Reproducibility of NIRS Assessment of Muscle Oxidative Capacity in Smokers With and Without COPD

Low muscle oxidative capacity contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). Near-infrared spectroscopy (NIRS) allows non-invasive determination of the muscle oxygen consumption (mV̇O2) recovery rate constant (k), which is proportional to oxidative capacity assuming two conditions are met: 1) exercise intensity is sufficient to fully-activate mitochondrial oxidative enzymes; 2) sufficient O2 availability. We aimed to determine reproducibility (coefficient of variation, CV; intraclass correlation coefficient, ICC) of NIRS k assessment in the gastrocnemius of 64 participants with (FEV1 64 ± 23%predicted) or without COPD (FEV1 98 ± 14%predicted). 10–15 s dynamic contractions preceded 6 min of intermittent arterial occlusions (5–10 s each, ∼250 mmHg) for k measurement. k was lower (P < 0.05) in COPD (1.43 ± 0.4 min−1; CV = 9.8 ± 5.9%, ICC = 0.88) than controls (1.74 ± 0.69 min−1; CV = 9.9 ± 8.4%; ICC = 0.93). Poor k reproducibility was more common when post-contraction mV̇O2 and deoxygenation were low, suggesting insufficient exercise intensity for mitochondrial activation and/or the NIRS signal contained little light reflected from active muscle. The NIRS assessment was well tolerated and reproducible for muscle dysfunction evaluation in COPD

Reliability and Physiological Interpretation of Pulmonary Gas Exchange by "Circulatory Equivalents" in Chronic Heart Failure

Peak ratios of pulmonary gas-exchange to ventilation during exercise (V˙O2/V˙E and V˙CO2/V˙E, termed "circulatory equivalents") are sensitive to heart failure (HF) severity, likely reflecting low and/or poorly distributed pulmonary perfusion. We tested whether peak V˙O2/V˙E and V˙CO2/V˙E would: (1) distinguish HF patients from controls; (2) be independent of incremental exercise protocol; and (3) correlate with lactate threshold (LT) and ventilatory compensation point (VCP), respectively.Twenty-four HF patients (61±11 years) with reduced ejection fraction (31±8%) and 11 controls (63±7 years) performed ramp-incremental cycle ergometry. Eighteen HF patients also performed slow (5±1 W/min), medium (9±4 W/min), and fast (19±6 W/min) ramps. Peak V˙O2/V˙E and V˙CO2/V˙E from X-Y plot, and LT and VCP from 9-panel plot, were determined by 2 independent, blinded, assessors. Peak V˙O2/V˙E (31.2±4.4 versus 41.8±4.8 mL/L; P<0.0001) and V˙CO2/V˙E (29.3±3.0 versus 36.9±4.0 mL/L; P<0.0001) were lower in HF than controls. Within individuals, there was no difference across 3 ramp rates in peak V˙O2/V˙E (P=0.62) or V˙CO2/V˙E (P=0.97). Coefficient of variation (CV) in peak V˙O2/V˙E was lower than for LT (5.1±2.1% versus 8.2±3.7%; P=0.014), and coefficient of variation in peak V˙CO2/V˙E was lower than for VCP (3.3±1.8% versus 8.7±4.2%; P<0.001). In all participants, peak V˙O2/V˙E was correlated with, but occurred earlier than, LT (r2=0.94; mean bias, -0.11 L/min), and peak V˙CO2/V˙E was correlated with, but occurred earlier than, VCP (r2=0.98; mean bias -0.08 L/min).Peak circulatory equivalents during exercise are strongly associated with (but not identical to) LT and VCP. Peak circulatory equivalents are reliable, objective, effort-independent indices of gas-exchange abnormality in HF

