Cardiac output and arteriovenous oxygen difference contribute to lower peak oxygen uptake in patients with fibromyalgia.

BACKGROUND: Patients with fibromyalgia (FM) exhibit low peak oxygen uptake ([Formula: see text]O2peak). We aimed to detect the contribution of cardiac output to ([Formula: see text]) and arteriovenous oxygen difference [Formula: see text] to [Formula: see text] from rest to peak exercise in patients with FM. METHODS: Thirty-five women with FM, aged 23 to 65 years, and 23 healthy controls performed a step incremental cycle ergometer test until volitional fatigue. Alveolar gas exchange and pulmonary ventilation were measured breath-by-breath and adjusted for fat-free body mass (FFM) where appropriate. [Formula: see text] (impedance cardiography) was monitored. [Formula: see text] was calculated using Fick's equation. Linear regression slopes for oxygen cost (∆[Formula: see text]O2/∆work rate) and [Formula: see text] to [Formula: see text]O2 (∆[Formula: see text]/∆[Formula: see text]O2) were calculated. Normally distributed data were reported as mean ± SD and non-normal data as median [interquartile range]. RESULTS: [Formula: see text]O2peak was lower in FM patients than in controls (22.2 ± 5.1 vs. 31.1 ± 7.9 mL∙min-1∙kg-1, P < 0.001; 35.7 ± 7.1 vs. 44.0 ± 8.6 mL∙min-1∙kg FFM-1, P < 0.001). [Formula: see text] and C(a-v)O2 were similar between groups at submaximal work rates, but peak [Formula: see text] (14.17 [13.34-16.03] vs. 16.06 [15.24-16.99] L∙min-1, P = 0.005) and C(a-v)O2 (11.6 ± 2.7 vs. 13.3 ± 3.1 mL O2∙100 mL blood-1, P = 0.031) were lower in the FM group. No significant group differences emerged in ∆[Formula: see text]O2/∆work rate (11.1 vs. 10.8 mL∙min-1∙W-1, P = 0.248) or ∆[Formula: see text]/∆[Formula: see text]O2 (6.58 vs. 5.75, P = 0.122) slopes. CONCLUSIONS: Both [Formula: see text] and C(a-v)O2 contribute to lower [Formula: see text]O2peak in FM. The exercise responses were normal and not suggestive of a muscle metabolism pathology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03300635. Registered 3 October 2017-Retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03300635 .

Muscle activity and acute stress in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) patients are likely to differ from healthy controls in muscle activity and in reactivity to experimental stress. METHODS: We compared psychophysiological reactivity to cognitive stress between 51 female FM patients aged 18 to 65 years and 31 age- and sex-matched healthy controls. They underwent a 20-minute protocol consisting of three phases of relaxation and two phases of cognitive stress. We recorded surface electromyography normalized to maximum voluntary muscle contraction (%EMG), the percentage of time with no muscle activity (EMG rest time), and subjective pain and stress intensities. We compared group reactivity using linear modelling and adjusted for psychological and life-style factors. RESULTS: The FM patients had a significantly higher mean %EMG (2.2 % vs. 1.0 %, p < 0.001), pain intensity (3.6 vs. 0.2, p < 0.001), and perceived stress (3.5 vs. 1.4, p < 0.001) and lower mean EMG rest time (26.7 % vs. 47.2 %, p < 0.001). In the FM patients, compared with controls, the pain intensity increased more during the second stress phase (0.71, p = 0.028), and the %EMG decreased more during the final relaxation phase (-0.29, p = 0.036). Within the FM patients, higher BMI predicted higher %EMG but lower stress. Leisure time physical activity predicted lower %EMG and stress and higher EMG rest time. Higher perceived stress predicted lower EMG rest time, and higher trait anxiety predicted higher pain and stress overall. CONCLUSIONS: Our results suggest that repeated cognitive stress increases pain intensity in FM patients. FM patients also had higher resting muscle activity, but their muscle activity did not increase with pain. Management of stress and anxiety might help control FM flare-ups. TRIAL REGISTRATION: Retrospectively registered on ClinicalTrials.gov ( NCT03300635 ).

Predictors of fibromyalgia: a population-based twin cohort study.

