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Objectives: Continuous positive airway pressure (CPAP) improves upper airway obstruction in patients with obstructive sleep apnoea (OSA), who often are overweight-obese. Although it is thought that CPAP improves long-term blood pressure control (BP), the impact of acute and short-term CPAP use on the cardiovascular system in obese patients has not been described in detail. Methods: Obese patients (body mass index, BMI > 25 kg/m2) with OSA were studied awake, supine during incremental CPAP titration (4–20 cmH2O, +2 cmH2O/3 mins). BP was measured continuously with a beat-to-beat BP monitor (Ohmeda 2300, Finapres Medical Systems, Amsterdam/NL), BP variability (BPV) was calculated as the standard deviation of BP at each CPAP level, the 95% confidence interval (95%CI) was calculated and changes in BP and BPV were reported. Results: 15 patients (12 male, 48 ± 10) years, BMI 38.9 ± 5.8 kg/m2) were studied; the baseline BP was 131.0 ± 10.2/85.1 ± 9.1 mmHg. BP and BPV increased linearly with CPAP titration (systolic BP r = 0.960, p <.001; diastolic BP r = 0.961, p <.001; systolic BPV r = 0.662, p =.026; diastolic BPV r = 0.886, p <.001). The systolic BP increased by +17% (+23.15 (7.9, 38.4) mmHg; p =.011) and the diastolic BP by +23% (+18.27 (2.33, 34.21) mmHg; p =.009), when titrating CPAP to 20 cmH2O. Systolic BPV increased by +96% (+5.10 (0.67, 9.53) mmHg; p <.001) and was maximal at 14 cmH2O, and diastolic BPV by +97% (+3.02 (0.26, 5.78) mmHg; p <.001) at 16 cmH2O. Conclusion: Short-term incremental CPAP leads to significant increases in BP and BPV in obese patients with OSA while awake. Careful titration of pressures is required to minimise the risk of nocturnal awakenings while improving BP control.

We described physical activity measures and hourly patterns in patients with chronic obstructive pulmonary disease (COPD) after stratification for generic and COPD-specific characteristics and, based on multiple physical activity measures, we identified clusters of patients. In total, 1001 patients with COPD (65% men; age, 67 years; forced expiratory volume in the first second [FEV 1 ], 49% predicted) were studied cross-sectionally. Demographics, anthropometrics, lung function and clinical data were assessed. Daily physical activity measures and hourly patterns were analysed based on data from a multisensor armband. Principal component analysis (PCA) and cluster analysis were applied to physical activity measures to identify clusters. Age, body mass index (BMI), dyspnoea grade and ADO index (including age, dyspnoea and airflow obstruction) were associated with physical activity measures and hourly patterns. Five clusters were identified based on three PCA components, which accounted for 60% of variance of the data. Importantly, couch potatoes (i.e. the most inactive cluster) were characterised by higher BMI, lower FEV 1 , worse dyspnoea and higher ADO index compared to other clusters (p < 0.05 for all). Daily physical activity measures and hourly patterns are heterogeneous in COPD. Clusters of patients were identified solely based on physical activity data. These findings may be useful to develop interventions aiming to promote physical activity in COPD.

