Department of Cardiology and Pneumology, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
DZHK German Center for Cardiovascular Research, Partner Site Göttingen, Göttingen, Germany.
Clin Epigenetics. 2023 Sep 11;15(1):149. doi: 10.1186/s13148-023-01561-2.
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.
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.
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.
主动脉瓣狭窄（AS）是最常见的心脏病之一，也是老年人发病率和死亡率的主要原因。经导管主动脉瓣植入术（TAVI）适用于有症状的严重 AS 患者，并降低了大多数此类患者的死亡率。然而，仍有相当一部分患者在 TAVI 后两年内死亡，因此人们有兴趣确定可预测结果并能指导 TAVI 前患者选择的参数。研究发现，心脏纤维化水平高是 TAVI 后心血管死亡率的独立预测因素。启动子甲基化通常导致基因下调，在全基因组转录组和甲基组研究中，发现同源盒基因 3（IRX3）在 AS 患者中发生高甲基化和下调。在一个经过充分描述的 100 例 TAVI 患者队列中，对心脏活检中的心脏纤维化水平进行了组织学定量，并进行了长达两年的随访，我们研究了 TAVI 后外周血中循环 IRX3 甲基化 DNA 是否与 AS 患者的心脏纤维化和/或死亡率相关，因此是否可以作为一种生物标志物，为 TAVI 后的结果提供更多信息。
与 IRX3 低甲基化患者相比，循环 IRX3 高甲基化患者的生存率显著提高，表明外周血高 IRX3 甲基化与改善预后相关。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素。虽然 IRX3 甲基化水平与心脏死亡无显著相关性，但循环 IRX3 启动子甲基化水平与心脏纤维化程度呈显著但非常微弱的负相关。外周 IRX3 甲基化水平越高，与心脏 IRX3 表达量越低呈负相关，反之亦然。
TAVI 时 AS 患者血液中 IRX3 甲基化水平较高与 TAVI 后总体生存率提高相关，至少部分反映了心肌 IRX3 表达。循环甲基化 IRX3 可能作为一种潜在的生物标志物，有助于指导 TAVI 前患者选择和 TAVI 后监测。
