Zeng Zhiwei, Li Fangzhou, Gai Shujie, Chen Runze, Wang Peng, Wang Juncheng, Yang Yuhui, Chen Jinhua, Zhang Xingyi, Wang Xueying, Han Yi, Lei Chuxiang, Li Xi, Liu Hanning, Zheng Zhe
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Road, Beijing, 100037, China.
Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
BMC Med. 2025 May 30;23(1):322. doi: 10.1186/s12916-025-04140-9.
BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), characterized by age-related somatic mutations in hematopoietic stem and progenitor cells, has been identified as a potential risk factor for cardiovascular events and mortality. However, the significance of CHIP in the context of coronary artery bypass grafting (CABG) remains unexplored. We aim to investigate the potential impact of CHIP on long-term outcomes of patients who underwent CABG. METHODS: We conducted a nested case-control study with 497 patients from the randomized Statin Therapy in Cardiac Surgery (STICS) cohort (ClinicalTrials.gov number NCT01573143). CHIP mutations were identified using ultra-deep sequencing of a targeted panel of 23 genes, with a mean depth of coverage of 16,043x. The relationship between CHIP and major adverse cardiovascular and cerebrovascular events (MACCE), including all-cause death, non-fatal ischemic stroke (IS), and non-fatal myocardial infarction (MI), was analyzed using Cox proportional hazards models and Fine-Gray regression to account for competing risks. We also validated our findings using data from the selected UK Biobank cohort of CABG to assess the generalizability. RESULTS: CHIP with a variant allele frequency (VAF) ≥ 2% was detected in 91 patients (18.3%), while CHIP with lower VAF (≥ 0.1%) was present in 46.3% of patients. DNMT3A and TET2 were the most frequently mutated genes. Over a median follow-up of 6.0 years (interquartile range [IQR], 3.5-6.5 years), CHIP (VAF ≥ 2%) was not significantly associated with MACCE (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 0.90-1.70) and non-fatal IS/MI (aHR: 0.96, 95% CI: 0.62-1.49) but was associated with an increased risk of all-cause death (aHR 1.73, 95% CI 1.08-2.78) and cardiovascular death (aHR 2.58, 95% CI 1.47-4.55) compared to their counterparts. However, CHIP with small clones (VAF 0.1%-2%) showed no significant association with any long-term outcomes. In the UK Biobank cohort of CABG, CHIP (VAF ≥ 2%) was also significantly associated with an increased risk of all-cause death (aHR: 2.00, 95% CI: 1.29-3.08) over a median follow-up of 11.1 years (IQR, 9.9-15.4 years). CONCLUSIONS: CHIP mutations are common in CABG patients and are associated with a higher risk of mortality, highlighting their potential role in long-term risk assessment and management.
背景：不确定潜能克隆造血（CHIP）以造血干细胞和祖细胞中与年龄相关的体细胞突变为特征，已被确定为心血管事件和死亡的潜在危险因素。然而，CHIP在冠状动脉旁路移植术（CABG）背景下的意义仍未得到探索。我们旨在研究CHIP对接受CABG患者长期预后的潜在影响。 方法：我们对来自心脏手术他汀类药物治疗随机试验（STICS）队列（ClinicalTrials.gov编号NCT01573143）的497例患者进行了巢式病例对照研究。使用对23个基因的靶向panel进行超深度测序来鉴定CHIP突变，平均覆盖深度为16,043倍。使用Cox比例风险模型和Fine-Gray回归分析CHIP与主要不良心血管和脑血管事件（MACCE）之间的关系，包括全因死亡、非致命性缺血性卒中（IS）和非致命性心肌梗死（MI），以考虑竞争风险。我们还使用来自选定的英国生物银行CABG队列的数据验证了我们的发现，以评估其普遍性。 结果：91例患者（18.3%）检测到变异等位基因频率（VAF）≥2%的CHIP，而VAF较低（≥0.1%）的CHIP存在于46.3%的患者中。DNMT3A和TET2是最常发生突变的基因。在中位随访6.0年（四分位间距[IQR]，3.5 - 6.5年）期间，CHIP（VAF≥2%）与MACCE（调整后风险比[aHR] 1.23，95%置信区间[CI] 0.90 - 1.70）和非致命性IS/MI（aHR：0.96，95% CI：0.62 - 1.49）无显著相关性，但与全因死亡风险增加（aHR 1.73，95% CI 1.08 - 2.78）和心血管死亡风险增加（aHR 2.58，95% CI 1.47 - 4.55）相关。然而，小克隆CHIP（VAF 0.1% - 2%）与任何长期预后均无显著相关性。在英国生物银行CABG队列中，在中位随访11.1年（IQR，9.9 - 15.4年）期间，CHIP（VAF≥2%）也与全因死亡风险增加显著相关（aHR：2.00，95% CI：1.29 - 3.08）。 结论：CHIP突变在CABG患者中很常见，并且与较高的死亡风险相关，突出了它们在长期风险评估和管理中的潜在作用。
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