Systemic and Pulmonary Vascular Remodelling in Chronic Obstructive Pulmonary Disease

BackgroundChronic Obstructive Pulmonary Disease (COPD) is associated with subclinical systemic atherosclerosis and pulmonary vascular remodelling characterized by intimal hyperplasia and luminal narrowing. We aimed to determine differences in the intimal thickening of systemic and pulmonary arteries in COPD subjects and smokers. Secondary aims include comparisons with a non-smokers group; determining the clinical variables associated with systemic and pulmonary intimal thickening, and the correlations between systemic and pulmonary remodelling changes.MethodsAll consecutive subjects undergoing lung resection were included and divided into 3 groups: 1) COPD, 2) smokers, and 3) non-smokers. Sections of the 5th intercostal artery and muscular pulmonary arteries were measured by histo-morphometry. Four parameters of intimal thickening were evaluated: 1) percentage of intimal area (%IA), 2) percentage of luminal narrowing, 3) intimal thickness index, and 4) intima-to-media ratio.ResultsIn the adjusted analysis, the systemic arteries of COPD subjects showed greater intimal thickening (%IA) than those of smokers (15.6±1.5% vs. 14.2±1.6%, p = 0.038). In the pulmonary arteries, significant differences were observed for %IA between the 2 groups (37.3±2.2% vs. 29.3±2.3%, p = 0.016). Among clinical factors, metabolic syndrome, gender and COPD status were associated with the systemic intimal thickening, while only COPD status was associated with pulmonary intimal thickening. A correlation between the %IA of the systemic and pulmonary arteries was observed (Spearman’s rho = 0.46, p = 0.008).ConclusionsGreater intimal thickening in systemic and pulmonary arteries is observed in COPD patients than in smokers. There is a correlation between systemic and pulmonary vascular remodelling in the overall population.     

细辛脑联合多索茶碱治疗慢性阻塞性肺病疗效观察

目的:观察细辛脑联合多索茶碱治疗慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效。方法:将164例AECOPD患者随机分为观察组（82例）和对照组（82例）,对照组予低流量吸氧、抗炎、抗感染、纠正水电解质紊乱等综合治疗,观察组在此基础上加用注射用细辛脑、多索茶碱静脉治疗。观察两组治疗前后症状、体征改善情况及血气分析变化。结果:观察组与对照组临床总有效率分别为93.9%、81.7%（P<0.05）,观察组在发热、咳嗽咳痰、喘息症状消失时间,以及肺部罗音减少50%以上时间均显著短于对照组（P<0.01）,在FEV1、FEV1/FVC、PEF、PaO₂、PaCO₂等指标也显著优于对照组（P<0.01）。结论:在常规治疗基础上加用细辛脑、多索茶碱可以有效提高AECOPD患者的临床疗效。     

细辛脑联合多索茶碱治疗慢性阻塞性肺病疗效观察

目的：观察细辛脑联合多索茶碱治疗慢性阻塞性肺疾病急性加重期（AECOPD）的临床疗效。方法：将164例AECOPD患者随机分为观察组（82例）和对照组（82例）,对照组予低流量吸氧、抗炎、抗感染、纠正水电解质紊乱等综合治疗,观察组在此基础上加用注射用细辛脑、多索茶碱静脉治疗。观察两组治疗前后症状、体征改善情况及血气分析变化。结果：观察组与对照组临床总有效率分别为93．9％、81．7％（P〈0．05）,观察组在发热、咳嗽咳痰、喘息症状消失时间,以及肺部罗音减少50％以上时间均显著短于对照组（P〈0．01）,在FEV1、FEV1／FVC、PEF、PaO2、PaCO2等指标也显著优于对照组（P〈0．01）。结论：在常规治疗基础上加用细辛脑、多索茶碱可以有效提高AECOPD患者的临床疗效。     

Periodontal Disease and Risk of Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Observational Studies

Background

Many epidemiological studies have found a positive association between periodontal disease (PD) and risk of chronic obstructive pulmonary disease (COPD), but this association is varied and even contradictory among studies. We performed a meta-analysis to ascertain the relationship between PD and COPD.

Methods

PubMed and Embase database were searched up to January 10, 2012, for relevant observational studies on the association between PD and risk of COPD. Data from the studies selected were extracted and analyzed independently by two authors. The meta-analysis was performed using the Comprehensive Meta-Analysis software.

