A Pulmonary Hypertension Model Induced by Continuous Pulmonary Air Embolization

Background

Our goal was to create a clinically relevant large animal model of pulmonary hypertension to serve as a platform allowing preclinical risk/benefit assessment of innovative therapies including artificial lung prototypes.

Methods

Small amounts of filtered air were continuously infused into the pulmonary circulation of sheep (n = 4) for 8 wk. Hemodynamics and blood gases were measured daily. After termination of air embolization, the sheep were observed for 1 additional wk to assess the constancy of the pulmonary artery pressure changes. At the end of wk 9, all sheep were sacrificed and necropsy was performed.

Results

All animals survived the study and developed pulmonary hypertension by wk 5. Mean pulmonary artery pressures were elevated from 14 ± 1 at baseline to 35 ± 1 mmHg at wk 8 (P < 0.01) and remained unchanged throughout wk 9. A similar increase in pulmonary vascular resistance was observed. Systemic arterial pressure and PaO₂ dropped slightly compared with baselines but remained in safe ranges. Histologic evidence of severe pulmonary arterial remodeling and significant right ventricle hypertrophy was observed.

Conclusions

We conclude that our 8-wk model of continuous air embolization produces reliable, chronic pulmonary hypertension in sheep with sustained hemodynamic changes, significant pulmonary vascular remodeling, and right ventricle hypertrophy.

Introduction

Clinically, pulmonary hypertension is defined as a sustained elevation of mean pulmonary arterial pressure to greater than 25 mm Hg at rest [1]. Pulmonary hypertension is characterized by progressive remodeling of the small pulmonary arteries, which promotes an increase in pulmonary arterial pressure and pulmonary vascular resistance, ultimately leading to right heart hypertrophy and failure. Idiopathic pulmonary arterial hypertension is rare with an extremely poor prognosis. Pulmonary hypertension presents more often associated with a common sequela of chronic lung conditions, especially chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis [2]. Regardless of advances in pharmaceutical therapy, pulmonary hypertension remains progressive and incurable 3, 4, 5, 6, 7. Medications have improved the quality of life for these patients, but many patients still require lung transplant. In 2007, emphysema and idiopathic pulmonary fibrosis accounted for more than 60% of lung transplants performed [8]. Also, pulmonary hypertension is one of the indications for lung transplant in patients with cystic fibrosis, another leading diagnosis group [9].

The role of a thoracic artificial lung in patients with pulmonary hypertension is unknown. An artificial lung may serve as a bridge until lung transplant is available. The function of the artificial lung in a setting of true clinical pulmonary hypertension and the effect of the high pulmonary vascular resistance on device function has not been adequately studied. A large animal model of chronic pulmonary hypertension is needed to evaluate the efficacy of an artificial lung device in this disease state.

Previous chronic large animal models with embolization have been reported 10, 11, 12. However, these models either showed only mild elevation of pulmonary pressure or inadequate morphological data of the lung and the right ventricle. Some models lack reproducibility due to high animal mortality 10, 12. The goal of the present study was to develop a reliable chronic pulmonary hypertension model in large animals by continuous pulmonary air embolization.