More than 50% of heart failure (HF) patients present without a major deficit of left ventricular (LV) systolic function and are presumed to suffer from diastolic HF (DHF) because diastolic LV distensibility is usually impaired in these patients. The vast majority (~80%) of DHF patients is exposed to metabolic risk factors. The MEDIA consortium therefore investigates:
How metabolic derangements contribute to DHF;
How diagnostic algorithms for DHF can be improved by assessing metabolic risk;
How correction of metabolic risk can open new therapeutic perspectives for DHF.
Hereto MEDIA will::
Expose animal models of DHF to intense metabolic risk in order to accelerate DHF development.
Perform mechanistic studies in cardiomyocytes derived from DHF animal models or from DHF patients. Because of the acquired nature of metabolic risk, these studies will focus on posttranslational modifications of proteins and on epigenetic control of hypertrophy development. Their relevance for global LV function will also be appraised;
Perform mechanistic studies on myocardial collagen synthesis, which is enhanced by metabolic risk, and execute a phase II trial in DHF with cardiac specific antifibrotic therapy;
Explore the use of biomarkers as premorbid identifiers of DHF in existing cohorts of patients exposed to metabolic risk;
Prospectively test biomarkers and arterial stiffening, which is accelerated by metabolic risk, for their diagnostic potential in a large DHF cohort;
Assess myocardial metabolic substrate preference with modern imaging techniques and improve diastolic LV dysfunction through modified substrate utilization in a phase II trial.
Expected results of MEDIA are:
Identification of metabolic risk-related mechanisms as therapeutic targets;
Improved diagnostic algorithms through inclusion of biomarkers and arterial stiffness tests.
Novel treatments consisting of modified myocardial substrate utilization and myocardial antifibrotic therapy.
VU University medical center Erasmus Universitair Medisch Centrum Rotterdam RUHR-Universitaet Bochum CHARITE – UniversitaetsMedizin Berlin Universidade do Porto Universiteit Antwerpen Fondation Transplantation Universiteit Maastricht Universitetet I Oslo Debreceni Eygetem Universita degli Studi di Brescia Cardiff University Universita degli Studi del Piemonte Orientale Amedeo Avogrado Universita degli Studi di Perugia University College Dublin Digna Biotech S.L Pluristem Ltd. Oxi Gen Lab SRL Universitaetslinikum Heidelberg
EU-MASCARA is a collaborative project that aims to improve diagnosis of cardiovascular diseases and prediction of cardiovascular risk by analyzing a panel of biomarkers. EU-MASCARA aims to examine genetic, proteomic and metabolomics markers together with markers of inflammation, oxidative stress and cardiac remodeling to study their incremental diagnostic and predictive value over and above existing diagnostic and predictive algorithms.
For this purpose a large number of cohorts from different European regions, both patient and population cohorts, that have been accurately assessed for cardiovascular phenotypes are readily available to the consortium. Access to clinical samples and to standardized cardiovascular phenotypes will be granted by a strong clinical platform as one of the key work packages of EU-MASCARA. Both cross-sectional and prospective analyses will be performed that will result in the development of improved risk prediction scores.
The consortium is heavily supported by contributions of SMEs in key areas of the proposed research: biomarker testing, data handling and analysis, assay development and project management. EU-MASCARA is further characterized by a strong integrative approach both within and across work packages, with results from one task informing strategies of research in other tasks. With a dedicated bioinformatics and health economic platform the most robust biomarkers will be selected and analyzed for their benefit in clinical practice. EU-MASCARA will rigorously validate biomarkers that have been proposed to be associated with cardiovascular disease and risk across different disease entities and also in independent general population samples. The most robust biomarkers will be implemented in novel biochip based assays for clinical use.