Results

Fourteen observational studies (one nested case-control, eight case-control, and five cross-sectional) involving 3,988 COPD patients were yielded. Based on random-effects meta-analysis, a significant association between PD and COPD was identified (odds ratio = 2.08, 95% confidence interval = 1.48–2.91; P<0.001), with sensitivity analysis showing that the result was robust. Subgroups analyses according to study design, ethnicity, assessment of PD/COPD, and adjusted/unadjusted odds ratios also revealed a significant association. Publication bias was detected.

Conclusions

Based on current evidence, PD is a significant and independent risk factor of COPD. However, whether a causal relationships exists remains unclear. Morever, we suggest performing randomized controlled trails to explore whether periodontal interventions are beneficial in regulating COPD pathogenesis and progression.     

Indacaterol for Chronic Obstructive Pulmonary Disease: Systematic Review and Meta-Analysis

Background

Inhaled bronchodilators are the first-line therapy for COPD. Indacaterol is a novel addition to existing long-acting bronchodilators.

Objectives

Systematic review of randomized controlled trials (RCT) on efficacy and safety of indacaterol as compared: 1) with placebo at different dosages, 2) with existing bronchodilators; (3) as add-on treatment to tiotropium.

Methods

We searched 13 electronic databases, including MEDLINE, EMBASE and CENTRAL, and contacted the manufacturer for unpublished data. Primary outcome was mean FEV1 change at 12^th week, secondary outcomes included changes in SGRQ, TDI and BODE index at 6 months, exacerbation at 1 year, and worsening of symptoms.

Results

Twelve eligible RCTs of moderate risk of bias included data from 10,977 patients. Compared to placebo, indacaterol improved FEV1 by a weighted mean difference (WMD) of 0.16 L (95%CI: 0.15, 0.18 L, p<0.001), homogeneously above the minimally important difference of 0.10 L. It offered clinically relevant improvement in all secondary outcomes except exacerbation. Magnitude of benefit did not differ significantly by dosage, but one treatment related death was reported at 300 ug. Efficacy of Indacaterol was similar to formoterol and salmeterol (FEV1 WMD = 0.04L, 95%CI: 0.01L, 0.07 L, p = 0.02); and tiotropium (FEV1 WMD = 0.01L, 95%CI: −0.01, 0.03L, p = 0.61). The use of indacaterol on top of tiotropium yielded additional improvement on FEV1 (WMD = 0.07 L, 95%CI: 0.05L, 0.10 L, p<0.001).

Conclusion

Indacaterol is safe and beneficial for patients with COPD at dosage ≤150 ug. It may serve as a good alternative to existing bronchodilators, or as an add-on to tiotropium for unresponsive patients. Use of higher dosage requires further justification.     

Prevalence and Global Initiative for Chronic Obstructive Lung Disease Group Distribution of Chronic Obstructive Pulmonary Disease Detected by Preoperative Pulmonary Function Test

Background

Despite being a major public health problem, chronic obstructive pulmonary disease (COPD) remains underdiagnosed, and only 2.4% COPD patients are aware of their disease in Korea. The objective of this study was to estimate the prevalence of COPD detected by spirometry performed as a preoperative screening test and to determine the Global Initiative for Chronic Obstructive Lung Disease (GOLD) group distribution and self-awareness of COPD.

Methods

We reviewed the medical records of adults (age, ≥40 years) who had undergone spirometry during preoperative screening between April and August 2013 at a tertiary hospital in Korea. COPD was defined as a postbronchodilator forced expiratory volume in 1 s/forced vital capacity ratio of <0.7. We analyzed self-administered COPD questionnaires for the assessment of the frequency of acute exacerbation over the previous year and dyspnea severity using the modified Medical Research Council dyspnea scale and COPD assessment test.

Results

Among 3029 patients aged >40 years who had undergone spirometry as a preoperative screening test, 474 (15.6%; 404 men; median age, 70 years; range, 44–93 years) were diagnosed with COPD. Only 26 (5.5%) patients reported previous diagnosis of COPD (2.1%), emphysema (0.8%), or chronic bronchitis (2.5%). The GOLD group distribution was as follows: 63.3% in group A, 31.2% in group B, 1.7% in group C, and 3.8% in group D.

