Chronic obstructive pulmonary disease: a novel risk factor for cardiovascular disease

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Canada and elsewhere. It affects 5% of all adult Canadians and is the fourth leading cause of death. Interestingly, the leading causes of hospitalizations and mortality among COPD patients are cardiovascular events. In the Lung Health Study, over 5 800 patients with mild to moderate COPD were studied. Forty-two to 48% of all hospitalizations that occurred over the study's 5-year follow-up period were related to cardiovascular complications. Various population-based studies suggest that independent of smoking, age, and gender, COPD increases the risk of cardiovascular morbidity and mortality twofold. Alarmingly, some bronchodilators, which are commonly used to treat symptoms in COPD, may increase the risk of cardiovascular morbidity and even mortality among COPD patients. In this paper, we discuss the epidemiologic evidence linking COPD and cardiovascular events as well as the potential mechanism(s) which may be responsible for this association.     

Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony

Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions. It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020. The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality. Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines. On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function. Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes. On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals. The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus. Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease. Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems.     

Chronic obstructive pulmonary disease, asthma and protective effects of food intake: from hypothesis to evidence?

Evidence for a role of diet in asthma and chronic obstructive pulmonary disease (COPD) has been accumulating rapidly over the past decade. Associations have been reported between the intake of fruit, fish, antioxidant vitamins, fatty acids, sodium or magnesium, and indicators of asthma and COPD. Several issues need to be addressed before causality of these associations can be established. The role of diet in the development of disease and the induction time and reversibility of the effect needs further investigation. The role of smoking habits in the relation of diet and respiratory disease also needs to be elucidated. Nevertheless, based on the available evidence, dietary guidelines could be proposed for the primary and secondary prevention of asthma and COPD that are in line with existing dietary guidelines for the prevention of coronary heart disease and cancer.     

Metabolomic profiling of anaerobic and aerobic energy metabolic pathways in chronic obstructive pulmonary disease

While there is no cure for chronic obstructive pulmonary disease (COPD), its progressive nature and the formidable challenge to manage its symptoms warrant a more extensive study of the pathogenesis and related mechanisms. A new emphasis on COPD study is the change of energy metabolism. For the first time, this study investigated the anaerobic and aerobic energy metabolic pathways in COPD using the metabolomic approach. Metabolomic analysis was used to investigate energy metabolites in 140 COPD patients. The significance of energy metabolism in COPD was comprehensively explored by the Global Initiative for Chronic Obstructive Lung Disease–GOLD grading, acute exacerbation vs. stable phase (either clinical stability or four-week stable phase), age group, smoking index, lung function, and COPD Assessment Test (CAT) score. Through comprehensive evaluation, we found that COPD patients have a significant imbalance in the aerobic and anaerobic energy metabolisms in resting state, and a high tendency of anaerobic energy supply mechanism that correlates positively with disease progression. This study highlighted the significance of anaerobic and low-efficiency energy supply pathways in lung injury and linked it to the energy-inflammation-lung ventilatory function and the motion limitation mechanism in COPD patients, which implies a novel therapeutic direction for this devastating disease.     

Chronic obstructive pulmonary disease and inhaled steroids alter surfactant protein D (SP-D) levels: a cross-sectional study

Background

Surfactant protein D (SP-D), an innate immune molecule, plays an important protective role during airway inflammation. Deficiency of this molecule induces emphysematous changes in murine lungs, but its significance in human COPD remains unclear.

Methods

We collected bronchoalveolar lavage fluid from 20 subjects with varying degrees of COPD (8 former smokers and 12 current smokers) and 15 asymptomatic healthy control subjects (5 never smokers, 3 remote former smokers, and 7 current smokers). All subjects underwent a complete medical history and pulmonary function testing. SP-D was measured by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis was performed using nonparametric methods and multivariable linear regression for control of confounding. The effect of corticosteroid treatment on SP-D synthesis was studied in vitro using an established model of isolated type II alveolar epithelial cell culture.

