MEDIA · The MEtabolic Road to DIAstolic Heart Failure

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:1) how metabolic derangements contribute to DHF; 2) how diagnostic algorithms for DHF can be improved by assessing metabolic risk; 3) how correction of metabolic risk can open new therapeutic perspectives for DHF.Hereto MEDIA will: 1) Expose animal models of DHF to intense metabolic risk in order to accelerate DHF development. 2) 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; 3) 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; 4) Explore the use of biomarkers as premorbid identifiers of DHF in existing cohorts of patients exposed to metabolic risk; 5) Prospectively test biomarkers and arterial stiffening, which is accelerated by metabolic risk, for their diagnostic potential in a large DHF cohort; 6) 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: 1) Identification of metabolic risk-related mechanisms as therapeutic targets; 2) Improved diagnostic algorithms through inclusion of biomarkers and arterial stiffness tests. 3) Novel treatments consisting of modified myocardial substrate utilization and myocardial antifibrotic therapy.