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.

Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease

“…The VAF of clonal populations was associated with the severity of the clinical outcome, suggesting a dose-response relationship [58]. Similarly, aortic valve stenosis patients with DNMT3A or TET2 variants who underwent aortic valve implantation surgery were observed to have heightened medium-term all-cause mortality compared to those without CHIP mutations [59]. These results were supported by the finding that mice with hematopoietic or myeloid Tet2-deficiency had greater cardiac dysfunction and worsened remodeling following induced heart failure [60].…”

Immune Dysregulation in HFpEF: A Target for Mesenchymal Stem/Stromal Cell Therapy

“…CHIP-related mutations can also impair the function of T cells. Clinical data reported by Zeiher et al showed that, among a population of patients with degenerative aortic stenosis undergoing transcatheter aortic valve implantation (TAVI), those carrying a DNMT3A mutation had an increased Th17/Treg ratio [15]. This was not observed in patients harboring a TET2 mutation.…”

“…In this view, recently uncovered genetic factors and acquired risk factors collaborate to induce a heightened chronic pro-inflammatory tone and multi-organ subclinical dysfunction, respectively, thus defining a HFpEF predisposition. In the premalignant syndrome of clonal hematopoiesis of indeterminate potential (CHIP), inactivating mutations in genes controlling hematopoietic stem cell turnover and differentiation leads to enhanced proliferation of myeloid cells with pro-inflammatory properties, and to an increased T helper 17 (Th17) / regulatory T cell (Treg) ratio [15] (first hit). Furthermore, pro-inflammatory circulating immune cells are recruited into the heart by danger signals produced in the myocardium in response to traditional risk factors such as elevated BP, aortic valve stenosis, smoking and/or aging (second hit), with endothelial activation facilitating the immune cell influx [9,[16][17][18][19][20].…”

Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity

“…In retrospective cohort studies of >10,000 participants, CHIP associated with atherosclerotic cardiovascular disease and related complications (myocardial infarction and stroke, albeit with lower burdens of risk than hematologic malignancy) [9,10,21]. Moreover, smaller retrospective studies reveal CHIP as a disease modifier in heart failure and valvulopathy [22,23], further suggesting a role for TET2 and DNMT3A mutant monocytes in disease exacerbation. Whereas a causative association between CHIP and atherosclerotic disease and heart failure in humans is further supported by studies in vitro and in mice, other disease correlations with CHIP lack robust causative and mechanistic evidence.…”