Results

Among former smokers, those with COPD had significantly lower SP-D levels than healthy subjects (median 502 and 1067 ng/mL, respectively, p = 0.01). In a multivariable linear regression model controlling for age, sex, race, and pack-years of tobacco, COPD was independently associated with lower SP-D levels (model coefficient -539, p = 0.04) and inhaled corticosteroid use was independently associated with higher SP-D levels (398, p = 0.046). To support the hypothesis that corticosteroids increase SP-D production we used type II alveolar epithelial cells isolated from adult rat lungs. These cells responded to dexamethasone treatment by a significant increase of SP-D mRNA (p = 0.041) and protein (p = 0.037) production after 4 days of culture.

Conclusion

Among former smokers, COPD is associated with lower levels of SP-D and inhaled corticosteroid use is associated with higher levels of SP-D in the lung. Dexamethasone induced SP-D mRNA and protein expression in isolated epithelial cells in vitro. Given the importance of this molecule as a modulator of innate immunity and inflammation in the lung, low levels may play a role in the pathogenesis and/or progression of COPD. Further, we speculate that inhaled steroids may induce SP-D expression and that this mechanism may contribute to their beneficial effects in COPD. Larger, prospective studies are warranted to further elucidate the role of surfactant protein D in modulating pulmonary inflammation and COPD pathogenesis.     

Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis

Background

Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in CHRNA coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of CHRNA variants on COPD.

Methods

We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on CHRNA. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.

Results

Among seven reported variants in CHRNA, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10^-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10^-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).

Conclusions

Our findings suggest that rs1051730 in CHRNA is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.     

Chronic obstructive pulmonary disease: A crosstalk on nucleotide compositional dynamics and codon usage patterns of the genes involved in disease

Chronic obstructive pulmonary disease (COPD), a lung disease, affects a large number of people worldwide, leading to death. Here, we analyzed the compositional features and trends of codon usage of the genes influencing COPD to understand molecular biology, genetics, and evolutionary relationships of these genes as no work was reported yet. Coding sequences of COPD genes were found to be rich in guanine-cytosine (GC) content. A high value (34-60) of the effective number of codons of the genes indicated low codon usage bias (CUB). Correspondence analysis suggested that the COPD genes were distinct in their codon usage patterns. Relative synonymous codon usage values of codons differed between the more preferred codons and the less-preferred ones. Correlation analysis between overall nucleotides and those at third codon position revealed that mutation pressure might influence the CUB of the genes. The high correlation between GC12 and GC3 signified that directional mutation pressure might have operated at all the three codon positions in COPD genes.     

Evidence of a defective thiol status of alveolar macrophages from COPD patients and smokers. Chronic obstructive pulmonary disease

In increasing numbers of pulmonary diseases an association with a loss of intracellular thiols, mainly glutathione, is postulated. Therefore, the quantitative measurement of thiols within different viable cells is a possible metabolic parameter for cellular function and defense capacity of all pulmonary immune cells including alveolar macrophages (AM), that are highly compromised by oxidative stress. In this study the cellular thiol content was determined using fluorochrom conjugated chloromethyl derivatives (5-chloromethylfluorescein diacetate, CMFDA) in flow cytometry. The procedure was evaluated in vitro using biochemical techniques for glutathione quantification. Based on this approach, AM obtained from bronchoalveolar lavage (BAL) of smokers and patients with chronic obstructive pulmonary disease (COPD) showed a significant thiol deficiency compared to a nonsmoker/non-COPD group. The cellular thiol expression of AM from smokers and COPD patients reached only 50 and 53% of the control group. Lowest thiol concentrations (47% of control) were detected within the smoker(+)/COPD(+) group. This intracellular thiol deficiency significantly correlated with reduced lung function (FEV(1), PaO(2)). With regard to the tightly regulated thiol metabolism of immune cells, these results imply the onset of functional disturbances in thiol deficient AM. The determination of the cellular thiol content of AM, obtained from BAL by flow cytometry, presents a simple and reliable tool to monitor the effect of therapeutic measures focusing on the stabilization of the cellular thiol status.     

