Clonal Hematopoiesis of Indeterminate Potential With Loss of
Tet2
Enhances Risk for Atrial Fibrillation Through
Nlrp3
Inflammasome Activation
Authors: Lin Amy Erica , Bapat Aneesh C. , Xiao Ling , Niroula Abhishek , Ye Jiangchuan , Wong Waihay J. , Agrawal Mridul , Farady Christopher J. , Boettcher Andreas , Hergott Christopher B. , McConkey Marie , Flores-Bringas Patricio , Shkolnik Veronica , Bick Alexander G. , Milan David , Natarajan Pradeep , Libby Peter , Ellinor Patrick T. , Ebert Benjamin L. 
Published: February 2024

BACKGROUND:
Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored.

METHODS:

CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of
Tet2
, hematopoietic-specific loss of
Tet2
and
Nlrp3
, or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from
Ldlr
−/−
mice with hematopoietic-specific loss of
Tet2
or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell–derived atrial cardiomyocytes were incubated with
Tet2
-deficient bone marrow–derived macrophages, wild-type control, or cytokines IL-1β (interleukin 1β) or IL-6 (interleukin 6).

RESULTS:

Analysis of the UK Biobank showed individuals with CHIP, in particular
TET2
CHIP, have increased incident AF. Hematopoietic-specific inactivation of
Tet2
increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of
Nlrp3
. Cardiomyocytes isolated from
Ldlr
−/−
mice with hematopoietic inactivation of
Tet2
and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atrial arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of
Tet2
-deficient macrophages or cytokines IL-1β or IL-6.

CONCLUSIONS:

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. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with
TET2
CHIP may be warranted.