The clinical effectiveness of the COPDnet integrated care model.

RATIONALE: Integrated care models have the potential to improve outcomes for patients with COPD. We therefore designed the COPDnet integrated care model and implemented it in two hospitals and affiliated primary care regions in the Netherlands. The COPDnet model consists of a comprehensive diagnostic trajectory ran in secondary care followed by a non-pharmacological intervention program of both monodisciplinary and multidisciplinary components. OBJECTIVE: To assess the clinical effectiveness of the COPDnet integrated care model on health status change in patients with COPD. METHODS: A total of 402 patients with COPD were offered care according to the COPDnet model. At baseline and between 7- and 9-months later health status was measured with the Clinical COPD Questionnaire (CCQ). Primary analysis was carried out for the sample at large. In addition, subgroup analyses were performed after stratification for the type of non-pharmacological intervention where patients had been referred to. RESULTS: The CCQ total score improved statistically significantly from 1.94 ± 1.04 to 1.73 ± 0.96 (P < 0.01) in the 154 patients with valid follow-up measurements. Subgroup analyses revealed significant improvements in the patients receiving pulmonary rehabilitation only. No change in health status was found in patients receiving pharmacotherapy only, carried out self-treatment or who participated in mono-disciplinary primary care offered by allied healthcare professionals. CONCLUSIONS: An improved health status was found in patients with COPD who received care according to the COPDnet integrated care model. Subgroups participating in an interdisciplinary pulmonary rehabilitation program predominantly accounted for this effect.

Budesonide + formoterol delivered via Spiromax® for the management of asthma and COPD: The potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler®.

BACKGROUND: Fixed-dose combinations of inhaled corticosteroids and long-acting ß2 agonists are commonly used for the treatment of asthma and COPD. However, the most frequently prescribed dry powder inhaler delivering this medicine - Symbicort® (budesonide and formoterol, BF) Turbuhaler® - is associated with poor inhalation technique, which can lead to poor disease control and high disease management costs. A recent study showed that patients make fewer inhaler errors when using the novel DuoResp® (BF) Spiromax® inhaler, compared with BF Turbuhaler®. Therefore switching patients from BF Turbuhaler® to BF Spiromax® could improve inhalation technique, and potentially lead to better disease control and healthcare cost savings. METHODS: A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler® to BF Spiromax® over three years in Germany, Italy, Sweden and the UK. The model estimated changes to the number, and associated cost, of unscheduled healthcare events. The model considered two scenarios: in Scenario 1, all patients were immediately switched from BF Turbuhaler® to BF Spiromax®; in Scenario 2, 4%, 8% and 12% of patients were switched in years 1, 2 and 3 of the model, respectively. RESULTS: In Scenario 1, per patient cost savings amounted to €60.10, €49.67, €94.14 and €38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were €100.86 million, €19.42 million, €36.65 million and €15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled €8.07 million, €1.55 million, €2.93 million and €1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were €4.81, €3.97, €7.53 and €3.06. CONCLUSIONS: We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler® to BF Spiromax® are likely to improve patients' disease control and generate considerable cost savings through healthcare events avoided.

[Effectiveness of the Assessment of Burden of COPD tool: a cluster-randomised controlled trial]. / Effectiviteit van de 'Ziektelastmeter COPD'.

OBJECTIVE: Assessment of the effectiveness of the Assessment of Burden of COPD (ABC) tool on disease-specific quality of life in patients with Chronic Obstructive Pulmonary Disease (COPD). DESIGN: Cluster-randomised controlled trial. METHOD: This concerned a trial in 39 Dutch primary care practices and 17 hospitals, involving 357 patients with COPD (postbronchodilator FEV1/FVC ratio < 0.7) aged ≥ 40 years. Healthcare providers were randomized to an intervention or control group. Patients in the intervention group were treated with the ABC tool. This innovative tool consists of a short validated questionnaire and a number of objective parameters, which collectively give a visual overview of the combined integral health; the tool subsequently produces an individualized treatment plan by means of a treatment algorithm. Patients in the control group received usual care. The primary outcome measure was the proportion of patients with a clinically relevant improvement in disease-specific quality of life measured, as measured by means of the St. George's Respiratory Questionnaire (SGRQ) score, between baseline and 18 months follow-up. Secondary outcomes included the SGRQ total score and the Patient Assessment of Chronic Illness Care (PACIC) score. RESULTS: At 18-month follow-up, a significant and clinically relevant improvement in the SGRQ score was seen in 34% of the patients (N=49) in the intervention group, and in the control group this figure was 22% (N=33). This difference between the two groups was significant (OR 1.85, 95% CI 1.08 to 3.16). Patients in the intervention group experienced a higher quality of care than patients in the control group (0.32 points difference in PACIC, 95% CI 0.14 to 0.50). CONCLUSION: Use of the ABC tool increases the disease-specific quality of life and the quality of care for COPD patients; it may therefore offer a valuable contribution to improvements in the daily care of COPD. Replication of this study in other (non-Dutch) health-care settings is recommended.