Conclusions

The prevalence of COPD diagnosed by preoperative spirometry was 15.6%, and only 5.5% patients were aware of their disease. Approximately one-third of the COPD patients belonged to GOLD groups B, C, and D, which require regular treatment.     

Biopersistent Granular Dust and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Objective

Applying a systematic review to identify studies eligible for meta-analysis of the association between occupational exposure to inorganic dust and the development of chronic obstructive pulmonary disease (COPD), and conducting a meta-analysis.

Data Sources

Searches of PubMed and Embase for the time period 1970–2010 yielded 257 cross-sectional and longitudinal studies on people exposed to inorganic dust at the workplace with data on lung function. These studies were independently abstracted and evaluated by two authors; any disagreement was resolved by a third reviewer. Of 55 publications accepted for meta-analysis, 27 investigated the effects of occupational exposure to biopersistent granular dust (bg-dust).

Methods

A random effects meta-analysis allowed us to provide an estimate of the average exposure effect on spirometric parameters presented in forest plots. Between-study heterogeneity was assessed by using I² statistics, with I²>25% indicating significant heterogeneity. Publication bias was investigated by visual inspection of funnel plots. The influence of individual studies was assessed by dropping the respective study before pooling study-specific estimates.

Results

The mean FEV1 of workers exposed to bg-dust was 160 ml lower or 5.7% less than predicted compared to workers with no/low exposure. The risk of an obstructive airway disease—defined as FEV1/FVC < 70%—increased by 7% per 1 mg· m^-3 respirable bg-dust.

Conclusion

Occupational inhalative exposure to bg-dust was associated with a statistically significant decreased FEV1 and FEV1/FVC revealing airway obstruction consistent with COPD.     

Association between Psoriasis and Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-analysis

Psoriasis is considered a systemic inflammatory disorder. Previous studies have reported conflicting positive or negative correlations between psoriasis and chronic obstructive pulmonary disease. We performed a meta-analysis to determine whether there is an associated risk between psoriasis and chronic obstructive pulmonary disease. We performed a complete 30-year literature search of MEDLINE, Embase, and Cochrane Central Register databases on this topic. Four observational studies with a total of 13,418 subjects were identified. The odds ratios of chronic obstructive pulmonary disease in subjects with psoriasis/mild-to-moderate psoriasis were analyzed using the random-effects model, while the odds ratios of chronic obstructive pulmonary disease in subjects with severe psoriasis and current smoking in subjects with psoriasis were analyzed using the fixed-effect model. We found that psoriasis patients were at a greater risk of developing chronic obstructive pulmonary disease than the general population (odds ratio, 1.90; 95% confidence interval, 1.36–2.65) and that the association between of psoriasis and with chronic obstructive pulmonary disease was stronger among patients with severe psoriasis (odds ratio, 2.15; 95% confidence interval, 1.26–3.67). Psoriasis patients should be advised to cease smoking to reduce their risk of COPD. Moreover, identification of this potential risk may enable earlier implementation of preventive measures for reduction comorbidity and mortality rates.     

Effects of N-Acetylcysteine in Ozone-Induced Chronic Obstructive Pulmonary Disease Model

Introduction

Chronic exposure to high levels of ozone induces emphysema and chronic inflammation in mice. We determined the recovery from ozone-induced injury and whether an antioxidant, N-acetylcysteine (NAC), could prevent or reverse the lung damage.

Methods

Mice were exposed to ozone (2.5 ppm, 3 hours/12 exposures, over 6 weeks) and studied 24 hours (24h) or 6 weeks (6W) later. Nac (100 mg/kg, intraperitoneally) was administered either before each exposure (preventive) or after completion of exposure (therapeutic) for 6 weeks.

Results

After ozone exposure, there was an increase in functional residual capacity, total lung volume, and lung compliance, and a reduction in the ratio of forced expiratory volume at 25 and 50 milliseconds to forced vital capacity (FEV₂₅/FVC, FEV₅₀/FVC). Mean linear intercept (L_m) and airway hyperresponsiveness (AHR) to acetylcholine increased, and remained unchanged at 6W after cessation of exposure. Preventive NAC reduced the number of BAL macrophages and airway smooth muscle (ASM) mass. Therapeutic NAC reversed AHR, and reduced ASM mass and apoptotic cells.

Conclusion

Emphysema and lung function changes were irreversible up to 6W after cessation of ozone exposure, and were not reversed by NAC. The beneficial effects of therapeutic NAC may be restricted to the ASM.     