Introduction: Obstructive sleep apnoea (OSA) is characterised by a loss of neuromuscular tone of the upper airway dilator muscles while asleep. This study investigated the effectiveness of transcutaneous electrical stimulation in patients with OSA. Patients and methods: This was a randomised, sham-controlled crossover trial using transcutaneous electrical stimulation of the upper airway dilator muscles in patients with confirmed OSA. Patients were randomly assigned to one night of sham stimulation and one night of active treatment. The primary outcome was the 4% oxygen desaturation index, responders were defined as patients with a reduction >25% in the oxygen desaturation index when compared with sham stimulation and/or with an index <5/hour in the active treatment night. Results: In 36 patients (age mean 50.8 (SD 11.2) years, male/female 30/6, body mass index median 29.6 (IQR 26.9-34.9) kg/m2, Epworth Sleepiness Scale 10.5 (4.6) points, oxygen desaturation index median 25.7 (16.0-49.1)/hour, apnoea-hypopnoea index median 28.1 (19.0-57.0)/hour) the primary outcome measure improved when comparing sham stimulation (median 26.9 (17.5-39.5)/hour) with active treatment (median 19.5 (11.6-40.0)/hour; p=0.026), a modest reduction of the mean by 4.1 (95% CI -0.6 to 8.9)/hour. Secondary outcome parameters of patients' perception indicated that stimulation was well tolerated. Responders (47.2%) were predominantly from the mild-to-moderate OSA category. In this subgroup, the oxygen desaturation index was reduced by 10.0 (95% CI 3.9 to 16.0)/hour (p<0.001) and the apnoea-hypopnoea index was reduced by 9.1 (95% CI 2.0 to 16.2)/hour (p=0.004). Conclusion: Transcutaneous electrical stimulation of the pharyngeal dilators during a single night in patients with OSA improves upper airway obstruction and is well tolerated. Trial registration number: NCT01661712.

Background: Loss of quadriceps muscle oxidative phenotype (OXPHEN) is an evident and debilitating feature of chronic obstructive pulmonary disease (COPD). We recently demonstrated involvement of the inflammatory classical NF-kappaB pathway in inflammation-induced impairments in muscle OXPHEN. The exact underlying mechanisms however are unclear. Interestingly, IkappaB kinase alpha (IKK-alpha: a key kinase in the alternative NF-kappaB pathway) was recently identified as a novel positive regulator of skeletal muscle OXPHEN. We hypothesised that inflammation-induced classical NF-kappaB activation contributes to loss of muscle OXPHEN in COPD by reducing IKK-alpha expression. Methods: Classical NF-kappaB signalling was activated (molecularly or by tumour necrosis factor alpha: TNF-alpha) in cultured myotubes and the impact on muscle OXPHEN and IKK-alpha levels was investigated. Moreover, the alternative NF-kappaB pathway was modulated to investigate the impact on muscle OXPHEN in absence or presence of an inflammatory stimulus. As a proof of concept, quadriceps muscle biopsies of COPD patients and healthy controls were analysed for expression levels of IKK-alpha, OXPHEN markers and TNF-alpha. Results: IKK-alpha knock-down in cultured myotubes decreased expression of OXPHEN markers and key OXPHEN regulators. Moreover, classical NF-kappaB activation (both by TNF-alpha and IKK-beta over-expression) reduced IKK-alpha levels and IKK-alpha over-expression prevented TNF-alpha-induced impairments in muscle OXPHEN. Importantly, muscle IKK-alpha protein abundance and OXPHEN was reduced in COPD patients compared to controls, which was more pronounced in patients with increased muscle TNF-alpha mRNA levels. Conclusion: Classical NF-kappaB activation impairs skeletal muscle OXPHEN by reducing IKK-alpha expression. TNF-alpha-induced reductions in muscle IKK-alpha may accelerate muscle OXPHEN deterioration in COPD.

