Background and Aims Both clonal haematopoiesis of indeterminate potential (CHIP) and atrial fibrillation (AF) are age-related conditions. This study investigated the potential role of CHIP in the development and progression of AF. Methods Deep-targeted sequencing of 24 CHIP mutations (a mean depth of coverage = 1000×) was performed in 1004 patients with AF and 3341 non-AF healthy subjects. Variant allele fraction ≥ 2.0% indicated the presence of CHIP mutations. The association between CHIP and AF was evaluated by the comparison of (i) the prevalence of CHIP mutations between AF and non-AF subjects and (ii) clinical characteristics discriminated by CHIP mutations within AF patients. Furthermore, the risk of clinical outcomes—the composite of heart failure, ischaemic stroke, or death—according to the presence of CHIP mutations in AF was investigated from the UK Biobank cohort. Results The mean age was 67.6 ± 6.9 vs. 58.5 ± 6.5 years in AF (paroxysmal, 39.0%; persistent, 61.0%) and non-AF cohorts, respectively. CHIP mutations with a variant allele fraction of ≥2.0% were found in 237 (23.6%) AF patients (DNMT3A, 13.5%; TET2, 6.6%; and ASXL1, 1.5%) and were more prevalent than non-AF subjects [356 (10.7%); P < .001] across the age. After multivariable adjustment (age, sex, smoking, body mass index, diabetes, and hypertension), CHIP mutations were 1.4-fold higher in AF [adjusted odds ratio (OR) 1.38; 95% confidence interval 1.10–1.74, P < .01]. The ORs of CHIP mutations were the highest in the long-standing persistent AF (adjusted OR 1.50; 95% confidence interval 1.14–1.99, P = .004) followed by persistent (adjusted OR 1.44) and paroxysmal (adjusted OR 1.33) AF. In gene-specific analyses, TET2 somatic mutation presented the highest association with AF (adjusted OR 1.65; 95% confidence interval 1.05–2.60, P = .030). AF patients with CHIP mutations were older and had a higher prevalence of diabetes, a longer AF duration, a higher E/E′, and a more severely enlarged left atrium than those without CHIP mutations (all P < .05). In UK Biobank analysis of 21 286 AF subjects (1297 with CHIP and 19 989 without CHIP), the CHIP mutation in AF is associated with a 1.32-fold higher risk of a composite clinical event (heart failure, ischaemic stroke, or death). Conclusions CHIP mutations, primarily DNMT3A or TET2, are more prevalent in patients with AF than non-AF subjects whilst their presence is associated with a more progressive nature of AF and unfavourable clinical outcomes.

中文翻译：

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不确定电位的克隆造血与心房颤动：一项东亚队列研究

背景和目的 不确定潜能克隆造血 (CHIP) 和心房颤动 (AF) 都是与年龄相关的疾病。本研究调查了 CHIP 在 AF 发生和进展中的潜在作用。方法 对 1004 名 AF 患者和 3341 名非 AF 健康受试者进行 24 个 CHIP 突变的深度靶向测序（平均覆盖深度 = 1000×）。变异等位基因分数≥2.0%表明存在CHIP突变。通过比较 (i) AF 和非 AF 受试者之间 CHIP 突变的患病率和 (ii) AF 患者中 CHIP 突变区分的临床特征来评估 CHIP 和 AF 之间的关联。此外，英国生物银行队列研究了根据 AF 中 CHIP 突变的存在而产生的临床结果风险（心力衰竭、缺血性中风或死亡的综合风险）。结果 AF 队列（阵发性，39.0%；持续性，61.0%）和非 AF 队列的平均年龄分别为 67.6 ± 6.9 岁和 58.5 ± 6.5 岁。在 237 名 (23.6%) AF 患者中发现了变异等位基因分数≥2.0% 的 CHIP 突变（DNMT3A，13.5%；TET2，6.6%；ASXL1，1.5%），并且比非 AF 受试者更普遍[356（ 10.7%）；P＜.001]跨越时代。经过多变量调整（年龄、性别、吸烟、体重指数、糖尿病和高血压）后，AF 中的 CHIP 突变高出 1.4 倍 [调整后的优势比 (OR) 1.38；调整后的比值比 (OR) 1.38；95% 置信区间 1.10–1.74，P < .01]。CHIP 突变的 OR 在长期持续性 AF 中最高（调整后 OR 1.50；95% 置信区间 1.14–1.99，P = 0.004），其次是持续性（调整后 OR 1.44）和阵发性（调整后 OR 1.33）AF。在基因特异性分析中，TET2 体细胞突变与 AF 的关联性最高（调整后 OR 1.65；95% 置信区间 1.05–2.60，P = .030）。与无 CHIP 突变的 AF 患者相比，携带 CHIP 突变的 AF 患者年龄较大，糖尿病患病率较高，AF 持续时间较长，E/E' 较高，左心房扩大更严重（所有 P < .05）。在英国生物银行对 21 286 名 AF 受试者（1297 名患有 CHIP 和 19 989 名未患有 CHIP）的分析中，AF 中的 CHIP 突变与复合临床事件（心力衰竭、缺血性中风或死亡）的风险增加 1.32 倍相关。结论 CHIP 突变（主要是 DNMT3A 或 TET2）在 AF 患者中比非 AF 受试者更常见，同时它们的存在与 AF 的进展性和不利的临床结果相关。