Effect of add-on therapy of tiotropium in COPD treated with theophylline

Background

Although combination therapy with bronchodilators is recommended for chronic obstructive pulmonary disease (COPD), there is insufficient evidence for the efficacy of some combinations of long-acting bronchodilators.

Objective

We investigated the effects of a combination therapy with tiotropium and theophylline in COPD patients.

Methods

In a 12-week, open-labeled, parallel-group randomized study, pulmonary functions and dyspnea scores were compared between the combination and theophylline alone therapy at baseline, and 4 and 8 weeks after randomization in COPD.

Results

Sixty-one COPD patients completed the trial (31 combination therapy, 30 theophylline alone; mean age 70 years; 58 males; mean dyspnea score 2.0 and forced expiratory volume in one second (FEV₁) 1.5 L [62.5% predicted]). FEV₁ in the combination group, but not in the theophylline alone, was significantly increased at 4 (1.56 ± 0.13 L, p < 0.001) and 8 weeks (1.60 ± 0.13 L, p < 0.001) from the baseline (1.40 ± 0.12 L). In the combination group, but not the theophylline alone group, the dyspnea score was significantly improved after 4 (p < 0.01) and 8 weeks (p < 0.05) compared with baseline. In 17 patients who did not receive theophylline at screening, treatment with 4 or 8 weeks of theophylline alone did not improve dyspnea score or FEV₁.

Conclusion

Addition of tiotropium therapy to theophylline treatment can improve dyspnea and pulmonary function in COPD. Although this study did not assess whether there was any benefit of adding theophylline to patients treated with tiotropium, tiotropium can be a useful addition in COPD already treated with theophylline.     

Measurement of the acute inflammatory response to walking exercise in COPD: effects of pulmonary rehabilitation

Objective:

This pilot study concerns the evaluation of the acute cytokine response to exercise and changes in this throughout a 7 week pulmonary rehabilitation programme.

Methods:

17 (10 male, 7 female) stable COPD patients, mean (SD) age 69 (8) yrs, mean FEV₁, 51.3 (17.3) % predicted entered into 7 weeks of rehabilitation. The acute cytokine response (ACR) was measured from serum cytokine levels; Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) taken pre, post and 1 hour post-maximal incremental shuttle walking test (ISWT). The ACR to maximal exercise was determined before rehabilitation (T0) and post rehabilitation (T7). The ACR (pre/post test) to iso-distance exercise (based on initial ISWT distance) was determined throughout the rehabilitation period at 2 (T2), 4 (T4) weeks and at the end (T7).

Results:

12 patients completed the study. Maximal ISWT distance significantly increased after rehabilitation. There was no significant change in baseline cytokine level throughout; or in pre/post-exercise cytokine levels prior to, during or following rehabilitation.

Conclusions:

There was no significant inflammatory response associated with maximal exercise before or after training. Cytokine responses to a fixed bout of exercise did not alter markedly throughout. Clinical PR is unlikely to exacerbate systemic inflammation in COPD.     

A meta-analysis on the efficacy of oral theophylline in patients with stable COPD

Background

Theophylline is a nonspecific inhibitor of phosphodiesterases that, despite exerting bronchodilator and anti-inflammatory effects, is a third-line therapy rarely used to treat chronic airflow limitation. We wished to evaluate the efficacy of oral theophylline as measured by improvements in trough (pre-dose) or peak (post-dose) FEV₁ and FVC in patients with clinically stable COPD.

Design

Meta-analysis of randomized, placebo-controlled trials reported as of June 2005 in which theophylline was orally administered to stable COPD patients and the functional evaluations included pre- and post-theophylline values for FEV₁ and FVC.

Results

A total of 18 trials were included in the meta-analysis. The weighted mean differences (WMD) with 95% confidence intervals (95% CI) for improvement over placebo in trough FEV₁ and FVC were 0.108L (0.053–0.163) and 0.186L (0.036–0.336), respectively, while peak FEV₁ and FVC improved by 0.096L (0.044–0.147) and 0.242L (0.11–0.374), respectively.

Conclusions

Treatment with oral theophylline improves both trough and peak FEV₁ and FVC in clinically stable COPD patients. These results support previously reported benefits of theophylline in COPD.     

Postoperative outcome after coronary artery bypass grafting in chronic obstructive pulmonary disease

BACKGROUND:

It is uncertain if the presence and severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is predictive of surgical morbidity and mortality after coronary artery bypass grafting (CABG).

