Hanna Peter, Hoover Donald B, Kirkland Logan G, Smith Elizabeth H, Poston Megan D, Peirce Stanley G, Garbe Chloe G, Cha Steven, Mori Shumpei, Brennan Jaclyn A, Armour John Andrew, Rytkin Eric, Efimov Igor R, Ajijola Olujimi A, Ardell Jeffrey L, Shivkumar Kalyanam
David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, California, USA.
Molecular, Cellular, and Integrative Physiology Program, University of California Los Angeles (UCLA), Los Angeles, California, USA.
Anat Rec (Hoboken). 2025 May 14. doi: 10.1002/ar.25686.
Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.
自主神经在心脏功能和病理过程中至关重要。然而，关于正常和病理状态下人类心脏中胆碱能神经和去甲肾上腺素能神经分布的数据尚缺乏。对非衰竭供体心脏进行压力灌注固定、成像和解剖。还获取了左心室心肌病样本。对固定的冰冻切片进行神经免疫染色，相邻组织进行透明处理以进行三维可视化。除窦房结外，胆碱能神经和去甲肾上腺素能神经在两个心房中分布均匀，窦房结处囊泡乙酰胆碱转运体（VAChT）神经占主导。在右心室（RV）和左心室（LV）区域，去甲肾上腺素能神经始终多于胆碱能神经。不同供体的左心室区域去甲肾上腺素能神经支配情况有所不同。与左心室样本相比，右心室的胆碱能神经支配更高，左心室样本中VAChT神经通常减少。三例心肌病病例出现明显的神经重塑。酪氨酸羟化酶（TH）神经密度在右心耳中增加，所有神经在左心耳中均有减少趋势。左心室胆碱能神经支配减少，TH神经支配不均一。去甲肾上腺素能神经存在于肉芽组织中，但在致密瘢痕区域不存在。一些边缘区域TH神经支配减少但无神经支配亢进。大多数心房区域的双重神经支配支持心房功能的平衡调节。对窦房结较高的胆碱能输入有利于迷走神经在心率调节中占主导。神经支配模式支持去甲肾上腺素能输入对心室，尤其是左心室起重要作用。心肌病时心房和心室神经均发生重塑，为不对称神经输入和心脏机电功能失调奠定了基础。