Epicardial Adipose Tissue in Patients with Chronic Obstructive Pulmonary Disease

Rationale

Epicardial Adipose Tissue (EAT) volume as determined by chest computed tomography (CT) is an independent marker of cardiovascular events in the general population. COPD patients have an increased risk of cardiovascular disease, however nothing is known about the EAT volume in this population.

Objectives

To assess EAT volume in COPD and explore its association with clinical and physiological variables of disease severity.

Methods

We measured EAT using low-dose CT in 171 stable COPD patients and 70 controls matched by age, smoking history and BMI. We determined blood pressure, cholesterol, glucose and HbA1c levels, microalbuminuria, lung function, BODE index, co-morbidity index and coronary artery calcium score (CAC). EAT volume were compared between groups. Uni and multivariate analyses explored the relationship between EAT volume and the COPD related variables.

Results

COPD patients had a higher EAT volume [143.7 (P_25–75, 108.3–196.6) vs 129.1 (P_25–75, 91.3–170.8) cm³, p = 0.02)] and the EAT volume was significantly associated with CAC (r = 0.38, p<0.001) and CRP (r = 0.32, p<0.001) but not with microalbuminuria (r = 0.12, p = 0.13). In COPD patients, EAT volume was associated with: age, pack-years, BMI, gender, FEV₁%, 6 MWD, MMRC and HTN. Multivariate analysis showed that only pack-years (B = 0.6, 95% CI: 0.5–1.3), BMI (B = 7.8, 95% CI: 5.7–9.9) and 6 MWD (B = −0.2, 95% CI: −0.3–−0.1), predicted EAT volume.

Conclusions

EAT volume is increased in COPD patients and is independently associated with smoking history, BMI and exercise capacity, all modifiable risk factors of future cardiovascular events. EAT volume could be a non-invasive marker of COPD patients at high risk for future cardiovascular events.     

Bronchiectasis as a Comorbidity of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Background

Bronchiectasis revealed by chest computed tomography in COPD patients and its comorbid effect on prognosis have not been addressed by large-sized studies. Understanding the presence of bronchiectasis in COPD is important for future intervention and preventing disease progression.

Methods

Observational studies were identified from electronic literature searches in Cochrane library, PubMed, ScienceDirect databases, American Thoracic Society and European Respiratory Society meeting abstracts. A systematic review and meta-analysis of studies was performed to summarize the factors associated with bronchiectasis in COPD patients. Primary outcomes included the risks for exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality. Odds ratios (ORs) were pooled by random effects models.

Results

Fourteen observational studies were eligible for the study. Compared with COPD without bronchiectasis, comorbid bronchiectasis in COPD increased the risk of exacerbation (1.97, 95% CI, 1.29–3.00), isolation of a potentially pathogenic microorganism (4.11, 95%CI, 2.16–7.82), severe airway obstruction (1.31, 95% CI, 1.09–1.58) and mortality (1.96, 95% CI, 1.04–3.70).

Conclusions

The presence of bronchiectasis in patients with COPD was associated with exacerbation frequency, isolation of a potentially pathogenic microorganism, severe airway obstruction and mortality.     

A Combined Pulmonary Function and Emphysema Score Prognostic Index for Staging in Chronic Obstructive Pulmonary Disease

Introduction

Chronic Obstructive Pulmonary Disease (COPD) is characterized by high morbidity and mortality. Lung computed tomography parameters, individually or as part of a composite index, may provide more prognostic information than pulmonary function tests alone.

Aim

To investigate the prognostic value of emphysema score and pulmonary artery measurements compared with lung function parameters in COPD and construct a prognostic index using a contingent staging approach.

Material-Methods

Predictors of mortality were assessed in COPD outpatients whose lung computed tomography, spirometry, lung volumes and gas transfer data were collected prospectively in a clinical database. Univariate and multivariate Cox proportional hazard analysis models with bootstrap techniques were used.

