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. 2023 Dec 6;9(2):244-256.
doi: 10.1016/j.jacbts.2023.09.013. eCollection 2024 Feb.

Noninvasive Stereotactic Radiotherapy for PADN in an Acute Canine Model of Pulmonary Arterial Hypertension

Wei Xu  1 , Ding-Yu Wang  1 , Zi-Yin Chen  2 , Qiang Gao  1 , Yi-Lun Zou  1 , Dang-Hui Sun  1 , Song Zhang  1 , Xin-Bo Zhao  1 , Yong-Tai Gong  1 , Yun Zhang  1 , Da-Xin Zhang  2 , Yue Li  1   3   4   5   6
Affiliations

Noninvasive Stereotactic Radiotherapy for PADN in an Acute Canine Model of Pulmonary Arterial Hypertension

Wei Xu et al. JACC Basic Transl Sci. .

Abstract

This study assesses the feasibility, safety, and effectiveness of noninvasive stereotactic body radiotherapy (SBRT) as an approach for pulmonary artery denervation in canine models. SBRT with CyberKnife resulted in reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance, and insignificantly increased cardiac output. In comparison to the control group, serum norepinephrine levels at 1 month and 6 months were significantly lower in the CyberKnife group. Computed tomography, pulmonary angiography, and histology analysis revealed that SBRT was associated with minimal collateral damage.

Keywords: noninvasive stereotactic body radiotherapy; pulmonary arterial hypertension; pulmonary artery; pulmonary artery denervation.

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Conflict of interest statement

Supported by grants from the State Key Program of National Natural Science Foundation of China (No.81830012, No82330014 to Dr Y. Li); National Natural Science Foundation of China (No.82070336 to Dr Y. Li); National Natural Science Foundation of China (No. 81974024 to Dr Gong)Youth Foundation of National Natural Science Foundation of China (No. 82100507 to Dr Zhang). This study was approved by the Animal Use and Management Ethics Committee of the First Affiliated Hospital of Harbin Medical University. The use of animals and all procedures were in agreement with the Guide for the Care and Use of Laboratory Animals (NIH Publication 2011; eighth edition). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Experimental Flow Chart (A) Animals were divided into groups. (B) Hemodynamic measurement procedure. CT = computed tomography; IV = intravenous; PADN = pulmonary artery denervation; TXA2 = thromboxane A2.
Figure 2
Figure 2
Workflow of Noninvasive SBRT for Pulmonary Artery Denervation (A) Beagles underwent a series of computed tomography (CT) scans, including native, contrast-enhanced, and respiration-correlated 4-dimensional CT. (B) Based on the CT scan data, the animals were located using lasers and skin markers. (C) The target volume (including the pulmonary artery) was delineated, and the target volume containing motion was generated according to the 4-dimensional CT. The plan target volume was expanded by 2 mm due to mechanical tolerance and setup tolerance. The delineation of organs at risk (OAR) included the heart, trachea, esophagus, spinal cord, and lungs. (D) The prescription dose was 45 Gy. The stereotactic radiosurgery plan was designed to improve the prescription dose coverage of the target volume while minimizing the dose to OAR. The green isodose line corresponds to a 45-Gy prescribed dose. The target area is almost entirely enveloped by 45 Gy whereas the dose of nearby OARs decreases rapidly. (E) Two orthogonal kilovolt x-ray tubes were used for position and image-guided alignment until the error was sub-millimeter and treatment was available. (F) CyberKnife was used for stereotactic body radiotherapy (SBRT).
Figure 3
Figure 3
Experimental Study Hemodynamics (A) Mean pulmonary artery pressure (mPAP) at baseline, 1 month, and 6 months with thromboxane A2 agonist (TXA2) pre- and post-TXA2 procedure for control and CyberKnife-treated animals. (B) Systolic pulmonary artery pressure (SPAP), (C) cardiac output (CO), (D) pulmonary vascular resistance (PVR), (E) pulmonary capillary wedge pressure (PCWP), (F) right ventricular systolic pressure (RVSP), (G) right arterial systolic pressure (RASP), and (H) heart rate (HR) at baseline, 1 month, and 6 months TXA2 agonist pre- and post-TXA2 procedure for control and CyberKnife-treated animals. Data are expressed as mean ± SD and compared with repeated measures analysis of variance. ∗P < 0.05 vs 1 month and 6 months. Control group n = 6. CyberKnife group n = 8.
Figure 4
Figure 4
Immunohistochemistry of Pulmonary Artery Nerve (A) Tyrosine hydroxylase (TH) staining of MPA, (B) LPA, and (C) RPA in control and CyberKnife groups at 6 months. Data are expressed as mean ± SD and compared with unpaired Student t test. ∗∗P < 0.01. ∗∗∗P < 0.001 vs control groups; n = 6 per group. LPA = left pulmonary artery; MPA = main pulmonary artery; RPA = right pulmonary artery.
Figure 5
Figure 5
Immunofluorescence of Pulmonary Artery Nerve (A) Immunofluorescence of MPA in control and CyberKnife groups at 6 months. (B) Immunofluorescence of RPA in control and CyberKnife groups at 6 months. Data are expressed as mean ± SD and compared with unpaired Student t test. ∗∗P < 0.01, ∗∗∗P < 0.001 vs control groups. n = 6 per group. Abbreviations as in Figure 4.
Figure 6
Figure 6
Systemic Sympathetic Activity Serum norepinephrine (NE) concentration in control and CyberKnife groups at baseline, 1 month, and 6 months. Data are expressed as mean ± SD and compared with repeated measures analysis of variance. ∗P < 0.05 vs 6 months. #P < 0.05 vs control group. n = 8 per group.
Figure 7
Figure 7
Non–Target Organ Injury (A) Representative images of pulmonary arteries (PAs), (B) lungs, and (C) right ventricle (RV) were stained with hematoxylin and eosin (HE) in control and CyberKnife groups. HE stain of PA and lungs showed that many inflammatory cells were infiltrated in CyberKnife groups compared with the control group, whereas RV showed no apparent damage.
Figure 8
Figure 8
CT and Pulmonary Angiography Evaluation Representative coronal CT images of the lung at (A) baseline and (B) 6 months in the CyberKnife group. Representative pulmonary angiography images at (C) baseline and (D) 6 months in the CyberKnife group. No significant fibrosis, inflammation, or other changes were observed at the 6-month endpoint. PA stenosis was also not observed 6 months after SBRT in the CyberKnife group. Abbreviations as in Figures 1, 2, and 7.
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