Piglet model of chronic pulmonary hypertension

Abstract

None of the animal models have been able to reproduce all aspects of CTEPH because of the rapid resolution of the thrombi in the pulmonary vasculature. The aim of this study was to develop an easily reproducible large-animal model of chronic pulmonary hypertension (PH) related to the development of a postobstructive and overflow vasculopathy. Chronic PH was induced in 5 piglets by ligation of the left pulmonary artery (PA) through a midline sternotomy followed by weekly transcatheter embolization of the right lower-lobe arteries. Sham-operated piglets (n = 5) served as controls. Hemodynamics, RV function, lung morphometry, and endothelin-1 (ET-1) pathway gene expression (ET-1 and its receptors ETA and ETB) were assessed after 5 weeks in the obstructed (left lung and right lower lobe) and unobstructed (right upper lobe) territories. All animals developed chronic PH within 5 weeks. Compared to controls, chronic-PH animals had higher mean PA pressure (28.5 ± 1.7 vs. 11.6 ± 1.8 mmHg, P = 0.0001) and total pulmonary resistance (784 ± 160 vs. 378 ± 51 dyn s(-1) cm(-5), P = 0.05). Echocardiography showed RV enlargement, RV wall thickening (56 ± 5 vs. 30 ± 4 mm, P = 0.0003), decreased tricuspid annular plane systolic excursion (11.3 ± 0.9 vs. 14.4 ± 0.4 mm, P = 0.01), and paradoxical septal motion. In obstructed territories, morphometry demonstrated increases in the number of bronchial arteries per bronchus (8.7 ± 0.9 vs. 2 ± 0.17, P < 0.0001) and in distal PA media thickness (60% ± 2.8% vs. 29% ± 0.9%, P < 0.0001), consistent with postobstructive vasculopathy. Distal PA media thickness was increased in unobstructed territories (70% ± 2.4% vs. 29% ± 0.9%, P < 0.0001). ET-1 was overexpressed in unobstructed territories, compared to controls and obstructed territories. In conclusion, the large-animal model described here is reproducible and led to the development of PH in a relatively short time frame.

Keywords: animal model; chronic thromboembolic pulmonary hypertension; pulmonary hypertension.

Figure 1

Echocardiography results comparing CTEPH (chronic thromboembolic pulmonary hypertension) and sham groups. Piglets in the CTEPH group had right ventricle (RV) remodeling with significant increases in thickness, tricuspid annulus diameter, and systolic pulmonary artery pressure and a significant decrease in tricuspid annular plane systolic excursion (TAPSE). Asterisk indicates P < 0.05 for the CTEPH group versus the sham group.

Figure 2

Hemodynamic measurements showing higher mean pulmonary artery pressure (mPAP) and total pulmonary resistance (TPR) values in the CTEPH (chronic thromboembolic pulmonary hypertension) group, compared to the sham group, from the first embolization to the fifth week. After 5 weeks of embolization, mPAP was >25 mmHg at rest. Asterisk indicates P < 0.05 for the CTEPH group versus the sham group.

Figure 3

Enhanced thoracic computed tomography showing right ventricle remodeling and enlargement (A), unresolved proximal obstruction of the right lower-lobe arteries (B), and bronchial artery hypertrophy (C).

Figure 4

Gross anatomy of the harvested lungs, showing the different vascular lung territories and the unresolved intravascular material. RLL: right lower lobe.

Figure 5

Results of the morphometric study showing pulmonary vasculopathy with media hypertrophy in obstructed and unobstructed territories, compared to the sham group. MT: media thickness; RUL: right upper lobe; Isch.: ischemia; RLL: right lower lobe.

Figure 6

Number of submucosal bronchial arteries per bronchus, showing hypertrophy of the systemic vessels supplying the ischemic lung (left lung and right lower lobe). Isch.: ischemia; RLL: right lower lobe; RUL: right upper lobe.

Figure 7

Fixed left lung section stained with hematoxylin and eosin stain (×20): enlarged and hypertrophic submucosal bronchial artery in a chronic thromboembolic pulmonary hypertension–group piglet.

Figure 8

Quantification of messenger RNA (mRNA), using real-time-polymerase chain reaction, for endothelin-1 (ET-1) and its receptors ETA and ETB in lung parenchyma. ET-1, ETA, and ETB were overexpressed in the right upper lobe subjected to high blood flow. ETA was overexpressed in the left lung subjected to chronic ischemia. Asterisk indicates P < 0.05 for the high-flow group versus the sham group; pound sign indicates P < 0.05 for the ischemia group versus the sham group.