Background: Loss of quadriceps muscle oxidative phenotype (OXPHEN) is an evident and debilitating feature of chronic obstructive pulmonary disease (COPD). We recently demonstrated involvement of the inflammatory classical NF-kappaB pathway in inflammation-induced impairments in muscle OXPHEN. The exact underlying mechanisms however are unclear. Interestingly, IkappaB kinase alpha (IKK-alpha: a key kinase in the alternative NF-kappaB pathway) was recently identified as a novel positive regulator of skeletal muscle OXPHEN. We hypothesised that inflammation-induced classical NF-kappaB activation contributes to loss of muscle OXPHEN in COPD by reducing IKK-alpha expression. Methods: Classical NF-kappaB signalling was activated (molecularly or by tumour necrosis factor alpha: TNF-alpha) in cultured myotubes and the impact on muscle OXPHEN and IKK-alpha levels was investigated. Moreover, the alternative NF-kappaB pathway was modulated to investigate the impact on muscle OXPHEN in absence or presence of an inflammatory stimulus. As a proof of concept, quadriceps muscle biopsies of COPD patients and healthy controls were analysed for expression levels of IKK-alpha, OXPHEN markers and TNF-alpha. Results: IKK-alpha knock-down in cultured myotubes decreased expression of OXPHEN markers and key OXPHEN regulators. Moreover, classical NF-kappaB activation (both by TNF-alpha and IKK-beta over-expression) reduced IKK-alpha levels and IKK-alpha over-expression prevented TNF-alpha-induced impairments in muscle OXPHEN. Importantly, muscle IKK-alpha protein abundance and OXPHEN was reduced in COPD patients compared to controls, which was more pronounced in patients with increased muscle TNF-alpha mRNA levels. Conclusion: Classical NF-kappaB activation impairs skeletal muscle OXPHEN by reducing IKK-alpha expression. TNF-alpha-induced reductions in muscle IKK-alpha may accelerate muscle OXPHEN deterioration in COPD.

Background: Physical inactivity in COPD is associated with poor outcomes. Therefore, it is important to understand the determinants of moderate-to-vigorous physical activity (MVPA) in COPD. We aimed to assess the mean level of MVPA after stratification for gender, forced expiratory volume in the first second (FEV1) and body-mass index (BMI). Methods: In 1064 COPD subjects (716 men; age: 67±8 years; BMI: 27±6 kg• m-2; FEV1: 50±21 % predicted) from 14 centers, MVPA time was assessed using the SenseWear Armband activity monitor for ≥4 days. Gender, FEV1 and BMI were used for stratification. Results: In total, 6300 days with MVPA data were obtained, with a median (IQR) MVPA time of 27 (11-59) min• day-1. 47% of the subjects had a MVPA time ≥30 min• day-1. Men had a higher MVPA time than women (29 (12-63) versus 24 (9-52) min• day-1, respectively; p=0.002). Figure 1 presents the mean time in MVPA after stratification for GOLD classes and BMI in men (A) and women (B). Conclusions: This multicenter study showed that MVPA time generally is BMI-dependent (higher BMI results in lower MVPA) and GOLD-dependent (higher GOLD results in lower MVPA) in men and women with COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by weight loss, muscle wasting (in advanced disease ultimately resulting in cachexia), and loss of muscle oxidative phenotype (oxphen). This study investigates the effect of inflammation (as a determinant of muscle wasting) on muscle oxphen by using cell studies combined with analyses of muscle biopsies of patients with COPD and control participants. We analyzed markers (citrate synthase, beta-hydroxyacyl-CoA dehydrogenase, and cytochrome c oxidase IV) and regulators (PGC-1alpha, PPAR-alpha, and Tfam) of oxphen in vastus lateralis muscle biopsies of patients with advanced COPD and healthy smoking control participants. Here 17 of 73 patients exhibited elevated muscle TNF-alpha mRNA levels. In these patients, significantly lower mRNA levels of all oxidative markers/regulators were found. Interestingly, these patients also had a significantly lower body mass index and tended to have less muscle mass. In cultured muscle cells, mitochondrial protein content and myosin heavy chain isoform I (but not II) protein and mRNA levels were reduced on chronic TNF-alpha stimulation. TNF-alpha also reduced mitochondrial respiration in a nuclear factor kappaB (NF-kappaB) -dependent manner. Importantly, TNF-alpha-induced NF-kappaB activation decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxphen. In conclusion, these results demonstrate that TNF-alpha impairs muscle oxphen in a NF-kappaB-dependent manner.-Remels, A. H. V., Gosker, H. R., Schrauwen, P., Hommelberg, P. P. H., Sliwinski, P., Polkey, M., Galdiz, J., Wouters, E. F. M., Langen, R. C. J., Schols, A. M. W. J. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?

