Descripción del proyecto
Factores de riesgo asociados al desarrollo y al tratamiento de la estenosis valvular aórtica degenerativa
La estenosis valvular aórtica degenerativa es la valvulopatía cardiaca más frecuente y no dispone de ningún tratamiento médico establecido para detener su progresión. El único tratamiento disponible consiste en la sustitución de la válvula aórtica mediante una valvuloplastia aórtica con catéter. Las mutaciones somáticas relacionadas con la expansión de la hematopoyesis clonal están asociadas a un mal pronóstico en los pacientes con estenosis que se someten a dicha intervención quirúrgica. El equipo del proyecto CHIP-AVS, financiado con fondos europeos, abordará los factores de riesgo asociados al desarrollo y al tratamiento de la estenosis de la válvula aórtica. El estudio se centrará en las mutaciones de los genes impulsores de la hematopoyesis clonal que afectan a los procesos que conducen a la estenosis, el tipo de mutaciones que dan lugar a un mal pronóstico y el efecto de la hematopoyesis clonal en la reversibilidad de la fibrosis cardíaca tras la valvuloplastia.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
60323 Frankfurt Am Main
Alemania