METHODS:

Retrospective study of patients who underwent CABG between 1998 and 2003 in a university-affiliated hospital for whom a preoperative spirometry was available. COPD was diagnosed in smokers or ex-smokers 50 years of age or older in the presence of irreversible airflow obstruction. Patients were divided into three groups depending on the spirometry: controls (forced expiratory volume in 1 s [FEV₁] 80% or more, FEV₁/forced vital capacity [FVC] greater than 0.7), mild to moderate COPD (FEV₁ 50% or more and FEV₁/FVC 0.7 or less) and severe COPD (FEV₁ less than 50% and FEV₁/FVC 0.7 or less).

RESULTS:

Among the 411 files studied, 322 (249 men, 68±8 years of age) were retained (controls, n=101; mild to moderate COPD, n=153; severe COPD, n=68). The mortality rate (3.0%, 2.6% and 0%, respectively) was comparable among the three groups. Patients with severe COPD had a slightly longer hospital stay than controls (mean difference 0.7±1.4 days, P<0.05). Pulmonary infections were more frequent in severe COPD (26.5%) compared with mild to moderate COPD (12.4%) and controls (12.9%), P<0.05. Atrial fibrillation tended to be more frequent in severe COPD than in the other two groups.

CONCLUSION:

Mortality rate associated with CABG surgery is not influenced by the presence and severity of airflow obstruction in patients with COPD. The incidence of pulmonary infections and length of hospital stay were increased in patients with severe COPD.     

A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease

BACKGROUND:

Patients with chronic obstructive pulmonary disease (COPD) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s (FEV₁) than those patients who have stopped smoking.

OBJECTIVES:

To assess the effect of tiotropium on pre-dose (trough) FEV₁ in patients with COPD followed in Canada.

METHODS:

A total of 913 patients were randomly assigned to receive either tiotropium 18 μg once daily (n=608) or placebo (usual care minus inhaled anticholinergics) (n=305) for 48 weeks in the present randomized, double-blind, parallel-group study. The effect of tiotropium on measurements of lung function (FEV₁, FEV₆ and forced vital capacity), symptoms, health-related quality of life (St George’s Respiratory Questionnaire) and exacerbations were examined.

RESULTS:

Tiotropium improved trough FEV₁ in both current and ex-smokers compared with placebo. Baseline FEV₁ in smokers and ex-smokers was 1.03 L and 0.93 L, respectively (P<0.001). At week 48, the mean difference between the tiotropium and placebo groups was 0.14±0.04 L (P<0.001) in the smoker group and 0.08±0.02 L (P<0.0001) in the ex-smoker group. Tiotropium also significantly improved trough forced vital capacity and FEV₆ compared with placebo throughout the treatment period (P<0.05, for all). Furthermore, tiotropium significantly improved the St George’s Respiratory Questionnaire total score compared with placebo at week 48 (40.9 versus 43.7 units, P<0.005).

CONCLUSIONS:

Compared with the placebo group, tiotropium provides sustained improvements in lung function in patients with COPD, with improvements for smokers and ex-smokers.     

Acute inflammatory and anabolic systemic responses to peak and constant-work-rate exercise bout in hospitalized patients with COPD

Study objectives:

To explore the acute systemic inflammatory and anabolic effects of cycling in hospital admitted patients with chronic obstructive pulmonary disease (COPD) and in patients with clinically stable disease.

Design:

Cross-sectional comparative study.

Setting:

University Hospital Gasthuisberg, a tertiary care setting.

Patients:

16 patients with clinically stable COPD (no acute exacerbation in the past 12 weeks; median age: 73 years (IQR: 60 to 75); median forced expiratory volume in the first second (FEV₁): 45% predicted (IQR: 33 to 58)) and 14 patients who were admitted to a hospital due an acute exacerbation of COPD (median age: 65 years (IQR: 59 to 74); median FEV₁ to on day 8 of hospital stay: 41% predicted (IQR: 33 to 54)).

Interventions:

None.

Measurements and results:

Circulating levels of C reactive protein, interleukin 6, interleukin 8 and insulin-like growth factor I were determined before, at the end and 2 and 30 minutes after a symptom-limited peak cycling test and before, at the end and 2 and 30 minutes after a symptom-limited constant-work-rate cycling test at 70% of the peak load. Non-significant changes in the circulating markers of inflammation and anabolism were found during or up to 30 minutes after ceasing the peak or constant-work-rate cycling exercise tests. The systemic responses of the hospitalized patients with COPD did not differ from those with clinically stable disease.