Results

169 patients were included (59.8% male, 61.1 years old; Forced Expiratory Volume in 1 second % predicted: 40.5±19.2). 20.1% died; mean survival was 115.4 months. Age (HR = 1.098, 95% Cl = 1.04–1.252) and emphysema score (HR = 1.034, 95% CI = 1.007–1.07) were the only independent predictors of mortality. Pulmonary artery dimensions were not associated with survival. An emphysema score of 55% was chosen as the optimal threshold and 30% and 65% as suboptimals. Where emphysema score was between 30% and 65% (intermediate risk) the optimal lung volume threshold, a functional residual capacity of 210% predicted, was applied. This contingent staging approach separated patients with an intermediate risk based on emphysema score alone into high risk (Functional Residual Capacity ≥210% predicted) or low risk (Functional Residual Capacity <210% predicted). This approach was more discriminatory for survival (HR = 3.123; 95% CI = 1.094–10.412) than either individual component alone.

Conclusion

Although to an extent limited by the small sample size, this preliminary study indicates that the composite Emphysema score-Functional Residual Capacity index might provide a better separation of high and low risk patients with COPD, than other individual predictors alone.     

Oxygen Therapy Use in Older Adults with Chronic Obstructive Pulmonary Disease

Rationale

Oxygen therapy improves survival and function in severely hypoxemic chronic obstructive pulmonary disease (COPD) patients based on two landmark studies conducted over 40 years ago. We hypothesize that oxygen users in the current era may be very different. We examined trends and subject characteristics associated with oxygen therapy use from 2001–2010 in the United States.

Methods

We examined Medicare beneficiaries with COPD who received oxygen from 2001 to 2010. COPD subjects were identified by: 1) ≥2 outpatient visits >30 days apart within one year with an encounter diagnosis of COPD; or 2) an acute care hospitalization with COPD as the primary or secondary discharge diagnosis. Oxygen therapy and sustained oxygen therapy were defined as ≥1 and ≥11 claims for oxygen, respectively, in the durable medical equipment file in a calendar year. Primary outcome measures were factors associated with oxygen therapy and sustained oxygen therapy over the study period.

Results

Oxygen therapy increased from 33.7% in 2001 to 40.5% in 2010 (p-value of trend <0.001). Sustained oxygen therapy use increased from 19.5% in 2001, peaked in 2008 to 26.9% and declined to 18.5% in 2010. The majority of subjects receiving oxygen therapy and sustained oxygen therapy were female. Besides gender, factors associated with any oxygen use or sustained oxygen therapy were non-Hispanic white race, low socioeconomic status and ≥2 comorbidities.

Conclusions

Any oxygen use among fee-for service Medicare beneficiaries with COPD is high. Current users of oxygen are older females with multiple comorbidities. Decline in sustained oxygen therapy use after 2008 may be related to reimbursement policy change.     

Inflammatory Markers and the Risk of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis

Systemic inflammatory factors are inconsistently associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis to summarize the evidence supporting the association between systemic inflammation and the risk of COPD. Pertinent studies were retrieved from PubMed, EmBase, and the Cochrane Library until April 2015. A random-effects model was used to process the data, and the analysis was further stratified by factors affecting these associations. Sensitivity analyses for publication bias were performed. We included 24 observational studies reporting data on 10,677 COPD patients and 28,660 controls. Overall, we noted that COPD was associated with elevated serum CRP (SMD: 1.21; 95%CI: 0.92–1.50; P < 0.001), leukocytes (SMD: 1.07; 95%: 0.25–1.88; P = 0.010), IL-6 (SMD: 0.90; 95%CI: 0.48–1.31; P < 0.001), IL-8 (SMD: 2.34; 95%CI: 0.69–4.00; P = 0.006), and fibrinogen levels (SMD: 0.87; 95%CI: 0.44–1.31; P < 0.001) when compared with control. However, COPD was not significantly associated with TNF-α levels when compared with control (SMD: 0.60; 95%CI: -0.46 to 1.67; P = 0.266). Our findings suggested that COPD was associated with elevated serum CRP, leukocytes, IL-6, IL-8, and fibrinogen, without any significant relationship with TNF-α.     

Effects of Anabolic Steroids on Chronic Obstructive Pulmonary Disease: A Meta-Analysis of Randomised Controlled Trials

Background

Anabolic steroids are known to improve body composition and muscle strength in healthy people. However, whether anabolic steroids improve the physical condition and function in patients with chronic obstructive pulmonary disease (COPD) remains undetermined. A meta-analysis was conducted to review the current evidence regarding the effects of anabolic steroids on COPD patients.

