Clonal hematopoiesis of indeterminate potential predicts new-onset myocarditis and pericarditis

Introduction Clonal hematopoiesis of indeterminate potential (CHIP) is the age-related clonal expansion of blood stem cells with leukemia-associated mutations. Mounting evidence suggests that certain CHIP variants contribute to atherosclerosis and heart failure through proinflammatory and immune-related pathways; however, CHIP’s role in immune-mediated cardiac conditions, including myocarditis and pericarditis, remains unclear. Purpose To test the associations of CHIP and gene-specific CHIP subtypes with new-onset myocarditis and pericarditis. Methods This study included UK Biobank participants with whole exome sequencing data and no history of cardiovascular disease at baseline. The primary study outcome was a composite of myocarditis and pericarditis ascertained through linkage to inpatient health records. Secondary analyses tested myocarditis and pericarditis as separate outcomes. Associations of any CHIP (variant allele fraction [VAF] ≥ 2%), large CHIP (VAF ≥10%), and the most common gene-specific CHIP subtypes (CHIP driven by mutations in DNMT3A or TET2) with incident myocarditis and pericarditis were evaluated using unadjusted cumulative incidence plots and multivariable-adjusted Cox regression models. Results This study included 335,907 participants with whole exome sequencing and no cardiovascular disease at baseline (mean age, 56.1 [SD, 8.1] years; female: n=185,811 [55.3%]), of whom 11,195 (3.3%) were CHIP carriers. Incident myocarditis and pericarditis events occurred in 155 (0.05%) and 182 (0.05%) participants, respectively, over a mean follow-up period of 13.6 (SD, 0.8) years. Unadjusted analyses revealed a higher incidence of the primary composite outcome of myocarditis and pericarditis, as well as these outcomes separately, in CHIP carriers versus non-carriers (Figure 1). The presence of CHIP was associated with a multivariable-adjusted hazard ratio of 1.67 (95% CI, 1.06-2.63; P=2.8×10-2) for the primary composite outcome, with a similar magnitude of effect observed for myocarditis and pericarditis separately. Excess risk was even more pronounced among individuals carrying large CHIP clones, those with DNMT3A mutations, and those with TET2 mutations, who had a two- to three-fold higher risk of myocarditis and pericarditis compared to non-carriers (adjusted hazard ratios: 1.99 [95% CI, 1.20-3.30], P=7.7×10-3 for large CHIP; 2.07 [95% CI, 1.23-3.49], P=6.1×10-3 for DNMT3A mutations; and 3.36 [95% CI, 1.49-7.57], P=3.4×10-3 for TET2 mutations) (Figure 2). Conclusions CHIP represents a strong risk factor for the development of myocarditis and pericarditis among midlife adults. Future work should evaluate the actionability of CHIP-related pathways to prevent and treat these immune-mediated cardiac conditions.