Arrhythmias & electrophysiology
Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation
Authors' conclusion
We identified a modest association between CHIP, particularly TET2 CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of Tet2, we propose altered calcium handling as an arrhythmogenic mechanism, dependent on Nlrp3 inflammasome activation.
Study context
- Population
- UK Biobank individuals; mouse models of hematopoietic Tet2 loss
- Comparison
- Clonal hematopoiesis of indeterminate potential (CHIP) vs no CHIP; hematopoietic Tet2 loss vs wild-type
- Outcome
- Incident AF by CHIP status and clone size; AF propensity in mice
Methodological detailsUK Biobank cohort analysis, mouse bone marrow transplantation models, in vitro coculture
- UK Biobank cohort analysis
- Mouse bone marrow transplantation models
- In vitro coculture
Main finding
As reported in the abstract
- Individuals with CHIP, in particular TET2 CHIP, have increased incident atrial fibrillation (AF)
- Hematopoietic Tet2 inactivation increases AF propensity in atherogenic and nonatherogenic mouse models, with increased Nlrp3 expression and CaMKII activation
- AF susceptibility prevented by inactivation of Nlrp3
- Cardiomyocytes from Ldlr-/- mice with hematopoietic Tet2 inactivation on Western diet have impaired sarcoplasmic reticulum calcium release, contributing to atrial arrhythmogenesis
- Abnormal SR calcium release recapitulated in cardiomyocyte cocultures with Tet2-deficient macrophages or IL-1β or IL-6
Original publication
Clonal Hematopoiesis of Indeterminate Potential With Loss of Tet2 Enhances Risk for Atrial Fibrillation Through Nlrp3 Inflammasome Activation. Circulation. Published 15 February 2024. doi:10.
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