https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Universitätsklinikum Köln Köln, Deutschland; 3Universitätsklinikum Düsseldorf Klinik für Kardiologie, Pneumologie und Angiologie Düsseldorf, Deutschland; 4Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland; 5Universitätsklinikum Bonn Institute of Innate Immunity Bonn, Deutschland
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). Clinical studies including both a broad range of CD mutations as well as a complete spectrum of allele frequencies and evaluating their effect on outcomes in severe aortic valve stenosis are currently lacking, and the impact of prevalent DNMT3a mutations on clinical outcomes has been subject of debate.
Aims:
This study aimed to evaluate the mutational landscape of CHIP and its’ influence on clinical outcomes in a clinical collective of patients with severe aortic stenosis.
Methods:
194 patients undergoing TAVR for severe aortic stenosis between 2019 and 2021 at the University Hospital Bonn underwent NGS sequencing using a targeted capture panel for a broad spectrum of CH driver mutations capable of detecting mutations at low Variant Allele Frequencies (VAF) (0.5%). Patients were classified as CHIP positive or negative according to the 2022 WHO definition (VAF ³2%, absence of hematologic malignancy or myeloproliferative disease). Patients were additionally divided into CHIP negative and having CHIP due to mutations other than DNMT3a. The primary endpoint was mortality during follow-up (median: 1048 days) after TAVR, associations with mortality were assessed for various driver genes.
Results:
We detected 354 CH mutations in 151 patients (77,8%), with 66 patients (34 %) being classified as CHIP positive and 85 additional patients (43,8%) harboring CH mutations below the definition threshold. Only 43 patients (22,1%) showed no CH mutations. DNMT3a (36%) and TET2 (28,4%) were the most prevalent, other prevalent CHIP mutations were found in DNA damage response (PPM1D, TP53) and spliceosome component (SF3B1, SRSF2, ZRSR2) genes. Patients with CHIP other than DNMT3a demonstrated elevated Interleukin-6 levels (p=0.031). 48 patients (24.7%) died during follow-up, including 21/66 patients with CHIP (31,8%) and 27/128 without CHIP (21.1%), resulting in a non-significant increase in mortality in the overall cohort of patients with CHIP (univariate Log-Rank, p=0.208). When adjusting for age and confounding variables CHIP had a significant association with mortality (HR: 2.713, 95% CI: 1.140-6.455, p=0.024). The presence of CH driver mutations at low VAF was not associated with mortality (p=0.377). When excluding DNMT3a CHIP, we found a significant association of non-DNMT3a CHIP with mortality both in univariate (p=0.022) and multivariate (HR: 4.676, 95%CI 1.744-12.535, p=0.002) analyses.
Conclusion:
We found CHIP to be highly frequent and CH-driver mutations to be almost ubiquitous in patients with severe AVS. Patients displayed a broad range of mutations, as expected DNMT3a and TET2 mutations were found to be highly prevalent. The presence of CHIP was associated with increased mortality only when adjusting for age, sex and comorbidities. When excluding patients who had CHIP solely due to mutations in DNMT3a, we found a significant association with mortality. This study provides valuable information regarding the spectrum of clonal hematopoiesis in aortic valve stenosis as well as the variations in effect sizes between different candidate driver gene mutations, adding to the evidence of the necessity of risk stratification both in patients with severe aortic valve stenosis and with different CHIP mutations.