Systems Medicine: from molecular features and models to the clinic in COPD

BACKGROUND AND HYPOTHESIS: Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. OBJECTIVE AND METHOD: Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. RESULTS: In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. CONCLUSIONS: The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them

THE ROLE OF THE NERVOUS SYSTEM IN THE MAINTENANCE OF PULMONARY ARTERIAL HYPERTENSION IN HEART FAILURE

Elevation of pressure in the pulmonary veins, with a consequent elevation of pressure in the pulmonary capillaries and pulmonary artery has for many years been invoked to explain pulmonary hypertension in both mitral stenosis and left ventricular failure. Ignoring the possibility of pul-monary vasoconstriction, this hypothesis was in complete accordance with the " mechanistic " concept of the regulation of pulmonary pressure, emphasized recently by Cournand (1947, 1950) and Hamilton (1951). It was based mainly on the relative refractoriness of the pulmonary circula-tion towards substances affecting the systemic circulation. It was soon established, however, that elevation of the pulmonary venous pressure is only partly responsible for the high pressure in the pulmonary artery that is observed in heart failure. Elevation of pulmonary " capillary " pressure beyond the colloid osmotic pressure of plasma causes an increase in the pulmonary pressure gradient (Dexter et al., 1950), as a result of an increase of the pulmonary arteriolar resistance. Lewis et al. (1952), emphasize that in mitral stenosis this increased arteriolar resistance is a physiological counterpart to the anatomical changes observed in the small pulmonary arteries by Parker and Weiss (1936) and Larrabee et al. (1949). In face of this " static " theory of increased pulmonary arteriolar resistance it seems hard to understand wh

Network modules uncover mechanisms of skeletal muscle dysfunction in COPD patients

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients often show skeletal muscle dysfunction that has a prominent negative impact on prognosis. The study aims to further explore underlying mechanisms of skeletal muscle dysfunction as a characteristic systemic effect of COPD, potentially modifiable with preventive interventions (i.e. muscle training). The research analyzes network module associated pathways and evaluates the findings using independent measurements. METHODS: We characterized the transcriptionally active network modules of interacting proteins in the vastus lateralis of COPD patients (n = 15, FEV1 46 ± 12% pred, age 68 ± 7 years) and healthy sedentary controls (n = 12, age 65 ± 9 years), at rest and after an 8-week endurance training program. Network modules were functionally evaluated using experimental data derived from the same study groups. RESULTS: At baseline, we identified four COPD specific network modules indicating abnormalities in creatinine metabolism, calcium homeostasis, oxidative stress and inflammatory responses, showing statistically significant associations with exercise capacity (VO2 peak, Watts peak, BODE index and blood lactate levels) (P < 0.05 each), but not with lung function (FEV1). Training-induced network modules displayed marked differences between COPD and controls. Healthy subjects specific training adaptations were significantly associated with cell bioenergetics (P < 0.05) which, in turn, showed strong relationships with training-induced plasma metabolomic changes; whereas, effects of training in COPD were constrained to muscle remodeling. CONCLUSION: In summary, altered muscle bioenergetics appears as the most striking finding, potentially driving other abnormal skeletal muscle responses. Trial registration The study was based on a retrospectively registered trial (May 2017), ClinicalTrials.gov identifier: NCT03169270.We want to acknowledge the support of the European Commission (FP7)grants SYNERGY-COPD (no. FP7-ICT-2009-270086), the AGAUR (2009SGR911 and 2014SGR1017), CERCA Programme / Generalitat de Catalunya (2014SGR661) and The ’ICREA Academia’ prize for excellence in research, ICREA foundation-Generalitat de Catalunya (to M.C.)