Chronic obstructive pulmonary disease (COPD) is characterized by weight loss, muscle wasting (in advanced disease ultimately resulting in cachexia), and loss of muscle oxidative phenotype (oxphen). This study investigates the effect of inflammation (as a determinant of muscle wasting) on muscle oxphen by using cell studies combined with analyses of muscle biopsies of patients with COPD and control participants. We analyzed markers (citrate synthase, beta-hydroxyacyl-CoA dehydrogenase, and cytochrome c oxidase IV) and regulators (PGC-1alpha, PPAR-alpha, and Tfam) of oxphen in vastus lateralis muscle biopsies of patients with advanced COPD and healthy smoking control participants. Here 17 of 73 patients exhibited elevated muscle TNF-alpha mRNA levels. In these patients, significantly lower mRNA levels of all oxidative markers/regulators were found. Interestingly, these patients also had a significantly lower body mass index and tended to have less muscle mass. In cultured muscle cells, mitochondrial protein content and myosin heavy chain isoform I (but not II) protein and mRNA levels were reduced on chronic TNF-alpha stimulation. TNF-alpha also reduced mitochondrial respiration in a nuclear factor kappaB (NF-kappaB) -dependent manner. Importantly, TNF-alpha-induced NF-kappaB activation decreased promoter transactivation and transcriptional activity of regulators of mitochondrial biogenesis and muscle oxphen. In conclusion, these results demonstrate that TNF-alpha impairs muscle oxphen in a NF-kappaB-dependent manner.-Remels, A. H. V., Gosker, H. R., Schrauwen, P., Hommelberg, P. P. H., Sliwinski, P., Polkey, M., Galdiz, J., Wouters, E. F. M., Langen, R. C. J., Schols, A. M. W. J. TNF-alpha impairs regulation of muscle oxidative phenotype: implications for cachexia?

Although many studies have reported improvement in lung function following LVRS, the magnitude of improvement and subsequent decline has not been evaluated against medical therapy after the second year. Methods: Existing pulmonary function records were collated for each participant since randomisation from the Brompton LVRS trial cohort. Longitudinal data analysis was used to profile the history of medically treated patients and the effect of LVRS. Results: Pulmonary function results were collated from survivors over a median of 25 (17 to 39) months. The estimated immediate increase in mean FEV1 following surgery was + 0.259 l (0.179, 0.339), with a rate of change of - 0.005 l (- 0.009, - 0.001) per month compared to medical therapy (p < 0.001). The changes in the secondary outcome measures (LVRS compared to medical therapy) were an increase in FVC (p = 0.004), decrease in RV (p < 0.001) and TLC (p < 0.001), with differences that were maintained over time. The initial reduction in RV/TLC ratio was sustained (p < 0.001), but the estimated initial increase in peak flow was accompanied by a gradual decline that was not statistically significant (p = 0.062). KCOc showed no immediate change, but there was a gradual sustained increase with time (p = 0.009). Mean oxygen saturations improved and continued to do so compared to patients on medical therapy (p = 0.001). Conclusion: The immediate increase in FEV1 is not sustained, although the mechanical improvements of LVRS on increasing FVC, reducing both the RV and RV/TLC ratio, appear to be maintained. The important benefits of LVRS may be the gradual and sustained increase in transfer factor accompanied by improved oxygen saturations.

