Skeletal muscle power and fatigue at the tolerable limit of ramp-incremental exercise in COPD

Muscle fatigue (a reduced power for a given activation) is common following exercise in COPD. Whether muscle fatigue, and reduced maximal voluntary locomotor power, are sufficient to limit whole-body exercise in COPD is unknown. We hypothesized in COPD: 1) exercise is terminated with a locomotor muscle power reserve; 2) reduction in maximal locomotor power is related to ventilatory limitation; and 3) muscle fatigue at intolerance is less than age-matched controls. We used a rapid switch from hyperbolic to isokinetic cycling to measure the decline in peak isokinetic power at the limit of incremental exercise ('performance fatigue') in 13 COPD (FEV1 49±17 %pred) and 12 controls. By establishing the baseline relationship between muscle activity and isokinetic power, we apportioned performance fatigue into the reduction in muscle activation and muscle fatigue. Peak isokinetic power at intolerance was ~130% of peak incremental power in controls (274±73 vs 212±84W, p<0.05), but ~260% in COPD (187±141 vs 72±34W, p<0.05) - greater than controls (p<0.05). Muscle fatigue as a fraction of baseline peak isokinetic power was not different in COPD vs controls (0.11±0.20 vs 0.19±0.11). Baseline to intolerance, the median frequency of maximal isokinetic muscle activity was unchanged in COPD but reduced in controls (+4.3±11.6 vs -5.5±7.6%, p<0.05). Performance fatigue as a fraction of peak incremental power was greater in COPD vs controls and related to resting (FEV1/FVC) and peak exercise (V̇E/MVV) pulmonary function (r2=0.47, r2=0.55, p<0.05). COPD patients are more fatigable than controls, but this fatigue is insufficient to constrain locomotor power and define exercise intolerance

Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD

Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10−392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the differences observed between pQTLs and eQTLs SNPs, we recommend that protein biomarker-disease association studies take into account the potential effect of common local SNPs and that pQTLs be integrated along with eQTLs to uncover disease mechanisms. Large-scale blood biomarker studies would also benefit from close attention to the ABO blood group

相対作用素エントロピーをめぐって(作用素不等式とその周辺)

Independent Ethics Committees and Institutional Review Boards for ClinicalTrial.gov: NCT01072396. (PDF 71 kb

Biological quality control for cardiopulmonary exercise testing in multicenter clinical trials.

BackgroundPrecision and accuracy assurance in cardiopulmonary exercise testing (CPET) facilitates multicenter clinical trials by maximizing statistical power and minimizing participant risk. Current guidelines recommend quality control that is largely based on precision at individual testing centers (minimizing test-retest variability). The aim of this study was to establish a multicenter biological quality control (BioQC) method that considers both precision and accuracy in CPET.MethodsBioQC testing was 6-min treadmill walking at 20 W and 70 W (below the lactate threshold) with healthy non-smoking laboratory staff (15 centers; ~16 months). Measurements were made twice within the initial 4 weeks and quarterly thereafter. Quality control was based on: 1) within-center precision (coefficient of variation [CV] for oxygen uptake [V̇O2], carbon dioxide output [V̇CO2], and minute ventilation [V̇E] within ±10%); and 2) a criterion that V̇O2 at 20 W and 70 W, and ∆V̇O2/∆WR were each within ±10 % predicted. "Failed" BioQC tests (i.e., those outside the predetermined criterion) prompted troubleshooting and repeated measurements. An additional retrospective analysis, using a composite z-score combining both BioQC precision and accuracy of V̇O2 at 70 W and ∆V̇O2/∆WR, was compared with the other methods.ResultsOf 129 tests (5 to 8 per center), 98 (76%) were accepted by within-center precision alone. Within-center CV was &lt;9%, but between-center CV remained high (9.6 to 12.5%). Only 43 (33%) tests had all V̇O2 measurements within the ±10% predicted criterion. However, a composite z-score of 0.67 identified 67 (52%) non-normal outlying tests, exclusion of which coincided with the minimum CV for CPET variables.ConclusionsStudy-wide BioQC using a composite z-score can increase study-wide precision and accuracy, and optimize the design and conduct of multicenter clinical trials involving CPET.Trial registrationClinicalTrials.gov identifier: NCT01072396; February 19, 2010

Muscle Oxidative Capacity Is Reduced in Both Upper and Lower Limbs in COPD.

