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Clonal hematopoesis of indeterminate potential and degenerative aortic valve stenosis

Project description

Risk factors associated with degenerative aortic valve stenosis development and treatment

Degenerative aortic valve stenosis is the most common heart valve disease without established medical therapy to halt disease progression. The only available treatment involves aortic valve replacement by transcatheter aortic valve replacement (TAVR). The somatic mutations associated with the expansion of clonal haematopoiesis (CH) are linked to a poor prognosis for patients with stenosis undergoing TAVR. The EU-funded CHIP-AVS project will address the risk factors associated with the development and treatment of aortic valve stenosis. The study will focus on mutations in CH-driver genes that affect the processes leading to stenosis, the type of mutations involved in mediating the poor prognosis, and the impact of CH on the reversibility of cardiac fibrosis after the TAVR.

Objective

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.

Host institution

JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN
Net EU contribution
€ 2 225 906,00
Address
THEODOR W ADORNO PLATZ 1
60323 Frankfurt Am Main
Germany

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Region
Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 225 906,00

Beneficiaries (1)