The vision of recovery today: what it is and what it means for services

In the past, practice in mental health was guided by the belief that individuals with serious mental illnesses do not recover. The course of their illness was either seen pessimistically, as deteriorative, or optimistically, as a maintenance course. Research over the past thirty to forty years has indicted that belief and shown that a vision of recovery can be achieved for many individuals. People with serious mental illnesses have themselves published accounts of their own recovery as well as advocated for the development of recovery promoting services. In North America and other regions, policies have been developed to make recovery the guiding vision of services. Today, particularly in the United States, much effort is going into the transformation of services and systems to achieve recovery outcomes. Despite these trends, the idea of recovery remains controversial and, some say, even illusory. This article clarifies the meaning of the term "recovery", reviews the research and first person accounts providing a rationale for recovery, and sets out implications for developing recovery oriented services.     

Risk of herpes zoster among patients with chronic obstructive pulmonary disease: a population-based study

Background

Systemic inflammation and dysregulated immune function in chronic obstructive pulmonary disease (COPD) is hypothesized to predispose patients to development of herpes zoster. However, the risk of herpes zoster among patients with COPD is undocumented. We therefore aimed to investigate the risk of herpes zoster among patients with COPD.

Methods

We conducted a cohort study using data from the Taiwan Longitudinal Health Insurance Database. We performed Cox regressions to compare the hazard ratio (HR) of herpes zoster in the COPD cohort and in an age- and sex-matched comparison cohort. We divided the patients with COPD into three groups according to use of steroid medications and performed a further analysis to examine the risk of herpes zoster.

Results

The study included 8486 patients with COPD and 33 944 matched control patients. After adjustment for potential confounding factors, patients with COPD were more likely to have incidents of herpes zoster (adjusted HR 1.68, 95% confidence interval [CI] 1.45–1.95). When compared with the comparison cohort, the adjusted HR of herpes zoster was 1.67 (95% CI 1.43–1.96) for patients with COPD not taking steroid medications. The adjusted HR of herpes zoster was slightly greater for patients with COPD using inhaled corticosteroids only (adjusted HR 2.09, 95% CI 1.38–3.16) and was greatest for patients with COPD using oral steroids (adjusted HR 3.00, 95% CI 2.40–3.75).

Interpretation

Patients with COPD were at increased risk of herpes zoster relative to the general population. The relative risk of herpes zoster was greatest for patients with COPD using oral steroids.Herpes zoster is caused by a reactivation of latent varicella-zoster virus residing in sensory ganglia after an earlier episode of varicella.¹ Herpes zoster is characterized by a painful vesicular dermatomal rash. It is commonly complicated with chronic pain (postherpetic neuralgia), resulting in reduced quality of life and functional disability to a degree comparable to that experienced by patients with congestive heart failure, diabetes mellitus and major depression.^1,2 Patients with herpes zoster experience more substantial role limitations resulting from emotional and physical problems than do patients with congestive heart failure or diabetes.³ Pain scores for postherpetic neuralgia have been shown to be as high as those for chronic pain from osteoarthritis and rheumatoid arthritis.³ Although aging is the most well-known risk factor for herpes zoster, people with diseases associated with impaired immunity, such as malignancy, HIV infection, diabetes and rheumatic diseases, are also at higher risk for herpes zoster.^4,5Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation that is associated with an abnormal inflammatory response by the small airways and alveoli to inhaled particles and pollutants.⁶ Disruption of local defence systems (e.g., damage to the innate immune system, impaired mucociliary clearance) predispose patients with COPD to respiratory tract infections. Each infection can cause exacerbation of COPD and further deterioration of lung function, which in turn increase predisposition to infection.^7,8There is increasing evidence that COPD is an autoimmune disease, with chronic systemic inflammation involving more than just the airways and lungs.⁶ Given that various immune-mediated diseases (e.g., rheumatoid arthritis, inflammatory bowel disease) have been reported to be associated with an increased risk of herpes zoster,^4,9,10 it is reasonable to hypothesize that the immune dysregulation found in COPD may put patients at higher risk of developing herpes zoster. In addition, inhaled or systemic corticosteroids used for management of COPD can increase susceptibility to herpes zoster by suppressing normal immune function.¹¹ However, data are limited regarding the risk of herpes zoster among patients with COPD.The goal of our study was to investigate whether patients with COPD have a higher incidence of herpes zoster than the general population. In addition, we aimed to examine the risk for herpes zoster with and without steroid therapy among patients with COPD relative to the general population.     

