Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
Department of Cardiovascular Research, Nanjing Medical University, Nanjing, China.
JACC Cardiovasc Interv. 2015 Dec 28;8(15):2013-2023. doi: 10.1016/j.jcin.2015.09.015.
This study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms.
SN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear.
Forty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution.
PADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction.
PADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.
本研究旨在探讨肺动脉去神经支配（PADN）对肺动脉高压（PAH）动物交感神经（SN）超微结构的变化以及血流动力学和肺动脉（PA）病理的影响，并探讨其潜在机制。
SN 过度活跃在 PAH 中起作用。先前的研究报告称，PADN 可短期改善肺动脉压（PAP）和心功能，但 PA 重塑及其相关机制仍不清楚。
40 只狗被随机（比例为 1:3）分为对照组（心房内注射 N-二甲基乙酰胺，3mg/kg）和实验组（心房内注射去氢单枞碱，3mg/kg）。8 周后，实验组中平均 PAP>25mmHg 的 20 只动物被随机（比例为 1:1）分为假手术组和 PADN 组。14 周时，测量血流动力学、中膜厚度和 PA 肌化以及肺组织中基因的信使核糖核酸表达。另外 35 只 PAH 狗用于测量 SN 传导速度、电子显微镜评估和神经分布。
PADN 随时间诱导明显的 SN 脱髓鞘和轴突丢失，并降低 SN 传导速度，导致平均 PAP（23.5±2.3mmHg 与 33.7±5.8mmHg）、肺血管阻力（3.5±2.3 Wood 单位与 7.7±1.7 Wood 单位）、中膜厚度（22.3±3.3%与 30.4±4.1%）和完全肌化（40.3±9.3%与 57.1±5.7%）显著降低，非肌化增加（29.8±6.1%与 12.9±4.9%）与假手术组相比（均 p<0.001）。PADN 抑制了与炎症、增殖和血管收缩相关的基因的信使核糖核酸表达。
PADN 通过可能在实验和临床有益的机制，在 PAH 动物中诱导永久性 SN 损伤和随后的血流动力学和 PA 重塑改善。
