Rebecca Tanner

Quadriceps wasting and physical inactivity in patients with COPD

Quadriceps weakness is an important complication of advanced chronic obstructive pulmonary disease (COPD) but few data exist concerning muscle bulk in early disease. We hypothesised that quadriceps bulk, measured by ultrasound rectus femoris cross-sectional area (USRFCSA), would be reduced in mild, as well as advanced, COPD compared with controls, and would correlate with physical activity. 161 patients with stable COPD and 40 healthy subjects had a measurement of USRFCSA and wore a multisensor armband to record physical activity. USRFCSA was reduced in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I patients compared with healthy subjects (p=0.0002). Stage II–IV patients had reduced USRFCSA (p<0.0001) compared with controls but were not significantly different from those with stage I disease. Physical activity level was reduced in stage I (p=0.002) and stage II–IV disease compared with controls. Using regression analysis, physical activity level was independently associated with USRFCSA in stage I (p=0.01) but not stage II–IV disease, where residual volume to total lung capacity ratio was the only independent predictor of physical activity level. Quadriceps wasting exists in patients with mild, as well as advanced, COPD, and is independently associated with physical inactivity in GOLD stage I disease. The identification of these patients may guide early lifestyle and therapeutic interventions.

Lung function indices for predicting mortality in COPD

Chronic obstructive pulmonary disease (COPD) is characterised by high morbidity and mortality. It remains unknown which aspect of lung function carries the most prognostic information and if simple spirometry is sufficient. Survival was assessed in COPD outpatients whose data had been added prospectively to a clinical audit database from the point of first full lung function testing including spirometry, lung volumes, gas transfer and arterial blood gases. Variables univariately associated with survival were entered into a multivariate Cox proportional hazard model. 604 patients were included (mean±sd age 61.9±9.7 years; forced expiratory volume in 1 s 37±18.1% predicted; 62.9% males); 229 (37.9%) died during a median follow-up of 83 months. Median survival was 91.9 (95% CI 80.8–103) months with survival rates at 3 and 5 years 0.83 and 0.66, respectively. Carbon monoxide transfer factor % pred quartiles (best quartile (>51%): HR 0.33, 95% CI 0.172–0.639; and second quartile (51–37.3%): HR 0.52, 95% CI 0.322–0.825; versus lowest quartile (<27.9%)), age (HR 1.04, 95% CI 1.02–1.06) and arterial oxygen partial pressure (HR 0.85, 95% CI 0.77–0.94) were the only parameters independently associated with mortality. Measurement of gas transfer provides additional prognostic information compared to spirometry in patients under hospital follow-up and could be considered routinely. Transfer factor not GOLD stage is the most powerful predictor of survival in patients with COPD http://ow.ly/mGmjG

Singing classes for chronic obstructive pulmonary disease: a randomized controlled trial

BackgroundThere is some evidence that singing lessons may be of benefit to patients with chronic obstructive pulmonary disease (COPD). It is not clear how much of this benefit is specific to singing and how much relates to the classes being a group activity that addresses social isolation.MethodsPatients were randomised to either singing classes or a film club for eight weeks. Response was assessed quantitatively through health status questionnaires, measures of breathing control, exercise capacity and physical activity and qualitatively, through structured interviews with a clinical psychologist.ResultsThe singing group (n=13 mean(SD) FEV1 44.4(14.4)% predicted) and film group (n=11 FEV1 63.5(25.5)%predicted) did not differ significantly at baseline. There was a significant difference between the response of the physical component score of the SF-36, favouring the singing group +12.9(19.0) vs -0.25(11.9) (p=0.02), but no difference in response of the mental component score of the SF-36, breathing control measures, exercise capacity or daily physical activity. In the qualitative element, positive effects on physical well-being were reported in the singing group but not the film group.ConclusionSinging classes have an impact on health status distinct from that achieved simply by taking part in a group activity.Trials registrationRegistration Current Controlled Trials - ISRCTN17544114

Skeletal muscle adiposity is associated with physical activity, exercise capacity and fibre shift in COPD

