Endothelial Function in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Results From Open-Label Cyclophosphamide Intervention Study. Front Med (Lausanne). 2021 Mar 22;8:642710. doi: 10.3389/fmed.2021.642710. PMID: 33829023; PMCID: PMC8019750. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019750/ (Full text)

Our Evolving Understanding of ME/CFS

Abstract:

The potential benefits of the scientific insights gleaned from years of treating ME/CFS for the emerging symptoms of COVID-19, and in particular Longhaul- or Longhauler-COVID-19 are discussed in this opinion article. Longhaul COVID-19 is the current name being given to the long-term sequelae (symptoms lasting beyond 6 weeks) of SARS-CoV-2 infection. Multiple case definitions for ME/CFS exist, but post-exertional malaise (PEM) is currently emerging as the ‘hallmark’ symptom. The inability to identify a unique trigger of ME/CFS, as well as the inability to identify a specific, diagnostic laboratory test, led many physicians to conclude that the illness was psychosomatic or non-existent. However, recent research in the US and the UK, championed by patient organizations and their use of the internet and social media, suggest underlying pathophysiologies, e.g., oxidative stress and mitochondrial dysfunction. The similarity and overlap of ME/CFS and Longhaul COVID-19 symptoms suggest to us similar pathological processes.

We put forward a unifying hypothesis that explains the precipitating events such as viral triggers and other documented exposures: For their overlap in symptoms, ME/CFS and Longhaul COVID-19 should be described as Post Active Phase of Infection Syndromes (PAPIS). We further propose that the underlying biochemical pathways and pathophysiological processes of similar symptoms are similar regardless of the initiating trigger. Exploration of the biochemical pathways and pathophysiological processes should yield effective therapies for these conditions and others that may exhibit these symptoms. ME/CFS patients have suffered far too long. Longhaul COVD-19 patients should not be subject to a similar fate. We caution that failure to meet the now combined challenges of ME/CFS and Longhaul COVID-19 will impose serious socioeconomic as well as clinical consequences for patients, the families of patients, and society as a whole.

Source: Friedman KJ, Murovska M, Pheby DFH, Zalewski P. Our Evolving Understanding of ME/CFS. Medicina (Kaunas). 2021 Feb 26;57(3):200. doi: 10.3390/medicina57030200. PMID: 33652622. https://www.mdpi.com/1648-9144/57/3/200 (Full text)

Chronic fatigue syndrome: Abnormally fast muscle fiber conduction in the membranes of motor units at low static force load

Abstract:

Objective: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are disorders of unknown etiology and unclear pathophysiology, with overlapping symptoms of – especially muscular -fatigue and pain. Studies have shown increased muscle fiber conduction velocity (CV) in the non-painful muscles of FM patients. We investigated whether CFS patients also show CV abnormalities.

Methods: Females with CFS (n = 25), with FM (n = 22), and healthy controls (n = 21) underwent surface electromyography of the biceps brachii, loaded up to 20% of maximum strength, during short static contractions. The mean CV and motor unit potential (MUP) velocities with their statistical distribution were measured.

Results: The CV changes with force differed between CFS-group and both FM-group and controls (P = 0.01). The CV of the CFS-group increased excessively with force (P < 0.001), whereas that of the controls increased only slightly and non-significantly, and that of the FM-group did not increase at all. In the CFS-group, the number of MUPs conveying very high conduction velocities increased abundantly with force and the MUPs narrowed.

Conclusion: Our results suggest disturbed muscle membrane function in CFS patients, in their motor units involved in low force generation. Central neural deregulation may contribute to this disturbance.

Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts

Abstract:

Although understanding of the biomedical basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is growing, the underlying pathological mechanisms remain uncertain. We recently reported a reduction in the proportion of basal oxygen consumption due to ATP synthesis by Complex V in ME/CFS patient-derived lymphoblast cell lines, suggesting mitochondrial respiratory inefficiency. This was accompanied by elevated respiratory capacity, elevated mammalian target of rapamycin complex 1 (mTORC1) signaling activity and elevated expression of enzymes involved in the TCA cycle, fatty acid β-oxidation and mitochondrial transport. These and other observations led us to hypothesise the dysregulation of pathways providing the mitochondria with oxidisable substrates.