Conclusions:

High-intensity cycling exercises did not increase the circulating levels of inflammatory markers in patients with chronic obstructive pulmonary disease, irrespective of their clinical stability.     

Effect of a noninvasive ventilatory support during exercise of a program in pulmonary rehabilitation in patients with COPD

Background:

Breathlessness is the most common symptom limiting exercise in patients with chronic obstructive pulmonary disease (COPD). Exercise training can improve both exercise tolerance and health status in these patients, intensity of exercise being of key importance. Nevertheless, in these patients extreme breathlessness and/or peripheral muscle fatigue may prevent patients from reaching higher levels of intensity.

Study objective:

This study was to determine whether inspiratory pressure support (IPS) applied during sub maximal exercise could enable individuals with severe but stable COPD to increase their exercise tolerance.

Participants:

Twelve subjects with severe stable COPD (mean (SD): age = 63(8.2) years; FEV₁ = 0.89(0.42) L (34)% predicted; FEV₁/FVC = 0.31(0.07) only nine subjects completed the study.

Intervention:

Each subject completed ten sessions of cycling at 25%–50% of their maximum power without NIVS and another ten sessions using NIVS.

Measurements and results:

Dyspnea was measured using Borg scale. Subjects reached high levels of dyspnea 4.7 (1.81) during the sessions without NIVS vs low levels of dyspnea during the sessions using NIVS 1.3 (0.6). Exercise time during the sessions without NIVS and with NIVS was 19.37 (3.4) and 33.75 (9.5) min, respectively. Maximal workload during the sessions without NIVS and with NIVS was 27 (3.7) and 50 (10.5) watt, respectively.

Conclusion:

We conclude that IPS delivered by nasal mask can improve exercise tolerance and dyspnea in stable severe COPD patients and hence this mode of ventilatory support may be useful in respiratory rehabilitation programs.     

COPD heterogeneity: Gender differences in the multidimensional BODE index

Background:

The BODE index was recently validated as a multidimensional tool for the evaluation of patients with COPD. The influence of gender on the BODE index has not been studied.

Hypothesis:

The contribution of each component of the disease to the BODE index may differ according to gender.

Methods:

We evaluated age, forced expiratory volume in one second (FEV₁), Modified Medical Research Council (MMRC) score, 6-min walk distance (6MWD), and body mass index (BMI) in 52 men and 52 women with COPD and the same BODE index. We compared the studied parameters between men and women and then performed a multiple regression analysis by gender.

Results:

We found statistically significant differences between men and women in all parameters: FEV₁ % (55 ± 17 vs 63 ± 18, p < 0.001), MMRC [1 (0–2) vs 1 (1–2) p = 0.03], BMI [28 (26–30) vs 25 (22–30), p = 0.05], and 6MWD [546 (451–592) vs 462 (419–520), p = 0.001]. Multiple regression analysis revealed that each component of the BODE index had different weight (β standardized coefficient) in men and women respectively: FEV₁% (0.74 vs 0.62), MMRC (0.31 vs 0.48), BMI (−0.09 vs −0.17), and 6MWD (0.13 vs 0.10).

Conclusions:

The contribution of each component to the BODE index differs by gender in subjects with similar BODE scores. Long term longitudinal studies will help determine the significance of our findings.     

Pulmonary rehabilitation program including respiratory conditioning for chronic obstructive pulmonary disease (COPD): Improved hyperinflation and expiratory flow during tidal breathing

Background

Pulmonary rehabilitation has generally relieved symptoms, strengthened exercise endurance and improved health-related quality of life (QOL) in patients with COPD, but recovery of pulmonary function remains questionable. This analysis of our innovative rehabilitation program is directed at documenting changes in patients’ expiratory airflow limitation, pulmonary symptoms and QOL. This program is designed to provide “respiratory conditioning”, a physical therapist-assisted intensive flexibility training that focuses on stretching and rib cage mobilization.

Methods

Thirty-one patients with COPD who attended rehabilitation sessions at Juntendo University Hospital from 1999 to 2006 were analyzed. Pulmonary function, expiratory flow limitation during tidal breathing, six minute walk distance (6MWD), respiratory muscle strength, and St. George Respiratory Questionnaire (SGRQ) were measured before and after pulmonary rehabilitation.