Quadriceps muscle phenotype varies widely between patients with chronic obstructive pulmonary disease (COPD) and cannot be determined without muscle biopsy. We hypothesised that measures of skeletal muscle adiposity could provide noninvasive biomarkers of muscle quality in this population. In 101 patients and 10 age-matched healthy controls, mid-thigh cross-sectional area, percentage intramuscular fat and skeletal muscle attenuation were calculated using computed tomography images and standard tissue attenuation ranges: fat -190– -30 HU; skeletal muscle -29–150 HU. Mean±sd percentage intramuscular fat was higher in the patient group (6.7±3.5% versus 4.3±1.2%, p = 0.03). Both percentage intramuscular fat and skeletal muscle attenuation were associated with physical activity level, exercise capacity and type I fibre proportion, independent of age, mid-thigh cross-sectional area and quadriceps strength. Combined with transfer factor of the lung for carbon monoxide, these variables could identify >80% of patients with fibre type shift with >65% specificity (area under the curve 0.83, 95% CI 0.72–0.95). Skeletal muscle adiposity assessed by computed tomography reflects multiple aspects of COPD related muscle dysfunction and may help to identify patients for trials of interventions targeted at specific muscle phenotypes. CT-based skeletal muscle adiposity markers reflect muscle quality in COPD and help identify patients with fibre shift http://ow.ly/xolWA

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

BACKGROUND: Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD. METHODS: This double-blind, randomized placebo-controlled trial investigated the effect of the ACE inhibitor, fosinopril, on quadriceps function in patients with COPD with quadriceps weakness. Primary outcomes were change in quadriceps endurance and atrophy signaling at 3 months. Quadriceps maximum voluntary contraction (QMVC), mid-thigh CT scan of the cross-sectional area (MTCSA), and incremental shuttle walk distance (ISWD) were secondary outcomes. RESULTS: Eighty patients were enrolled (mean [SD], 65 [8] years, FEV1 43% [21%] predicted, 53% men). Sixty-seven patients (31 fosinopril, 36 placebo) completed the trial. The treatment group demonstrated a significant reduction in systolic BP (Δ−10.5 mm Hg; 95% CI, −19.9 to −1.1; P = .03) and serum ACE activity (Δ−20.4 IU/L; 95% CI, −31.0 to −9.8; P < .001) compared with placebo. No significant between-group differences were observed in the primary end points of quadriceps endurance half-time (Δ0.5 s; 95% CI, −13.3-14.3; P = .94) or atrogin-1 messenger RNA expression (Δ−0.03 arbitrary units; 95% CI, −0.32-0.26; P = .84). QMVC improved in both groups (fosinopril: Δ1.1 kg; 95% CI, 0.03-2.2; P = .045 vs placebo: Δ3.6 kg; 95% CI, 2.1-5.0; P < .0001) with a greater increase in the placebo arm (between-group, P = .009). No change was shown in the MTCSA (P = .09) or ISWD (P = .51). CONCLUSIONS: This randomized controlled trial found that ACE inhibition, using fosinopril for 3 months, did not improve quadriceps function or exercise performance in patients with COPD with quadriceps weakness. TRIAL REGISTRY: Current Controlled Trials; No.: ISRCTN05581879; URL: www.controlled-trials.com

An evaluation of factors associated with completion and benefit from pulmonary rehabilitation in COPD.

Background Pulmonary Rehabilitation (PR) is an important treatment for patients with chronic obstructive pulmonary disease (COPD) but it is not established whether any baseline parameter can predict response or compliance. Aim To identify whether baseline measures can predict who will complete the programme and who will achieve a clinically significant benefit from a Minimum Clinical Important Difference (MCID) in terms of exercise capacity and health-related quality of life (HRQoL). Methods Data were collected prospectively from patients with COPD at their baseline assessment for an outpatient PR programme in one of eight centres across London. ‘Completion’ was defined as attending at least 75% of the designated PR visits and return for the follow-up evaluation. The MCID for outcome measures was based on published data. Results 787 outpatients with COPD (68.1±10.5 years old; 49.6% males) were included. Patients who completed PR (n=449, 57.1%) were significantly older with less severe airflow obstruction, lower anxiety and depression scores, less dyspnoea and better HRQoL. Only baseline CAT score (OR=0.925; 95% CI 0.879 to 0.974; p=0.003) was retained in multivariate analysis. Patients with the lowest baseline walking distance were most likely to achieve the MCID for exercise capacity. No baseline variable could independently predict achievement of an MCID in HRQoL. Conclusions Patients with better HRQoL are more likely to complete PR while worse baseline exercise performance makes the achievement of a positive MCID in exercise capacity more likely. However, no baseline parameter could predict who would benefit the most in terms of HRQoL.

