What is the clinical evidence from this study?

Study design: Cohort. Population: Severe aortic valve stenosis (n=194). Intervention: Clonal hematopoiesis of indeterminate potential (CHIP) vs. No CHIP. Primary outcome: Mortality (excluding 90-day procedure-related mortality) (HR 2.143, 95% CI 1.029-4.461, p=0.042).

May 5, 2025Open Access

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

Q: What does this research mean for the field?

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased mortality (HR 2.143) compared to patients without CHIP in severe aortic valve stenosis after TAVR, particularly when excluding DNMT3A-CHIP. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Result

Clonal hematopoiesis of indeterminate potential (CHIP) was associated with increased mortality (HR 2.143) compared to patients without CHIP in severe aortic valve stenosis after TAVR.

Study Design

Type

Cohort (n=194)

Multicenter

Structured PICO

Does the presence of CHIP increase mortality in patients with severe aortic valve stenosis undergoing TAVR?

Population

194 patients with severe aortic valve stenosis undergoing transcatheter aortic valve replacement (TAVR), median age 74 years, 37.8% female, of central European (97%) and middle eastern or Arabic (3%) origin.

Intervention

Presence of clonal hematopoiesis of indeterminate potential (CHIP) defined as variant allele frequency (VAF) ≥ 2% or ≥ 4% in X-linked genes, and specifically non-DNMT3A CHIP.

Comparator

Absence of CHIP.

Outcome

Mortality over a median follow-up of 1048 days.hard clinical

In patients with severe aortic valve stenosis undergoing TAVR, the presence of CHIP, particularly non-DNMT3A CHIP, is highly prevalent and independently associated with increased long-term mortality.

Main Result

Effect estimate: HR 2.143 (95% CI 1.029-4.461)

Absolute Event Rate: 31.8% vs 21.1%

p-value: p=0.042

Limitations

Observational nature of the study prevents inferring causality
Limited overall sample size
Cross-sectional analysis of established high-grade AVS prevents distinguishing causality of CHIP in AVS development
Exact causes of mortality were not available for all patients

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.

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