Impact of clonal hematopoiesis of indeterminate potential on progression and echocardiographic worsening of mild-to-moderate aortic stenosis

Background Clonal hematopoiesis of indeterminate potential (CHIP) has been shown to occur frequently in patients with severe degenerative aortic stenosis (AS) and to be associated with significant increase in mortality even after successful transcatheter aortic valve replacement. However, limited data exist on the impact of CHIP-driver mutations on progression of mild-to-moderate AS. Purpose The aim of this study was to assess the association between baseline CHIP-driver mutations and a worsening course of AS. Methods Seventy patients with mild or moderate AS from the PROGRESSA trial with available peripheral blood mononuclear cell samples and an echocardiographic follow-up between 5 and 10 years were included. Next-generation sequencing was performed using a pre-defined panel of 56 genes. Frequency of CHIP-driver mutations and their impact on progression of AS severity were assessed. Progression was defined as an increase in AS category (mild AS to moderate AS or moderate AS to severe AS) or progression to AS requiring aortic valve replacement. Results Median age of the population was 70 years. A total of 14 patients (20%) were carriers of at least one CHIP-driver mutation with a variant allele frequency (VAF) ≥ 2%, with most common mutations being DNTM3A, TET2, and ASXL1. There were no differences in baseline clinical, echocardiographic, or laboratory parameters between patients with and without CHIP-driver mutations. Among patients with a CHIP-driver mutation, 85.7% showed AS progression compared with only 50% among those without CHIP (p-value=0.018). The annualized progression rate was 12.4% per year in CHIP-carriers compared with 6.8% per year in non-carriers. When excluding patients who had only a DNMT3A-CHIP-driver mutation (n=6), all (100%) carriers showed AS progression vs only 51.6% of non-carriers (p-value=0.009), with an annualized progression rate of 13.9% vs 7.1% per year, respectively. Analysis of the most widely used echocardiographic parameter to assess AS severity showed that patients with a CHIP-driver mutation exhibited a greater annual increase in mean transvalvular gradient (Pmean) compared with those without mutations (median [IQR]: 1.05 [0.69-1.92] vs 0.49 [0.16-1.35] mmHg per year, p-value= 0.034). A trend was observed in the annual increase in Pmean with increasing numbers of CHIP-driver mutations (no CHIP-driver mutations: 0.49 (0.16-1.35); 1 CHIP-driver mutation: 0.96 (0.65-1.43), and 2 CHIP-driver mutations: 2.37 (1.21-3.53) mmHg per year). Conclusion The presence of CHIP-driver mutations (VAF ≥ 2) at baseline was associated with increased progression and echocardiographic worsening of AS. These findings could provide new insights into the mechanisms driving AS progression and pave the way for personalized therapeutic strategies aimed at slowing its course.