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

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.