Regulation of muscle oxidative phenotype by hypoxia in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF)|
|- candidate number||3821|
|- NTR Number||NTR1402|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||11-aug-2008|
|- Secondary IDs||MEC 08-2-059 |
|- Public Title||Regulation of muscle oxidative phenotype by hypoxia in Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF)|
|- Scientific Title||Regulation of muscle oxidative phenotype by hypoxia in Chronic Obstructive Pulmonary Disease and Chronic Heart Failure|
|- hypothesis||Muscle hypoxia, either chronic or intermittent (exercise-induced), is responsible for the altered muscle oxidative phenotype in chronic obstructive pulmonary disease and chronic heart failure through modulation of the regulatory molecules PGC-1/PPARs and HIF-1alpha.|
COPD is associated with a higher adipose tissue inflammatory status compared to healthy persons which is associated with systemic inflammation.
|- Healt Condition(s) or Problem(s) studied||Musculoskeletal disorders (MSDs), Chronic Obstructive Pulmonary Disease (COPD), Systemic inflammation, Heart failure, Hypoxia, COPD, Chronic, Phenotype , Adipose tissue inflammation|
|- Inclusion criteria||1. COPD patients: COPD according to GOLD criteria. |
2. CHF patients: diagnosis heart failure with an ejection fraction <40% determined by echocardiography;
3. Healthy persons.
|- Exclusion criteria||COPD patients: |
malignancy, cardiac failure, distal arteriopathy, recent surgery, severe endocrine, hepatic or renal disorders, oxygen therapy and recent participation in a revalidation program (previous 6 months).
unstable disease, unstable angina pectoris, correctable cause of heart failure or valvular heart disease, restrictive or hypertrophic cardiomyopathy, malignancy, pulmonary disease (including primary pulmonary hypertension and COPD), distal arteriopathy, recent surgery, severe endocrine, hepatic or renal disorders and recent participation in a revalidation program (previous 6 months).
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||Single arm|
|- planned startdate ||1-okt-2008|
|- planned closingdate||1-okt-2011|
|- Target number of participants||90|
|- Interventions||In this cross-sectional study, muscle biopsies will be obtained before and after exercise and tested for molecular markers of hypoxia. All subjects will be characterized thoroughly including measurement of lung function, exercise capacity, muscle function and body composition measurement. In addition, adipose tissue biopsies will be obtained from the COPD patients and healthy persons to investigate adipose tissue inflammatory status.|
|- Primary outcome||1. Main outcome parameters are the expression levels of HIF-1á, PGC-1 and PPARs (before and after exercise), which will be measured at protein and mRNA level by western blotting and PCR respectively;|
2. Also, markers of hypoxia such as vascular endothelial growth factor (VEGF), carbonic anhydrase-9 (CA-9) and heme oxygenase-1 (HO-1) will be investigated using real time PCR;
3. Beside this, metabolic enzyme activities (citrate synthase, â-hydroxyacyl-CoA dehydrogenase, phosphofructokinase) and muscle fiber type proportions will be determined to assess muscle oxidative phenotype;
4. Main outcomes in the adipose tissue biopsies comprise of adipocyte size, gene expression levels of inflammatory and hypoxia-related genes and adipose tissue macrophage infiltration.
|- Secondary outcome||Secondary outcome parameters are skeletal muscle function and exercise capacity.|
|- Timepoints||Day 1 and day 8.|
|- Trial web site||N/A|
|- status||stopped: trial finished|
|- CONTACT FOR PUBLIC QUERIES||Dr. B. Borst, van den|
|- CONTACT for SCIENTIFIC QUERIES||Dr. B. Borst, van den|
|- Sponsor/Initiator ||University Maastricht (UM)|
(Source(s) of Monetary or Material Support)
|University Maastricht (UM)|
|- Brief summary||Rationale: |
Chronic Obstructive Pulmonary Disease (COPD) and Chronic Heart Failure (CHF) are major causes of morbidity and mortality throughout the world. These chronic diseases are not only characterized by their local impairment, but also by their disabling impaired exercise performance. Peripheral skeletal muscle dysfunction has been identified as an important contributor to exercise intolerance. Muscular impairment involves a slow-to-fast shift in fiber types and a reduced oxidative capacity of the skeletal muscle cells. It is likely that muscle hypoxia is a major determinant of these processes, considering the fact that chronic or exercise-induced hypoxemia and underperfusion are obvious features of COPD and CHF respectively. Positive key mediators of muscle oxidative metabolism and slow twitch fiber phenotype are peroxisome proliferator-activated receptors (PPARs) and PPARã co-activator-1 (PGC-1) whereas hypoxia-inducible factor-1á (HIF-1á) is an important mediator in hypoxia sensing and stimulator of glycolytic metabolism. We hypothesize that muscle hypoxia, either chronic or intermittent (exercise-induced), is responsible for the altered muscle oxidative phenotype in COPD and CHF through modulation of the regulatory molecules PGC-1/PPARs and HIF-1á.
Systemic inflammation is believed to play an important role in COPD. Classically, it has been hypothesized that greater concentrations of circulating inflammatory mediators “spill-over” from the pulmonary compartment. However, for this no convincing evidence has been published. Alternatively, adipose tissue has been described as a potent producer of inflammation and hypoxia has been proposed to trigger an inflammatory response of the adipose tissue. We hypothesize that COPD patients have greater adipose tissue inflammatory status compared to healthy persons and that hypoxia is a mediator of this inflammatory trigger.
The aim of this study is to identify direct markers of muscle hypoxia in COPD and CHF patients in relation to the altered muscle oxidative phenotype and the putative mediators HIF-1á and PPARs/PGC-1. Insight in the underlying molecular mechanisms of the influence of hypoxia on muscle oxidative phenotype may lead to novel intervention strategies to reverse muscle weakness in COPD and CHF.
The second aim of this study is to investigate whether adipose tissue is an extrapulmonary source of inflammation in COPD patients.
In this cross-sectional study, muscle biopsies will be obtained before and after exercise and tested for molecular markers of hypoxia. In addition, all subjects will be characterized thoroughly including measurement of lung function, exercise capacity, muscle function and body composition measurement. Fasting adipose tissue biopsies will be obtained in COPD patients and healthy persons.
|- Main changes (audit trail)|
|- RECORD||11-aug-2008 - 2-sep-2011|
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