A Low Mortality Model of Chronic Pulmonary Hypertension in Sheep

Abstract

BACKGROUND Pulmonary hypertension and right ventricular failure are major contributors to morbidity and mortality in chronic lung disease. Therefore, large animal models of pulmonary hypertension and right ventricular hypertrophy are needed to study underlying disease mechanisms and test new treatment modalities. The objective of this study was to create a low-mortality model of chronic pulmonary hypertension and right ventricular hypertrophy in sheep. METHODS The vena cavae of nine sheep weighing 62 ± 2 (SEM) kg were injected with 0.375 g of dextran beads (sephadex) everyday for 60 days. Pulmonary hemodynamics were assessed via pulmonary artery catheterization prior to the first injection and again on days 14, 28, 35, 42, 49, and 56. At the end of the experiment, the heart was removed, dissected, and weighed to determine the ratio of right ventricular mass to left ventricle plus septal mass (RV:LV+S). RESULTS All sheep survived to 60 days. The average pulmonary artery pressure rose from 17 ± 1 mmHg at baseline to 35 ± 3 mmHg on day 56 with no significant change in cardiac output (8.7 ± 0.7 to 9.8 ± 0.7 L/min, p = 0.89). The RV:LV+S was significantly higher (0.42 ± 0.01, p < 0.001) than a historic group of untreated normal animals (0.35 ± 0.01, n = 13). CONCLUSIONS This study provides a low-mortality large animal model of moderate chronic pulmonary hypertension and right ventricular hypertrophy.

Cardiorespiratory physiological perturbations after acute smoke-induced lung injury and during extracorporeal membrane oxygenation support in sheep

“…Another predictor for the severity of the injury was the mean pulmonary artery pressure, which was highest for the injured/treated sheep as illustrated in Figure 24. The baseline values for MPAP were higher than the 17 ± 1 mmHg reported in another study that used sheep for experiments 42 . The baseline CVP in all of the sheep in the present report was > 10 mmHg ( Figure 25), which was much higher than the 5.5 ± 1.2 mmHg reported elsewhere 42…”

“…The resting HR of sheep is 50-80 beats/min 32 . In a study that instrumented conscious sheep, the baseline heart rate was registered as 106 ± 9 beats/min 42 . In the present report, all of the sheep had a relatively high HR, thereby suggesting that stress and pain were contributing factors ( Figure 22).…”

Hemodynamic Design Requirements for In-Series Thoracic Artificial Lung Attachment in a Model of Pulmonary Hypertension

“…The sheep pulmonary hypertension model utilized here has RV hypertrophy and normal cardiac output despite mean PA pressures of 35 mmHg when awake. 14 It is likely, therefore, that the hypertrophied RV is less affected by the ΔZ 1 than the normal RV. Furthermore, as Figure 6 demonstrates, the first harmonic adds less than 10% to RV stroke power requirements and thus only a small change in the oxygen consumption requirements.…”

“…This model is characterized in detail elsewhere. 14 In brief, 0.75 gm of Sephadex G-50 (100-300 μm) beads (Sigma-Aldrich CO, St. Louis, MO) were injected into the pulmonary circulation every other day for 60 days. Mean PA pressures in these sheep were 28±2 mmHg during surgery just prior to initiating the experimental procedure below.…”

The Implantable Pediatric Artificial Lung

“…Saline lavage has been used in pediatric models of acute lung disease since it involves depletion of pulmonary surfactant (20, 21), but does not create PAH and is not generally performed in recovery experiments since severe lung injury is induced (9, 10, 21). Injecting substances into the pulmonary circulation, either beads (sephalex (11, 22) or ceramic (23)) or serial air embolisms (12), have been used to develop models of PAH. These methods often require weeks or months to develop, pushing the animal out of the appropriate size and age range.…”