Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation

Abstract

Aims: Clonal haematopoiesis of indeterminate potential (CHIP), defined as the presence of an expanded somatic blood cell clone without other haematological abnormalities, was recently shown to increase with age and is associated with coronary artery disease and calcification. The most commonly mutated CHIP genes, DNMT3A and TET2, were shown to regulate inflammatory potential of circulating leucocytes. The incidence of degenerative calcified aortic valve (AV) stenosis increases with age and correlates with chronic inflammation. We assessed the incidence of CHIP and its association with inflammatory blood cell phenotypes in patients with AV stenosis undergoing transfemoral aortic valve implantation (TAVI).

Methods and results: Targeted amplicon sequencing for DNMT3A and TET2 was performed in 279 patients with severe AV stenosis undergoing TAVI. Somatic DNMT3A- or TET2-CHIP-driver mutations with a VAF ≥ 2% were detected in 93 out of 279 patients (33.3%), with an age-dependent increase in the incidence from 25% (55-69 years) to 52.9% (90-100 years). Patients with DNMT3A- or TET2-CHIP-driver mutations did not differ from patients without such mutations in clinical parameters, concomitant atherosclerotic disease, blood cell counts, inflammatory markers, or procedural characteristics. However, patients with DNMT3A- or TET2-CHIP-driver mutations had a profoundly increased medium-term all-cause mortality following successful TAVI. Differential myeloid and T-cell distributions revealed pro-inflammatory T-cell polarization in DNMT3A-mutation carriers and increased pro-inflammatory non-classical monocytes in TET2-mutation carriers.

Conclusion: This is the first study to show that acquired somatic mutations in the most commonly mutated CHIP-driver genes occur frequently in patients with severe degenerative AV stenosis, are associated with increased pro-inflammatory leucocyte subsets, and confer a profound increase in mortality following successful TAVI.

Keywords: Aortic valve disease; Clonal haematopoiesis; Inflammation; TAVI.

Take home figure

Overall survival of patients with DNMT3A- or TET2-CHIP-driver mutations with a variant allele frequency ≥ 2% vs. patients without DNMT3A or TET2 mutations. ^*Patients with follow-up <30 days have been excluded in order to remove mortality due to peri-procedural complications.

Figure 1

(A) Th17/T reg ratio in carriers of a DNMT3A-CHIP-driver mutation and patients without DNMT3A/TET2-mutations. (B) Number of non-classical monocytes in carriers of TET2-CHIP-driver mutations and patients without TET2/DNMT3A mutations. TAVI, transcatheter aortic valve implantation.