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克隆性造血与左心室射血分数降低的心力衰竭进展风险。

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

机构信息

Cardiology Department, Hospital Virgen de la Arrixaca, IMIB-Arrixaca and University of Murcia, Murcia, Spain; Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain.

Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, (CIBERCV), Madrid, Spain; Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

出版信息

J Am Coll Cardiol. 2021 Apr 13;77(14):1747-1759. doi: 10.1016/j.jacc.2021.02.028.

DOI:10.1016/j.jacc.2021.02.028

PMID:33832602

Abstract

BACKGROUND

Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.

OBJECTIVES

The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.

METHODS

The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.

RESULTS

CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.

CONCLUSIONS

Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.

摘要

背景

由造血细胞中的体细胞突变驱动的克隆性造血，通常称为不确定潜能的克隆性造血（CHIP），已在基于人群的研究和缺血性心力衰竭（HF）及左心室射血分数降低（LVEF）的患者中与不良心血管结局相关。然而，CHIP 对 HF 进展的影响，包括非缺血性病因，尚不清楚。

目的

本研究旨在评估克隆性造血对 HF 进展的临床影响，而不考虑其病因。

方法

研究队列包括 62 名 HF 和 LVEF<45%的患者（年龄 74±7 岁，74%为男性，52%为非缺血性，LVEF 为 30±8%）。使用深度测序在 54 个基因中检测 CHIP 突变，突变等位基因分数>2%。患者至少随访 3.5 年，以观察各种不良事件，包括死亡、HF 相关死亡和 HF 住院。

结果

24 名（38.7%）患者检测到 CHIP 突变，但全因死亡率无显著差异（p=0.151）。调整危险因素后，在 DNA 甲基转移酶 3α（DNMT3A）或 Tet 甲基胞嘧啶双加氧酶 2（TET2）中存在突变的患者，HF 进展方面的死亡率（危险比[HR]：2.79；95%置信区间[CI]：1.31 至 5.92；p=0.008）、死亡或 HF 住院（HR：3.84；95%CI：1.84 至 8.04；p<0.001）和 HF 相关死亡或 HF 住院（HR：4.41；95%CI：2.15 至 9.03；p<0.001）均加快。在单基因特异性分析中，DNMT3A 或 TET2 的体细胞突变与 HF 相关死亡或 HF 住院具有预后意义（HR：4.50；95%CI：2.07 至 9.74；p<0.001，DNMT3A 突变；HR：3.18；95%CI：1.52 至 6.66；p=0.002，TET2 突变）。这种相关性仍然显著，与缺血性/非缺血性病因无关。