IntroductionSkeletal muscle atrophy, weakness, mitochondrial loss, and dysfunction are characteristics of chronic obstructive pulmonary disease (COPD). It remains unclear whether muscle dysfunction occurs in both upper and lower limbs, because findings are inconsistent in the few studies where upper and lower limb muscle performance properties were compared within an individual. This study determined whether muscle oxidative capacity is low in upper and lower limbs of COPD patients compared with controls.MethodsOxidative capacity of the forearm and medial gastrocnemius was measured using near-infrared spectroscopy to determine the muscle O2 consumption recovery rate constant (k, min) in 20 COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2/3/4, n = 7/7/6) and 20 smokers with normal spirometry (CON). Muscle k is linearly proportional to oxidative capacity. Steps per day and vector magnitude units per minute (VMU·min) were assessed using triaxial accelerometry. Differences between group and limb were assessed by two-way ANOVA.ResultsThere was a significant main effect of group (F = 11.2, ηp = 0.13, P = 0.001): k was lower in both upper and lower limb muscles in COPD (1.01 ± 0.17 and 1.05 ± 0.24 min) compared with CON (1.29 ± 0.49 and 1.54 ± 0.60 min). There was no effect on k of limb (F = 1.8, ηp = 0.02, P = 0.18) or group-limb interaction (P = 0.35). (VMU·min) was significantly lower in COPD (-38%; P = 0.042). Steps per day did not differ between COPD (4738 ± 3194) and CON (6372 ± 2107; P = 0.286), although the difference exceeded a clinically important threshold (&gt;600-1100 steps per day).ConclusionsCompared with CON, muscle oxidative capacity was lower in COPD in both upper (-20%) and lower (-30%) limbs. These data suggest that mitochondrial loss in COPD is not isolated to locomotor muscles

Diffusing Capacity of Carbon Monoxide in&nbsp;Assessment of COPD

BackgroundDiffusing capacity of the lung for carbon monoxide (Dlco) is inconsistently obtained in patients with COPD, and the added benefit of Dlco testing beyond that of more common tools is unknown.ObjectiveThe goal of this study was to determine whether lower Dlco is associated with increased COPD morbidity independent of emphysema assessed via spirometry and CT imaging.MethodsData for 1,806 participants with COPD from the Genetic Epidemiology of COPD (COPDGene) study 5-year visit were analyzed, including pulmonary function testing, quality of life, symptoms, exercise performance, and exacerbation rates. Dlco percent predicted was primarily analyzed as a continuous variable and additionally categorized into four groups: (1) Dlco and FEV1 &gt; 50%&nbsp;(reference); (2) only Dlco&nbsp;≤ 50%; (3) only FEV1&nbsp;≤ 50%; and (4) both&nbsp;≤ 50%&nbsp;predicted. Outcomes were modeled by using multivariable linear and negative binomial regression, including emphysema and FEV1 percent predicted among other confounders.ResultsIn multivariable analyses, every 10%&nbsp;predicted decrease in Dlco was associated with symptoms and quality of life (COPD Assessment Test, 0.53 [P&nbsp;&lt; .001]; St. George's Respiratory Questionnaire, 1.67 [P&nbsp;&lt; .001]; Medical Outcomes Study Short Form 36 Physical Function, -0.89 [P&nbsp;&lt; .001]), exercise performance (6-min walk distance, -45.35 feet; P&nbsp;&lt; .001), and severe exacerbation rate (rate ratio, 1.14; P&nbsp;&lt; .001). When categorized, severe impairment in Dlco alone, FEV1 alone, or both Dlco and FEV1 were associated with significantly worse morbidity compared with the reference group (P&nbsp;&lt; .05 for all outcomes).ConclusionsImpairment in Dlco was associated with increased COPD symptoms, reduced exercise performance, and severe exacerbation risk even after accounting for spirometry and CT evidence of emphysema. These findings suggest that Dlco should be considered for inclusion in future multidimensional tools assessing COPD

Dynamic airway function during exercise in COPD assessed via impulse oscillometry before and after inhaled bronchodilators

