意义不明的克隆性造血对老年射血分数降低心力衰竭患者预后的影响

Effect of clonal hematopoiesis with indeterminant potential on the prognosis of elderly patients with heart failure with reduced ejection fraction

目的探讨意义不明的克隆性造血(CHIP)对老年射血分数降低心力衰竭(HFrEF)患者随访发生不良心脑血管事件(MACCE)的影响。方法前瞻性队列研究。连续选取2020年1月至2022年1月北京安贞医院收治的老年HFrEF患者145例,根据全基因组序列的CHIP状态分组,分为CHIP组[变异等位基因频率(VAF)≥2%,48例]和非CHIP组(VAF<2%,97例)。随访截至2023年1月31日,主要观察终点是MACCE,为死亡、HF加重再入院、非致死性心肌梗死和非致死性卒中的复合结局。结果145例老年HFrEF患者,年龄65~90岁,平均为(78.1±10.4)岁。48例(33.1%)合并有CHIP,最常见突变是DNMT3A或TET2基因,分别占所有突变的47.9%(23/48)和37.5%(18/48)。与非CHIP患者相比,CHIP组患者年龄更大,血肌酐、N末端B型利钠肽前体(NT-proBNP)和白介素6(IL-6)水平更高(均为P<0.05)。中位随访16个月(12~33个月)期间,51例患者(35.2%)发生MACCE,包括6例(4.1%)死亡、22例(15.2%)因HF加重入院、13例(9.0%)心肌梗死和10例(6.9%)卒中。与非CHIP组比较,CHIP组的因HF加重入院(HR=1.768,95%CI:1.073~2.837,P=0.025)、心肌梗死(HR=1.551,95%CI:1.049~2.236,P=0.042)、卒中(HR=1.538,95%CI:1.082~2.439,P=0.035)和MACCE事件(HR=1.737,95%CI:1.052~2493,P=0.032)均显著增高。Cox多因素回归分析显示,校正相关因素后,CHIP仍与MACCE显著正相关(HR=1.737)。此外,年龄(HR=1.642)、HF病程(HR=1.869)、IL-6(HR=1.756)、NT-proBNP(HR=2.211)和血肌酐水平(HR=1.528)均是发生MACCE的独立影响因素。受试者工作特征曲线结果显示,与加入CHIP前比较,加入CHIP后,模型预测MACCE的准确性明显提高(P=0.038)。结论CHIP在老年HFrEF患者很常见,与临床预后不佳有关。CHIP可成为老年HFrEF患者的新风险因素,有助于预后的进一步风险分层。

Objective To evaluate the effect of clonal hematopoiesis with indeterminant potential(CHIP)on major adverse cardiac and cerebrovascular events(MACCE)in elderly patients with heart failure with reduced ejection fraction(HFrEF).Methods This was a prospective cohort study.A total of 145 elderly HFrEF patients who were admitted to Beijing Anzhen Hospital from January 2020 to January 2022 were selected consecutively.According to the CHIP status of the whole genome sequence,all were divided into the CHIP group[48 cases,variant allele frequency(VAF)≥2%]and the non-CHIP group(97 cases,VAF<2%).The deadline for follow-up was January 31,2023,and the primary endpoint was MACCE,which was a composite outcome of death,readmission for heart failure exacerbation,non-fatal myocardial infarction and non-fatal stroke.Results A total of 145 elderly patients with HFrEF were included,with an average age of(78.1±10.4)years.48 cases(33.1%)had CHIP,and the most common mutations sites were the DNMT3A or TET2 genes,accounting for 47.9%(23/48)and 37.5%(18/48),respectively.Compared with non-CHIP patients,CHIP patients were older,had higher levels of serum creatinine,N-terminal pro-B-type natriuretic peptide(NT-proBNP)and interleukin 6(IL-6)(all P<0.05).During a median follow-up of 16 months(12-33 months),51 patients(35.2%)had MACCE,including 6 died(4.1%),22 cases(15.2%)of readmission for heart failure exacerbation,13 cases(9.0%)of myocardial infarction and 10 cases(6.9%)of stroke.Compared with the non-CHIP group,the CHIP group was associated with significantly increased risk of readmission for heart failure exacerbation(HR=1.768,95%CI:1.073-2.837,P=0.025),myocardial infarction(HR=1.551,95%CI:1.049-2.236,P=0.042),stroke(HR=1.538,95%CI:1.082-2.439,P=0.035)and MACCE(HR=1.737,95%CI:1.052-2493,P=0.032).Multivariate Cox regression analyses detected that after adjusting for related factors,CHIP remained significantly positively correlated with MACCE(HR=1.737).In addition,age(HR=1.642),heart failure duration(HR=1.869),levels of IL-6(HR=1.756),NT-proBNP(HR=2.211),and serum creatinine(HR=1.528)were all independent factors for the MACCE.The results of receiver operating characteristic curve showed a markedly higher accuracy of adding CHIP model’s prediction for MACCE than without CHIP(P=0.038).Conclusions CHIP is common in aged patients with HFrEF and is associated with a poor clinical prognosis.It’s evaluation may be helpful for further risk stratification of prognosis.