Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis.

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-09-11 DOI:10.1186/s13148-023-01561-2
Leon Kanwischer, Xingbo Xu, Afifa Binta Saifuddin, Sabine Maamari, Xiaoying Tan, Fouzi Alnour, Björn Tampe, Thomas Meyer, Michael Zeisberg, Gerd Hasenfuss, Miriam Puls, Elisabeth M Zeisberg
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Abstract

Background: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI.

Results: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa.

Conclusions: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring.

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严重主动脉狭窄患者经导管主动脉瓣植入术后,循环甲基化IRX3水平低与预后较差有关。
背景:主动脉狭窄(AS)是最常见的心脏病之一,也是老年人发病和死亡的主要原因。经导管主动脉瓣植入术(TAVI)适用于有症状的严重AS患者,可降低大多数患者的死亡率。然而,很大一部分人在TAVI后的头两年内死亡,因此有兴趣确定预测结果并指导TAVI前患者选择的参数。高水平的心脏纤维化已被确定为TAVI后心血管死亡率的独立预测因素。启动子超甲基化通常导致基因下调,易洛魁人同源框3(IRX3)基因在全基因组转录组和甲基组中被鉴定为在AS患者中超甲基化和下调。在一个由100名TAVI患者组成的队列中,心脏纤维化水平在心脏活检中进行了组织学量化,并进行了长达两年的随访,我们研究了外周血中IRX3的循环甲基化DNA是否与接受TAVI的AS患者的心脏纤维化和/或死亡率相关,从而可以作为一种生物标志物来增加TAVI后的结果信息。结果:与低水平IRX3的患者相比,循环IRX3中甲基化水平高的患者显示出显著提高的生存率甲基化表明高外周IRX3甲基化与改善的结果相关。在多变量环境中,外周IRX3甲基化是全因死亡率的独立预测因子。虽然IRX3甲基化水平与心脏死亡没有显著相关性,但循环IRX3启动子甲基化水平和心脏纤维化程度之间存在显著但非常弱的负相关性。外周IRX3甲基化水平的升高进一步与心脏IRX3表达的降低相关,反之亦然。结论:TAVI时AS患者血液中高水平的IRX3甲基化与TAVI后更好的总生存率相关,并且至少部分反映了心肌IRX3的表达。循环甲基化IRX3可能有助于作为一种潜在的生物标志物,帮助指导TAVI前患者的选择和TAVI后的监测。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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