PHYSICAL PERFORMANCE AND BODY COMPOSITION IN MAINTENANCE HEMODIALYSIS (MHD) PATIENTS

BackgroundMHD patients (pts) often display protein-energy wasting, sarcopenia & diminished physical performance. This study was undertaken to assess the relationship between body composition & physical performance in MHD pts.MethodsBody composition, assessed by dual energy x-ray absorptiometry and body mass index (BMI), were compared to 3 measures of physical performance: 6-minute walking distance (6-MW), sit-to-stand testing and stair climb. 52 clinically stable MHD pts (≥6 mo) and 21 matched normal controls were examined in this ongoing study.ResultsPts were 53±13SD yrs, 33% female; 38% diabetic; dialysis vintage was 62±52 months. Normals were 52 years and 43% female. MHD pts had higher % body fat than Normals. 6-MW and sit to stand cycles were much lower in MHD men and women than in Normal men and women. 6MW in MHD and Normals were 445 vs 630 meters, respectively (p<.001). In men but not women, time to climb 22 stairs was greater in MHD pts then in Normals (p=.03). Unadjusted analyses in MHD indicated that 6-MW distance correlated negatively with lean body mass index (LBMI, kg of LBM/m2; r=-0.37; p<0.01) and % body fat (r=-0.33; p= 0.02); stair climb time correlated negatively with lean leg mass (r=-0.32, p=0.03) and total leg mass (r=-0.29, p=0.045).). Sit-to-stand did not correlate with any body composition measure. 6-MW adjusted for age and gender correlated negatively with LBMI (r=-0.29; p=0.04).There were no associations between BMI (range, 19.8-44.2 kg/m2) and physical performance.ConclusionsThese findings indicate that adult MHD pts had a higher % body fat. Measures of physical performance were markedly reduced in MHD pts as compared to Normals. Physical performance in MHD, measured especially by 6-MW, correlated negatively with some measures of body composition, particularly with LBMI

A New Bronchodilator Response Grading Strategy Identifies Distinct Patient Populations

Rationale: A positive bronchodilator response (BDR) according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines require both 200 ml and 12% increase in forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) after bronchodilator inhalation. This dual criterion is insensitive in those with high or low FEV1. Objectives: To establish BDR criteria with volume or percentage FEV1 change. Methods: The largest FEV1 and FVC were identified from three pre- and three post-bronchodilator maneuvers in COPDGene (Genetic Epidemiology of COPD) participants. A total of 7,741 individuals with coefficient of variation less than 15% for both FEV1 and FVC formed bronchodilator categories of FEV1 response: negative (≤0.00% or ≤0.00 L), minimal (>0.00% to ≤9.00% or >0.00 L to ≤0.09 L), mild (>9.00% to ≤16.00% or >0.09 L to ≤0.16 L), moderate (>16.00% to ≤26.00% or >0.16 L to ≤0.26 L), and marked (>26.00% or >0.26 L). These response size categories are based on empirical limits considering average FEV1 increase of approximately 160 ml and the clinically important difference for FEV1. To compare flow and volume response characteristics, BDR-FEV1 category assignments were applied for the BDR-FVC response. Results: Twenty percent met mild and 31% met moderate or marked BDR-FEV1 criteria, whereas 12% met mild and 33% met moderate or marked BDR-FVC criteria. In contrast, only 20.6% met ATS/ERS positive criteria. Compared with the negative BDR-FEV1 category, the minimal, mild, moderate, and marked BDR-FEV1 categories were associated with greater 6-minute-walk distance and lower St. George’s Respiratory Questionnaire and modified Medical Research Council dyspnea scale scores. Compared with negative BDR, moderate and marked BDR-FEV1 categories were associated with fewer exacerbations, and minimal BDR was associated with lower computed tomography airway wall thickness. Compared with the negative category, all BDR-FVC categories were associated with increasing emphysema percentage and gas trapping percentage. Moderate and marked BDR-FVC categories were associated with higher St. George’s Respiratory Questionnaire scores but fewer exacerbations and lower dyspnea scores. Conclusions: BDR grading by FEV1 volume or percentage response identified subjects otherwise missed by ATS/ERS criteria. BDR grades were associated with functional exercise performance, quality of life, exacerbation frequency, dyspnea, and radiological airway measures. BDR grades in FEV1 and FVC indicate different clinical and radiological characteristics

Effect of tiotropium on spontaneous expiratory flow–volume curves during exercise in GOLD 1-2 COPD