Results

In participants ages 68±7 years, the FEV₁% predicted was 39.3±15.7%. 6MWD, SGRQ and respiratory muscle strength were significantly improved after pulmonary rehabilitation. Although neither FEV₁% predicted nor FEV₁/FVC was affected to a significant extent, indicating little effect on airflow limitation, expiratory flow limitation in supine as well as seated during tidal breathing improved significantly. Moreover, rehabilitation significantly diminished TLC% predicted, FRC% predicted, RV% predicted and RV/TLC values, thus indicating a reduction of hyperinflation of the lungs at rest.

Conclusions

The present results suggest that our rehabilitation program with respiratory conditioning significantly lowered the hyperinflation of lungs at rest as well as the expiratory flow limitation during tidal breathing. In patients with COPD, overall pulmonary function improved, exercise endurance increased and health-related QOL was enhanced.Key Words: Expiratory flow limitation, hyperinflation, negative expiratory pressure, pulmonary rehabilitation, respiratory conditioning     

Protective effect of silymarin during coronary artery bypass grafting surgery

BACKGROUND:

An inflammatory response and systemic oxidative stress are directly caused by coronary artery bypass grafting (CABG) surgery. Cytokines, such as interleukin (IL) 1β, IL-6 and tumour necrosis factor-α (TNF-α), can also be stimulated. Reducing the release of pro-inflammatory cytokines plays an important role in limiting the postoperative inflammatory response. Silymarin has strong anti-inflammatory, antioxidant and cytoprotective properties.

OBJECTIVE:

To investigate the protective anti-inflammatory and antioxidant properties of silymarin against the inflammation and oxidative stresss inherent to CABG surgery.

METHODS:

Of the 102 patients undergoing elective first-time CABG surgery that were recruited, 50 (49.02%) received silymarin treatment and 52 (50.9%) were controls. Plasma cytokine levels (IL-1β, IL-6 and TNF-α) were measured preoperatively, 6 h and 24 h after CABG surgery. C-reactive protein (CRP) levels, trolox equivalent antioxidant capacity (TEAC) and glutathione (GSH) and malondialdehyde (MDA) levels were analyzed.

RESULTS:

Postoperative cytokine levels in the silymarin group were significantly lower compared with preoperative levels, and were significantly lower compared with postoperative control group levels. The area under the curve for cytokines and CRP for the silymarin group were significantly lower compared with preoperative levels, and were significantly lower compared with postoperative control group levels. Postoperative levels of TEAC and MDA in the silymarin-treated group were significantly lower than in the control group. GSH levels were significantly elevated in the silymarin group compared with control. No side effects or mortality were associated with the use of silymarin.

CONCLUSION:

The anti-inflammatory and antioxidant effects of silymarin treatment provided protection against reperfusion injury and inflammation after CABG surgery.     

Comparison of oxygenation in peripheral muscle during submaximal aerobic exercise, in persons with COPD and healthy, matched-control persons

Objective

The purpose of this study was to compare peripheral muscle oxygenation in persons with chronic obstructive pulmonary disease (COPD) to healthy control persons, during submaximal exercise.

Methods

Eight persons with COPD (forced expiratory volume in one second [FEV₁] = 1.00 ± 0.27 L) and eight healthy control persons (FEV₁ = 1.88 ± 0.55L) performed a submaximal graded exercise test (GXT), and completed 4 min of constant load exercise (CON) at 50% of peak GXT. Measurements included oxygen uptake, heart rate, arterial oxygen saturation and peripheral muscle oxygenation (%StO₂) at rest, during exercise, and recovery.

Results

Significantly greater workloads were attained for controls compared with COPD for peak GXT and CON. No significant differences in %StO₂ were observed between groups at: rest (GXT: 29.5 ± 22.8 vs 30.4 ± 17.3%; CON: 33.3 ± 15.4 vs 35.1 ± 17.2%); peak GXT (29.4 ± 19.4 vs 26.5 ± 15.9%); 4 min of CON (25.9 ± 13.5 vs 34.5 ± 21.8%); and recovery (GXT: 46.6 ± 29.1 vs 44.3 ± 21.7%; CON: 40.9 ± 21.5 vs 44.5 ± 23.2%).

Conclusion

These results suggest that peripheral skeletal muscle oxygenation is not compromised in COPD during submaximal exercise, and limitations in exercise capacity are most likely a result of muscle disuse and poor lung function.     