The economic burden of asthma and chronic obstructive pulmonary disease and the impact of poor inhalation technique with commonly prescribed dry powder inhalers in three European countries.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic inflammatory respiratory diseases, which impose a substantial burden on healthcare systems and society. Fixed-dose combinations (FDCs) of inhaled corticosteroids (ICS) and long-acting ß2 agonists (LABA), often administered using dry powder inhalers (DPIs), are frequently prescribed to control persistent asthma and COPD. Use of DPIs has been associated with poor inhalation technique, which can lead to increased healthcare resource use and costs. METHODS: A model was developed to estimate the healthcare resource use and costs associated with asthma and COPD management in people using commonly prescribed DPIs (budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®)) over 1 year in Spain, Sweden and the United Kingdom (UK). The model considered direct costs (inhaler acquisition costs and scheduled and unscheduled healthcare costs), indirect costs (productive days lost), and estimated the contribution of poor inhalation technique to the burden of illness. RESULTS: The direct cost burden of managing asthma and COPD for people using budesonide + formoterol Turbuhaler(®) or fluticasone + salmeterol Accuhaler(®) in 2015 was estimated at €813 million, €560 million, and €774 million for Spain, Sweden and the UK, respectively. Poor inhalation technique comprised 2.2-7.7 % of direct costs, totalling €105 million across the three countries. When lost productivity costs were included, total expenditure increased to €1.4 billion, €1.7 billion and €3.3 billion in Spain, Sweden and the UK, respectively, with €782 million attributable to poor inhalation technique across the three countries. Sensitivity analyses showed that the model results were most sensitive to changes in the proportion of patients prescribed ICS and LABA FDCs, and least sensitive to differences in the number of antimicrobials and oral corticosteroids prescribed. CONCLUSIONS: The cost of managing asthma and COPD using commonly prescribed DPIs is considerable. A substantial, and avoidable, contributor to this burden is poor inhalation technique. Measures that can improve inhalation technique with current DPIs, such as easier-to-use inhalers or better patient training, could offer benefits to patients and healthcare providers through improving disease outcomes and lowering costs.

Inhaler technique: facts and fantasies. A view from the Aerosol Drug Management Improvement Team (ADMIT).

Health professionals tasked with advising patients with asthma and chronic obstructive pulmonary disease (COPD) how to use inhaler devices properly and what to do about unwanted effects will be aware of a variety of commonly held precepts. The evidence for many of these is, however, lacking or old and therefore in need of re-examination. Few would disagree that facilitating and encouraging regular and proper use of inhaler devices for the treatment of asthma and COPD is critical for successful outcomes. It seems logical that the abandonment of unnecessary or ill-founded practices forms an integral part of this process: the use of inhalers is bewildering enough, particularly with regular introduction of new drugs, devices and ancillary equipment, without unnecessary and pointless adages. We review the evidence, or lack thereof, underlying ten items of inhaler 'lore' commonly passed on by health professionals to each other and thence to patients. The exercise is intended as a pragmatic, evidence-informed review by a group of clinicians with appropriate experience. It is not intended to be an exhaustive review of the literature; rather, we aim to stimulate debate, and to encourage researchers to challenge some of these ideas and to provide new, updated evidence on which to base relevant, meaningful advice in the future. The discussion on each item is followed by a formal, expert opinion by members of the ADMIT Working Group.

Persistence of impaired health status of Q fever patients 4 years after the first Dutch outbreak.

