Author + information
- Received July 14, 2015
- Revision received September 21, 2015
- Accepted September 21, 2015
- Published online December 28, 2015.
- Ling Zhou, MD∗,
- Juan Zhang, MD∗,
- Xiao-Min Jiang, MD†,
- Du-Jiang Xie, MD∗,
- Jin-Song Wang, MD∗,
- Li Li, MD∗,
- Bin Li, PhD†,
- Zhi-Mei Wang, MD‡,
- Alexander M.K. Rothman, MD§,
- Allan Lawrie, PhD§ and
- Shao-Liang Chen, MD∗,‡∗ ()
- ∗Division of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- †Department of Cardiovascular Research, Nanjing Medical University, Nanjing, China
- ‡Division of Cardiology, Nanjing Heart Center, Nanjing, China
- §Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom
- ↵∗Reprint requests and correspondence:
Dr. Shao-Liang Chen, Cardiology Department, Nanjing First Hospital, Nanjing Medical University, 68 Changle Road, Nanjing 210006, China.
Objectives 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.
Background 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.
Methods 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.
Results 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.
Conclusions 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.
- electron microscopy
- pathological remodeling
- pulmonary arterial hypertension
- pulmonary artery denervation
- sympathetic nerves
This study was granted by National Natural Scientific Funding of China (NSF81270191) and Jiangsu Provincial Outstanding Medical Program (BL20142338). Dr. Rothman has received research funding from Medtronic; and has received consulting fees from SoniVie. Dr. Chen is the fellow of the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine and Clinical Medical Research Center of Jiangsu Province, China. The first two authors contributed equally to this work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received July 14, 2015.
- Revision received September 21, 2015.
- Accepted September 21, 2015.
- 2015 American College of Cardiology Foundation