Relevance of Clonal Hematopoiesis in Immune Cells for Degenerative Aortic Valve Stenosis

Clonal hematopoiesis of indeterminate potential (CHIP), defined as the presence of somatic mutations in subjects without other hematologic abnormalities has been recently associated with several cardiovascular diseases. Degenerative aortic valve stenosis (AVS), a prototypical cardiovascular age-related disorder resulting from calcification and inflammation processes for which no medical treatment is currently available, has become the subject of scientific research in this field. In this review we describe the clinical relevance of CHIP in patients with AVS, as well as its effects on left ventricular dysfunction and heart failure, particularly about compensatory hypertrophy and diastolic dysfunction assessed by echocardiographic parameters. CHIP-driver mutations <i>DNMT3A</i> and <i>TET2</i> have been found in a third of all patients with severe AVS undergoing transcatheter aortic valve replacement in most studies; and several short-term and long-term studies have reported an increased mortality rate associated with the presence of CHIP in these patients. Additionally, we discuss potential mechanistic insights involving inflammatory pathways both from a clinical and from an experimental approach. These include primarily fluorescence-activated cell sorting (FACS) analyses or single-cell RNA sequencing (sc-RNA-seq) analyses from circulating leukocytes of patients with AVS, showing an increase in proinflammatory interleukines, and analyses on valve tissue exhibiting higher transcript levels of immunoglobulins, as well as murine models mimicking the consequences of AVS that could shed some light on potential causal link between CHIP and AVS. Lastly, we summarize prospects for novel therapeutic strategies, with efforts focusing on developing both general and more specific inflammatory therapies targeting inflammatory pathways. Future research will need to assess the incidence and progression of milder stages of aortic stenosis and evaluate potential interactions with different types of acquired mutations.