Category: Exercise

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)

Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Evidence is emerging that individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may suffer from chronic vascular dysfunction as a result of illness-related oxidative stress and vascular inflammation. The study aimed to examine the impact of maximal-intensity aerobic exercise on vascular function 48 and 72 h into recovery.

Methods: ME/CFS (n = 11) with gender and age-matched controls (n = 11) were randomly assigned to either a 48 h or 72 h protocol. Each participant had measures of brachial blood pressure, augmentation index (AIx75, standardized to 75 bpm) and carotid-radial pulse wave velocity (crPWV) taken. This was followed by a maximal incremental cycle exercise test. Resting measures were repeated 48 or 72 h later (depending on group allocation).

Results: No significant differences were found when ME/CFS were directly compared to controls at baseline. During recovery, the 48 h control group experienced a significant 7.2% reduction in AIx75 from baseline measures (p < 0.05), while the matched ME/CFS experienced no change in AIx75. The 72 h ME/CFS group experienced a non-significant increase of 1.4% from baseline measures. The 48 h and 72 h ME/CFS groups both experienced non-significant improvements in crPWV (0.56 ms−1 and 1.55 ms−1, respectively).

Conclusions: The findings suggest that those with ME/CFS may not experience exercise-induced vasodilation due to chronic vascular damage, which may be a contributor to the onset of post-exertional malaise (PEM).

Source: Bond J, Nielsen T, Hodges L. Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Environmental Research and Public Health. 2021; 18(5):2366. https://doi.org/10.3390/ijerph18052366 https://www.mdpi.com/1660-4601/18/5/2366/htm (Full text)

Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) affects tens of millions worldwide; the causes of exertional intolerance are poorly understood. The ME/CFS label overlaps with postural orthostatic tachycardia (POTS) and fibromyalgia, and objective evidence of small fiber neuropathy (SFN) is reported in ∼50% of POTS and fibromyalgia patients.

Research Question

Can invasive cardiopulmonary exercise testing (iCPET) and PGP9.5-immunolabeled lower-leg skin biopsies inform the pathophysiology of ME/CFS exertional intolerance and potential relationships with SFN?

Study Design and Methods

We analyzed 1516 upright invasive iCPETs performed to investigate exertional intolerance. After excluding patients with intrinsic heart or lung disease and selecting those with right atrial pressures (RAP) <6.5 mmHg, results from 160 patients meeting ME/CFS criteria who had skin-biopsy test results were compared to 36 controls. Rest-to-peak changes in cardiac output (Qc) were compared to oxygen uptake (Qc/VO 2 slope) to identify participants with low, normal, or high pulmonary blood flow by Qc/VO 2 tertiles.

Results

During exercise, the 160 ME/CFS patients averaged lower RAP (1.9±2 vs. 8.3±1.5; P<0.0001) and peak VO 2 (80%±21 vs. 101.4%±17; P<0.0001) than controls. The low-flow tertile had lower peak Qc than the normal and high-flow tertiles (88.4±19% vs. 99.5±23.8% vs. 99.9±19.5% predicted; P<0.01). In contrast, systemic oxygen extraction was impaired in high-flow versus low and normal-flow participants (0.74±0.1% vs. 0.88±0.11 vs. 0.86±0.1; P<0.0001) in association with peripheral left-to-right shunting. Among the 160 ME/CFS patient biopsies, 31% was consistent with SFN (epidermal innervation ≤5.0% of predicted; P < 0.0001). Denervation severity did not correlate with exertional measures.

Interpretation

These results identify two types of peripheral neurovascular dysregulation that are biologically plausible contributors to ME/CFS exertional intolerance–depressed Qc from impaired venous return, and impaired peripheral oxygen extraction. In patients with small-fiber pathology, neuropathic dysregulation causing microvascular dilation may limit exertion by shunting oxygenated blood from capillary beds and reducing cardiac return.