BACKGROUND: Fibromyalgia (FM) is a pain syndrome, the mechanisms and predictors of which are still unclear. We have earlier validated a set of FM-symptom questions for detecting possible FM in an epidemiological survey and thereby identified a cluster with "possible FM". This study explores prospectively predictors for membership of that FM-symptom cluster. METHODS: A population-based sample of 8343 subjects of the older Finnish Twin Cohort replied to health questionnaires in 1975, 1981, and 1990. Their answers to the set of FM-symptom questions in 1990 classified them in three latent classes (LC): LC1 with no or few symptoms, LC2 with some symptoms, and LC3 with many FM symptoms. We analysed putative predictors for these symptom classes using baseline (1975 and 1981) data on regional pain, headache, migraine, sleeping, body mass index (BMI), physical activity, smoking, and zygosity, adjusted for age, gender, and education. Those with a high likelihood of having fibromyalgia at baseline were excluded from the analysis. In the final multivariate regression model, regional pain, sleeping problems, and overweight were all predictors for membership in the class with many FM symptoms. RESULTS: The strongest non-genetic predictor was frequent headache (OR 8.6, CI 95% 3.8-19.2), followed by persistent back pain (OR 4.7, CI 95% 3.3-6.7) and persistent neck pain (OR 3.3, CI 95% 1.8-6.0). CONCLUSIONS: Regional pain, frequent headache, and persistent back or neck pain, sleeping problems, and overweight are predictors for having a cluster of symptoms consistent with fibromyalgia.

Machine learning identifies fatigue as a key symptom of fibromyalgia reflected in tyrosine, purine, pyrimidine, and glutaminergic metabolism.

Fibromyalgia patients vary in clinical phenotype and treatment can be challenging. The pathophysiology of fibromyalgia is incompletely understood but appears to involve metabolic changes at rest or in response to stress. We enrolled 54 fibromyalgia patients and 31 healthy controls to this prospective study. Symptoms were assessed using the Fibromyalgia Impact Questionnaire (FIQ) and blood samples were collected for metabolomics analysis at baseline and after an oral glucose tolerance test and a cardiopulmonary exercise test. We identified key symptoms of fibromyalgia and related them to changes in metabolic pathways with supervised and unsupervised machine learning methods. Algorithms trained with the FIQ information assigned the fibromyalgia diagnosis in new data with balanced accuracy of 88% while fatigue alone already provided the diagnosis with 86% accuracy. Supervised analyses reduced the metabolomic information from 77 to 13 key markers. With these metabolites, fibromyalgia could be identified in new cases with 79% accuracy. In addition, 5-hydroxyindole-3-acetic acid and glutamine levels correlated with the severity of fatigue. Patients differed from controls at baseline in tyrosine and purine pathways, and in the pyrimidine pathway after the stress challenges. Several key markers are involved in glutaminergic neurotransmission. This data-driven analysis highlights fatigue as a key symptom of fibromyalgia. Fibromyalgia is associated with metabolic changes which also reflect the degree of fatigue. Responses to metabolic and physical stresses result in a metabolic pattern that allows discrimination of fibromyalgia patients from controls and narrows the focus on key pathophysiological processes in fibromyalgia as treatment targets.

Heart rate variability responses to cognitive stress in fibromyalgia are characterised by inadequate autonomous system stress responses: a clinical trial.

Fibromyalgia (FM) is associated with sympathetically dominant dysautonomia, but the connection between dysautonomia and FM symptoms is unclear. Dysautonomia can be analysed with heart rate variability (HRV) and it has been proposed that FM patients comprise subgroups with differing profiles of symptom severity. In our study, 51 female FM patients aged 18 to 65 years and 31 age-matched healthy female controls followed a 20-min protocol of alternating relaxation and cognitive stress (mental arithmetic). Heart rates and electrocardiograms were registered. The HRV measures of heart rate (HR), mean interval between heart beats (RRmean), root mean squared interval differences of successive beats (RMSSD), and the standard deviation of intervals between normal heart beats (SDNN) were analysed with generalized linear modelling. Features in HRV reactivity which differed between FM patients and controls were used to cluster the FM patients and cluster characteristics were analysed. FM patients had higher baseline HR (72.3 [SD 12.7] vs 64.5 [7.80], p < 0.001) and lower RRmean (0.844 [0.134] vs 0.934 [0.118], p = 0.002), compared with controls. They also reacted to repeated cognitive stress with an attenuated rise in HR (- 4.41 [95% CI - 7.88 to - 0.93], p = 0.013) and attenuated decrease of RRmean (0.06 [95 CI 0.03 to 0.09], p < 0.001), compared with controls. Clustering of FM patients by HRV reactivity resulted in three clusters characterised by (1) normal levels of HRV and HRV reactivity with low levels of depressive mood and anxiety, (2) reduced levels of HRV and impaired HRV reactivity with increased levels of depressive mood and high levels of anxiety, and (3) lowest HRV and most impaired HRV reactivity with the highest scores for depressive mood and anxiety. Our results show that FM patients have lower HRV than healthy controls and their autonomous reactions to cognitive stress are attenuated. Dysautonomia in FM associates with mood disturbance. Trial registration ClinicalTrials.gov (NCT03300635). Registered October 3 2017-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03300635 .

