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. 2025 Apr;47(2):2149-2157.
doi: 10.1007/s11357-024-01367-x. Epub 2024 Oct 26.

Clonal hematopoiesis in cardiovascular aging: Insights from the verona heart study

Katarzyna Malgorzata Kwiatkowska #  1 , Nicola Martinelli #  2 , Luca Bertamini  3   2   4 , Sara De Fanti  5 , Oliviero Olivieri  2 , Claudia Sala  3 , Gastone Castellani  3   6 , Luciano Xumerle  7 , Elisa Zago  7 , Fabiana Busti  2   4 , Cristina Giuliani  8 , Paolo Garagnani #  3   6 , Domenico Girelli #  2   4
Affiliations

Clonal hematopoiesis in cardiovascular aging: Insights from the verona heart study

Katarzyna Malgorzata Kwiatkowska et al. Geroscience. 2025 Apr.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP), marked by the accumulation of somatic mutations in hematopoietic stem cells, significantly elevates the risk of all-cause mortality, mainly due to cardiovascular events. Therefore, investigating this pathophysiological phenomenon is crucial for understanding cardiovascular aging and enhancing both health span and lifespan. In the present study, we examined samples of subjects enrolled within the angiographically controlled Verona Heart Study (VHS), which provides a robust model for cardiovascular aging, particularly regarding coronary artery disease (CAD). We analyzed 44 older subjects diagnosed with coronary artery disease (CAD) and 42 healthy, sex- and age-matched controls (CAD-FREE). Employing deep sequencing and an amplicon-based approach, we focused on 11 key genetic regions in ASXL1, DNMT3A, IDH1, IDH2, JAK2, PPM1D, SF3B1, SRSF2, TET2, TP53, and U2AF1 genes to investigate clonal hematopoiesis. Subjects in the CAD group exhibited a significantly higher variant burden than those in the CAD-FREE group, both in terms of the total number of somatic variants and disruptive variants affecting protein function. This increased mutational load was notably influenced by six specific genetic regions: ASXL1, DNMT3A, IDH2, JAK2, TET2, and U2AF1, which displayed elevated variant rates in the CAD subjects. Moreover, ASXL1, DNMT3A, IDH2, JAK2, SF3B1, TET2, and TP53 exhibited substantially higher levels of disruptive variants in the CAD group. In summary, our findings highlight a correlation between clonal hematopoiesis and the accumulation of disruptive variants in specific genomic regions in the VHS cohort, thereby shedding light on their potential role in cardiovascular aging.

Keywords: Aging; Clonal hematopoiesis; Coronary artery disease; Somatic mutations.

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Conflict of interest statement

Declarations. Ethical approval: VHS complies with the Declaration of Helsinki and was approved by the ethics committee of the local institution (Azienda Ospedaliera Universitaria Integrata, Verona). A written informed consent was obtained from all the participants. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Graph of total number of variants (a) and gene-wise distribution (b) of putative somatic variants in the study population subdivided in CAD and CAD-FREE. Table in upper-right corner reports p values from Mann–Whitney U test
Fig. 2
Fig. 2
(a) Graph of distribution of putative somatic variants within four classes of functional impact on protein function in CAD and CAD-FREE with values in brackets reporting absolute number of variants, and (b) graph of distribution of disruptive variants in CAD and CAD-FREE
Fig. 3
Fig. 3
Prevalence of disruptive somatic variants (of high and moderate impact) in CAD and CAD-FREE groups considering the eight genes for which at least one alteration of high or moderate impact was observed among cases or controls. Significant p values (< 0.05) obtained from Fisher’s test are indicated with asterisk
See this image and copyright information in PMC

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