A significant proportion of Q fever patients from the first Dutch Q fever outbreak in 2007 showed impairment in health status up to 1 year after infection. Interested in whether this decrease in health status persisted, we set out to determine the health status in the same cohort of patients, 4 years after primary infection and to compare health status scores at the individual patient level between 1 and 4 years follow-up. Health status was assessed with the Nijmegen Clinical Screening Instrument (NCSI). Patients were serologically tested to exclude patients with possible, probable or proven chronic Q fever. Results on the NCSI sub-domains at group level [2008 (n = 54) and 2011 (n = 46)] showed a persistent significant percentage of patients exhibiting clinically relevant ('severe') scores for all NCSI sub-domains. After 4 years, undue fatigue was present in 46% and exactly half of all patients experienced a severely impaired general quality of life. Patients with NCSI scores available in both 2008 and 2011 (n = 37) showed no difference in all sub-domain scores, except for a small decrease in dyspnoea emotions in 2011. In this group, a significant proportion of patients either improved or worsened in one or more sub-domains of health status. We conclude that at the group level, health status of Q fever patients remained impaired 4 years after primary infection. At the individual patient level, health status may change.

Molecular drug susceptibility testing in the Netherlands: performance of the MTBDRplus and MTBDRsl assays.

BACKGROUND: The performance of molecular drug susceptibility testing in countries with a low prevalence of drug resistance, such as the Netherlands, has not been adequately studied. OBJECTIVE: To evaluate the diagnostic accuracy of the GenoType(®) MTBDRplus and MTBDRsl assays to detect resistance to first- and second-line anti-tuberculosis drugs in the context of a nationwide screening programme in the Netherlands. RESULTS: The MTBDRplus assay had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 99%, 80% and 100% for detecting rifampicin resistance. The sensitivity, specificity, PPV and NPV of either a katG or inhA mutation for detecting isoniazid resistance were 88%, 100%, 100% and 99%. The MTBDRsl assay had a sensitivity, specificity, PPV and NPV of 100%, 99%, 83%, and 100% for detecting moxifloxacin resistance; 62%, 71%, 58% and 74%, respectively, for detecting ethambutol resistance; 86%, 99%, 86% and 99% for detecting amikacin resistance; and 50%, 96%, 71% and 91% for detecting capreomycin resistance. CONCLUSION: The MTBDRplus and MTBDRsl assays may aid in decision making in tuberculosis treatment in low-level drug resistance settings and should preferably be used to exclude resistance.

Rapid diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis using a molecular-based diagnostic algorithm.

There is an urgent need for rapid and accurate diagnosis of pyrazinamide-resistant multidrug-resistant tuberculosis (MDR-TB). No diagnostic algorithm has been validated in this population. We hypothesized that pncA sequencing added to rpoB mutation analysis can accurately identify patients with pyrazinamide-resistant MDR-TB. We identified from the Dutch national database (2007-11) patients with a positive Mycobacterium tuberculosis culture containing a mutation in the rpoB gene. In these cases, we prospectively sequenced the pncA gene. Results from the rpoB and pncA mutation analysis (pncA added to rpoB) were compared with phenotypic susceptibility testing results to rifampicin, isoniazid and pyrazinamide (reference standard) using the Mycobacterial Growth Indicator Tube 960 system. We included 83 clinical M. tuberculosis isolates containing rpoB mutations in the primary analysis. Rifampicin resistance was seen in 72 isolates (87%), isoniazid resistance in 73 isolates (88%) and MDR-TB in 65 isolates (78%). Phenotypic reference testing identified pyrazinamide-resistant MDR-TB in 31 isolates (48%). Sensitivity of pncA sequencing added to rpoB mutation analysis for detecting pyrazinamide-resistant MDR-TB was 96.8%, the specificity was 94.2%, the positive predictive value was 90.9%, the negative predictive value was 98.0%, the positive likelihood was 16.8 and the negative likelihood was 0.03. In conclusion, pyrazinamide-resistant MDR-TB can be accurately detected using pncA sequencing added to rpoB mutation analysis. We propose to include pncA sequencing in every isolate with an rpoB mutation, allowing for stratification of MDR-TB treatment according to pyrazinamide susceptibility.

Effects of long-acting bronchodilators and prednisolone on inspiratory lung function parameters in stable COPD.