Acute Dietary Nitrate Supplementation and Exercise Performance in COPD: A Double-Blind, Placebo-Controlled, Randomised Controlled Pilot Study

Background Dietary nitrate supplementation can enhance exercise performance in healthy people, but it is not clear if it is beneficial in COPD. We investigated the hypotheses that acute nitrate dosing would improve exercise performance and reduce the oxygen cost of submaximal exercise in people with COPD. Methods We performed a double-blind, placebo-controlled, cross-over single dose study. Subjects were randomised to consume either nitrate-rich beetroot juice (containing 12.9mmoles nitrate) or placebo (nitrate-depleted beetroot juice) 3 hours prior to endurance cycle ergometry, performed at 70% of maximal workload assessed by a prior incremental exercise test. After a minimum washout period of 7 days the protocol was repeated with the crossover beverage. Results 21 subjects successfully completed the study (age 68±7years; BMI 25.2±5.5kg/m2; FEV1 percentage predicted 50.1±21.6%; peak VO2 18.0±5.9ml/min/kg). Resting diastolic blood pressure fell significantly with nitrate supplementation compared to placebo (-7±8mmHg nitrate vs. -1±8mmHg placebo; p = 0.008). Median endurance time did not differ significantly; nitrate 5.65 (3.90–10.40) minutes vs. placebo 6.40 (4.01–9.67) minutes (p = 0.50). However, isotime oxygen consumption (VO2) was lower following nitrate supplementation (16.6±6.0ml/min/kg nitrate vs. 17.2±6.0ml/min/kg placebo; p = 0.043), and consequently nitrate supplementation caused a significant lowering of the amplitude of the VO2-percentage isotime curve. Conclusions Acute administration of oral nitrate did not enhance endurance exercise performance; however the observation that beetroot juice caused reduced oxygen consumption at isotime suggests that further investigation of this treatment approach is warranted, perhaps targeting a more hypoxic phenotype. Trial Registration ISRCTN Registry ISRCTN66099139

Dynamic laryngeal narrowing during exercise: a mechanism for generating intrinsic PEEP in COPD?

Introduction Patients with COPD commonly exhibit pursed-lip breathing during exercise, a strategy that, by increasing intrinsic positive end-expiratory pressure, may optimise lung mechanics and exercise tolerance. A similar role for laryngeal narrowing in modulating exercise airways resistance and the respiratory cycle volume–time course is postulated, yet remains unstudied in COPD. The aim of this study was to assess the characteristics of laryngeal narrowing and its role in exercise intolerance and dynamic hyperinflation in COPD. Methods We studied 19 patients (n=8 mild–moderate; n=11 severe COPD) and healthy age and sex matched controls (n=11). Baseline physiological characteristics and clinical status were assessed prior to an incremental maximal cardiopulmonary exercise test with continuous laryngoscopy. Laryngeal narrowing measures were calculated at the glottic and supra-glottic aperture at rest and peak exercise. Results At rest, expiratory laryngeal narrowing was pronounced at the glottic level in patients and related to FEV1 in the whole cohort (r=−0.71, p<0.001) and patients alone (r=−0.53, p=0.018). During exercise, glottic narrowing was inversely related to peak ventilation in all subjects (r=−0.55, p=0.0015) and patients (r=−0.71, p<0.001) and peak exercise tidal volume (r=−0.58, p=0.0062 and r=−0.55, p=0.0076, respectively). Exercise glottic narrowing was also inversely related to peak oxygen uptake (% predicted) in all subjects (r=−0.65, p<0.001) and patients considered alone (r=−0.58, p=0.014). Exercise inspiratory duty cycle was related to exercise glottic narrowing for all subjects (r=−0.69, p<0.001) and patients (r=−0.62, p<0.001). Conclusions Dynamic laryngeal narrowing during expiration is prevalent in patients with COPD and is related to disease severity, respiratory duty cycle and exercise capacity.