Assessing airway function during exercise provides useful information regarding mechanical properties of the airways and the extent of ventilatory limitation in COPD. The primary aim of this study was to use impulse oscillometry (IOS) to assess dynamic changes in airway impedance across a range of exercise intensities in patients with GOLD 1-4, before and after albuterol administration. A secondary aim was to assess the reproducibility of IOS measures during exercise. Fifteen patients with COPD (8 males/7 females; age = 66 ± 8 yr; prebronchodilator FEV1 = 54.3 ± 23.6%Pred) performed incremental cycle ergometry before and 90 min after inhaled albuterol. Pulmonary ventilation and gas exchange were measured continuously, and IOS-derived indices of airway impedance were measured every 2 min immediately preceding inspiratory capacity maneuvers. Test-retest reproducibility of exercise IOS was assessed as mean difference between replicate tests in five healthy subjects (3 males/2 females). At rest and during incremental exercise, albuterol significantly increased airway reactance (X5) and decreased airway resistance (R5, R5-R20), impedance (Z5), and end-expiratory lung volume (60% ± 12% vs. 58% ± 12% TLC, main effect P = 0.003). At peak exercise, there were moderate-to-strong associations between IOS variables and IC, and between IOS variables and concavity in the expiratory limb of the spontaneous flow-volume curve. Exercise IOS exhibited moderate reproducibility in healthy subjects which was strongest with R5 (mean diff. = -0.01 ± 0.05 kPa/L/s; ICC = 0.68), R5-R20 (mean diff. = -0.004 ± 0.028 kPa/L/s; ICC = 0.65), and Z5 (mean diff. = -0.006 ± 0.021 kPa/L/s; ICC = 0.69). In patients with COPD, exercise evoked increases in airway resistance and decreases in reactance that were ameliorated by inhaled bronchodilators. The technique of exercise IOS may aid in the clinical assessment of dynamic airway function during exercise.NEW &amp; NOTEWORTHY This study provides a novel, mechanistic insight into dynamic airway function during exercise in COPD, before and after inhaled bronchodilators. The use of impulse oscillometry (IOS) to evaluate airway function is unique among exercise studies. We show strong correlations among IOS variables, dynamic hyperinflation, and shape-changes in the spontaneous expiratory flow-volume curve. This approach may aid in the clinical assessment of airway function during exercise

Hepatic insulin sensitizing substance: a novel ‘sensocrine' mechanism to increase insulin sensitivity in anaesthetized rats

1. We recently described the sensory nitrergic nature of the hepatic insulin sensitizing substance (HISS) mechanism linked to postprandial activation of anterior hepatic plexus fibres in rabbits. This study is designed to assess the involvement of the sensory pathways in this mechanism. 2. Selective sensory denervation of the anterior hepatic plexus (AHP) was achieved by a 3-day perineurial treatment with 2% capsaicin solution in Wistar rats (230–250 g). After 1 week, hyperinsulinaemic (100 μU kg(−1)) euglycaemic (5.5 mmol kg(−1)) glucose clamp studies were performed to estimate insulin sensitivity. 3. The rats with regional AHP sensory denervation exhibited a significantly decreased insulin sensitivity, that is, 9.1±1.0 mg kg(−1) min(−1) glucose reinstalled euglycaemia vs 13.3±1.9 mg kg(−1) min(−1) glucose (P<0.01) in control rats. 4. Acute partial hepatic denervation by AHP cut was without effect on insulin sensitivity, whereas chronic hepatic denervation induced insulin resistance was similar to that achieved by regional AHP capsaicin treatment. 5. Intraportal administration of L-NAME (10 mg kg(−1)) decreased, whereas capsaicin (0.3 mg kg(−1) min(−1)) increased insulin sensitivity. Neither atropine (1 mg kg(−1)) nor acetylcholine (1–10 μg mg min(−1)) produced any significant effect. In animals with preceding regional capsaicin desensitization, none of the pharmacological manoeuvres modified the resulting insulin-resistant state. 6. Cysteamine (200 mg kg(−1) s.c.) is known to cause functional somatostatin depletion-induced insulin resistance similar to that produced by either chronic partial hepatic denervation or perineurial AHP capsaicin desensitization. Intraportal capsaicin (0.3 mg kg(−1) min(−1)) was unable to modify insulin resistance achieved by cysteamine. 7. We conclude that capsaicin-sensitive sensory fibres play a crucial role in neurogenic insulin sensitization known as the HISS mechanism without involvement of anatomical reflex-mediated circuits. The results also suggest that HISS is identical to somatostatin of AHP sensory neural origin

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p&lt;0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p&lt;0.001), decreased functional performance (6-min walk distance (6MWD): p&lt;0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p&lt;0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity