FIBRO-TARGETS, which stands for "Targeting cardiac fibrosis for heart failure treatment", aims to shed light on the main mechanisms involved in myocardial interstitial fibrosis, which is characterised by stiffness of the heart tissue; it leads to an alteration in the contraction and relaxation functions of the heart, which ultimately leads to heart failure. The teams will then develop and validate new molecules and targeted therapeutic strategies to limit this fibrosis. The project brings together 11 European partners in 6 countries, i.e. more than 35 professionals from research organisations, industry and public institutions.
Following heart muscle disease, the heart undergoes remodelling, of which myocardial interstitial fibrosis is a key mechanism. This fibrosis is characterised by a change in the structure of the heart tissue which becomes more rigid. It results from the excessive accumulation of proteins constituting the extracellular matrix and changes in their properties. This matrix remodelling alters the diastolic and systolic functions, ultimately leading to heart failure, the symptoms of which are breathlessness, congestion, oedema and fatigue.
Heart failure is a serious and often irreversible disease and it is estimated that over 6.5 million people in Europe suffer from it. It is the leading cause of hospitalisation in people aged over 65. Its frequency is increasing at an alarming rate due to the ageing of the population and the explosion of cardiovascular risk factors (diabetes, obesity, high blood pressure). Early intervention on major mechanisms including myocardial interstitial fibrosis could slow the progression and worsening of heart failure.
"Until now, the only way to quantify fibrosis is by biopsy, which is an invasive and not very accurate method for estimating the degree of total fibrosis. For the last ten years, cardiac imaging has allowed a good anatomical and functional evaluation of the myocardium. But these two methods are not predictive. This is therefore the challenge of the FIBRO-TARGETS project, which proposes an innovative approach for the early detection of cardiac anomalies using myocardial interstitial fibrosis markers. This is the first time that the FIBRO-TARGETS project has been carried out," explains Professor Faiez Zannad, researcher at the Inserm U1116 unit, Centre d'Investigation Clinique P. Drouin Inserm 9501 in Nancy, coordinator of the FIBRO-TARGETS and HOMAGE projects.
Thanks to the numerous data collected by the FIBRO-TARGETS consortium, myocardial interstitial fibrosis has been identified as a major therapeutic target for the prevention and treatment of heart failure.
The FIBRO-TARGETS project therefore aims to identify precisely the main mechanisms involved in myocardial interstitial fibrosis and to design therapeutic approaches targeting some of these mechanisms. Cardiac fibroblasts (specific cells of the cardiac muscle) represent 60 to 70% of cardiac cells and are the main source of production of the extracellular proteins responsible for fibrosis. Now that these mechanisms have been identified, the aim is to intervene directly on the proliferation of fibroblasts and the synthesis of the extra-cellular matrix with molecules of therapeutic interest for the prevention, repair or slowing of cardiac remodelling.
The objectives of FIBRO-TARGETS are first to confirm the main biological mechanisms involved in myocardial interstitial fibrosis. Then, the aim will be to experimentally validate new molecules and targeted therapeutic strategies aimed at improving the quality of the cellular matrix and limiting myocardial interstitial fibrosis. This will then allow the establishment of potential clinical scenarios to treat heart failure. Finally, the targets can be used as biomarkers to predict and qualify the response to treatments against myocardial interstitial fibrosis.
To achieve these objectives, the European researchers will attempt to elucidate the mechanisms of cardiac interstitial fibrosis using existing in vitro and in vivo models and/or those developed during the project, through experimental physiology and pharmacology, molecular biology and pharmaceutical chemistry studies. They will also validate the relevance of the new therapeutic approaches developed during the project. The second, translational stage will consist of classifying patients at risk who are most likely to respond to targeted therapies according to personalised medicine. This classification into groups of patients will be based on profiles determined using imaging and circulating markers associated with the proposed new targets.
The successful completion of FIBRO-TARGETS will contribute to solving a major public health problem of the 21st century, particularly affecting the elderly.