Association Between Aortic Valve Sclerosis and Clonal Hematopoiesis of Indeterminate Potential

Abstract

Background: The mechanism and medical treatment target for degenerative aortic valve disease, including aortic stenosis, is not well studied. In this study, we investigated the effect of clonal hematopoiesis of indeterminate potential (CHIP) on the development of aortic valve sclerosis (AVS), a calcified aortic valve without significant stenosis.

Methods: Participants with AVS (valves ≥2 mm thick, high echogenicity, and a peak transaortic velocity of <2.5 m/sec) and an age- and sex-matched control group were enrolled. Twenty-four CHIP genes with common variants in cardiovascular disease were used to generate a next-generation sequencing panel. The primary endpoint was the CHIP detection rate between the AVS and control groups. Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for differences in baseline characteristics.

Results: From April 2020 to April 2022, 187 participants (125 with AVS and 62 controls) were enrolled; the mean age was 72.6±8.5 yrs, and 54.5% were male. An average of 1.3 CHIP variants was observed. CHIP detection, defined by a variant allele frequency (VAF) of ≥0.5%, was similar between the groups. However, the AVS group had larger CHIP clones: 49 (39.2%) participants had a VAF of ≥1% (vs. 13 [21.0%] in the control group; P=0.020), and 25 (20.0%) had a VAF of ≥2% (vs. 4 [6.5%]; P=0.028). AVS is independently associated with a VAF of ≥1% (adjusted odds ratio: 2.44, 95% confidence interval: 1.11-5.36; P=0.027). This trend was concordant and clearer in the IPTW cohort.

Conclusions: Participants with AVS more commonly had larger CHIP clones than age- and sex-matched controls. Further studies are warranted to identify causality between AVS and CHIP.

Keywords: Aortic valve sclerosis; Clonal hematopoiesis; High-throughput nucleotide sequencing; Inflammation; Variant allele frequency.

Fig. 1

Distribution of CHIP-associated gene variants in the study cohort. Variant frequencies in (A) the aortic valve sclerosis group and (B) the age- and sex-matched control group. Abbreviation: CHIP, clonal hematopoiesis of indeterminate potential.

Fig. 2

Distributions of CHIP variants. Numbers of CHIP variants in (A) participants with aortic valve sclerosis (AVS) and (B) participants in the control group. (C) The proportions of CHIP variants in participants with AVS and in the age- and sex-matched control group, stratified by variant allele frequencies (VAFs) of ≥0.5%, ≥1%, or ≥2%. Abbreviation: CHIP, clonal hematopoiesis of indeterminate potential.

Fig. 3

Participants with aortic valve sclerosis (AVS) had a higher chance of having larger clonal hematopoiesis indeterminate potential (CHIP) clones than participants in the age- and sex-matched control group. Two representative cases are shown. (Left panel) A 76-yr-old man with a normal aortic valve is shown in parasternal view upon transthoracic echocardiography. He had a history of dyslipidemia and percutaneous coronary revascularization (in the left anterior descending artery) but no evidence of a CHIP variant (variant allele frequency [VAF]: 0%). (Right panel) A 72-yr-old man with AVS (red arrows) and a CHIP variant in TET2 (VAF: 3.4%). The patient had a history of hypertension and diabetes mellitus.