In our current study, we aimed to revisit this hypothesis by applying a combination of whole-cell transcriptomics, proteomics and energy stress signaling activity measures using subsets of up to 34 ME/CFS and 31 healthy control lymphoblast cell lines from our growing library. While levels of glycolytic enzymes were unchanged in accordance with our previous observations of unaltered glycolytic rates, the whole-cell proteomes of ME/CFS lymphoblasts contained elevated levels of enzymes involved in the TCA cycle (p = 1.03 × 10-4), the pentose phosphate pathway (p = 0.034, G6PD p = 5.5 × 10-4), mitochondrial fatty acid β-oxidation (p = 9.2 × 10-3), and degradation of amino acids including glutamine/glutamate (GLS p = 0.034, GLUD1 p = 0.048, GOT2 p = 0.026), branched-chain amino acids (BCKDHA p = 0.028, BCKDHB p = 0.031) and essential amino acids (FAH p = 0.036, GCDH p = 0.006). The activity of the major cellular energy stress sensor, AMPK, was elevated but the increase did not reach statistical significance. The results suggest that ME/CFS metabolism is dysregulated such that alternatives to glycolysis are more heavily utilised than in controls to provide the mitochondria with oxidisable substrates.

Source: Missailidis D, Sanislav O, Allan CY, Smith PK, Annesley SJ, Fisher PR. Dysregulated Provision of Oxidisable Substrates to the Mitochondria in ME/CFS Lymphoblasts. Int J Mol Sci. 2021 Feb 19;22(4):2046. doi: 10.3390/ijms22042046. PMID: 33669532; PMCID: PMC7921983. https://www.mdpi.com/1422-0067/22/4/2046/htm (Full text)

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Here the hypothesis is advanced that maladaptive mechanisms that prevent recovery in some intensive care unit (ICU) patients may also underlie Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Specifically, these mechanisms are: (a) suppression of the pituitary gland’s pulsatile secretion of tropic hormones, and (b) a “vicious circle” between inflammation, oxidative and nitrosative stress (O&NS), and low thyroid hormone function. This hypothesis should be investigated through collaborative research projects.

Introduction:

Critical illness refers to the physiological response to virtually any severe injury or infection, such as sepsis, liver disease, HIV infection, head injury, pancreatitis, burns, cardiac surgery, etc. (1). Researchers make a distinction between the acute phase of critical illness—in the first hours or days following severe trauma or infection; and the chronic or prolonged phase—in the case of patients that survive the acute phase but for unknown reasons do not start recovering and continue to require intensive care (i.e., “chronic ICU patients”). Independent of the nature of the critical illness, the acute phase is associated with an excessive response of pro-inflammatory cytokines (2) and is characterized by a uniform dysregulation of the endocrine axes (3). In prolonged critical illness, this dysregulation is maintained even once the initial inflammatory surge has settled (4). Regardless of the initial injury or infection, patients that suffer from prolonged critical illness experience profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc. (1, 5, 6). Whereas, the acute phase is considered to be an adaptive response to the severe stress of injury or infection (shifting energy and resources to essential organs and repair), the physiological mechanisms in the prolonged phase are now increasingly considered to be maladaptive responses to the stress of severe injury or infection, hindering recovery (7–10). Some have also suggested that the non-recovery from endocrine disturbances could explain the development of “post-intensive care syndrome” (PICS) (11); i.e., “the cognitive, psychiatric and/or physical disability after treatment in ICUs” (12, 13).

Source: Dominic Stanculescu, Lars Larsson and Jonas Bergquist. Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front. Med., 28 January 2021 | https://doi.org/10.3389/fmed.2021.628029 https://www.frontiersin.org/articles/10.3389/fmed.2021.628029/full (Full text)