Significance of Patent Foramen Ovale in Patients with GOLD Stage II Chronic Obstructive Pulmonary Disease (COPD)

Background: Patent foramen ovale (PFO) is a common finding in adults. A PFO is associated with right to left shunting but its importance in the aetiology of hypoxia in early COPD remains uncertain, although it has not proved possible to demonstrate a role for PFOs in the aetiology of hypoxia in patients with Global Initiative for chronic Obstructive Lung Disease (GOLD) stage III/IV disease. We compared the characteristics of GOLD stage II patients with or without a PFO and assessed its impact on exercise performance. Methods: In 22 GOLD stage II COPD patients we measured exercise performance, arterial oxygen tension and lung function and used contrast transcranial Doppler ultrasonography (TCD) to assess the presence of a PFO. Patients (n=20) underwent TCD measurements during incremental cycle ergometry with respiratory pressures measured using an esophageal balloon catheter (n=13). Results:Twelve individuals (54%) had a PFO. Patients with a PFO were more hypoxic; mean(SD) partial pressure of oxygen in arterial blood (PaO2)10.2(1.1) kilopascals (kPa) vs. 11.7(0.9)kPa (p<0.01), but the presence of a PFO was not associated with reduced exercise performance either on cycle ergometry or a 6 Minute Walk Test (6MWT). A strong relationship was noted between the esophageal pressure swing (PSwingEs) and the degree of shunting observed during exercise (r=0.7; p<0.001). Conclusions:The presence of a PFO in GOLD stage II COPD patients does not appear to influence exercise performance despite increased right-to-left shunting.

S53 Studying fibre specific gene expression in COPD using laser capture micro-dissection in human skeletal muscle

Background Approximately 30% of patients with Chronic Obstructive Pulmonary Disease (COPD) exhibit peripheral skeletal muscle dysfunction and a shift towards type II glycolytic fibres in the quadriceps compared to healthy controls (Nanatek et al, 2013). Previous work to elucidate the molecular mechanisms underlying these changes has relied on whole biopsy samples and may have missed fibre-specific pathways; thus a method to evaluate fibre specific signalling pathways would be useful. Objective To describe a novel laser capture micro-dissection (LCM) method to examine fibre-specific signalling in quadriceps biopsies. Methods First larger Intercostal muscle biopsies were used to validate the methodology since they yielded more RNA. Fibres were classified as type-2 positive or type-2 negative based on immunoreactivity with a type-2 fibre specific anti-myosin Heavy Chain Alexa FLUOR 488 antibody. The type-2 negative fibre population was hence assumed to contain type-1 fibres, which was confirmed by the type-2 negative fibre population exhibiting a higher myhc7/2 mRNA ratio and expressing higher levels of genes associated with type-1 fibres, e.g. TNNT-1 and STARS, and lower levels of genes associated with type-2 fibres, e.g. TGF-B, myostatin, GAPDH and HDAC-4 (n = 2). We then examined OCT-embedded vastus lateralis muscle biopsy specimens. 10micron cryosections underwent fixation with 4% paraformaldehyde before immunostaining. LCM (PALM Microbeam, Zeiss, UK) was used to capture type I and type II fibre populations, before RNA extraction with RNAeasy FFPE kit (Qiagen, USA) and rtPCR to obtain cDNA. Sybr-II qPCR was performed on fibre populations for target genes MHC I, MHC IIa, MHC IIx, HDAC-4 and RPLPO. Results Preliminary results from three 10micron slices indicate that this technique is feasible to study fibre-specific signalling in COPD. LCM following immunostaining captures distinct fibre populations (Figure 1) confirmed by a higher MHC I content in ‘type I fibres’, with ‘type II’ fibres containing more MHC IIa, MHC IIx and HDAC-4 as would be expected. Gene expression is normalised against RPLPO. Abstract S53 Figure 1. Gene expression (normalised for RPLPO) for Type I (red) and Type II (blue) quadriceps muscle fibres in COPD using three 10 micron sections for Laser Capture Micro-Dissection. Fold difference compared to type I fibres shown Conclusion LCM can be used to study fibre specific inflammatory signalling in the skeletal muscle of COPD patients and immunostaining with MHC antibodies is a feasible way to distinguish between fibre types when capturing composite fibre populations.