Clonal hematopoesis of indeterminate potential and degenerative aortic valve stenosis

Introduction

Degenerative aortic valve stenosis is the most common acquired heart valve disease and will continue to increase as a result of an aging population. There is currently no medical therapy established to halt the progression of aortic stenosis, and the only definitive treatment is aortic valve replacement, either by surgery or transcatheter aortic valve replacement (TAVR).

Prognosis Without Treatment

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 the progression of calcific aortic valve disease (CAVD) to severe stenosis is still poor.

Research Findings

We demonstrated that somatic mutations associated with the expansion of hematopoietic cells (“clonal haematopoiesis” (CH)) are associated with a poor prognosis for patients with aortic valve stenosis undergoing TAVR.

Objectives of the Application

This application aims to address the following major points:

1. Determine how mutations in the most prevalent CH-driver gene DNMT3A may directly or indirectly affect the pathophysiological processes leading to aortic valve stenosis.
2. Identify which type of mutation is particularly involved in mediating the poor prognosis.
3. Assess the impact of CH on the reversibility of cardiac fibrosis after successful replacement of the aortic valve.
4. Determine the relation of CH with senescence and inflammaging.

Methodology

We will use cutting-edge single-cell and omics technologies to decipher the pathophysiological effects in patient tissues and circulating blood samples. Additionally, we will explore the pathomechanisms induced by the DNMT3A CH-driver mutation by assessing cellular communication processes in vitro.

Expected Outcomes

The discovery of relevant 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 outcomes.