Methods

A comprehensive literature search of PubMed and EMBASE was performed to identify randomised controlled trials that examine the effects of anabolic steroids on COPD patients. Weighted mean differences (WMDs) with 95% confidence intervals were calculated to determine differences between anabolic steroid administration and control conditions.

Results

Eight eligible studies involving 273 COPD patients were identified in this meta-analysis. Significant improvements were found in body weight (0.956 kg), fat-free mass (1.606 kg), St. George''s Respiratory Questionnaire total score (−6.336) and symptom score (−12.148). The apparent improvements in maximal inspiratory pressure (2.740 cmH₂O) and maximal expiratory pressure (12.679 cmH₂O) were not significant. The effects on handgrip strength, forced expiratory volume in one second (FEV₁), predicted FEV₁ percent, PaO₂, PaCO₂ and six-min walk distance were negative, with WMDs of −0.245 kg, −0.096 L/sec, −1.996% of predicted, −1.648 cmHg, −0.039 cmHg and −16.102 meters, respectively.

Conclusions

Limited evidence available from the published literature suggests that the benefit of anabolic steroids on COPD patients cannot be denied. However, further studies are needed to identify the specific benefits and adverse effects of anabolic steroids on COPD patients and to determine the optimal populations and regimes of anabolic steroids in COPD patients.     

Predicting Daily Physical Activity in Patients with Chronic Obstructive Pulmonary Disease

Background

Objectively measuring daily physical activity (PA) using an accelerometer is a relatively expensive and time-consuming undertaking. In routine clinical practice it would be useful to estimate PA in patients with chronic obstructive pulmonary disease (COPD) with more simple methods.

Objectives

To evaluate whether PA can be estimated by simple tests commonly used in clinical practice in patients with COPD.

Methods

The average number of steps per day was measured for 7 days with a SenseWear Pro™ accelerometer and used as gold standard for PA. A physical activity level (PAL) of <1.4 was considered very inactive. Univariate and multivariate analyses were used to examine the relationship between the 6-minute walking distance (6MWD), the number of stands in the Sit-to-Stand Test (STST), hand-grip strength and the total energy expenditure as assessed by the Zutphen Physical Activity Questionnaire (TEE_ZPAQ). ROC curve analysis was used to identify patients with an extremely inactive lifestyle (PAL<1.4).

Results

In 70 patients with COPD (21 females) with a mean [SD] FEV₁ of 43.0 [22.0] %predicted, PA was found to be significantly and independently associated with the 6MWD (r = 0.69, 95% CI 0.54 to 0.80, p<0.001), STST (r = 0.51, 95% CI 0.31 to 0.66, p = 0.001) and TEEZPAQ (r = 0.50, 95% CI 0.30 to 0.66, p<0.001) but not with hand-grip strength. However, ROC curve analysis demonstrated that these tests cannot be used to reliably identify patients with an extremely inactive lifestyle.

Conclusions

In patients with COPD simple tests such as the 6-Minute Walk Test, the Sit-to-Stand Test and the Zutphen Physical Activity Questionnaire cannot be used to reliably predict physical inactivity.     

Unequal Twice-Daily,Sustained-Release Theophylline Dosing in Chronic Obstructive Pulmonary Disease

Three regimens of sustained-release theophylline (SRT), Theostat® were administered to 12 male patients with chronic obstructive pulmonary disease in a randomized cross-over trial. Each 7-day treatment consisted of

treatment A—8 mg/kg at 0700 hr and 4 mg/kg at 1900 hr

treatment B—6 mg/kg at 0700 hr and 6 mg/kg at 1900 hr

treatment C—4 mg/kg at 0700 hr and 8 mg/kg at 1900 hr.

Peak expiratory flow (PEF) was recorded each day at 0700, 1100, 1500, 1900 and 2300 hr and theophylline plasma levels were determined on the 7th day of each treatment sequence. Cosinor analysis of the data revealed significant circadian rhythms in PEF for each treatment: the mesor (24-hr average) was significantly higher with C and acrophases (Φ, peak time of PEF rhythm) were located at 1426 hr for A and 1425 hr for C; a shift of the acrophase to an earlier timing was detected for B (Φ = 0958 hr. These findings suggest that an unequal, twice-daily SRT dosing with the greater amount of drug at night may be beneficial in the treatment of COPD.     

Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

Background

In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.

Objectives

To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function.

Methods

62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45⁺CD34⁺CD133⁺ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects.

Results

Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries.

Conclusions

Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.