University of Glasgow Medizinische Universitaet Graz Emergentec Biodevelopment GMBH Katholieke Universiteit Leuven Medizinische Hoschchule Hannover CHARITE – UniversitaetsMedizin Berlin Mosaiques Diagnostics GMBH Istituto Auxologico Italiano Universita degli Studi di Milano-Biocca NIVERSITA' DEGLI STUDI DI MILANO-BICOCCA Universiteit Maastricht ACS Biomarker Fundación Investigación Biomédica, Clínico Universidad de Valencia Kite Innovation (Europe) LimitedRandox Clinics Limited
As more people survive into old age, the prevalence of heart failure (HF), one of the most common and debilitating diseases in older people, will rise still further. Delaying or preventing HF will have great benefit to those at personal risk, their families, society and the economy.
HOMAGE aims to provide a biomarker (BM) approach that will a help identify:
Patients at high risk of developing HF before the onset of symptoms
Subsets of patients who are more likely to respond to specifically targeted therapies (personalized medicine).
In available cohorts, we will identify the most promising ‘omics-based BM profiles for the pre-symptomatic diagnosis and future prediction of HF in patients at risk.
The predictive value of the BMs for other co-morbidities commonly associated with HF and ageing will also be investigated. Furthermore, in a prospective trial, we will investigate the potential for targeting preventive therapy at patients with the greatest likelihood of response and the lowest risk of adverse effects.
Our selection of innovative ‘omics-based BMs is based on knowledge of biological pathways of the disease, which may facilitate identification of ‘Biotargets' for future therapies. On the economic side, HOMAGE will act as an economic catalyst for European SMEs in the field of cardiovascular and ageing BMs, estimated to peak annual turnovers of up to 800 M€.
Institut National de la Santé et Recherche Médicale Foundation Transplantation ACS Biomarker Randox Clinics Limited Medizinische Universitaet Graz The University of Manchester University College Dublin University of Hull Universiteit Maastricht
Istituto di Richerche Farmacologiche Mario Negri Medizinische Hoschchule Hannover Katholieke Universiteit Leuven London School of Hygiene and Tropical Medicine Emory University University of Glasgow
The Fibro-Targets project is a multi-disciplinary 4 years program involving 10 partners ambitioning "the identification, characterisation and validation of in vitro and in vivo models of novel therapeutically relevant targets" for myocardial interstitial fibrosis (MIF) in heart failure. The project is based on the hypothesis that the intervention on novel fibrosis-related targets involved in the processes of fibroblast differentiation to myofibroblasts, the predominance of collagen synthesis over degradation and/or collagen maturation may allow for interstitial repair, thus providing a new strategy for the prevention and treatment of adverse cardiac remodeling involved in the transition to and the progression of heart failure. From a large body of existing multi-omics, literature data and previous hypothesis-driven research conducted by members of the consortium, a number of specific extracellular and intracellular targets have been identified whose involvement in MIF is beginning to be understood and that may be targeted by specific therapies. The specific aims of the Fibro-Targets are:
(i) To provide further evidence on the mechanisms of action of the above targets
(ii) To validate experimentally that new anti-fibrotic strategies can be developed based on the above targets
(iii) To approach the potential clinical scenario of the above targets for HF therapy
To reach these aims the following studies will be performed:
(i) Observational and interventional experimental studies in already existing and/or de novo generated appropriate in vitro and in vivo models.
(ii) Clinical studies, stratifying large scale populations of patients available to the consortium, at risk to develop HF and likely to be responsive to specific novel and/or exiting anti-fibrotic therapies. The stratification will be based on specific "fibrogenetic" phenotypic profiles using multi-panel imaging and circulating markers descriptive of mechanisms involving the proposed novel targets.
Institut National de la Santé et Recherche Médicale; University College Dublin; Foundation Transplantation; Universiteit Maastricht; Medizinische Hoschchule Hannover; Medizinische Universitaet Wien; GreenPharma S.A.S.; Firalis S.A.S.; Innovative Technologies in Biological Systems; Fundación Pública Miguel Servet