Children's National Heart Institute, Children's National Hospital, Washington, District of Columbia, United States.
Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Hospital, Washington, District of Columbia, United States.
Am J Physiol Heart Circ Physiol. 2024 Dec 1;327(6):H1413-H1430. doi: 10.1152/ajpheart.00474.2024. Epub 2024 Oct 25.
Nearly 1% of babies are born with congenital heart disease-many of whom will require heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate drug therapies, and inform clinical care decisions related to surgical repair and postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we collected right atrial tissue samples from pediatric patients ( = 117) undergoing heart surgery. Patients were stratified into five age groups. We measured age-dependent adaptations in cardiac gene expression and used computational modeling to simulate action potential and calcium transients. Enrichment of differentially expressed genes revealed age-dependent changes in several key biological processes (e.g., cell cycle, structural organization), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited age-dependent trends, with changes in calcium handling () and repolarization () most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We observed a shift in repolarization reserve, with lower expression in younger patients, a finding potentially tied to an increased amplitude of that could be triggered by elevated sympathetic activation in pediatric patients. Collectively, this study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology, shedding light on molecular mechanisms underlying cardiac maturation and function throughout development. To date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is limited. In this study, we demonstrate age-dependent adaptations in the gene expression profile of >100 atrial tissue samples collected from congenital heart disease patients. We coupled transcriptomics datasets with computational modeling to simulate action potentials and calcium transients for different pediatric age groups.
近 1%的婴儿出生时患有先天性心脏病，其中许多人在生命的头几年需要心脏手术。对心脏成熟的深入了解有助于扩展我们对胎儿期发育过程中心脏病的认识，确定适合年龄的药物治疗方法，并为与手术修复和术后管理相关的临床护理决策提供信息。然而，迄今为止，我们对心肌细胞在出生后发育过程中经历的时间变化的了解是有限的。在这项研究中，我们从接受心脏手术的儿科患者（n = 117）中收集右心房组织样本。患者分为五个年龄组。我们测量了心脏基因表达的年龄依赖性适应，并使用计算模型模拟动作电位和钙瞬变。差异表达基因的富集揭示了几个关键生物学过程（例如，细胞周期，结构组织）、心脏离子通道和钙处理基因的年龄依赖性变化。基因相关的离子电流变化表现出年龄依赖性趋势，钙处理（）和复极化（）的变化与动作电位平台电位的年龄依赖性降低和三角化增加分别最强相关。我们观察到复极化储备的转变，年轻患者的表达降低，这一发现可能与儿科患者交感神经激活引起的 振幅增加有关。总的来说，这项研究提供了对人类心脏基因表达和电生理学随年龄变化的宝贵见解，揭示了心脏成熟和功能的分子机制在整个发育过程中的作用。
