Salameh Shatha, Guerrelli Devon, Miller Jacob A, Desai Manan, Moise Nicolae, Yerebakan Can, Bruce Alisa, Sinha Pranava, d'Udekem Yves, Weinberg Seth H, Posnack Nikki Gillum
bioRxiv. 2024 Apr 23:2024.04.19.589826. doi: 10.1101/2024.04.19.589826.
Nearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective 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 cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models.
Right atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). 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 (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, 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 also note a shift in repolarization reserve, with lower expression in younger patients, a finding likely tied to the increased amplitude of triggered by elevated sympathetic activation in pediatric patients.
This study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.
全球每年有近1%（即130万）的婴儿患有先天性心脏病（CHD）——其中许多婴儿在生命的头几年需要进行姑息性或矫正性心脏手术。深入了解心脏成熟过程有助于拓展我们对妊娠期发生的心脏疾病的认识，确定适合不同年龄段的心血管药物治疗方法，并为与手术修复、心肌保护或术后管理相关的临床护理决策提供依据。然而，迄今为止，我们对心肌细胞在出生后发育过程中所经历的时间变化的了解主要局限于动物模型。
从117例因（非青紫型）CHD接受矫正手术的新生儿、婴儿和儿科患者中采集右心房组织样本。患者被分为五个年龄组：新生儿（0 - 30天）、婴儿（31 - 364天）、幼儿至学龄前儿童（1 - 5岁）、学龄儿童（6 - 11岁）以及青少年至青年成人（12 - 32岁）。我们测量了心脏基因表达随年龄的适应性变化，并使用计算模型模拟动作电位和钙瞬变。
对差异表达基因（DEG）进行富集分析，揭示了几个关键生物学过程（细胞周期、细胞分裂、有丝分裂）、心脏离子通道和钙处理基因随年龄的变化。离子电流的基因相关变化在发育阶段呈现出线性趋势和突然转变，钙处理（ ）和复极化（ ）的变化分别与动作电位平台期电位随年龄的降低和三角化的增加最为密切相关。我们还注意到复极化储备的变化，年轻患者中 表达较低，这一发现可能与儿科患者交感神经激活增强引发的 振幅增加有关。
本研究为CHD患者心脏基因表达和电生理随年龄的变化提供了有价值的见解，揭示了不同发育阶段心脏发育和功能的分子机制。
