Background:Cyanotic congenital heart disease (CCHD) is a complex pathophysiological condition involving systemic chronic hypoxia (CH). Some patients with CCHD are unoperated for various reasons and remain chronically hypoxic throughout their lives, which heightens the risk of heart failure as they age. Hypoxia activates cellular metabolic adaptation to balance energy demands by accumulating hypoxia-inducible factor 1-α (HIF-1α). This study aims to determine the effect of CH on cardiac metabolism and function in patients with CCHD and its association with age. The role of HIF-1α in this process was investigated, and potential therapeutic targets were explored.Methods:Patients with CCHD (n=25) were evaluated for cardiac metabolism and function with positron emission tomography/computed tomography and magnetic resonance imaging. Heart tissue samples were subjected to metabolomic and protein analyses. CH rodent models were generated to enable continuous observation of changes in cardiac metabolism and function. The role of HIF-1α in cardiac metabolic adaptation to CH was investigated with genetically modified animals and isotope-labeled metabolomic pathway tracing studies.Results:Prepubertal patients with CCHD had glucose-dominant cardiac metabolism and normal cardiac function. In comparison, among patients who had entered puberty, the levels of myocardial glucose uptake and glycolytic intermediates were significantly decreased, but fatty acids were significantly increased, along with decreased left ventricular ejection fraction. These clinical phenotypes were replicated in CH rodent models. In patients with CCHD and animals exposed to CH, myocardial HIF-1α was upregulated before puberty but was significantly downregulated during puberty. In cardiomyocyte-specific Hif-1α–knockout mice, CH failed to initiate the switch of myocardial substrates from fatty acids to glucose, thereby inhibiting ATP production and impairing cardiac function. Increased insulin resistance during puberty suppressed myocardial HIF-1α and was responsible for cardiac metabolic maladaptation in animals exposed to CH. Pioglitazone significantly reduced myocardial insulin resistance, restored glucose metabolism, and improved cardiac function in pubertal CH animals.Conclusions:In patients with CCHD, maladaptation of cardiac metabolism occurred during puberty, along with impaired cardiac function. HIF-1α was identified as the key regulator of cardiac metabolic adaptation in animals exposed to CH, and pubertal insulin resistance could suppress its expression. Pioglitazone administration during puberty might help improve cardiac function in patients with CCHD.

中文翻译：

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抑制心肌缺氧诱导因子 1α 会损害青春期紫绀型先天性心脏病患者的代谢适应和心脏功能

背景：紫绀型先天性心脏病 (CCHD) 是一种复杂的病理生理状况，涉及全身性慢性缺氧 (CH)。一些 CCHD 患者由于各种原因未进行手术，并且终生长期处于缺氧状态，随着年龄的增长，这会增加心力衰竭的风险。缺氧激活细胞代谢适应，通过积累缺氧诱导因子 1-α (HIF-1α) 来平衡能量需求。本研究旨在确定 CH 对 CCHD 患者心脏代谢和功能的影响及其与年龄的关系。研究了HIF-1α在该过程中的作用，并探索了潜在的治疗靶点。方法：采用正电子发射断层扫描/计算机断层扫描和磁共振成像评估CCHD患者（n=25）的心脏代谢和功能。对心脏组织样本进行代谢组学和蛋白质分析。生成 CH 啮齿动物模型以连续观察心脏代谢和功能的变化。HIF-1α 在心脏代谢适应 CH 中的作用通过转基因动物和同位素标记的代谢组学途径追踪研究进行研究。结果：青春期前 CCHD 患者的心脏代谢以葡萄糖为主，心脏功能正常。相比之下，在进入青春期的患者中，心肌葡萄糖摄取和糖酵解中间体的水平显着降低，但脂肪酸显着增加，同时左心室射血分数降低。这些临床表型在 CH 啮齿动物模型中被复制。在 CCHD 患者和暴露于 CH 的动物中，心肌 HIF-1α 在青春期前上调，但在青春期显着下调。在心肌细胞特异性Hif-1α–敲除小鼠，CH未能启动心肌功能的转换。青春期胰岛素抵抗的增加抑制了心肌 HIF-1α，并且是暴露于 CH 的动物心脏代谢适应不良的原因。吡格列酮可显着降低青春期 CH 动物的心肌胰岛素抵抗，恢复葡萄糖代谢，改善心功能。HIF-1α 被确定为暴露于 CH 的动物心脏代谢适应的关键调节因子，青春期胰岛素抵抗可以抑制其表达。