MEDIA

The MEtabolic Road to DIAstolic Heart Failure

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Diastolic heart failure (DHF) accounts for over half of all heart failure cases. European researchers are successfully translating novel basic mechanisms of DHF into useful clinical diagnostics and therapeutic applications.

Descrizione progetto (Article)

DHF is characterised by normal left ventricular (LV) systolic function and diastolic dysfunction. While DHF is an intrinsic myocardial dysfunction, recently it was also linked to non-cardiac comorbidity (simultaneous presence of two chronic conditions).

With the support of EU funding, the project 'The metabolic road to diastolic heart failure' (http://www.diastolicheartfailure.eu (MEDIA)) is dedicated to elucidating the mechanism of this connection and translating it into clinical implications. Researchers from 12 countries are participating in this 5-year project to be completed by the end of 2015.

The project has already provided a new paradigm on how comorbidities affect myocardial dysfunction in DHF. Apparently, comorbidities drive myocardial dysfunction in DHF through induction of coronary microvascular endothelial inflammation, which affects the surrounding cardiomyocytes. This causes stiffening of cardiomyocytes and results in cardiomyocyte hypertrophy.

Scientific project achievements include creating a unique metabolic risk-related DHF animal model (ZSF1 obese rats). Phosphorylation of the giant cytoskeletal protein titin by calcium calmodulin kinase was demonstrated, and abnormal calcium handling was linked to diastolic distensibility. Oxidative stress was shown to alter the extension characteristics of titin, preventing the refolding of the titin molecule.

MEDIA investigators are using the pathophysiology of DHF to guide new diagnostic and therapeutic approaches. Clinical characterisation of late diastolic LV dysfunction was performed in patients with pre-existing metabolic risk. After evaluating 1 428 patients, it was found that body mass index, arterial hypertension, gender and age were significant predictors of diastolic LV dysfunction.

Finally, a uniform protocol for echocardiographic stress testing in DHF patients was developed and applied to DHF patients. The protocol allowed for discrimination of DHF patients from healthy controls using echocardiographic exercise stress testing.

Currently, MEDIA is translating basic findings into clinical recommendations. Several ongoing clinical trials focus on a biomarker-guided approach to anti-fibrotic drugs in DHF patients, as well as on the development of diagnostic algorithms.