秋水仙碱与克隆造血纵向动力学:LoDoCo2试验的探索性亚研究。

IF 22.3 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Niekbachsh Mohammadnia, Liying Xue, Lucas T W Vestjens, Md Mesbah Uddin, Abhishek Niroula, Dominique P V de Kleijn, Arend Mosterd, Aernoud T L Fiolet, Tetsushi Nakao, John W Eikelboom, Aysun Cetinyurek-Yavuz, Gina M Peloso, Willem A Bax, Niels P Riksen, Pradeep Natarajan, Jan H Cornel, Saloua El Messaoudi, Michael C Honigberg
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引用次数: 0

摘要

背景:克隆造血(CH)是一种与年龄相关的血液学疾病,与心血管事件的风险增加有关。较大的CH克隆与心血管风险的相关性更强。临床前数据表明,炎症信号驱动CH克隆和CH相关心血管疾病的扩张。然而,抗炎治疗对人类CH克隆动力学的影响尚不清楚。目的:测试随机分配秋水仙碱与安慰剂与慢性冠状动脉疾病参与者CH生长的关系,以及秋水仙碱使用与炎症生物标志物随时间变化的关系。方法:在低剂量秋水仙碱2 (LoDoCo2)试验的探索性亚研究中,使用高覆盖率靶向测序在四个时间点检测CH驱动突变并量化变异等位基因频率:基线,30天开放标签秋水仙碱运行期(每天0.5 mg)后,随机分配到秋水仙碱或安慰剂一年后,以及研究结束时(中位随访时间为25.0个月)。克隆动力学采用广义线性混合模型进行评估。另外在基线、随机化和随机化后一年测量白细胞介素-6 (IL-6)和高敏c反应蛋白。结果:总共有854名参与者在四个时间点提供了2047个观察结果,包括在预随机化秋水仙碱磨合期之前和之后。随机分配到安慰剂组与CH克隆大小每年增加14.9%相关(β时间=0.14 [95%CI 0.08至0.21]),而秋水仙碱组增加6.3%(秋水仙碱组β时间:0.06 [95%CI -0.01至0.14]),尽管治疗组之间的差异无统计学意义(p相互作用=0.13)。与安慰剂相比,秋水仙碱与TET2 CH克隆生长减弱相关(秋水仙碱的β时间:0.09 [95%CI -0.04至0.22];与安慰剂相比:β时间=0.27 [95%CI 0.16至0.37];p相互作用=0.04)。在非dnmt3a CH患者中,接受秋水仙碱组与安慰剂组相比,IL-6水平在一年内增加的程度较小(分别增加29.4%和97.3%;p相互作用=0.01)。结论:在这项探索性分析中,低剂量秋水仙碱治疗与TET2 CH克隆扩增减弱相关,这些发现表明秋水仙碱可能抑制关键CH驱动突变的增殖优势,并降低其相关的心血管疾病风险。有必要在前瞻性研究中进一步验证。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Colchicine and Longitudinal Dynamics of Clonal Hematopoiesis: An Exploratory Substudy of the LoDoCo2 Trial.

Background: Clonal hematopoiesis (CH) is an aging-related hematologic condition associated with increased risk for cardiovascular events. Larger CH clones associate more strongly with cardiovascular risk. Preclinical data indicate that inflammatory signaling drives expansion of CH clones and CH-associated cardiovascular disease. However, the effect of anti-inflammatory therapies on CH clonal dynamics in humans is unclear.

Objectives: The goal of this study was to test the association of randomization to colchicine vs placebo with CH growth in participants with chronic coronary artery disease. It also assessed the association of colchicine use with change in inflammatory biomarkers over time according to CH status.

Methods: In this exploratory substudy of the LoDoCo2 (Low-Dose Colchicine 2) trial, high-coverage targeted sequencing was used to detect CH driver mutations and to quantify variant allele frequency at 4 timepoints: baseline, after a 30-day open-label colchicine run-in phase (0.5 mg daily), 1 year postrandomization to colchicine or placebo, and at end of study (median follow-up of 25.0 months). Clonal dynamics were assessed by using a generalized linear mixed model. High-sensitivity C-reactive protein and interleukin-6 were additionally measured at baseline, randomization, and 1 year postrandomization.

Results: In total, 854 participants contributed 2,047 observations across 4 timepoints, including before and after the prerandomization colchicine run-in period. Randomization to placebo was associated with a 14.9% annual increase in CH clone size (βtime = 0.14; 95% CI: 0.08 to 0.21) vs a nonsignificant 6.3% increase with colchicine (βtime on colchicine: 0.06; 95% CI: -0.01 to 0.14), although this difference between treatment arms was not statistically significant (Pinteraction = 0.13). Compared with placebo, colchicine was associated with attenuated clonal growth in TET2 CH (βtime on colchicine: 0.09 [95% CI: -0.04 to 0.22]; βtime placebo: 0.27 [95% CI: 0.16 to 0.37]; Pinteraction= 0.04). Among individuals with non-DNMT3A CH, interleukin-6 levels increased to a lesser extent in those receiving colchicine vs placebo over 1 year (30.0% vs 98.1% increase, respectively; Pinteraction = 0.01).

Conclusions: In this exploratory analysis, treatment with low-dose colchicine was associated with attenuated clonal expansion in TET2 CH. These findings suggest the potential for colchicine to curb the proliferative advantage of key CH driver mutations and to mitigate their associated risk of cardiovascular disease. Further validation in prospective studies is warranted.

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来源期刊
CiteScore
42.70
自引率
3.30%
发文量
5097
审稿时长
2-4 weeks
期刊介绍: The Journal of the American College of Cardiology (JACC) publishes peer-reviewed articles highlighting all aspects of cardiovascular disease, including original clinical studies, experimental investigations with clear clinical relevance, state-of-the-art papers and viewpoints. Content Profile: -Original Investigations -JACC State-of-the-Art Reviews -JACC Review Topics of the Week -Guidelines & Clinical Documents -JACC Guideline Comparisons -JACC Scientific Expert Panels -Cardiovascular Medicine & Society -Editorial Comments (accompanying every Original Investigation) -Research Letters -Fellows-in-Training/Early Career Professional Pages -Editor’s Pages from the Editor-in-Chief or other invited thought leaders
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