Genetic polymorphism of matrix metalloproteinase 9 and susceptibility to chronic obstructive pulmonary disease: A meta-analysis

BackgroundTo systematically analyze the influence of genetic polymorphisms of matrix metalloproteinase 9 (MMP9) on susceptibility to chronic obstructive pulmonary disease (COPD).MethodsRelevant literatures reporting MMP9 and susceptibility to COPD in PubMed, Web of Science, VIP, Wanfang and CNKI databases were searched using the key words "matrix metalloproteinases 9/MMP9, COPD/chronic obstructive pulmonary disease". Data of eligible literatures were extracted and analyzed for the odds ratio (OR) and corresponding 95% CI.ResultsA total of 16 independent studies reporting MMP9-1562C/T and COPD patients were enrolled and analyzed. None of the genetic models revealed the relationship between MMP9-1562C/T and susceptibility to COPD. Subgroup analyses identified lower risk of COPD in Chinese population carrying the TT genotype for theMMP9 rs3918242 relative to those carrying CT and CC genotypes (P=0.03, OR=0.67, 95% CI=0.46-0.97).ConclusionsChinese population carrying the TT genotype for the MMP-9 rs3918242 present lower susceptibility to COPD relative to those carrying CT and CC genotypes.     

Validity of six activity monitors in chronic obstructive pulmonary disease: a comparison with indirect calorimetry

Reduced physical activity is an important feature of Chronic Obstructive Pulmonary Disease (COPD). Various activity monitors are available but their validity is poorly established. The aim was to evaluate the validity of six monitors in patients with COPD. We hypothesized triaxial monitors to be more valid compared to uniaxial monitors. Thirty-nine patients (age 68±7 years, FEV(1) 54±18%predicted) performed a one-hour standardized activity protocol. Patients wore 6 monitors (Kenz Lifecorder (Kenz), Actiwatch, RT3, Actigraph GT3X (Actigraph), Dynaport MiniMod (MiniMod), and SenseWear Armband (SenseWear)) as well as a portable metabolic system (Oxycon Mobile). Validity was evaluated by correlation analysis between indirect calorimetry (VO(2)) and the monitor outputs: Metabolic Equivalent of Task [METs] (SenseWear, MiniMod), activity counts (Actiwatch), vector magnitude units (Actigraph, RT3) and arbitrary units (Kenz) over the whole protocol and slow versus fast walking. Minute-by-minute correlations were highest for the MiniMod (r?=?0.82), Actigraph (r?=?0.79), SenseWear (r?=?0.73) and RT3 (r?=?0.73). Over the whole protocol, the mean correlations were best for the SenseWear (r?=?0.76), Kenz (r?=?0.52), Actigraph (r?=?0.49) and MiniMod (r?=?0.45). The MiniMod (r?=?0.94) and Actigraph (r?=?0.88) performed better in detecting different walking speeds. The Dynaport MiniMod, Actigraph GT3X and SenseWear Armband (all triaxial monitors) are the most valid monitors during standardized physical activities. The Dynaport MiniMod and Actigraph GT3X discriminate best between different walking speeds.