Voros Charalampos, Papadimas Georgios, Theodora Marianna, Mavrogianni Despoina, Athanasiou Diamantis, Sapantzoglou Ioakeim, Bananis Kyriakos, Athanasiou Antonia, Athanasiou Aikaterini, Tsimpoukelis Charalampos, Papapanagiotou Ioannis, Vaitsis Dimitrios, Koulakmanidis Aristotelis-Marios, Daskalaki Maria Anastasia, Topalis Vasileios, Thomakos Nikolaos, Antsaklis Panagiotis, Chatzinikolaou Fotios, Loutradis Dimitrios, Daskalakis Georgios
Department of Obstetrics and Gynecology, 'Alexandra' General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece.
Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece.
Biomedicines. 2025 Aug 21;13(8):2044. doi: 10.3390/biomedicines13082044.
Numerous infants have been conceived by in vitro fertilization (IVF) and other assisted reproductive technologies (ART). Increasing evidence indicates that these approaches induce minor alterations in molecules during the initial phases of embryogenesis. This narrative review examines the molecular pathophysiology of embryonic cardiogenesis in the context of assisted reproductive technology, emphasizing transcriptional and epigenetic regulation. Essential transcription factors for cardiac development, including NKX2-5, GATA4, TBX5, ISL1, MEF2C, and HAND1/2, play a crucial role in mesodermal specification, heart tube formation, and chamber morphogenesis. Animal models and human preimplantation embryos have demonstrated that ART-related procedures, including gamete micromanipulation, supraphysiological hormone exposure, and extended in vitro culture, can alter the expression or epigenetic programming of these genes. Subsequent to ART, researchers have identified anomalous patterns of DNA methylation, alterations in histones, and modifications in chromatin accessibility in cardiogenic loci. These alterations indicate that errors occurred during the initial reprogramming process, potentially resulting in structural congenital heart abnormalities (CHDs) or modifications in cardiac function later in life. Analysis of the placental epigenome in babies conceived using assisted reproductive technology reveals that imprinted and developmental genes critical for cardiac development remain dysfunctional. This review proposes a mechanistic theory about the potential subtle alterations in the cardiogenic gene network induced by ART, synthesizing findings from molecular embryology, transcriptomics, and epigenomics. Understanding these molecular issues is crucial not only for enhancing ART protocols but also for evaluating the cardiovascular risk of children conceived by ART postnatally and for early intervention.
许多婴儿通过体外受精（IVF）和其他辅助生殖技术（ART）受孕。越来越多的证据表明，这些方法在胚胎发育的初始阶段会诱导分子发生微小变化。这篇叙述性综述在辅助生殖技术的背景下研究了胚胎心脏发生的分子病理生理学，强调转录和表观遗传调控。心脏发育的关键转录因子，包括NKX2-5、GATA4、TBX5、ISL1、MEF2C和HAND1/2，在中胚层特化、心管形成和心室形态发生中起关键作用。动物模型和人类植入前胚胎已证明，与ART相关的程序，包括配子显微操作、超生理激素暴露和延长体外培养，可改变这些基因的表达或表观遗传编程。在ART之后，研究人员在心脏发生位点发现了DNA甲基化的异常模式、组蛋白的改变和染色质可及性的修饰。这些改变表明在初始重编程过程中发生了错误，可能导致结构性先天性心脏病（CHD）或后期心脏功能的改变。对使用辅助生殖技术受孕的婴儿的胎盘表观基因组分析表明，对心脏发育至关重要的印记基因和发育基因仍然功能失调。这篇综述提出了一种关于ART诱导的心脏发生基因网络潜在细微变化的机制理论，综合了分子胚胎学、转录组学和表观基因组学的研究结果。了解这些分子问题不仅对于改进ART方案至关重要，而且对于评估ART受孕儿童出生后的心血管风险以及早期干预也至关重要。
