exercise intolerance – Page 5 – American ME and CFS Society

Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol

Abstract:

Introduction: Multiple studies have shown that peak oxygen consumption is reduced in the majority of ME/CFS patients, using the golden standard for measuring exercise intolerance: cardiopulmonary exercise testing (CPET). A 2-day CPET protocol has shown different results on day 2 in ME/CFS patients compared to sedentary controls. No comparison is known between ME/CFS and idiopathic chronic fatigue (ICF) for 2-day CPET protocols. We compared ME/CFS patients with patients with chronic fatigue who did not fulfil the ME/CFS criteria in a male population and hypothesized a different pattern of response would be present during the 2nd day CPET.

Methods: Fifty-one female patients with ICF completed a 2-day CPET protocol and were compared to an age/sex-matched group of 50 female ME/CFS patients. Measures of oxygen consumption (VO₂), heart rate (HR), systolic and diastolic blood pressure, workload (Work), and respiratory exchange ratio (RER) were collected at maximal (peak) and ventilatory threshold (VT) intensities.

Results: Baseline characteristics for both groups were similar for age, BMI, BSA, and disease duration. A significance difference was present in the number of patients with fibromyalgia (seven ME/CFS patients vs zero ICF patients). Heart rate at rest and the RER did not differ significantly between CPET 1 and CPET 2. All other CPET parameters at the ventilatory threshold and maximum exercise differed significantly (p-value between 0.002 and <0.0001). ME/CFS patients showed a deterioration of performance on CPET2 as reflected by VO₂ and workload at peak exercise and ventilatory threshold, whereas ICF patients showed improved performance on CPET2 with no significant change in peak workload.

Conclusion: This study confirms that female ME/CFS patients have a reduction in exercise capacity in response to a second day CPET. These results are similar to published results in female ME/CFS populations. Patients diagnosed with ICF show a different response on day 2, more similar to sedentary and healthy controls.

Source: van Campen CLMC, Visser FC. Female Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome or Idiopathic Chronic Fatigue: Comparison of Responses to a Two-Day Cardiopulmonary Exercise Testing Protocol. Healthcare (Basel). 2021 Jun 5;9(6):682. doi: 10.3390/healthcare9060682. PMID: 34198913. https://pubmed.ncbi.nlm.nih.gov/34198913/

Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings

Abstract:

PURPOSE OF REVIEW: Here, we review potential causes of muscle dysfunction seen in many patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) such as the effects of oxidative and nitrosative stress (O&NS) and mitochondrial impairments together with reduced heat shock protein production and a range of metabolic abnormalities.

RECENT FINDINGS: Several studies published in the last few years have highlighted the existence of chronic O&NS, inflammation, impaired mitochondrial function and reduced heat shock protein production in many patients with ME/CFS. These studies have also highlighted the detrimental effects of chronically elevated O&NS on muscle functions such as reducing the time to muscle fatigue during exercise and impairing muscle contractility.

Mechanisms have also been revealed by which chronic O&NS and or impaired heat shock production may impair muscle repair following exercise and indeed the adaptive responses in the striated muscle to acute and chronic increases in physical activity. The presence of chronic O&NS, low-grade inflammation and impaired heat shock protein production may well explain the objective findings of increased muscle fatigue, impaired contractility and multiple dimensions of exercise intolerance in many patients with ME/CFS.

Source: Gerwyn M, Maes M. Mechanisms Explaining Muscle Fatigue and Muscle Pain in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): a Review of Recent Findings. Curr Rheumatol Rep. 2017 Jan;19(1):1. doi: 10.1007/s11926-017-0628-x. https://www.ncbi.nlm.nih.gov/pubmed/28116577

Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms?

Letter to the Editor:

With interest we read the article by Billing-Ross et al. [1] about 193 patients with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda or Canadian Consensus criteria and undergoing sequencing of the mtDNA, the DePaul Symptom questionnaire and the Medical Outcome Survey Short Form-36. The study showed that CFS is associated with mtDNA haplogroups J, U and H, that 8 mtDNA single nucleotide polymorphisms (SNPs) were associated with 16 symptom categories, and that three haplogroups were associated with six symptom categories [1]. We have the following comments and concerns.

The main limitation of this study is that only the mtDNA was investigated for sequence variants. Since it is well-known that mitochondrial disorders (MIDs) may be also caused by mutations in nDNA-located genes, particularly in children [2], disease-causing mutations or SNPs facilitating the development of CFS may have been missed. Furthermore, MIDs may not only be due to respiratory chain dysfunction but also due to disruption of other mitochondrial pathways, such as the beta-oxidation, the hem synthesis, the calcium handling, the coenzyme-Q metabolism, or the urea cycle. There is also consensus that investigations of mtDNA mutations or SNPs in mtDNA from lymphocytes may not be constructive since some mutations may not be present or heteroplasmy rates may be lower than in more severely affected tissues [3].

