CLINICAL AND TRANSLATIONAL RESEARCH
Leader: Patrick Rossignol, CIC Nancy
Objectives and resources:
FHU-CARTAGE is in a unique position as to allow for the premorbid detection of markers of age-related cardiovascular (CV) diseases (mainly heart failure, and vascular ageing related diseases) and common comorbidities (chronic kidney disease and diabetes, but also cognitive decline, frailty and loss of autonomy in older patients), as well as for the validation of innovative markers stemming from our basic research, with diagnostic, prognostic and therapeutic value, using large, highly informative cohorts (with standardized high-tech phenotyping: see Table) and RCTs (Table below).
The objectives of the WP2 are dual. The first is to set up a regional clinical and translational clinical research platform which will provide clinicians and researchers with all the necessary support and standards to design and conduct new projects on CV ageing; ultimately it will contribute to improved data sharing and joint projects. The second objective will be to conduct this translational research, gathering both cohorts and clinical trials, with the main aim to implement and assess personalized, biomarkerguided new therapeutic approaches.
Set up a strategic committee including all team leaders in order to acquire a real time overview of the existing and planned research activities and coordinate the use of regional clinical research facilities (CIC-P (mostly dedicated to CV and ageing clinical research, CIC-EC and CIC-IT platforms, CRB (Nancy CHU integrated biobanking resource, co-headed by P. Rossignol, member of The National Biobank Network Initiative d’Avenir), ESPRI, BIOBASE, URC, Metz-CRC, Academic Research organization EDDH), taking advantage of the leadership of Nancy CIC-P at both the national (Investissement d’Avenir F-CRIN (F-Clinical Research Infrastructure Network), the French affiliate of ECRIN-ERIC: INI-CRCT (Cardiovascular and Renal clinical trialists) network of excellence (coord. P. Rossignol: >20 French teams: cardiologists nephrologists, intensivists, epidemiologists, GPs, basic researchers), disease management programs, Agence de Biomedecine; CIC CV network coordination) and international level (EU FP7 HOMAGE and FIBROTARGETS general coordination: websites).
Set up an interface committee with WP1 and WP3 to achieve fast translation from bench to bedside for the use of new Biomarkers.
The two research axes described below were selected by CARTAGE based on their relevance to the FHU general topic and overall excellence of the partners:
Axis 1: Validate the diagnostic and prognostic values and clinical relevance of biological and bioimaging markers: (biomarkers)
The most common decision a physician has to make is whether to treat a patient or not and, if so, with what. Our program will provide key steps in this direction. This project will go beyond the state of the art by providing robust and reliable BMs for the early detection of patients at risk of developing accelerated CV ageing-related comorbidities that will improve management. Identifying common dysregulated pathways among patients with similar CV comorbidities will allow adapting therapeutic strategies to subpopulations more prone to respond to targeted therapies and improving their benefit/risk ratio 4, 10-15. In short, WP2 will lead to the identification of considerably improved tools to measure the activity of biological pathways, identified by the WP, that drive the progression of CV ageing and comorbidities and to identify "biotargets‟ for future specific prognosis and intervention Improving diagnostic strategies is a major goal, not only to identify patients with a high rate of cardiovascular ageing, but also to determine the risk of CV related-diseases at the individual level and, at later stages, to specify the response and adaptive capacities of the organism and the best appropriate treatments and monitoring modalities. The main originality of our multiparametric diagnostic program is likely to be the systematic crossing of information obtained by biomarkers: (i) from functional and molecular imaging techniques, at the regional level of diseased organs, and (ii) from blood or other fluid samples, at the level of genetic, environmental and pathophysiological adaptation factors.
The MRI research program will be conducted by the IADI team (INSERM U947), a full partner of the FHU-CARTAGE project, and by the CIC-IT lab (INSERM). The main technological objectives are: (i) reducing/cancelling motion artefacts for imaging of heart, vessels and target organs of CV ageing (brain,
kidney), (ii) adding and combining new functional information to improve tissue characterization (vascular compliance and resistance, CV scar and remodeling, T1 and T2 mapping, diffusion and tractography, etc.), these techniques being highly sensitive to motion, (iii) establishing a short, robust and multiparametric “one shot” investigation in free breathing for assessing CV ageing and for further patient monitoring.
PET imaging with 18F-fluorodesoxyglucose (18F-FDG) has been developed by our teams in the Nancyclotep experimental imaging platform for the combined analysis of heart and brain functions and for assessing arterial inflammation in experimental animal models, as well as in patients. Several new biotracers are being developed and tested in Nancyclotep.
Develop clinical research and run randomized clinical trials (RCTs)15-19 on the 2 major thematic axes of FHU-CARTAGE: heart failure and vascular ageing related diseases. These RCTs provide the highest level of evidence, enabling to modify and improve clinical practices, as implemented 15 within WP3, and disseminated by WP4 and 5. (Clinical setting)
4 Benetos A, Labat C… et al. Tracking and fixed ranking of leukocyte telomere length across the adult life course. Ageing Cell. 2013;12:615-21
10 Zannad F etal. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from The Randomized Aldactone Evaluation Study (RALES). RALES Investigators.
15 Benetos A, Gautier S, Labat C, Salvi P… Lacolley P...Guillemin F. Mortality and cardiovascular events are best predicted by low central/peripheral pulse pressure amplification but not by high blood pressure levels in elderly nursing home subjects: The Partage Study. J Am Coll Cardiol. 2012;60:1503-11.
18 Fellström B..., Zannad F; The Aurora Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009, 360:1395-407
19 Ortiz A… Rossignol P, et al on behalf of ERA-EDTA EURECAM WG. Epidemiology, contributors and clinical trials targeting the unacceptably high mortality rates of chronic kidney failure Lancet. 2014;383:1831-43.