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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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Relationships between measured maximum O2 transport (VO2), y-axis; and, estimated cellular oxygenation (PmO2), x-axis, in COPD patients. The different symbols correspond to classical GOLD stages: squares, GOLD II; circles GOLD III; and, triangles, GOLD IV (measured VO2 obtained from [32]). The symbols connected with discontinuous lines correspond to the same patient (same VO2) with estimated PmO2 values corresponding to different mitochondrial oxidative capacities (Vmax values and VO2/Vmax ratios). For a given patient, the lower the VO2/Vmax ratio, the lower was the estimated PmO2. The colors correspond to the mitochondrial ROS generation: green, mitochondrial ROS levels similar to those seen in healthy subjects; red, abnormally high mitochondrial ROS levels; and, violet, high ROS levels that persist after exercise withdrawal. The lower the PmO2, the higher were mitochondrial ROS levels.
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Figure 3: Relationships between measured maximum O2 transport (VO2), y-axis; and, estimated cellular oxygenation (PmO2), x-axis, in COPD patients. The different symbols correspond to classical GOLD stages: squares, GOLD II; circles GOLD III; and, triangles, GOLD IV (measured VO2 obtained from [32]). The symbols connected with discontinuous lines correspond to the same patient (same VO2) with estimated PmO2 values corresponding to different mitochondrial oxidative capacities (Vmax values and VO2/Vmax ratios). For a given patient, the lower the VO2/Vmax ratio, the lower was the estimated PmO2. The colors correspond to the mitochondrial ROS generation: green, mitochondrial ROS levels similar to those seen in healthy subjects; red, abnormally high mitochondrial ROS levels; and, violet, high ROS levels that persist after exercise withdrawal. The lower the PmO2, the higher were mitochondrial ROS levels.

Mentions: Skeletal muscle dysfunction in COPD patients. Figure 3 displays the relationships between estimated skeletal muscle PO2 (PmO2) and mitochondrial ROS production for different levels of maximum O2 transport and mitochondrial utilization capacity in a group of COPD patients with mild to severe disease [32], as explained in the figure legend. The central messages of this analysis were: i) PmO2 at maximal exercise is determined by the ratio between O2 transport to mitochondrial and O2 utilization capacity (VO2max/Vmax ratio), such that the lower the maximum O2 transport potential for a given mitochondrial capacity, the lower PmO2; ii) tissue oxygenation levels were not related with GOLD stages; and, iii) low PmO2 values associated with abnormally high mitochondrial ROS production at peak exercise were predicted to occur in these patients. The analysis of the relative impact of the determinants of skeletal muscle oxygenation using the integrated model of O2 pathway and mitochondrial ROS generation also indicated: (1) how functional heterogeneities of skeletal muscle VO2max/Vmax ratios may generate both very low and very high PmO2 in the skeleletal muscle of these patients; and (2) the high impact of lung heterogeneity decreasing overall O2 transport, as compared with the rather moderate role of skeletal muscle heterogeneity on mean PmO2.


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)

Relationships between measured maximum O2 transport (VO2), y-axis; and, estimated cellular oxygenation (PmO2), x-axis, in COPD patients. The different symbols correspond to classical GOLD stages: squares, GOLD II; circles GOLD III; and, triangles, GOLD IV (measured VO2 obtained from [32]). The symbols connected with discontinuous lines correspond to the same patient (same VO2) with estimated PmO2 values corresponding to different mitochondrial oxidative capacities (Vmax values and VO2/Vmax ratios). For a given patient, the lower the VO2/Vmax ratio, the lower was the estimated PmO2. The colors correspond to the mitochondrial ROS generation: green, mitochondrial ROS levels similar to those seen in healthy subjects; red, abnormally high mitochondrial ROS levels; and, violet, high ROS levels that persist after exercise withdrawal. The lower the PmO2, the higher were mitochondrial ROS levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Relationships between measured maximum O2 transport (VO2), y-axis; and, estimated cellular oxygenation (PmO2), x-axis, in COPD patients. The different symbols correspond to classical GOLD stages: squares, GOLD II; circles GOLD III; and, triangles, GOLD IV (measured VO2 obtained from [32]). The symbols connected with discontinuous lines correspond to the same patient (same VO2) with estimated PmO2 values corresponding to different mitochondrial oxidative capacities (Vmax values and VO2/Vmax ratios). For a given patient, the lower the VO2/Vmax ratio, the lower was the estimated PmO2. The colors correspond to the mitochondrial ROS generation: green, mitochondrial ROS levels similar to those seen in healthy subjects; red, abnormally high mitochondrial ROS levels; and, violet, high ROS levels that persist after exercise withdrawal. The lower the PmO2, the higher were mitochondrial ROS levels.
Mentions: Skeletal muscle dysfunction in COPD patients. Figure 3 displays the relationships between estimated skeletal muscle PO2 (PmO2) and mitochondrial ROS production for different levels of maximum O2 transport and mitochondrial utilization capacity in a group of COPD patients with mild to severe disease [32], as explained in the figure legend. The central messages of this analysis were: i) PmO2 at maximal exercise is determined by the ratio between O2 transport to mitochondrial and O2 utilization capacity (VO2max/Vmax ratio), such that the lower the maximum O2 transport potential for a given mitochondrial capacity, the lower PmO2; ii) tissue oxygenation levels were not related with GOLD stages; and, iii) low PmO2 values associated with abnormally high mitochondrial ROS production at peak exercise were predicted to occur in these patients. The analysis of the relative impact of the determinants of skeletal muscle oxygenation using the integrated model of O2 pathway and mitochondrial ROS generation also indicated: (1) how functional heterogeneities of skeletal muscle VO2max/Vmax ratios may generate both very low and very high PmO2 in the skeleletal muscle of these patients; and (2) the high impact of lung heterogeneity decreasing overall O2 transport, as compared with the rather moderate role of skeletal muscle heterogeneity on mean PmO2.

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