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. 2023 Jul 19;8(11):1424-1435.
doi: 10.1016/j.jacbts.2023.04.010. eCollection 2023 Nov.

Negative Impact of TET2 Mutations on Long-Term Survival After Transcatheter Aortic Valve Replacement

Fanny Lassalle  1 , Nicolas Duployez  2 , Flavien Vincent  1 , Antoine Rauch  1 , Tom Denimal  1 , Mickael Rosa  1 , Julien Labreuche  3 , David Dombrowicz  1 , Bart Staels  1 , Claude Preudhomme  2 , Sophie Susen  1 , Eric Van Belle  1 , Annabelle Dupont  1
Affiliations

Negative Impact of TET2 Mutations on Long-Term Survival After Transcatheter Aortic Valve Replacement

Fanny Lassalle et al. JACC Basic Transl Sci. .

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is considered as being a novel age-related risk factor for cardiovascular diseases. By capture-sequencing of a 67-gene panel, we established a large spectrum of CHIP in 258 patients with aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR) and assessed their association with long-term survival after TAVR. One or several CHIP variants in 35 genes were identified in 68% of the cohort, DNMT3A and TET2 being the 2 most frequently mutated genes. Patients carrying a TET2-CHIP-driver variant with low variant allele frequency (2%-10%) had a significant decrease in overall survival 5 years after TAVR.

Keywords: aortic valve stenosis; clonal hematopoiesis; survival; transcatheter aortic valve replacement.

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Conflict of interest statement

Dr Staels is supported by grants from the Fondation Leducq convention 6CVD01 “Defining and targeting epigenetic pathways in monocytes and macrophages that contribute to cardiovascular disease,” the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-0046), and is a recipient of an Advanced ERC Grant (694717). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: AVS is an elderly pathology mediated by inflammation. CHIP has been recently described as a novel age-related risk factor for cardiovascular diseases. This study describes in a cohort of 258 patients a large profile and a high prevalence of CHIP-driver genes in AVS. Moreover, patients carrying TET2 mutations with low VAF (2%-10%) have a decreased overall survival at 5 years after TAVR. These findings contribute to the understanding of the pathogenesis of AVS and might help decision making in the management of patients with AVS undergoing TAVR. TRANSLATIONAL OUTLOOK: Additional functional studies in relevant preclinical models are still needed to unravel the exact mechanisms by which CHIP-driver variants contribute to AVS and impact the clinical prognosis after TAVR, especially in TET2. Our findings need to be validated in larger studies of consecutive patients before being used for decision making in the management of patients with severe AVS undergoing TAVR. There are a number of studies that showed that TET2 deficiency in murine models leads to an enhanced inflammation, particularly via IL-1β and NLRP3 inflammasome. Our study emphasizes the fact that IL-1β and the inflammasome could be novel therapeutic targets in AVS and for the improvement of survival after TAVR for patients who are carrying TET2 somatic variants.

Figures

None
Graphical abstract
Figure 1
Figure 1
Large Profile of CHIP in Our Patients Studied by Captured-Based High-Throughput Sequencing (A) Prevalence of clonal hematopoiesis of indeterminate potential (CHIP) according to age. (B) Proportion of common CHIP variants in individuals in whom a variant was identified (176 CHIP-positive patients, 392 variants). (C) Molecular landscape showing covariants in 176 CHIP-positive patients. Black boxes indicate several mutations within the same gene. Each column represents 1 patient.
Figure 2
Figure 2
Scatter Plot of VAF for Each CHIP-Driver Variant The number of variants identified for each gene is as follows: DNMT3A = 119, TET2 = 110, PPM1D = 25, ASXL1 = 27, Splicing = 30, TP53 = 16, CBL = 10, others = 55. Splicing includes SF3B1, SRSF2, and U2AF1. The median VAF is shown as horizontal line. Three values are not shown in this graph because of VAFs higher than 50% (1 DNMT3A, VAF 73%, and 2 TET2: VAF 64% and 75%). CHIP = clonal hematopoiesis of indeterminate potential; VAF = variant allele frequency.
Figure 3
Figure 3
Incidence of Deaths in CHIP-Positive (VAF ≥2%) Patients Depending on the Genes The bubble size represents the number of patients mutated for the gene on the horizontal axis (also given in absolute number). Genes for which there were fewer than 3 patients mutated were excluded. Abbreviations as in Figure 2.
Figure 4
Figure 4
Kaplan-Meier Survival Analyses of AVS Patients During 5 Years of Follow-Up After TAVR (A) Defined by different subgroups depending on the mutated genes. (B) Depending on the TET2-CHIP-driver gene. Patients with a VAF <2% or >10% were excluded, as well as patients who died in the first 30 days after the procedure. AVS = aortic valve stenosis; TAVR = transcatheter aortic valve replacement; CHIP = clonal hematopoiesis of indeterminate potential.
Figure 5
Figure 5
Circulating Concentrations of IL-1β, IL-6, IL-8, and TNF-α Cytokines Before TAVR in TET2-Positive (n = 8) and TET2-Negative Patients (n = 24) IL = interleukin; TAVR = transcatheter aortic valve replacement; TNF = tumor necrosis factor.
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