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Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.

Roca J, Vargas C, Cano I, Selivanov V, Barreiro E, Maier D, Falciani F, Wagner P, Cascante M, Garcia-Aymerich J, Kalko S, De Mas I, Tegnér J, Escarrabill J, Agustí A, Gomez-Cabrero D, Synergy-COPD consorti - J Transl Med (2014)

Bottom Line: To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.

Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.

Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

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Oxidative stress in COPD. Upper panel: Muscle oxidative stress. Individual and mean group effects of an 8-week endurance training program on protein carbonylation (left) and protein nitration (right) in the vastus lateralis of healthy subjects (controls) and patients with COPD. At baseline (rest, pre-training measurements), COPD patients showed higher nitroso-redox disequilibrium than healthy subjects. A trend toward a decrease in oxidative stress was observed after training in COPD patients [28]. Bottom panel: Association between muscle and blood. COPD patients at baseline (rest, pre-training) showed an association of protein carbonylation levels between skeletal muscle and blood [28] (reproduced from[28]with permission).
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Figure 4: Oxidative stress in COPD. Upper panel: Muscle oxidative stress. Individual and mean group effects of an 8-week endurance training program on protein carbonylation (left) and protein nitration (right) in the vastus lateralis of healthy subjects (controls) and patients with COPD. At baseline (rest, pre-training measurements), COPD patients showed higher nitroso-redox disequilibrium than healthy subjects. A trend toward a decrease in oxidative stress was observed after training in COPD patients [28]. Bottom panel: Association between muscle and blood. COPD patients at baseline (rest, pre-training) showed an association of protein carbonylation levels between skeletal muscle and blood [28] (reproduced from[28]with permission).

Mentions: The Biobridge dataset [27,28,33] clearly indicated that COPD patients at rest, before training, showed nitroso-redox disequilibrium both in blood and skeletal muscle compared to healthy controls (Figure 4, upper panel). Moreover, a significant association of protein carbonylation levels between blood and skeletal muscle was observed in the patients (Figure 4, bottom panel) [28] in whom low-grade inflammation in peripheral blood, but not in skeletal muscle, was observed. The plasma metabolomic analysis in COPD was fully consistent with abnormal skeletal muscle abnormalities reported in these patients [27], namely: decreased oxidative capacity leading to abnormal ROS generation [28,44,45], up-regulation of glycolysis [46] and altered aminoacid metabolism [27,46] (Figure 5). The transcriptomic analysis showed lower and abnormal skeletal muscle gene expression at baseline in COPD patients compared to healthy subjects with clear differences between COPD patients with preserved skeletal muscle mass and those showing muscle wasting [33].


Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.

Roca J, Vargas C, Cano I, Selivanov V, Barreiro E, Maier D, Falciani F, Wagner P, Cascante M, Garcia-Aymerich J, Kalko S, De Mas I, Tegnér J, Escarrabill J, Agustí A, Gomez-Cabrero D, Synergy-COPD consorti - J Transl Med (2014)

Oxidative stress in COPD. Upper panel: Muscle oxidative stress. Individual and mean group effects of an 8-week endurance training program on protein carbonylation (left) and protein nitration (right) in the vastus lateralis of healthy subjects (controls) and patients with COPD. At baseline (rest, pre-training measurements), COPD patients showed higher nitroso-redox disequilibrium than healthy subjects. A trend toward a decrease in oxidative stress was observed after training in COPD patients [28]. Bottom panel: Association between muscle and blood. COPD patients at baseline (rest, pre-training) showed an association of protein carbonylation levels between skeletal muscle and blood [28] (reproduced from[28]with permission).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255905&req=5

Figure 4: Oxidative stress in COPD. Upper panel: Muscle oxidative stress. Individual and mean group effects of an 8-week endurance training program on protein carbonylation (left) and protein nitration (right) in the vastus lateralis of healthy subjects (controls) and patients with COPD. At baseline (rest, pre-training measurements), COPD patients showed higher nitroso-redox disequilibrium than healthy subjects. A trend toward a decrease in oxidative stress was observed after training in COPD patients [28]. Bottom panel: Association between muscle and blood. COPD patients at baseline (rest, pre-training) showed an association of protein carbonylation levels between skeletal muscle and blood [28] (reproduced from[28]with permission).
Mentions: The Biobridge dataset [27,28,33] clearly indicated that COPD patients at rest, before training, showed nitroso-redox disequilibrium both in blood and skeletal muscle compared to healthy controls (Figure 4, upper panel). Moreover, a significant association of protein carbonylation levels between blood and skeletal muscle was observed in the patients (Figure 4, bottom panel) [28] in whom low-grade inflammation in peripheral blood, but not in skeletal muscle, was observed. The plasma metabolomic analysis in COPD was fully consistent with abnormal skeletal muscle abnormalities reported in these patients [27], namely: decreased oxidative capacity leading to abnormal ROS generation [28,44,45], up-regulation of glycolysis [46] and altered aminoacid metabolism [27,46] (Figure 5). The transcriptomic analysis showed lower and abnormal skeletal muscle gene expression at baseline in COPD patients compared to healthy subjects with clear differences between COPD patients with preserved skeletal muscle mass and those showing muscle wasting [33].

Bottom Line: To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction.An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people).Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics.

Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena.

Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering.

Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

Show MeSH
Related in: MedlinePlus