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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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Related in: MedlinePlus

Lung injury caused by inhaled irritants like tobacco smoking generates peripheral lung inflammation that may cause "spill over" of different types of cytokines into the systemic circulation. According to this hypothesis, systemic inflammation causes skeletal muscle dysfunction and muscle wasting, but it may also cause and worsen co-morbidities (reproduced from [30]with permission)
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Figure 1: Lung injury caused by inhaled irritants like tobacco smoking generates peripheral lung inflammation that may cause "spill over" of different types of cytokines into the systemic circulation. According to this hypothesis, systemic inflammation causes skeletal muscle dysfunction and muscle wasting, but it may also cause and worsen co-morbidities (reproduced from [30]with permission)

Mentions: The current chapter focuses on the biomedical dimensions of the project taking into consideration the implications on the healthcare scenario. Figure 1 depicts relevant bio-pathological processes involved in COPD displayed according to the classical "spill over" hypothesis [30] to explain the systemic effects of the disease. Two main limitations of this hypothesis are; i) its over-simplistic explanation of the phenomenon of systemic low-grade inflammation, not confirmed by ECLIPSE [6,11] and other studies [28] and, ii) lack of a proper consideration of the co-morbidity challenge. An implicit assumption of the hypothesis is that COPD heterogeneity is ultimately driven by the pulmonary events of the disease.


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)

Lung injury caused by inhaled irritants like tobacco smoking generates peripheral lung inflammation that may cause "spill over" of different types of cytokines into the systemic circulation. According to this hypothesis, systemic inflammation causes skeletal muscle dysfunction and muscle wasting, but it may also cause and worsen co-morbidities (reproduced from [30]with permission)
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Lung injury caused by inhaled irritants like tobacco smoking generates peripheral lung inflammation that may cause "spill over" of different types of cytokines into the systemic circulation. According to this hypothesis, systemic inflammation causes skeletal muscle dysfunction and muscle wasting, but it may also cause and worsen co-morbidities (reproduced from [30]with permission)
Mentions: The current chapter focuses on the biomedical dimensions of the project taking into consideration the implications on the healthcare scenario. Figure 1 depicts relevant bio-pathological processes involved in COPD displayed according to the classical "spill over" hypothesis [30] to explain the systemic effects of the disease. Two main limitations of this hypothesis are; i) its over-simplistic explanation of the phenomenon of systemic low-grade inflammation, not confirmed by ECLIPSE [6,11] and other studies [28] and, ii) lack of a proper consideration of the co-morbidity challenge. An implicit assumption of the hypothesis is that COPD heterogeneity is ultimately driven by the pulmonary events of the disease.

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