BACKGROUND: In chronic obstructive pulmonary disease (COPD), there is a poor correlation between forced expiratory volume in 1 s (FEV1) and dyspnea following bronchodilator use. Better correlations have been observed between inspiratory lung function parameters (ILPs) and dyspnea, which drives our interest in ILPs. However, the acute and prolonged effects of long-acting bronchodilators and oral corticosteroids on ILPs have not been well investigated. Therefore, the aim of this study was to investigate the effects of these treatments on the ILPs, FEV1, dyspnea (visual analog scale (VAS)) and clinical COPD questionnaire (CCQ). METHODS: Twenty-eight stable COPD patients had their ILPs and FEV1 measured both before and 2 h after the use of a single dose of 18 mcg bronchodilator tiotropium and 50 mcg salmeterol. Thereafter, the patients were randomized to 2 weeks of treatment with 30 mg oral prednisolone once daily or oral placebo in combination with daily treatment with these two bronchodilators. Four weeks after the cessation of the randomized treatment, the ILPs and FEV1 were again measured. After each intervention, any change in the VAS score was assessed. RESULTS: With both bronchodilators, significant improvements in ILPs were demonstrated (p < 0.005), with the exception of changes in ILPs inspiratory capacity (IC) and forced inspiratory flow at 50% of the vital capacity (FIF50) after tiotropium inhalation. After 2 weeks of treatment with prednisolone, significant differences were found for ILP forced inspiratory volume in 1 s (FIV1) and FEV1 compared with placebo. These differences were no longer present 4 weeks after the cessation of prednisolone. Significant relationships between ILPs and VAS scores were only found after 2 weeks of treatment with prednisolone or placebo. CONCLUSIONS: After a single dose of long-acting bronchodilator salmeterol, significant improvements are observed in all ILPs and in FIV1 and PIF after tiotropium. Two weeks of oral corticosteroid treatment improved the FIV1 and FEV1. The dyspnea VAS score was only significantly correlated with the ILPs after 2 weeks of oral corticosteroid treatment.

Non-invasive ventilation abolishes the IL-6 response to exercise in muscle-wasted COPD patients: a pilot study.

Systemic inflammation in patients with chronic obstructive pulmonary disease (COPD) has been related to the development of comorbidities. The level of systemic inflammatory mediators is aggravated as a response to exercise in these patients. The aim of this study was to investigate whether unloading of the respiratory muscles attenuates the inflammatory response to exercise in COPD patients. In a cross-over design, eight muscle-wasted stable COPD patients performed 40 W constant work-rate cycle exercise with and without non-invasive ventilation support (NIV vs control). Patients exercised until symptom limitation for maximally 20 min. Blood samples were taken at rest and at isotime or immediately after exercise. Duration of control and NIV-supported exercise was similar, both 12.9 ± 2.8 min. Interleukin- 6 (IL-6) plasma levels increased significantly by 25 ± 9% in response to control exercise, but not in response to NIV-supported exercise. Leukocyte concentrations increased similarly after control and NIV-supported exercise by ∼15%. Plasma concentrations of C-reactive protein, carbonylated proteins, and production of reactive oxygen species by blood cells were not affected by both exercise modes. This study demonstrates that NIV abolishes the IL-6 response to exercise in muscle-wasted patients with COPD. These data suggest that the respiratory muscles contribute to exercise-induced IL-6 release in these patients.

Prescription of inhalers in asthma and COPD: towards a rational, rapid and effective approach.

Inhaled medication is the cornerstone of the pharmacological treatment of patients with asthma and COPD. The major two classes of inhaled medication include corticosteroids (ICS) and bronchodilators. There is a wide diversity in molecules in both classes. Moreover, there is a wide variation in delivery systems. The correct use of inhalers is not granted and patients often incur in many mistakes when using pMDIs and DPIs, despite repeated instructions. A better matching between patient and device could be accomplished if the physician is aware of: (1) the patient characteristics (disease, severity, fluctuation in airflow obstruction, etc); (2) what class of medication is indicated; (3) where in the lung the medication should be delivered; and, (4) how this can be best achieved by a given device in this specific patient. We focus on the prescription of pMDIs and DPIs at the GP office or at the outpatient clinic of the hospital, and we propose an evidence based approach enabling the caregiver to make a rational choice in only a few minutes by just considering the following four simple questions: Who?, What? Where? and How? (the so-called 3W-H approach).

[Medicinal intervention for COPD; even in patients with mild or moderate COPD?]. / Medicamenteuze interventie bij COPD, ook bij patiënten met lichte en matige COPD?