Elevated highly sensitive C-reactive protein in fibromyalgia associates with symptom severity.

Objectives: Fibromyalgia (FM), a common pain syndrome, is thought to be a non-inflammatory, nociplastic condition, but evidence implicating neuroinflammation has been increasing. Systemic inflammation may be associated with more severe symptoms in some FM patients. We studied healthy controls and FM patients with and without systemic inflammation detectable using high-sensitivity CRP (hsCRP) measurement. Methods: We measured hsCRP levels and gathered clinical and questionnaire data [including the Fibromyalgia Impact Questionnaire (FIQ)] from 40 female FM patients and 30 age-matched healthy women. An hsCRP level >3 mg/l was considered elevated. Results: FM patients had significantly higher mean hsCRP levels than controls, explained by overweight and lower leisure-time physical activity. Eight FM patients had elevated hsCRP levels and 29 had normal hsCRP levels. Levels of hsCRP were significantly correlated with FIQ scores. Patients with elevated hsCRP had higher FIQ scores, with worse physical functioning and greater pain and were less likely to be employed than patients with normal hsCRP. These patient groups did not differ by blood count, liver function or lipid profiles, nor by education, psychological measures, sleep disturbance, smoking or comorbidities. Conclusion: Some FM patients have elevated hsCRP, mostly due to overweight and physical inactivity. They have worse symptoms and their ability to work is impaired. Measurement of hsCRP may help to identify FM patients in greatest need of interventions supporting working ability. Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov), NCT03300635.

Glucose tolerance in fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) patients have an increased risk for glucose metabolism disturbances, and impaired glucose tolerance may be associated with symptom severity. Elevated levels of plasma lactate have been detected in FM patients. Both pyruvate and lactate are produced in glucose metabolism and reflect oxidative metabolism. The objective of our study was to analyse disturbances in glucose, pyruvate, or lactate metabolism in FM patients. METHODS: We measured plasma levels of glucose, pyruvate, and lactate during an oral glucose tolerance test in 40 non-diabetic, female FM patients and 30 age- and gender-matched healthy controls. RESULTS: FM patients showed a higher glycaemic response to the glucose load at 1 hour (F [1,68] = 10.4, P = .006) and 2 hours (F [1,68] = 7.80, P = .02), and higher glucose area under the curve (13.8 [SD 2.92] vs 11.6 [SD 2.31], P < .01), than healthy controls. Group differences were explained by higher body mass index and percentage of smokers among the FM patients. Pyruvate and lactate levels were similar in both groups. DISCUSSION: Impaired glucose regulation in FM patients is likely not due to FM itself, but to associated lifestyle factors. Our results highlight the importance of assessing the glucose regulation status and the lifestyle factors affecting glucose regulation in FM patients for prevention or early treatment of diabetes and associated complications. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03300635).

FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders.

