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. 2025 May 5.
doi: 10.1007/s00392-025-02658-9. Online ahead of print.

Mutational landscape and impact of clonal hematopoiesis of indeterminate potential in severe aortic valve stenosis

Raúl Nicolas Jamin #  1 , Baravan Al-Kassou #  2 , Theresa Kleuker  2 , Jasmin Shamekhi  2 , Benedikt Bartsch  2 , Ansgar Ackerschott  2 , Muntadher Al Zaidi  2 , Hannah Billig  2 , Claus Moritz Graef  3 , Malte Kelm  4 , Stephan Baldus  5 , Georg Nickenig  2 , Eicke Latz  6   7 , Sebastian Zimmer  2
Affiliations

Mutational landscape and impact of clonal hematopoiesis of indeterminate potential in severe aortic valve stenosis

Raúl Nicolas Jamin et al. Clin Res Cardiol. .

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been progressively established as a risk factor for cardiovascular disease and associated with worsened outcomes in patients with aortic valve stenosis (AVS). This cohort study aimed to evaluate the mutational landscape of CHIP and its' influence on clinical outcomes.

Methods: 194 patients with AVS undergoing transcatheter aortic valve replacement (TAVR) were sequenced using a capture panel for multiple CH driver mutations and follow up conducted for three years.

Results: We found high prevalences (77.8%) of a broad spectrum of CH-driver mutations across 38 genes, with 34% of patients fulfilling the diagnostic criteria for CHIP. Evaluating the impact of CHIP driver mutations on outcomes, the presence of CHIP was associated with mortality only when adjusting for confounding factors (HR: 2.143, 95% CI: 1.029-4.461, p = 0.042), while the presence of CH driver mutations at low VAF showed no association with mortality (p = 0.377). However, when excluding DNMT3A-CHIP, we found a significant association of CHIP with mortality in univariate (p = 0.022) and multivariable (HR: 2.976, 95% CI: 1.381-6.411, p = 0.005) analyses.

Conclusions: As the first study to evaluate a broad spectrum of CH driver mutations at all variant allele frequencies in the context of aortic valve stenosis, we found CHIP to be a frequent phenomenon and CH-driver mutations to be highly prevalent in patients with severe AVS. CHIP, other than DNMT3A-CHIP, was associated with increased mortality even after successful TAVR. The presence of CH driver mutations at low allele frequencies was not associated with mortality.

Keywords: Aortic valve stenosis; Clonal hematopoiesis; Transcatheter aortic valve replacement.

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Conflict of interest statement

Declarations. Conflict of interest: SZ has received speaker fees from AstraZeneca, Medtronic, Abiomed, Edwards, Boehringer Ingelheim, Daiichi, Boston Scientific, Novartis, Abbott, Pfizer, ACIST, Bristol Myers Squibb, Bayer, Boston Scientific. All other authors have nothing to disclose.

References

    1. Osnabrugge RLJ, Mylotte D, Head SJ et al (2013) Aortic stenosis in the elderly. J Am Coll Cardiol 62:1002–1012. https://doi.org/10.1016/j.jacc.2013.05.015 - DOI - PubMed
    1. Moncla L-HM, Briend M, Bossé Y, Mathieu P (2023) Calcific aortic valve disease: mechanisms, prevention and treatment. Nat Rev Cardiol 20:546–559. https://doi.org/10.1038/s41569-023-00845-7 - DOI - PubMed
    1. Généreux P, Sharma RP, Cubeddu RJ et al (2023) The mortality burden of untreated aortic stenosis. J Am Coll Cardiol 82:2101–2109. https://doi.org/10.1016/j.jacc.2023.09.796 - DOI - PubMed
    1. Weeks LD, Marinac CR, Redd R et al (2022) Age-related diseases of inflammation in myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 139:1246–1250. https://doi.org/10.1182/blood.2021014418 - DOI - PubMed - PMC
    1. Abplanalp WT, John D, Cremer S et al (2021) Single-cell RNA-sequencing reveals profound changes in circulating immune cells in patients with heart failure. Cardiovasc Res 117:484–494. https://doi.org/10.1093/cvr/cvaa101 - DOI - PubMed

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