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/

Source: Finsterer J, Zarrouk-Mahjoub S. Is chronic fatigue syndrome truly associated with haplogroups or mtDNA single nucleotide polymorphisms? J Transl Med. 2016 Jun 18;14(1):182. doi: 10.1186/s12967-016-0939-0. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912808/ (Full article)

In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients.

To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

Source: Lengert N, Drossel B. In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Biophys Chem. 2015 Jul;202:21-31. doi: 10.1016/j.bpc.2015.03.009. Epub 2015 Apr 4. https://www.ncbi.nlm.nih.gov/pubmed/25899994

Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome

Abstract:

Patients with chronic fatigue syndrome (CFS) frequently demonstrate intolerance to physical exertion that is often reported as increased and long-lasting fatigue. Because no specific metabolic alterations have been identified in CFS patients, we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue.

After exhausting handgrip exercise, muscle metabolites were trapped in the forearm tissues of 39 CFS patients and 29 normal control (NC) by sudden occlusion for up to 5 minutes. A nonocclusive condition of similar duration was used as control. Repeated fatigue and pain ratings were obtained before and after exercise. Mechanical and heat hyperalgesia were assessed by quantitative sensory testing. All subjects fulfilled the 1994 Fukuda Criteria for CFS.

Normal control and CFS subjects exercised for 6.6 (2.4) and 7.0 (2.7) minutes (P > 0.05). Forearm occlusion lasted for 4.7 (1.3) and 4.9 (1.8) minutes in NC and CFS subjects, respectively (P > 0.05). Although fatigue ratings of CFS subjects increased from 4.8 (2.0) to 5.6 (2.1) visual analogue scale (VAS) units during forearm occlusion, they decreased from 5.0 (1.8) to 4.8 (2.0) VAS units during the control condition without occlusion (P = 0.04). A similar time course of fatigue ratings was observed in NC (P > 0.05), although their ratings were significantly lower than those of CFS subjects (P < 0.001). Quantitative sensory testing demonstrated heat and mechanical hyperalgesia in CFS subjects.

Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise-related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit.

Source: Staud R, Mokthech M, Price DD, Robinson ME. Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome. Pain. 2015 Apr;156(4):750-9. doi: 10.1097/j.pain.0000000000000110. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366335/ (Full article)

Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome

Abstract:

This study examined the effects of maximal incremental exercise on cerebral oxygenation in chronic fatigue syndrome (CFS) subjects. Furthermore, we tested the hypothesis that CFS subjects have a reduced oxygen delivery to the brain during exercise.

Six female CFS and eight control (CON) subjects (similar in height, weight, body mass index and physical activity level) performed an incremental cycle ergometer test to exhaustion, while changes in cerebral oxy-haemoglobin (HbO2), deoxy-haemoglobin (HHb), total blood volume (tHb = HbO2 + HHb) and O2 saturation [tissue oxygenation index (TOI), %)] was monitored in the left prefrontal lobe using a near-infrared spectrophotometer. Heart rate (HR) and rating of perceived exertion (RPE) were recorded at each workload throughout the test.

Predicted VO2peak in CFS (1331 +/- 377 ml) subjects was significantly (P < or = 0.05) lower than the CON group (1990 +/- 332 ml), and CFS subjects achieved volitional exhaustion significantly faster (CFS: 351 +/- 224 s; CON: 715 +/- 176 s) at a lower power output (CFS: 100 +/- 39 W; CON: 163 +/- 34 W). CFS subjects also exhibited a significantly lower maximum HR (CFS: 154 +/- 13 bpm; CON: 186 +/- 11 bpm) and consistently reported a higher RPE at the same absolute workload when compared with CON subjects. Prefrontal cortex HbO2, HHb and tHb were significantly lower at maximal exercise in CFS versus CON, as was TOI during exercise and recovery.

The CFS subjects exhibited significant exercise intolerance and reduced prefrontal oxygenation and tHb response when compared with CON subjects. These data suggest that the altered cerebral oxygenation and blood volume may contribute to the reduced exercise load in CFS, and supports the contention that CFS, in part, is mediated centrally.