Abbreviation:

Ca-vO2/[Hb] ( Arterial–mixed venous oxygen content difference/hemoglobin concentration), iCPET ( Invasive cardiopulmonary exercise test), NAM ( National Academy of Medicine, formerly the Institute of Medicine), ME/CFS ( Myalgic encephalomyelitis/chronic fatigue syndrome), MM ( Mitochondrial myopathy), mPAP ( Mean pulmonary artery pressure), PAWP ( Pulmonary arterial wedge pressure), PLF ( Preload failure), POTS ( Postural orthostatic tachycardia syndrome), PVR ( Pulmonary vascular resistance), RAP ( Right atrial pressure), Qc ( Cardiac output), SFN ( Small fiber neuropathy), VO2 ( Oxygen uptake), vPO2 ( Venous oxygen tension)

Source: Phillip Joseph, MD, Carlo Arevalo, MD, Rudolf K.F. Oliveira, MD, PhD, Donna Felsenstein, MD, Anne Louise Oaklander, MD, PhD, David M. Systrom, MD. Insights from Invasive Cardiopulmonary Exercise Testing of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. February 09, 2021. DOI:https://doi.org/10.1016/j.chest.2021.01.082 https://journal.chestnet.org/article/S0012-3692(21)00256-7/fulltext

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) share many symptoms of fatigue, pain, and cognitive dysfunction that are not relieved by rest. Patterns of serum metabolites in ME/CFS and GWI are different from control groups and suggest potential dysfunction of energy and lipid metabolism. The metabolomics of cerebrospinal fluid was contrasted between ME/CFS, GWI and sedentary controls in 2 sets of subjects who had lumbar punctures after either (a) rest or (b) submaximal exercise stress tests. Postexercise GWI and control subjects were subdivided according to acquired transient postexertional postural tachycardia. Banked cerebrospinal fluid specimens were assayed using Biocrates AbsoluteIDQ® p180 kits for quantitative targeted metabolomics studies of amino acids, amines, acylcarnitines, sphingolipids, lysophospholipids, alkyl and ether phosphocholines.

Glutamate was significantly higher in the subgroup of postexercise GWI subjects who did not develop postural tachycardia after exercise compared to nonexercise and other postexercise groups. The only difference between nonexercise groups was higher lysoPC a C28:0 in GWI than ME/CFS suggesting this biochemical or phospholipase activities may have potential as a biomarker to distinguish between the 2 diseases. Exercise effects were suggested by elevation of short chain acylcarnitine C5-OH (C3-DC-M) in postexercise controls compared to nonexercise ME/CFS. Limitations include small subgroup sample sizes and absence of postexercise ME/CFS specimens. Mechanisms of glutamate neuroexcitotoxicity may contribute to neuropathology and “neuroinflammation” in the GWI subset who did not develop postural tachycardia after exercise. Dysfunctional lipid metabolism may distinguish the predominantly female ME/CFS group from predominantly male GWI subjects.

Source: Baraniuk JN, Kern G, Narayan V, Cheema A. Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome. PLoS One. 2021 Jan 13;16(1):e0244116. doi: 10.1371/journal.pone.0244116. PMID: 33440400. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244116 (Full text)

Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Introduction: The post-exertional malaise of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was modeled by comparing micro-RNA (miRNA) in cerebrospinal fluid from subjects who had no exercise versus submaximal exercise.

Materials and Methods: Differentially expressed miRNAs were examined by informatics methods to predict potential targets and regulatory pathways affected by exercise.

Results: miR-608, miR-328, miR-200a-5p, miR-93-3p, and miR-92a-3p had higher levels in subjects who rested overnight (nonexercise n=45) compared to subjects who had exercised before their lumbar punctures (n=15). The combination was examined in DIANA MiRpath v3.0, TarBase, Cytoscape, and Ingenuity software® to select the intersection of target mRNAs. DIANA found 33 targets that may be elevated after exercise, including TGFBR1, IGFR1, and CDC42. Adhesion and adherens junctions were the most frequent pathways. Ingenuity selected seven targets that had complementary mechanistic pathways involving GNAQ, ADCY3, RAP1B, and PIK3R3. Potential target cells expressing high levels of these genes included choroid plexus, neurons, and microglia.

Conclusion: The reduction of this combination of miRNAs in cerebrospinal fluid after exercise suggested upregulation of phosphoinositol signaling pathways and altered adhesion during the post-exertional malaise of ME/CFS.

Clinical Trial Registration Nos.: NCT01291758 and NCT00810225.