OBJECTIVE: To validate new mitochondrial myopathy serum biomarkers for diagnostic use. METHODS: We analyzed serum FGF21 (S-FGF21) and GDF15 from patients with (1) mitochondrial diseases and (2) nonmitochondrial disorders partially overlapping with mitochondrial disorder phenotypes. We (3) did a meta-analysis of S-FGF21 in mitochondrial disease and (4) analyzed S-Fgf21 and skeletal muscle Fgf21 expression in 6 mouse models with different muscle-manifesting mitochondrial dysfunctions. RESULTS: We report that S-FGF21 consistently increases in primary mitochondrial myopathy, especially in patients with mitochondrial translation defects or mitochondrial DNA (mtDNA) deletions (675 and 347 pg/mL, respectively; controls: 66 pg/mL, p < 0.0001 for both). This is corroborated in mice (mtDNA deletions 1,163 vs 379 pg/mL, p < 0.0001). However, patients and mice with structural respiratory chain subunit or assembly factor defects showed low induction (human 335 pg/mL, p < 0.05; mice 335 pg/mL, not significant). Overall specificities of FGF21 and GDF15 to find patients with mitochondrial myopathy were 89.3% vs 86.4%, and sensitivities 67.3% and 76.0%, respectively. However, GDF15 was increased also in a wide range of nonmitochondrial conditions. CONCLUSIONS: S-FGF21 is a specific biomarker for muscle-manifesting defects of mitochondrial translation, including mitochondrial transfer-RNA mutations and primary and secondary mtDNA deletions, the most common causes of mitochondrial disease. However, normal S-FGF21 does not exclude structural respiratory chain complex or assembly factor defects, important to acknowledge in diagnostics. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that elevated S-FGF21 accurately distinguishes patients with mitochondrial myopathies from patients with other conditions, and FGF21 and GDF15 mitochondrial myopathy from other myopathies.

The burden of symptoms predicts early retirement: a twin cohort study on fibromyalgia-associated symptoms.

OBJECTIVE: To assess whether symptoms of fibromyalgia (FM) predict disability retirement or mortality. METHODS: All Finnish Twin Cohort members and diagnosed FM-patients who had answered the same health questionnaire in 1990-1992 were studied. A sample of 10,608 working aged individuals of the cohort was classified in homogenous groups based on symptom profile with latent class analysis, using a battery of questions addressing FM-associated symptoms validated between FM-patients and twins. This resulted in three classes: no or few symptoms (LC1), some symptoms (LC2), and high load of FM-symptoms (LC3). In a 14-year follow-up, 1990-2004, information on disability retirement was obtained from official pension registers. Further linkage with Population Register Centre data for 1990-2009 yielded information on the vital status of the cohort subjects. Those with malignancies or inflammatory rheumatic diseases were excluded. RESULTS: Cumulative incidence of early disability retirement was 9.5% among all 8448 individuals (after exclusions), and 26% in LC3. Adjusted hrs for early retirement were 1.0 (reference class) in LC1, 1.5 (95%CI 1.2-1.7) in LC2, and 2.9 (2.4-3.6) in LC3 for all causes and 1.8 (1.4-2.5) in LC2 and 5.0 (3.6-6.9) in LC3 for musculoskeletal disorders. In 173,675 person-years, the high symptom class (LC3) had a 43% (95% CI 17-75%) increased overall mortality risk, which was fully accounted for by adjustment for lifestyle factors, mainly smoking. CONCLUSION: Symptoms associated with FM strongly correlate with early disability retirement. Lifestyle problems associated with high symptom load need prompt management to avoid increased risk of mortality.

Clustering of symptoms associated with fibromyalgia in a Finnish Twin Cohort.

The objective was to assess the prevalence and heritability of symptoms associated with fibromyalgia in a population-based working-age twin sample. The study was based on the 12,502 like-sexed twins of the Finnish Twin Cohort and 49 diagnosed fibromyalgia patients who answered the same questionnaire in 1990-1992. Questions that were considered to best match symptoms of fibromyalgia were validated between the twins and the fibromyalgia patients. Latent class analysis was used to classify the subjects into more homogeneous groups with respect to the symptom items. The pairwise distribution of symptom classes in relation to zygosity and gender was modelled using quantitative genetic models to estimate heritability. Responses to all fibromyalgia-related items were obtained from 10,608 twins. A similar proportion of men (12%) and women (13%) was placed in the third latent class, which best represented possible fibromyalgia patients. Subjects in this class had a similar symptom profile as the diagnosed fibromyalgia patient group, but they were less severely affected. The two other latent classes represented subjects that were virtually symptom free and subjects with some symptoms. The heritability of liability to symptom class membership was estimated to be 51% (95% CI 45-56%). The prevalence of symptoms associated with fibromyalgia in our population-based sample unselected for disease status was comparable to the prevalence of widespread pain reported in population based studies. The symptoms known to be associated with fibromyalgia seem to have a strong genetic background.