Use of continuous negative pressure around the chest increases exercise performance in chronic obstructive pulmonary disease patients: A pilot study

BACKGROUND:

Patients with severe chronic obstructive pulmonary disease (COPD) often have intrinsic positive end-expiratory pressure. Continuous positive airway pressure has been shown to decrease the inspiratory work of breathing and increases exercise capacity in these patients.

OBJECTIVE:

To determine whether continuous negative pressure (CNP) around the chest is able to bring the positive end-expiratory pressure closer to atmospheric pressure, thereby reducing the threshold load and increasing exercise capability.

METHODS:

A pilot study was undertaken with eight COPD patients who had been hospitalized for exacerbation and were close to discharge. For CNP, a shell (around the thorax from under the axillae to the mid abdomen) and wrap were used. Each of the eight patients was assessed with a 6 min walk test in three modes (in randomized order) with 30 min of rest in between: a control walk with no shell or wrap; a sham CNP in which the applied CNP was negligible; and CNP, with pressure chosen by the patient that provided maximal relief of dyspnea at rest.

RESULTS:

At the end of each of the 6 min walk tests, there was no difference in heart rate, oxygen saturation or level of dyspnea among the three test modes. Respiratory rate was reduced with CNP compared with sham. The patients walked furthest with CNP compared with control (mean ± SD) (313±66.2 m versus 257±65.2 m; P<0.01) and compared with sham.

CONCLUSIONS:

In the present pilot study, COPD patients improved their exercise performance with CNP.     

Evaluation of von Willebrand factor in COPD patients

OBJECTIVE:

To compare the absolute serum von Willebrand factor (vWF) levels and relative serum vWF activity in patients with clinically stable COPD, smokers without airway obstruction, and healthy never-smokers.

METHODS:

The study included 57 subjects, in three groups: COPD (n = 36); smoker (n = 12); and control (n = 9). During the selection phase, all participants underwent chest X-rays, spirometry, and blood testing. Absolute serum vWF levels and relative serum vWF activity were obtained by turbidimetry and ELISA, respectively. The modified Medical Research Council scale (cut-off score = 2) was used in order to classify COPD patients as symptomatic or mildly symptomatic/asymptomatic.

RESULTS:

Absolute vWF levels were significantly lower in the control group than in the smoker and COPD groups: 989 ± 436 pg/mL vs. 2,220 ± 746 pg/mL (p < 0.001) and 1,865 ± 592 pg/mL (p < 0.01). Relative serum vWF activity was significantly higher in the COPD group than in the smoker group (136.7 ± 46.0% vs. 92.8 ± 34.0%; p < 0.05), as well as being significantly higher in the symptomatic COPD subgroup than in the mildly symptomatic/asymptomatic COPD subgroup (154 ± 48% vs. 119 ± 8%; p < 0.05). In all three groups, there was a negative correlation between FEV₁ (% of predicted) and relative serum vWF activity (r² = −0.13; p = 0.009).

CONCLUSIONS:

Our results suggest that increases in vWF levels and activity contribute to the persistence of systemic inflammation, as well as increasing cardiovascular risk, in COPD patients.     

Effects of bronchoscopic lung volume reduction using transbronchial infusion of autologous blood and thrombin in patients with severe chronic obstructive pulmonary disease

Background

Existing medical treatments have limitations in the management of very severe chronic obstructive pulmonary disease (COPD).

Methods

We performed bronchoscopic lung volume reduction (BLVR) using transbronchial infusion of autologous blood and thrombin (BLVR with blood) in three patients with very severe COPD whose dyspnea could not be relieved by maximum medical management. Two patients underwent BLVR with blood in the left and right lungs at intervals of a half-year or a year, and one patient underwent this procedure in only the right lung. We assessed the changes in pulmonary function, exercise capacity and quality of life before and after BLVR with blood in a total of five procedures.

Results

The subjects were 58- to 74-year-old males. Their forced expiratory volume in one second (FEV₁) percent predicted ranged from 14.8% to 23.4%. BLVR with blood achieved significant improvements as follows (values before → after the procedure, mean ± standard deviation): FEV₁ 0.45r the L → 0.76r the L (P=0.004), inspiratory capacity 1.50cityo L → 2.05±.05c L (P=0.015), 3-minute walk test 46.8nuteo m → 89.6±34.5 m (P=0.004). Lung function peaked several months after BLVR with blood and returned to nearly the baseline level in 6 months, but exercise capacity was better than that at baseline for at least 12 months. St. George’s Respiratory Questionnaire (SGRQ), measured in two patients before and 12 months after the procedure, showed remarkable improvements (−15.6 and −11.9 units).