Source: Narayan V, Shivapurkar N, Baraniuk JN. Informatics Inference of Exercise-Induced Modulation of Brain Pathways Based on Cerebrospinal Fluid Micro-RNAs in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Netw Syst Med. 2020 Nov 18;3(1):142-158. doi: 10.1089/nsm.2019.0009. PMID: 33274349; PMCID: PMC7703497.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703497/ (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)

Validation of the Severity of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Other Measures than History: Activity Bracelet, Cardiopulmonary Exercise Testing and a Validated Activity Questionnaire: SF-36

Abstract:

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe and disabling chronic disease. Grading patient’s symptom and disease severity for comparison and therapeutic decision-making is necessary. Clinical grading that depends on patient self-report is subject to inter-individual variability. Having more objective measures to grade and confirm clinical grading would be desirable. Therefore, the aim of this study was to validate the clinical severity grading that has been proposed by the authors of the ME International Consensus Criteria (ICC) using more standardized measures like questionnaires, and objective measures such as physical activity tracking and cardiopulmonary exercise testing.

Methods and results: The clinical database of a subspecialty ME/CFS clinic was searched for patients who had completed the SF 36 questionnaire, worn a SensewearTM armband for five days, and undergone a cardiopulmonary exercise test. Only patients who completed all three investigations within 3 months from each other—to improve the likelihood of stable disease—were included in the analysis. Two-hundred-eighty-nine patients were analyzed: 121 were graded as mild, 98 as moderate and 70 as having severe disease. The mean (SD) physical activity subscale of the SF-36 was 70 (11) for mild, 43 (8) for moderate and 15 (10) for severe ME/CFS patients. The mean (SD) number of steps per day was 8235 (1004) for mild, 5195 (1231) for moderate and 2031 (824) for severe disease. The mean (SD) percent predicted oxygen consumption at the ventilatory threshold was 47 (11)% for mild, 38 (7)% for moderate and 30 (7)% for severe disease. The percent peak oxygen consumption was 90 (14)% for mild, 64 (8)% for moderate and 48 (9)% for severe disease. All comparisons were p < 0.0001.

Conclusion: This study confirms the validity of the ICC severity grading. Grading assigned by clinicians on the basis of patient self-report created groups that differed significantly on measures of activity using the SF-36 physical function subscale and objective measures of steps per day and exercise capacity. There was variability in function within severity grading groups, so grading based on self-report can be strengthened by the use of these supplementary measures.

Source: van Campen, C.L.M.C.; Rowe, P.C.; Visser, F.C. Validation of the Severity of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Other Measures than History: Activity Bracelet, Cardiopulmonary Exercise Testing and a Validated Activity Questionnaire: SF-36. Healthcare 2020, 8, 273 https://www.mdpi.com/2227-9032/8/3/273/htm (Full text)

Two-Day Cardiopulmonary Exercise Testing in Females With a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison With Patients With Mild and Moderate Disease

Abstract:

Introduction: Effort intolerance along with a prolonged recovery from exercise and post-exertional exacerbation of symptoms are characteristic features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The gold standard to measure the degree of physical activity intolerance is cardiopulmonary exercise testing (CPET). Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, and that a 2-day CPET protocol further discriminates between ME/CFS patients and sedentary controls. Limited information is present on ME/CFS patients with a severe form of the disease. Therefore, the aim of this study was to compare the effects of a 2-day CPET protocol in female ME/CFS patients with a severe grade of the disease to mildly and moderately affected ME/CFS patients.

Methods and results: We studied 82 female patients who had undergone a 2-day CPET protocol. Measures of oxygen consumption (VO2), heart rate (HR) and workload both at peak exercise and at the ventilatory threshold (VT) were collected. ME/CFS disease severity was graded according to the International Consensus Criteria. Thirty-one patients were clinically graded as having mild disease, 31 with moderate and 20 with severe disease. Baseline characteristics did not differ between the 3 groups. Within each severity group, all analyzed CPET parameters (peak VO2, VO2 at VT, peak workload and the workload at VT) decreased significantly from day-1 to day-2 (p-Value between 0.003 and <0.0001). The magnitude of the change in CPET parameters from day-1 to day-2 was similar between mild, moderate, and severe groups, except for the difference in peak workload between mild and severe patients (p = 0.019). The peak workload decreases from day-1 to day-2 was largest in the severe ME/CFS group (-19 (11) %).

Conclusion: This relatively large 2-day CPET protocol study confirms previous findings of the reduction of various exercise variables in ME/CFS patients on day-2 testing. This is the first study to demonstrate that disease severity negatively influences exercise capacity in female ME/CFS patients. Finally, this study shows that the deterioration in peak workload from day-1 to day-2 is largest in the severe ME/CFS patient group.

