Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias

Abstract

Background and aims: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.

Methods: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested.

Results: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR.

Conclusions: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Keywords: Aging; Arrhythmia; Atrial fibrillation; Cardiac arrest; Genomics; Prevention.

Structured Graphical Abstract

In 410 702 middle-aged adults from the UK Biobank, clonal haematopoiesis of indeterminate potential (CHIP) was associated with incident arrhythmias independent of other cardiovascular diseases such as coronary artery disease and heart failure, with the strongest associations observed for cardiac arrest. Gene-stratified analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. CI, confidence interval; HR, hazard ratio.

Figure 1

Cumulative incidence of (A) supraventricular arrhythmias, (B) bradyarrhythmias, and (C) ventricular arrhythmias during follow-up. Cumulative incidence functions were constructed using models accounting for all-cause mortality as a competing risk and represent the cumulative incidence of the co-primary study outcomes (i.e. supraventricular arrhythmia, bradyarrhythmia, and ventricular arrhythmia) during a median follow-up of 11.1 (IQR, 10.4–11.8) years. Follow-up was truncated at 12.5 years. CHIP indicates clonal haematopoiesis of indeterminate potential; VAF, variant allele frequency

Figure 2

Cumulative incidence of (A) any arrhythmia, (B) atrial fibrillation, and (C) cardiac arrest during follow-up. Cumulative incidence functions were constructed using models accounting for all-cause mortality as a competing risk and represent the cumulative incidence of secondary study outcomes (i.e. any arrhythmia, atrial fibrillation, and cardiac arrest) during a median follow-up of 11.1 (IQR, 10.4–11.8) years. Follow-up was truncated at 12.5 years. CHIP indicates clonal haematopoiesis of indeterminate potential; VAF, variant allele frequency

Figure 3

Multivariable-adjusted associations of CHIP and gene-specific CHIP subtypes with myocardial fibrosis. All models represent logistic regression models in which participants without CHIP (n = 33 671) constitute the reference group, adjusted for age, age², sex, age × sex, time between blood draw and imaging visit, genetic ancestry, smoking status, BMI, systolic blood pressure, antihypertensive medication use, alcohol intake frequency, history of any cancer, type 2 diabetes mellitus, and coronary artery disease at baseline. Myocardial fibrosis was evaluated using rank-based inverse-normal-transformed T1 times, modelled as a binary variable in which the top 20th percentile of T1 time serves as the outcome of interest (i.e. ‘1’). CHIP indicates clonal haematopoiesis of indeterminate potential; CI, confidence interval; OR, odds ratio; VAF, variant allele frequency

Figure 4

(A) Cumulative incidence of incident arrhythmias across CHRS categories and (B) multi-variable-adjusted associations of CHRS categories with incident arrhythmias. (A) Cumulative incidence functions were constructed using models accounting for all-cause mortality as a competing risk and represent the cumulative incidence of the co-primary study outcomes (i.e. supraventricular arrhythmia, bradyarrhythmia, and ventricular arrhythmia) during a median follow-up of 11.1 (IQR, 10.4–11.8) years. Follow-up for cumulative incidence functions was truncated at 12.5 years. (B) Forest plots represent Cox regression models in which participants without CHIP (n = 396 810) constitute the reference group, adjusted for age, age², sex, genetic ancestry, smoking status, BMI, systolic blood pressure, antihypertensive medication use, alcohol intake frequency, history of any cancer, type 2 diabetes mellitus, and coronary artery disease. CHIP indicates clonal haematopoiesis of indeterminate potential; CHRS, clonal haematopoiesis risk score; CI, confidence interval; HR, hazard ratio; VAF, variant allele frequency