The classification of COPD based only on the presence of airway obstruction fails to provide insight into the burden of the disease, quality of life and prognosis. The severity of symptoms, degree of exercise intolerance and presence of comorbidity are also determinants for classifying the severity of the disease. COPD starts with abnormalities in the bronchiolar compartment which cause obstruction in the airways. This results in incomplete expiration; first during exercise and later, also at rest. This is called dynamic hyperinflation or air trapping. Such changes in the mechanics of breathing occur early in course of the disease, even in mild COPD (the GOLD I stage), and contribute to physical inactivity and deconditioning. Maximal bronchodilation--more precisely: bronchiolodilation--reduces the mechanism of dynamic hyperinflation inasmuch as the condition allows. This has a positive effect on the symptoms of dyspnoea during exercise and thus on exercise capacity and trainability, even early on in the disease. Medicinal therapy has a positive effect on the progression of COPD, also in the early stages of disease.

Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections.

Concentrations of antimycobacterial drugs are an intermediary link between doses administered and eventual response to the drugs. Few pharmacokinetic (PK) studies have focused on drug treatment for nontuberculous mycobacterial (NTM) disease, although a favourable treatment response occurs in just over 50% of patients despite drug treatment for ≥1 year. A prospective, descriptive PK study was performed to assess the plasma pharmacokinetics of rifampicin, ethambutol, clarithromycin, 14-OH-clarithromycin, azithromycin, isoniazid and moxifloxacin. Intensive PK sampling was performed in 14 patients with clinically relevant NTM lung disease. PK parameters were assessed and were compared with available data from the literature. Exposure to clarithromycin when combined with rifampicin was very low [area under the concentration-time curve over 12 h (AUC(0-12 h), geometric mean 2.6 h·mg/L, range 1.6-3.2 h·mg/L; peak concentration in plasma (C(max)), geometric mean 0.3 mg/L, range 0.1-0.7 mg/L]. The mean parent-to-metabolite ratios for clarithromycin to 14-OH-clarithromycin were 0.4 and 0.3 for AUC(0-12 h) and C(max), instead of the typical ratio of ca. 3, probably reflecting increased metabolism of clarithromycin to its (virtually inactive) 14-OH metabolite. Exposure to rifampicin was relatively high, with all patients having a rifampicin C(max) within the reference range. The majority of ethambutol C(max) values were within the reference range. The current study re-emphasises the relevant PK interaction between clarithromycin and rifampicin. This calls for a re-evaluation of dosing strategies in NTM lung disease, as suboptimal drug exposure may contribute to inadequate response to treatment of NTM disease.

The effect of bronchodilators administered via aerochamber or a nebulizer on inspiratory lung function parameters.

BACKGROUND: In chronic obstructive pulmonary disease (COPD) the clinical efficacy of bronchodilator therapy delivered via a nebulizer versus an aerochamber on FEV1 is controversial. No studies comparing changes in inspiratory pulmonary function parameters (ILPs) using these inhaler devices are currently available. This information might be of interest because due to dynamic bronchial compression, the relationship between the ILPs and dyspnea is more reliable than that between FEV1 and dyspnea. Therefore, our study aimed to investigate whether changes in ILPs after use of these inhaler devices were similar to the changes in FEV1 and correlate with VAS (Visual Analogue Scale). METHODS: Forty-one stable COPD patients participated in a crossover trial. Spirometry was performed before and after two puffs Combivent (200 mcg salbutamol and 20 mcg ipratropium per puff) using an aerochamber or 2 mL of Combivent (2.5 mg salbutamol and 250 mcg ipratropium per mL) using a nebulizer. Differences in lung function parameters and changes in VAS were measured. RESULTS: ILP values improved significantly from baseline after Combivent administration using both devices (p ≤ 0.004). With both devices, the mean percent changes were significantly greater for FEV(1) than the ILPs (p ≤ 0.003), except for IC (p = 0.19). The mean VAS score did not differ significantly between the devices (p = 0.33), but significant correlations were found between the VAS and forced inspiratory flow at 50% of the vital capacity (FIF(50)) and peak inspiratory flow (PIF) when a nebulizer was used. With an aerochamber, no significant correlations between lung function parameters and VAS were found. CONCLUSIONS: The present study demonstrates that ILPs improved significantly after using either device. Although significant correlations were found between the VAS and FIF(50) and PIF for the nebulizer, in stable COPD patients, the pMDI plus spacer is a better route of administration than a nebulizer.

Mycobacterium genavense in the Netherlands: an opportunistic pathogen in HIV and non-HIV immunocompromised patients. An observational study in 14 cases.