Source: van Campen CLM, Rowe PC, Visser FC. Two-Day Cardiopulmonary Exercise Testing in Females with a Severe Grade of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Comparison with Patients with Mild and Moderate Disease. Healthcare (Basel). 2020;8(3):E192. Published 2020 Jun 30. doi:10.3390/healthcare8030192 https://pubmed.ncbi.nlm.nih.gov/32629923/

Elevated Perceived Exertion in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis

Abstract:

Purpose: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia (FM) are two debilitating illnesses primarily characterized by chronic symptoms of fatigue and musculoskeletal pain, respectively. Some investigators have observed an elevated sense of effort in these patient groups, however, this effect has not been substantiated via quantitative review. As such, we conducted a meta-analysis of perceived exertion (RPE) responses to aerobic exercise in ME/CFS and FM compared to healthy adults.

Methods: Case-control studies involving adults with ME/CFS or FM that measured RPE and heart rate responses to acute aerobic exercise were included. Data sources included: PubMed, Scopus/Embase, CINAHL, CENTRAL, and Google Scholar. Risk of bias was assessed by evaluating each study’s description of participant characteristics, matching procedures, and administration of RPE scales. Hedges’ d effect sizes for RPE were calculated and aggregated using random effects models and potential moderators were explored with meta-regression analysis.

Results: Forty-one effects were extracted from 37 studies involving 1016 patients and 686 healthy controls. We observed a large (Hedges’ d=0.85; 95% CI: 0.62, 1.08) effect indicating higher RPE in patients than controls. The mean effect size was significantly moderated (p<0.001; R=0.38) by whether RPE data were analyzed at a peak or submaximal intensity (b=0.60, z=4.6, p<0.001) and the type of patient group that was studied (b = 0.25, z = 2.08, p=0.04).

Conclusions: People with ME/CFS and FM perceive aerobic exercise as more effortful than healthy adults, but the exact causes are unclear. The large magnitude of this effect merits further exploration of underlying mechanisms which could provide insight into the pathophysiology of ME/CFS and FM or the broader debate about the nature of central and/or peripheral signals that influence RPE.

Source: Barhorst EE, Andrae WE, Rayne TJ, Falvo MJ, Cook DB, Lindheimer JB. Elevated Perceived Exertion in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis [published online ahead of print, 2020 Jun 15]. Med Sci Sports Exerc. 2020;10.1249/MSS.0000000000002421. doi:10.1249/MSS.0000000000002421 https://pubmed.ncbi.nlm.nih.gov/32555018/

Properties of Measurements Obtained During Cardiopulmonary Exercise Testing in Individuals With Myalgic encephalomyelitis/chronic Fatigue Syndrome

Abstract:

Background: Diminished cardiopulmonary exercise test (CPET) performance indicates the physiological basis for reduced capacity for activities of daily living and work. Thus, it may be a biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objective: To determine statistical properties of cardiac, pulmonary, and metabolic measurements obtained during CPET in people with ME/CFS.

Methods: Fifty-one females with ME/CFS and 10 sedentary females with similar age and body mass received cardiac, pulmonary, and metabolic measurements during 2 CPETs separated by 24 hours. Two-way analysis of variance and effect size calculations (Cohen’s d) were used to assess the magnitude and statistical significance of differences in measurements between groups. Reliability of CPET measurements was estimated using intraclass correlation coefficients (formula 2,1; ICC2,1). Responsiveness of CPET measurements was assessed using minimum detectable change outside the 95% confidence interval (MDC95) and coefficients of variation (CoV).

Results: CPET measurements demonstrated moderate to high reliability for individuals with ME/CFS. Comparing subjects with ME/CFS and control subjects yielded moderate to large effect sizes on all CPET measurements. MDC95 for all individuals with ME/CFS generally exceeded control subjects and CoVs for CPET measurements were comparable between groups.

Conclusions: CPET measurements demonstrate adequate responsiveness and reproducibility for research and clinical applications.

Source: Davenport TE, Stevens SR, Stevens MAJ, Snell CR, Van Ness JM. Properties of measurements obtained during cardiopulmonary exercise testing in individuals with myalgic encephalomyelitis/chronic fatigue syndrome [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203170. doi:10.3233/WOR-203170