This substudy of a large, randomized, controlled trial (NCT01072396) examined tiotropium (18 μg qd) effects on dynamic hyperinflation during constant work rate treadmill exercise. Areas-under-the-spontaneous expiratory flow-volume (SEFV)-curves were compared in 20 COPD patients and 16 age-matched untreated controls, using rectangular area ratio (RAR) between peak intrabreath and end-expiratory flow. Seven patients exhibited SEFV curve concavity with RAR ≤ 0.5 (RARlow) in ≥1 test without tiotropium; (mean ± SD FEV₁: 1.60 ± 0.59 L; 63.4 ± 14.0%predicted). In RAR(low) patients, tiotropium increased end-exercise inspiratory capacity (IC, 2.10 ± 0.05 vs. 1.89 ± 0.05 L, tiotropium vs. placebo; p = 0.045) and RAR (0.57 ± 0.02 vs. 0.53 ± 0.02; p  0.5 (n = 13; RAR(high), had higher screening FEV₁ (2.15 ± 0.47 L; 79.6 ± 10.1%predicted) versus RARlow patients and no difference in end-exercise IC and RAR between tiotropium and placebo (IC: 2.24 ± 0.03 vs. 2.17 ± 0.03 L; RAR: 0.63 ± 0.005 vs. 0.62 ± 0.005). RAR and%predicted IC at peak exercise were positively correlated in RAR(low) patients (R² = 0.43, p = 0.0002)

Physiological Correlates of Endurance Time Variability during Constant-Workrate Cycling Exercise in Patients with COPD

RATIONALE: The endurance time (T(end)) during constant-workrate cycling exercise (CET) is highly variable in COPD. We investigated pulmonary and physiological variables that may contribute to these variations in T(end). METHODS: Ninety-two patients with COPD completed a CET performed at 80% of peak workrate capacity (W(peak)). Patients were divided into tertiles of T(end) [Group 1: <4 min; Group 2: 4-6 min; Group 3: >6 min]. Disease severity (FEV(1)), aerobic fitness (W(peak), peak oxygen consumption [VO2(peak)], ventilatory threshold [VO2(VT)]), quadriceps strength (MVC), symptom scores at the end of CET and exercise intensity during CET (heart rate at the end of CET to heart rate at peak incremental exercise ratio [HR(CET)/HR(peak)]) were analyzed as potential variables influencing T(end). RESULTS: W(peak), VO2(peak), VO2(VT), MVC, leg fatigue at end of CET, and HR(CET)/HR(peak) were lower in group 1 than in group 2 or 3 (p≤0.05). VO2(VT) and leg fatigue at end of CET independently predicted T(end) in multiple regression analysis (r = 0.50, p = 0.001). CONCLUSION: T(end) was independently related to the aerobic fitness and to tolerance to leg fatigue at the end of exercise. A large fraction of the variability in T(end) was not explained by the physiological parameters assessed in the present study. Individualization of exercise intensity during CET should help in reducing variations in T(end) among patients with COPD

Outcome measures in chronic obstructive pulmonary disease (COPD): strengths and limitations

Current methods for assessing clinical outcomes in COPD mainly rely on physiological tests combined with the use of questionnaires. The present review considers commonly used outcome measures such as lung function, health status, exercise capacity and physical activity, dyspnoea, exacerbations, the multi-dimensional BODE score, and mortality. Based on current published data, we provide a concise overview of the principles, strengths and weaknesses, and discuss open questions related to each methodology. Reviewed is the current set of markers for measuring clinically relevant outcomes with particular emphasis on their limitations and opportunities that should be recognized when assessing and interpreting their use in clinical trials of COPD

Leptin Administration Favors Muscle Mass Accretion by Decreasing FoxO3a and Increasing PGC-1α in ob/ob Mice

Absence of leptin has been associated with reduced skeletal muscle mass in leptin-deficient ob/ob mice. The aim of our study was to examine the effect of leptin on the catabolic and anabolic pathways regulating muscle mass. Gastrocnemius, extensor digitorum longus and soleus muscle mass as well as fiber size were significantly lower in ob/ob mice compared to wild type littermates, being significantly increased by leptin administration (P<0.001). This effect was associated with an inactivation of the muscle atrophy-related transcription factor forkhead box class O3 (FoxO3a) (P<0.05), and with a decrease in the protein expression levels of the E3 ubiquitin-ligases muscle atrophy F-box (MAFbx) (P<0.05) and muscle RING finger 1 (MuRF1) (P<0.05). Moreover, leptin increased (P<0.01) protein expression levels of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a regulator of muscle fiber type, and decreased (P<0.05) myostatin protein, a negative regulator of muscle growth. Leptin administration also activated (P<0.01) the regulators of cell cycle progression proliferating cell nuclear antigen (PCNA) and cyclin D1, and increased (P<0.01) myofibrillar protein troponin T. The present study provides evidence that leptin treatment may increase muscle mass of ob/ob mice by inhibiting myofibrillar protein degradation as well as enhancing muscle cell proliferation

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