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Review
. 2025 Jul 30;15(15):1915.
doi: 10.3390/diagnostics15151915.

Clonal Hematopoiesis of Intermediate Potential in Atrial Fibrillation: A Critical View of Current Knowledge as a Springboard for Future Research

Affiliations
Review

Clonal Hematopoiesis of Intermediate Potential in Atrial Fibrillation: A Critical View of Current Knowledge as a Springboard for Future Research

Elena Chatzikalil et al. Diagnostics (Basel). .

Abstract

Clonal hematopoiesis of intermediate potential (CHIP) is the presence of a clonally expanded hematopoietic stem cell because of a mutation in individuals without evidence of hematologic malignancy, dysplasia, or cytopenia. Interestingly, CHIP is associated with a two-fold increase in cardiovascular risk, independently of traditional risk factors. Recent studies using deep-targeted sequencing have revealed that CHIP mutations, primarily TET2 and DNMT3A, present a higher incidence in patients with AF compared to healthy controls. Moreover, the presence of the aforementioned mutations is positively correlated with the progression and the severity of the AF clinical course. Regarding the predisposition of AF, it has been proven that TET2 and ASXL1 mutations, and not DNMT3A mutation, are associated with higher interleukin-6 (IL-6) levels. IL-6 levels, being indices of cardiac remodeling, predispose to an elevated risk for AF in healthy subjects. Currently conducted research has focused on elaborating the mechanisms driving the association between AF and CHIP and on the evaluation of potential interventions to reduce the risk of AF development. The aims of our review are (i) to summarize published evidence regarding the presence of CHIP mutations as a contributor to AF severity and predisposition, and (ii) to highlight the potential benefits of investigating the correlations between CHIP and AF for AF-diagnosed patients.

Keywords: CHIP; DNMT3A mutation; TET2 mutation; atrial fibrillation; cardiovascular remodeling.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pathophysiologic interconnections between CHIP and AF. The accumulation of age-related somatic mutations leads to the formation of clonal populations that lead to CHIP in the peripheral blood. Mutated hematopoietic cells infiltrate the bloodstream and myocardium, promoting atherosclerosis and adversely affecting cardiac function via several pathogenetic mechanisms, including atrial fibrosis, inflammation, and elevated red cell distribution width, resulting in structural and electrical remodeling of the heart. A pivotal mechanism interconnecting CHIP and AF is an inflammasome-mediated response, particularly through the interleukin-1/interleukin-6 signaling axis, which also causes abnormal calcium release, further enhancing electrical remodeling. The above mechanisms combined create a vicious cycle that promotes clonal expansion and the progression of AF. [AF: atrial fibrillation; AIM2: inflammation related gene absent in melanoma 2; CA: calcium; CA phosphorylation: CA-mediated phosphorylation; CHIP: clonal hematopoiesis of indeterminate potential; HSC: hematopoietic stem cells; IL-1: interleukin-1; IL-6: interleukin-6; IL-8: interleukin-8; VAF: variant allele frequency] (Figure created by Biorender software version 4.0, Toronto, Canada, publication license: # KV28DAWCU5).
Figure 2
Figure 2
Illustration of shared risk factors (age, lifestyle factors, and cardiometabolic factors) and pathophysiological links between CHIP and AF, along with the identified CHIP mutations playing a role in AF pathogenesis. [CHIP: clonal hematopoiesis of intermediate potential, HSC: hematopoietic stem cell] (Figure created by Biorender software version 4.0., Toronto, Canada, publication license: # U28DA6J3E).

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