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Clonal Hematopoiesis and Risk of New-Onset Myocarditis and Pericarditis

Art Schuermans^1,2,3,4, Spencer Flynn^1,2,5,4, Abhishek Niroula^1,6,7

¹Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

JAMA Cardiology

|August 30, 2025

Insights

Clonal hematopoiesis of indeterminate potential (CHIP) significantly increases the risk of developing myocarditis and pericarditis. Early detection and targeting CHIP pathways may offer new prevention strategies for these heart conditions.

Area of Science:

Cardiovascular Medicine
Hematology
Genetics

Background:

Clonal hematopoiesis of indeterminate potential (CHIP) involves age-related expansion of hematopoietic stem cells with mutations.
Certain CHIP mutations are linked to cardiovascular diseases like atherosclerosis and heart failure via immune pathways.

Purpose of the Study:

To investigate the association between CHIP and the development of myocarditis and pericarditis.
To determine if CHIP is a risk factor for these specific inflammatory heart conditions.

Main Methods:

An observational, population-based cohort study using UK Biobank data from 2006-2010.
Included participants with whole-exome sequencing, excluding those with pre-existing cardiovascular disease or malignancy.
Utilized Cox regression to analyze associations between CHIP (any and large) and incident myocarditis/pericarditis over a median 13.6-year follow-up.

Main Results:

CHIP was associated with a significantly increased risk of myocarditis and pericarditis (HR 1.75 for any CHIP, HR 2.07 for large CHIP).
Specific mutations like DNMT3A and TET2 showed increased risks for pericarditis and myocarditis, respectively.
CHIP demonstrated a stronger association with myocarditis/pericarditis than with other cardiovascular diseases and was linked to noncardiac immune-mediated inflammatory diseases.

Conclusions:

CHIP is identified as a significant risk factor for myocarditis and pericarditis in middle-aged adults.
Targeting CHIP and its associated pathways presents a potential strategy for preventing or treating these inflammatory heart conditions.

Read full analysis

Abstract

Importance:

Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of hematopoietic stem cells with leukemia-associated mutations. Certain CHIP mutations promote atherosclerosis and heart failure through immune-related pathways.

Objective:

To test whether CHIP is associated with the development of myocarditis and pericarditis.

Design, Setting, And Participants:

This observational population-based cohort study used data from the UK Biobank. Enrollment occurred between 2006 and 2010. Participants with whole-exome sequencing, no prevalent cardiovascular disease or hematological malignancy, and complete covariate data were included. Follow-up occurred for a median of 13.6 (IQR, 12.8-14.2) years. Analyses were conducted from November 2024 to July 2025.

Exposures:

Any CHIP (variant allele frequency [VAF] ≥2%) and large CHIP (VAF ≥10%) constituted coprimary study exposures. Secondary analyses considered DNMT3A and TET2 CHIP as separate exposures.

Main Outcomes And Measures:

The primary outcome was a composite of incident myocarditis and pericarditis. Cox regression tested associations of CHIP with myocarditis and pericarditis, adjusting for age, sex, race and ancestry, and cardiovascular risk factors. Secondary analyses considered myocarditis and pericarditis as separate outcomes. Additional analyses compared associations of CHIP with myocarditis and pericarditis with those with other cardiovascular diseases, and tested the bidirectional associations between CHIP and noncardiac immune-mediated inflammatory diseases.

Results:

Among 335 426 participants (mean age, 56.1 years; 185 429 female [55.3%] and 149 997 male [44.7%]), 11 057 had any CHIP (3.3%), 7271 had large CHIP (2.2%), and 382 developed myocarditis or pericarditis (0.11%). Any and large CHIP were associated with multivariable-adjusted hazard ratios of 1.75 (95% CI, 1.14-2.68; P = .01) and 2.07 (95% CI, 1.28-3.33; P = .003), respectively, for the primary composite outcome of incident myocarditis and pericarditis. Increased risks were observed for DNMT3A and TET2 CHIP, with hazard ratios of 2.22 (95% CI, 1.17-4.21; P = .01) for DNMT3A with pericarditis and 3.65 (95% CI, 1.16-11.49; P = .03) for TET2 with myocarditis. CHIP associated with myocarditis and pericarditis more strongly than with other cardiovascular diseases (eg, coronary artery disease and heart failure). Any CHIP was also associated with 1.27-fold risk (95% CI, 1.16-1.39; P < .001) of developing noncardiac immune-mediated inflammatory diseases, without evidence for reverse causation.

Conclusions And Relevance:

In this study, CHIP was a strong risk factor for myocarditis and pericarditis among middle-aged adults. Targeting CHIP and its downstream pathways may represent a strategy for preventing or treating pericarditis and myocarditis.

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