Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline.

Abstract

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.