Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jun 1;9(6):497-506.
doi: 10.1001/jamacardio.2024.0459.

Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

Seyedmohammad Saadatagah  1   2 , Mohammadreza Naderian  3 , Mesbah Uddin  4 , Ozan Dikilitas  3   5 , Abhishek Niroula  5   6   7   8 , Art Schuermans  4   5   9 , Elizabeth Selvin  10 , Ron C Hoogeveen  1 , Kunihiro Matsushita  10 , Vijay Nambi  1   11 , Bing Yu  12 , Lin Yee Chen  13 , Alexander G Bick  14 , Benjamin L Ebert  5   8   15   16   17 , Michael C Honigberg  4   5   17 , Na Li  1 , Amil Shah  18 , Pradeep Natarajan  4   5   17 , Iftikhar J Kullo  3   19 , Christie M Ballantyne  1
Affiliations

Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

Seyedmohammad Saadatagah et al. JAMA Cardiol. .

Abstract

Importance: Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling.

Objective: To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes.

Design, setting, and participants: This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023.

Exposures: CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices.

Main outcome measure: Incident AF.

Results: A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index.

Conclusions and relevance: Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Selvin reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Hoogeveen reported receiving grants and consultant fees from Denka Seiken outside the submitted work. Dr Matsushita reported receiving grants from the National Institutes of Health during the conduct of the study and personal fees from Fukuda Denshi, AMGA, and Kowa Company outside the submitted work. Dr Nambi reported receiving grant support from the National Institutes of Health, stock options from Insera, and serving as site principal investigator for Roche outside the submitted work. Dr Bick reported receiving personal fees from TenSixteen Bio outside the submitted work. Dr Ebert reported receiving grants from Novartis and Calico and personal fees from Neomorph Inc, TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics outside the submitted work. Dr Honigberg reported receiving grants from the National Heart, Lung, and Blood Institute, the American Heart Association, and Genentech; advisory board fees from Miga Health; and personal fees from CRISPR Therapeutics and Comanche Biopharma outside the submitted work. Dr Shah reported receiving research support from Novartis and advisory board fees from Philips Ultrasound and Janssen outside the submitted work. Dr Natarajan reported receiving grants from Allelica, Amgen, Apple, Boston Scientific, Genentech/Roche, and Novartis; personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Creative Education Concepts, CRISPR Therapeutics, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, Merck, and Novartis; advisory board fees from Esperion Therapeutics, Preciseli, and TenSixteen Bio; and equity from MyOme, Preciseli, and TenSixteen Bio outside the submitted work. Dr Ballantyne reported receiving grants from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Esperion, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Regeneron, and Roche Diagnostic and consulting/personal fees from Abbott Diagnostics, Alnylam Pharmaceuticals, Althera, Amarin, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Gilead, Illumina, Ionis, Matinas BioPharma Inc, Merck, New Amsterdam, Novartis, Novo Nordisk, Pfizer, Regeneron, Roche Diagnostic, and TenSixteen Bio outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Plots for Atrial Fibrillation (AF)–Free Survival Based on Clonal Hematopoiesis of Indeterminate Potential (CHIP) Status and Driver Variant
Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) data are depicted. A and B, AF-free survival based on CHIP status is depicted comparing individuals without CHIP, those with small CHIP, and those with large CHIP. C and D, AF-free survival based on the driver gene is depicted comparing individuals without CHIP, those with a DNMT3A gene variation, those with a TET2 gene variation, and those with an ASXL1 gene variation.
Figure 2.
Figure 2.. Association of Clonal Hematopoiesis of Indeterminate Potential (CHIP) Status and Incident Atrial Fibrillation (AF) in the Atherosclerosis Risk in Communities (ARIC) Study, UK Biobank (UKB), and Pooled Analysis
Data are presented as hazard ratio (HR) and 95% CI. The model adjusted for age, sex, race in ARIC and ancestry in UKB, hypertension, diabetes, estimated glomerular filtration rate, smoking status, alcohol use, body mass index, coronary heart disease, and heart failure. ARIC data were also adjusted for field center.
Figure 3.
Figure 3.. Association of Clonal Hematopoiesis of Indeterminate Potential (CHIP) With Inflammatory Marker Levels, Cardiac Biomarker Levels, and Echocardiographic Measures
Quantile regression models adjusted for age, sex, race in ARIC and ancestry in UKB, hypertension, diabetes, estimated glomerular filtration rate, smoking status, alcohol use, body mass index, coronary heart disease, and heart failure. Coefficients represent the alteration in the median of the standardized natural log–transformed value of the biomarker based on CHIP status. Standardized natural log–transformed values were used for all markers. EDVi indicates left ventricular end-diastolic volume index; ESVi, left ventricular end-systolic volume index; hs-TnI, high-sensitivity troponin I; hs-TnT, high-sensitivity troponin T; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IL-18, interleukin 18; LADi, left atrial diameter index; LVEF, left ventricular ejection fraction; LVMi, left ventricular mass index; NT-proBNP, N-terminal pro–B-type natriuretic peptide. aIndicates statistical significance in multiple comparisons.
Figure 4.
Figure 4.. Rate of Incident Atrial Fibrillation (AF) Based on TET2/ASXL1 Status and Inflammatory Marker Levels, Cardiac Biomarker Levels, and Echocardiographic Measures
Individuals were categorized into 4 groups defined by clonal hematopoiesis of indeterminate potential (CHIP) status (no CHIP or large TET2/ASXL1 CHIP) and parameters below or above the median (low or high). EDVi indicates left ventricular end-diastolic volume index; ESVi, left ventricular end-systolic volume index; hs-CRP, high-sensitivity C-reactive protein; hs-TnI, high-sensitivity troponin I; hs-TnT, high-sensitivity troponin T; IL-6, interleukin-6; IL-18, interleukin-18; LADi, left atrial diameter index; LVEF, left ventricular ejection fraction; LVMi, left ventricular mass index; NT-proBNP, N-terminal pro–B-type natriuretic peptide.
See this image and copyright information in PMC

References

    1. Roth GA, Mensah GA, Johnson CO, et al. ; GBD-NHLBI-JACC Global Burden of Cardiovascular Diseases Writing Group . Global burden of cardiovascular diseases and risk factors, 1990-2019: update from the GBD 2019 Study. J Am Coll Cardiol. 2020;76(25):2982-3021. doi:10.1016/j.jacc.2020.11.010 - DOI - PMC - PubMed
    1. Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol. 2008;1(1):62-73. doi:10.1161/CIRCEP.107.754564 - DOI - PubMed
    1. Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. 2014;19(5):681-694. doi:10.1007/s10741-013-9405-8 - DOI - PubMed
    1. Mesquita T, Lin YN, Ibrahim A. Chronic low-grade inflammation in heart failure with preserved ejection fraction. Aging Cell. 2021;20(9):e13453. doi:10.1111/acel.13453 - DOI - PMC - PubMed
    1. Scott L Jr, Li N, Dobrev D. Role of inflammatory signaling in atrial fibrillation. Int J Cardiol. 2019;287:195-200. doi:10.1016/j.ijcard.2018.10.020 - DOI - PMC - PubMed

MeSH terms