Although many studies have reported improvement in lung function following LVRS, the magnitude of improvement and subsequent decline has not been evaluated against medical therapy after the second year. Methods: Existing pulmonary function records were collated for each participant since randomisation from the Brompton LVRS trial cohort. Longitudinal data analysis was used to profile the history of medically treated patients and the effect of LVRS. Results: Pulmonary function results were collated from survivors over a median of 25 (17 to 39) months. The estimated immediate increase in mean FEV1 following surgery was + 0.259 l (0.179, 0.339), with a rate of change of - 0.005 l (- 0.009, - 0.001) per month compared to medical therapy (p < 0.001). The changes in the secondary outcome measures (LVRS compared to medical therapy) were an increase in FVC (p = 0.004), decrease in RV (p < 0.001) and TLC (p < 0.001), with differences that were maintained over time. The initial reduction in RV/TLC ratio was sustained (p < 0.001), but the estimated initial increase in peak flow was accompanied by a gradual decline that was not statistically significant (p = 0.062). KCOc showed no immediate change, but there was a gradual sustained increase with time (p = 0.009). Mean oxygen saturations improved and continued to do so compared to patients on medical therapy (p = 0.001). Conclusion: The immediate increase in FEV1 is not sustained, although the mechanical improvements of LVRS on increasing FVC, reducing both the RV and RV/TLC ratio, appear to be maintained. The important benefits of LVRS may be the gradual and sustained increase in transfer factor accompanied by improved oxygen saturations.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease with associated systemic complications including loss of muscle mass and function and increased cardiovascular risk. We hypothesised that elevated fibrinogen would be associated with muscle dysfunction and cardiovascular risk. Methods: ERICA is a multicentre, observational study of patients with COPD. Assessments include: spirometry (FEV1%), fibrinogen, aortic stiffness (pulse wave velocity (PWV)), quadriceps maximum voluntary contraction (QMVC) force, 6-minute walking distance (6MWD), Short Physical Performance Battery (SPPB) and MRC breathlessness. Results: Thus far 378 patients (151 male), have been evaluated. Mean ±SD age was 67±8 yrs, BMI 27±5 kg/m2, FEV1 53±16 % predicted, Fibrinogen 3.5±0.9 g/L, aortic PWV 10.2±2.8 m/s, QMVC 31±1 kg, 6MWD 343±127 m, SPPB10±2, MRC median (IQR) 3 (2-4). Patients were stratified according to tertiles of fibrinogen <3 n=126, 3-3.5 n=118, >3.5 g/L n=134. Tertiles showed a difference in FEV1%, 6MWD, QMVC, SPPB and MRC (ANOVA p<0.05) which remained after adjustment for age and sex in QMVC and 6MWD, but not PWV. Conclusions: Tertiles of fibrinogen identified differences in lung function and breathlessness, muscle strength and function, but not aortic stiffness: a measure of CV risk. The association of elevated fibrinogen with loss of muscle strength and function suggests that its modulation may improve physical outcomes for patients with COPD. Funded by GlaxoSmithKline and the UK Technology Strategy Board.

Background: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease with associated systemic complications including loss of muscle mass and function and increased cardiovascular risk. We hypothesised that elevated fibrinogen would be associated with muscle dysfunction and cardiovascular risk. Methods: ERICA is a multicentre, observational study of patients with COPD. Assessments include: spirometry (FEV1%), fibrinogen, aortic stiffness (pulse wave velocity (PWV)), quadriceps maximum voluntary contraction (QMVC) force, 6-minute walking distance (6MWD), Short Physical Performance Battery (SPPB) and MRC breathlessness. Results: Thus far 378 patients (151 male), have been evaluated. Mean ±SD age was 67±8 yrs, BMI 27±5 kg/m2, FEV1 53±16 % predicted, Fibrinogen 3.5±0.9 g/L, aortic PWV 10.2±2.8 m/s, QMVC 31±1 kg, 6MWD 343±127 m, SPPB10±2, MRC median (IQR) 3 (2-4). Patients were stratified according to tertiles of fibrinogen <3 n=126, 3-3.5 n=118, >3.5 g/L n=134. Tertiles showed a difference in FEV1%, 6MWD, QMVC, SPPB and MRC (ANOVA p<0.05) which remained after adjustment for age and sex in QMVC and 6MWD, but not PWV. Conclusions: Tertiles of fibrinogen identified differences in lung function and breathlessness, muscle strength and function, but not aortic stiffness: a measure of CV risk. The association of elevated fibrinogen with loss of muscle strength and function suggests that its modulation may improve physical outcomes for patients with COPD. Funded by GlaxoSmithKline and the UK Technology Strategy Board.