Source: Patrick Neary J, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imaging. 2008 Nov;28(6):364-72. doi: 10.1111/j.1475-097X.2008.00822.x. Epub 2008 Jul 29. https://www.ncbi.nlm.nih.gov/pubmed/18671793

Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome

Abstract:

The elevated RNase L enzyme activity observed in some Chronic Fatigue Syndrome (CFS) patients may be linked to the low exercise tolerance and functional impairment that typify this disease. The purpose of this investigation was to determine if specific indicators of physical performance can predict abnormal RNase L activity in CFS patients. Seventy-three CFS patients performed a graded exercise test to voluntary exhaustion. Forty-six patients had elevated RNase L levels. This measure was employed as the dependent variable in a discriminant function analysis, with peak V02, exercise duration and Karnofsky Performance Scores (KPS) serving as the independent variables. All three variables entered the single significant function (p < 0.001). The elevated RNase L group had a lower peak V02 and duration than the normal group, but a higher KPS. The results suggest that both exercise testing and the RNase L biomarker have potential to aid in the diagnosis of CFS.

Source: Snell CR, Vanness JM, Strayer DR, Stevens SR. Physical performance and prediction of 2-5A synthetase/RNase L antiviral pathway activity in patients with chronic fatigue syndrome. In Vivo. 2002 Mar-Apr;16(2):107-9. http://www.ncbi.nlm.nih.gov/pubmed/12073768

Chronic fatigue, arthralgia, and malaise

A 25 year old female veterinary nurse presented with a six year history of general malaise and severe fatigue. Associated with this she described frequent (monthly) episodes of polyarthralgia affecting all joints but with a predilection for the small joints of the hands and the wrists. When present this was accompanied by mild morning stiffness. In addition she experienced colicky abdominal pain, sometimes with diarrhoea, occasionally with blood mixed with her faeces. Other complaints consisted of low back pain, sore gritty eyes, and an inability to perform any physical exercise at the time of these symptoms. Her symptoms had been remarkably consistent, with no recent change to their pattern.

Six years ago she had been on a working holiday at a veterinary practice situated in New York state, USA. After eating a dish made with “blue fish” she had immediately developed severe nausea, vomiting, and malaise. Although all her acute symptoms resolved, her other symptoms started on return to the United Kingdom. She was investigated twice, at different hospitals, before being referred to this department. It had been found that her symptoms were helped by treatment with 30 mg prednisolone daily for the severe episodes and a maintenance dose of 5 mg daily. Severe episodes were occurring three to four times a year. Non-steroidal anti-inflammatory drugs, sulphasalazine, and other treatments of inflammatory bowel disease had not helped her symptoms. On all occasions the examination and investigations had been reported as normal including markers of inflammation, connective tissue disease, and radiological and histological gastrointestinal studies. No blood had been seen in her faeces. No diagnosis was made other than a seronegative arthralgia.

You can read the rest of this article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1010225/pdf/annrheumd00353-0014.pdf

Source: Gompels MM, Spickett GP. Chronic fatigue, arthralgia, and malaise. Ann Rheum Dis. 1996 Aug;55(8):502-3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1010225/

Cardiac function at rest and with exercise in the chronic fatigue syndrome

Abstract:

To evaluate a possible cardiac pathophysiology of the chronic fatigue syndrome, we compared the resting cardiac function and exercise performance of 41 patients to those of an age-matched and sex-matched normal control group.

Persistent fatigue following an acute apparently viral illness was the major complaint of all patients; none had specific cardiac symptoms nor abnormal physical findings. Electrocardiographic spatial patterns were normal in the patients, and there were no differences in the body surface sum of positive T-wave integrals between the patients (240 microV.x 10(2) +/- 107 microV.s x10(2)) and control (244 microV.x 10(2) +/- 108 microV.s x 10(2) subjects. Twenty-four hour ambulatory ECGs revealed no differences in sinus rates and incidences of ventricular dysrhythmias in the two populations. Left ventricular dimensions and systolic fractional shortening values were also similar in both groups; moreover none of the patients had segmental wall motion abnormalities.

On graded exercise testing, 20 of 32 normal subjects achieved target (85 percent of age-maximum) heart rates, compared to four of 31 patients (p less than 0.001). The duration of exercise averaged 12 +/- 4 minutes for the normal subjects and 9+/- 4 minutes for the patients (p less than 0.01). The temporal profile of exercise heart rates was dissimilar in the two groups, with patients’ rates consistently and progressively less than those of normal subjects. Peak heart rate averaged 152 +/- 16 beats per minute for the normal group vs 124 +/- 19 beats per minute for the patients (p less than 0.0001); in age-related terms, respectively, 82 +/- 6 percent of the maximum heart rate vs 66 +/- 10 percent (p less than 0.0001).

Thus, patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved.

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Source: Montague TJ, Marrie TJ, Klassen GA, Bewick DJ, Horacek BM. Cardiac function at rest and with exercise in the chronic fatigue syndrome. Chest. 1989 Apr;95(4):779-84. http://www.ncbi.nlm.nih.gov/pubmed/2924607