Current Status of Pulmonary Rehabilitation: Introductory Remarks on Pulmonary Rehabilitation, the Importance and the Practice.

In 1994, the Pulmonary Education and Research Foundation released a VHS tape, a program for the health-care professional, entitled "Essentials of Pulmonary Rehabilitation—Taking Control of Life Aga..

Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men

SummaryBackgroundSkeletal muscle dysfunction contributes to exercise limitation in COPD. The role of the nitric oxide synthase (NOS) system in muscle dysfunction is ill defined. Reduced levels of endothelial NOS (eNOS) and elevated levels of inducible NOS (iNOS) in the skeletal muscle of COPD patients have been recently reported. We hypothesized that resistance exercise training (R) and/or testosterone supplementation (T) would alter the transcription and expression of the NOS isoenzymes in COPD skeletal muscle.MethodsVastus lateralis biopsies were obtained before and after a 10-week intervention in 40 men with severe COPD(age 67.7 ± 8.3, FEV1 41.4 ± 12.6% predicted): placebo + no training (P) (n = 11), placebo + resistance training (PR) (n = 8), testosterone + no training (T) (n = 11) and testosterone + resistance training (TR) (n = 10) groups. eNOS, nNOS and iNOS mRNA and protein levels were measured in each sample. mRNA and protein levels were measured using real-time PCR and enzyme-linked immunosorbant assay, respectively.ResultseNOS mRNA increased in the TR group compared to P and T groups (P < 0.001). eNOS protein was increased in TR and T groups after intervention (P < 0.05) but not in the PR group. nNOS protein increased in the PR, T, and TR groups (P < 0.05). iNOS protein decreased only in the TR group (P = 0.01).ConclusionResistance training and testosterone supplementation increased eNOS and nNOS proteins and decreased iNOS protein in the skeletal muscles of men with COPD. These changes in NO system might explain some of the favorable effects of these therapies

A Novel Waveform to Extract Exercise Gas Exchange Response Dynamics: The Chirp Waveform

Characterizing exercise gas exchange response dynamics reveals important information about physiological control processes and cardiopulmonary dysfunction. However, current methods for extracting exercise response dynamics typically use multiple step-wise transitions, limiting applicability of this technique. PURPOSE: We designed a new protocol (chirp waveform) to extract exercise gas exchange response dynamics in a single visit. We tested the hypothesis that gas exchange response dynamics extracted from chirp forcing would be similar to those extracted from step-wise transitions. METHODS: Thirty-one participants (14 young healthy, 7 older healthy, and 10 patients with chronic obstructive pulmonary disease) visited the laboratory on three occasions. On visit 1, participants performed a ramp incremental test to determine the gas exchange threshold (GET). On visits 2-3, participants performed either a chirp or step-wise protocol in a randomized order. Chirp forcing consisted of sinusoidal fluctuations in work rate with constant amplitude and progressive shortening of sine periods. Square protocol consisted of 3 square-wave transitions each of 6 min duration. Work rate amplitude (from 20 W to ~95% of the individual’s GET) and exercise duration (30 min) were the same in both protocols. The input-output relationship was characterized using a first-order linear transfer function containing a system gain (K) and time constant (τ) [G(s)= K/(τ×s+1)]. Parameter identification was performed in Matlab using the Matlab System Identification toolbox. Agreement between measures was established using Bland-Altman analysis and Rothery’s Concordance Coefficient (RCC). RESULTS: No systematic bias (mean difference of chirp minus square-wave; Δmean) and good reliability was found for V̇O2 K [Δmean: 0.25(1.03) mL/min/W, p=0.179; RCC: 0.773, p=0.004], V̇O2 τ [Δmean: 0.30(7.08) s, p=0.815; RCC: 0.837, p2 K [Δmean: -0.19(1.57) mL/min/W, p=0.512; RCC: 0.827, pp=0.009] and good reliability (RCC: 0.794, p2 τ. CONCLUSION: The chirp waveform allows extraction of gas exchange response dynamics similar to those obtained from standard methods, thus overcoming the need for multiple tests