Mycobacterium genavense is an opportunistic non-tuberculous mycobacterium previously mostly associated with HIV-infected patients with CD4 counts below 100/µL. In this retrospective observational study of medical charts we studied all Dutch patients in whom M. genavense was detected between January 2002 and January 2010. Of the 14 patients identified, 13 (93%) showed clinically relevant M. genavense disease. All patients with M. genavense disease were severely immunocompromised, including HIV-infected patients, solid organ transplant recipients, those with chronic steroid use in combination with other immune modulating drugs, recipients of chemotherapy for non-Hodgkin lymphoma, and those with immunodeficiency syndromes. Two patients had non-disseminated pulmonary M. genavense disease. Of the 12 patients treated, eight (75%) showed a favourable outcome. Four patients died in this study, three despite treatment for M. genavense disease. We conclude that M. genavense is a clinically relevant pathogen in severely immunocompromised patients that causes predominantly disseminated disease with serious morbidity and mortality. M. genavense is increasingly seen among non-HIV immunocompromised patients.

Characterization of a novel variant of Mycobacterium chimaera.

In this study, nonchromogenic mycobacteria were isolated from pulmonary samples of three patients in the Netherlands. All isolates had identical, unique 16S rRNA gene and 16S-23S ITS sequences, which were closely related to those of Mycobacterium chimaera and Mycobacterium marseillense. The biochemical features of the isolates differed slightly from those of M. chimaera, suggesting that the isolates may represent a possible separate species within the Mycobacterium avium complex (MAC). However, the cell-wall mycolic acid pattern, analysed by HPLC, and the partial sequences of the hsp65 and rpoB genes were identical to those of M. chimaera. We concluded that the isolates represent a novel variant of M. chimaera. The results of this analysis have led us to question the currently used methods of species definition for members of the genus Mycobacterium, which are based largely on 16S rRNA or rpoB gene sequencing. Definitions based on a single genetic target are likely to be insufficient. Genetic divergence, especially in the MAC, yields strains that cannot be confidently assigned to a specific species based on the analysis of a single genetic target.

[Diaphragm and skeletal muscle dysfunction in COPD]. / L'atteinte du diaphragme et du quadriceps dans la BPCO: une manifestation systémique de cette maladie ?

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is often accompanied by skeletal muscle alterations, resulting in enhanced morbidity and mortality. STATE OF THE ART: Many studies have highlighted important structural and biochemical modifications in limb and respiratory muscles in COPD. Reviewing the similarities and differences between the two most studied muscles in COPD, the quadriceps and the diaphragm, may provide important clues about the mechanisms dictating muscle changes that occur in this disease. PERSPECTIVES: Though these two muscle groups share a common systemic environment, discrepancies are observed in their respective alterations. These phenotypic differences suggest that, in addition to systemic factors, the local microenvironment must participate in the reorganization seen in these two muscles in COPD. CONCLUSIONS: The current review introduces the alterations observed in the quadriceps and diaphragm in the context of COPD and suggests possible signaling pathways involved in the development of muscle dysfunction.

Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure.

BACKGROUND AND PURPOSE: Diaphragm muscle weakness occurs in patients with heart failure (HF) and is associated with exercise intolerance and increased mortality. Reduced sensitivity of diaphragm fibres to calcium contributes to diaphragm weakness in HF. Here we have investigated the ability of the calcium sensitizer levosimendan to restore the reduced calcium sensitivity of diaphragm fibres from rats with HF. EXPERIMENTAL APPROACH: Coronary artery ligation in rats was used as an animal model for HF. Sham-operated rats served as controls. Fifteen weeks after induction of HF or sham operations animals were killed and muscle fibres were isolated from the diaphragm. Diaphragm fibres were skinned and activated with solutions containing incremental calcium concentrations and 10 µM levosimendan or vehicle (0.02% DMSO). Developed force was measured at each calcium concentration, and force-calcium concentration relationships were plotted. KEY RESULTS: Calcium sensitivity of force generation was reduced in diaphragm muscle fibres from HF rats, compared with fibres from control rats (P < 0.01). Maximal force generation was ∼25% lower in HF diaphragm fibres than in control fibres (P < 0.05). Levosimendan significantly increased calcium sensitivity of force generation in diaphragm fibres from HF and control rats, without affecting maximal force generation. CONCLUSIONS AND IMPLICATIONS: Levosimendan enhanced the force generating capacity of diaphragm fibres from HF rats by increasing the sensitivity of force generation to calcium concentration. These results provide strong support for testing the effect of calcium sensitizers on diaphragm muscle weakness in patients with HF.