Conclusions

BLVR with blood is an effective palliative treatment for very severe COPD.     

Treatment of giant emphysamous bulla with endobronchial valves in patients with chronic obstructive pulmonary disease: a case series

Background

Giant emphysamtous bulla (GEB) can negatively affect the pulmonary functions of chronic obstructive pulmonary diseases (COPD) patients, including decreased forced expiratory volume in 1 s (FEV₁) and increased functional residual capacity (FRC). The aim of this study was to evaluate the efficacy of endobronchial valve (EBV) to treat bullae and to find efficacy predictors of successful treatment.

Methods

Five COPD patients with giant bulla were treated using EBVs. Before the EBV deployment, collateral ventilation (CV) between the targeted and adjacent lobes was evaluated with Chartis system.

Results

In the two patients with negative CV, the mean value of FEV₁ increased from 27.1±11.4% of predicted value before EBV treatment to 32.8±12.0% (P>0.05) at 1 month after EBV treatment, than to 31.7±24.5% (P>0.05) at 6 months after EBV treatment. Only one patient, whose bulla occupied the whole right middle lung, displayed sustained improvement of FEV₁ at 6 months after EBV treatment. In the three patients with positive CV, the mean value of FEV₁ decreased from 28.8±19.0% of predicted value before EBV treatment to 24.8±12.6% (P>0.05) at 1 month after EBV treatment, than to 22.1±10.8% (P>0.05) at 6 months after EBV treatment.

Conclusions

EBV is an effective measure to treat highly selected COPD patients with giant bulla. Although, EBV treatment can achieve transient improvement of lung function at patients with CV negative bulla, long-term benefit was merely observed at the patient with a bulla at right middle lobe (RML).     

Evaluation of atopy in patients with COPD

OBJECTIVE:

To determine the prevalence of atopy and to evaluate clinical, laboratory, and radiological profiles in patients with COPD.

METHODS:

This was a cross-sectional study involving outpatients with stable COPD (defined by the clinical history and a post-bronchodilator FEV₁/FVC < 70% of the predicted value). The patients completed a questionnaire regarding clinical characteristics and atopy, after which they underwent nasal lavage cytology, skin prick testing, chest X-rays, arterial blood gas analyses, and determination of total serum IgE.

RESULTS:

Of the 149 subjects studied, 53 (35.6%), 49 (32.8%), and 88 (59.1%) presented with nasal eosinophilia, a positive skin prick test result, and symptoms of allergic rhinitis, respectively. Correspondence analysis confirmed these findings, showing two distinct patterns of disease expression: atopy in patients with COPD that was less severe; and no evidence of atopy in those with COPD that was more severe (reduced FEV₁ and hyperinflation). There was a statistically significant association between nasal eosinophilia and a positive bronchodilator response.

CONCLUSIONS:

Using simple and reproducible methods, we were able to show that there is a high frequency of atopy in patients with COPD. Monitoring inflammation in the upper airways can be a useful tool for evaluating respiratory diseases in the elderly and in those with concomitant asthma and COPD, a clinical entity not yet fully understood.     

Severe iron deficiency blunts the response of the iron regulatory gene Hamp and pro-inflammatory cytokines to lipopolysaccharide

Background

Expression of the key iron regulatory hormone hepcidin is increased by some stimuli (iron loading, inflammation) but decreased by others (increased erythropoiesis, iron deficiency). We investigated the response of hepcidin to increased erythropoiesis and iron deficiency in the presence of an acute inflammation to assess the relative strengths of these stimuli.

Design and Methods

Sprague-Dawley rats were maintained on control or iron-deficient diets and treated with lipopolysaccharide to induce inflammation or phenylhydrazine to stimulate erythropoiesis. The levels of Hamp, IL-6 and α2m mRNA were determined by qualitative real-time polymerase chain reaction and those of serum interleukin-6 and tumor necrosis factor-α were measured by enzyme-linked immunosorbent assay. Cultured RAW264.7 and HuH7 cells were used in associated studies.

