Description du projet
Des facteurs de risque associés au développement et au traitement de la sténose aortique dégénérative
La sténose aortique dégénérative est la maladie valvulaire cardiaque la plus fréquente sans traitement médical établi pour stopper sa progression. Le seul traitement disponible consiste à procéder au remplacement de la valve aortique par voie transcathéter (TAVR). Les mutations somatiques associées à l’expansion de l’hématopoïèse clonale (CH) sont liées à un mauvais pronostic chez les patients atteints de sténose qui subissent un TAVR. Le projet CHIP-AVS, financé par l’UE, s’intéressera aux facteurs de risque associés au développement et au traitement de la sténose aortique dégénérative. L’étude se concentrera sur les mutations des gènes moteurs de la CH qui affectent les processus menant à la sténose, le type de mutations impliquées dans la médiation du mauvais pronostic, et l’impact de la CH sur la réversibilité de la fibrose cardiaque après le TAVR.
Objectif
Degenerative aortic valve stenosis is the most common acquire heart valve disease and will continue to increase as a result of an aging population. There is currently no medical therapy established to halt progression of aortic stenosis and the only definitive treatment is aortic valve replacement either by surgery or transcatheter aortic valve replacement (TAVR). Without valve replacement, the 2 year mortality rate approximates 50 % once patients are symptomatic. Although a number of general risk factors have been described for developing calcified aortic valve disease, risk prediction for progression of CAVD to severe stenosis is still poor. We demonstrated that somatic mutations associated with expansion of hematopoietic cells (“clonal haematopoiesis“ (CH)) are associated with a poor prognosis of patients with aortic valve stenosis undergoing TAVR.
This application aims to address the following major points. We will determine 1) how mutations in the most prevalent CH-driver gene DNMT3A may directly or indirectly affect the pathophysiological processes leading to aortic valve stenosis, and 2) which type of mutation is particularly involved in mediating the poor prognosis. 3) We will determine the impact of CH on the reversibility of cardiac fibrosis after successful replacement of the aortic valve, and 4) determine the relation of CH with senescence and inflammaging. We will use cutting edge single cell and omics technologies to decipher the pathophysiological effects in patient tissues and circulating blood samples and will explore the pathomechanisms induced by DNMT3A CH-driver mutation by assessing cellular communication processes in vitro.
The discovery of relevant of immune system mediated complexities in the progression of aortic valve stenosis and consequent cardiac fibrosis is expected to identify biomarkers and possible novel therapeutic targets to specifically intervene in patients with a high risk for worse outcome.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
60323 Frankfurt Am Main
Allemagne