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

A new bronchodilator response grading strategy ıdentifies 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 fromthree 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% to 0.00 L to 9.00% to 16.00% to 0.16 L to 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.United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI)National Center for Advancing Translational Sciences through UCLA CTSI Gran

Identifying a Heart Rate Recovery Criterion After a 6-Minute Walk Test in COPD

Background: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?. Study Design and Methods: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations. Results: HRR after 6MWT (bt/min) was categorized in quintiles: ≤ 5 (23.0% of participants), 6– 10 (20.7%), 11– 15 (18.9%), 16– 22 (18.5%) and ≥ 23 (18.9%). Compared to HRR≤ 5, HRR≥ 11 was associated with (p\u3c 0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤ 10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58– 0.66) for identifying FEV1\u3c 30%pred. HRR≥ 11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤ 10 bt/min was associated with (p\u3c 0.001): ≥ 2 exacerbations in the previous year (OR=1.76[1.33– 2.34]); CAT≥ 10 (OR=1.42[1.18– 1.71]); mMRC≥ 2 (OR=1.42[1.19– 1.69]); GOLD 4 (OR=1.98[1.44– 2.73]) and GOLD D (OR=1.51[1.18– 1.95]). HRR≤ 10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07– 3.12], P=0.027). Conclusion: HRR≤ 10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤ 10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations

A novel spirometric measure identifies mild COPD unidentified by standard criteria

BACKGROUND: In chronic obstructive pulmonary disease, both smaller and larger airways are affected. FEV1 mainly reflects large airways obstruction, while the later fraction of forced exhalation reflects reduction in terminal expiratory flow. In this study, the objective was to evaluate the relationship between spirometric ratios, including the ratio of forced expiratory volume in 3 and 6 seconds (FEV3/FEV6), and small airways measures and gas trapping at quantitative chest CT scanning, and clinical outcomes in the Genetic Epidemiology of COPD (COPDGene) cohort. METHODS: Seven thousand eight hundred fifty-three current and ex-smokers were evaluated for airflow obstruction by using recently defined linear iteratively derived equations of Hansen et al to determine lower limit of normal (LLN) equations for prebronchodilator FEV1/FVC, FEV1/FEV6, FEV3/FEV6, and FEV3/FVC. General linear and ordinal regression models were applied to the relationship between prebronchodilator spirometric and radiologic and clinical data. RESULTS: Of the 10,311 participants included in the COPDGene phase I study, participants with incomplete quantitative CT scanning or relevant spirometric data were excluded, resulting in 7,853 participants in the present study. Of 4,386 participants with FEV1/FVC greater than or equal to the LLN, 15.4% had abnormal FEV3/FEV6. Compared with normal FEV3/FEV6 and FEV1/FVC, abnormal FEV3/FEV6 was associated with significantly greater gas trapping; St. George's Respiratory Questionnaire score; modified Medical Research Council dyspnea score; and BMI, airflow obstruction, dyspnea, and exercise index and with shorter 6-min walking distance (all P < .0001) but not with CT scanning evidence of emphysema. CONCLUSIONS: Current and ex-smokers with prebronchodilator FEV3/FEV6 less than the LLN as the sole abnormality identifies a distinct population with evidence of small airways disease in quantitative CT scanning, impaired indexes of physical function and quality of life otherwise deemed normal by using the current spirometric definition.United States Department of Health & Human Services - R01 HL 08 9856 - R01 HL 08 9897National Institutes of Health (NIH) - USA - 1KL2TR001419NIH National Heart Lung & Blood Institute (NHLBI) - UL1TR001417 - KL2TR001419 - UL1TR001881NIH National Center for Advancing Translational Sciences (NCATS) - U01HL089897 - U01HL089856 - R01HL124233 - R01HL089856 - R01HL08989

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