Results

The increase in hepatic hepcidin levels induced by lipopolysaccharide was not affected by phenylhydrazine treatment but was blunted by iron deficiency. Lipopolysaccharide-treated iron-deficient animals also showed lower liver α2m mRNA and reduced serum interleukin-6 and tumor necrosis factor-α, suggesting a more generalized effect of iron deficiency. Similarly, RAW 264.7 cells treated with iron chelators and then stimulated with lipopolysaccharide showed lower IL-6 mRNA than cells treated with lipopolysaccharide alone. Huh7 cells treated with an iron chelator showed a blunted hepcidin response to interleukin-6, suggesting that the response of hepatic parenchymal cells to inflammatory cytokines may also be iron-dependent.

Conclusions

In any one physiological situation, net hepcidin levels are determined by the relative strengths of competing stimuli. The ability of severe iron deficiency to blunt the response to lipopolysaccharide of both hepcidin and other markers of inflammation suggests that adequate iron levels are necessary for a full acute phase response.     

Plasma nitric oxide metabolite levels increase during successive exercise stress testing – A link to delayed ischemic preconditioning?

BACKGROUND:

Animal studies have shown that nitric oxide is involved in delayed ischemic preconditioning.

OBJECTIVES:

To determine whether plasma nitrates and nitrites (NO_x⁻, as measure of nitric oxide) are modified by two consecutive effort tests and whether these changes translate into clinical improvement

METHODS:

Twenty-two patients with ischemic heart disease each performed two effort tests at 24-h intervals. Plasma NO_x⁻ level was determined and compared before and after both stress tests. Peak effort, double product at peak effort and maximal ST segment depression were considered clinical endpoints and were compared between the two tests.

RESULTS:

Plasma NO_x⁻increased slightly after the first exercise test compared with pretest value (17.05±1.6 μmol/mL versus 15.38±1.4 μmol/mL). In turn, after the second test there was a significant rise in NO_x⁻ level (23.65±2.2 μmol/mL versus 15.10±1.3 μmol/mL, P<0.03). The pretest values were almost identical between the two tests. Peak effort and double product at peak effort remained unchanged between the two tests. Although ischemic stress was the same, ST depression was significantly lower (P<0.01) for the second test (0.85±0.06 mm versus 1.73±0.16 mm).

CONCLUSION:

Our study shows an increased plasma NO_x⁻level after the second of two consecutive exercise stress tests at 24-h intervals, along with a decrease of electrocardiographic consequences of approximately the same ischemic stress. These findings are consistent with experimental data in animals, which point to nitric oxide as a trigger and effector of ischemic preconditioning.     

Plasma homocysteine is elevated in COPD patients and is related to COPD severity

Background:

Although recent studies have found that total plasma homocysteine (tHCY) and chronic obstructive pulmonary disease (COPD) are both risk factors for cardiac disease, there have been few studies of plasma homocysteine levels in COPD patients. We tested the hypothesis that total plasma homocysteine (tHCY) would be elevated in patients diagnosed with COPD compared with controls.

Methods:

We studied 29 COPD outpatients and 25 asymptomatic subjects (controls) over age 55 years with measurement of forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), St. Georges Respiratory Questionnaire (SGRQ) score, tHCY and serum C-reactive protein (sCRP).

Results:

There was no difference between controls vs. COPD patients in mean age or gender but mean (SD) FEV₁ was 2.25 (0.77) vs 1.43 (0.60) L; FEV₁% predicted 76.1 (17.2) vs 49.1 (16.3) p < 0.001 in both cases. Median (IQR) tHCY was 8.22 (6.63, 9.55) in controls vs 10.96 (7.56, 13.60) micromol/l for COPD, p = 0.006 and sCRP 0.89 (0.47, 2.55) vs 2.05 (0.86, 6.19) mg/l, p = 0.023. tHCY(log) was also higher in (r, p) smokers (0.448, 0.001), patients with low FEV₁% (−0.397, 0.003), males (0.475, <0.001), but high SGRQ Total score (0.289, 0.034), and high sCRP (0.316, 0.038). tHCY(log) was independently related to (regression coefficient, p) sCRP(log) (0.087, 0.024), male gender (0.345, <0.001) and presence of COPD (0.194, 0.031). Median (IQR) tHCY GOLD Stage I and II 8.05 (7.28, 11.04), GOLD Stage III and IV: 11.83(9.30, 18.30); p = 0.023.

Conclusions:

Plasma homocysteine is significantly elevated in COPD patients relative to age and sex-matched controls and is related to serum CRP and COPD severity.