PURPOSE: We are developing a clinically relevant large animal model of chronic pulmonary hypertension (PH) to provide a research platform for this highly morbid disease.
METHODS: Four adult sheep were instrumented with a pulmonary artery catheter and femoral arterial catheter under general anesthesia, transfered to ICU after recovery with free access to water and food throughout experiment. Baseline values of hemodynamics and blood gases were measured. Filtered air was continuously infused into pulmonary circulation from Superior Vena Cava via pulmonary artery catheter for 8 weeks atthe rate of 6-80 ml/hour to titrate normal blood gases and arterial blood pressure. Air infusion was terminated at the end of week 8 and sheep were observed for one additional week to access constancy of pulmonary artery pressure and sacrificed at the end of week 9 electively for heart and lung pathological investigation. Hemodynamics was continuously monitored and blood gases were recorded daily.
RESULTS: All animals survived the study and met the PH criteria within 3 weeks of continuous air infusion. Mean pulmonary artery pressure stayed >25mmHg steadily from week 4 and elevated significantly to 35±1mmHg at week 8 from 14±2(at baseline) and it maintained elevated (32-35mmHg) during the 9th week of discontinuing air infusion. Comparing with baseline, cardiac output was lower at completion (3.9 L/min vs 6.8L/min) and central venous pressure was higher (16mmHg vs 1.8 mmHg) while heart rate, artery pressure and blood gases remained within normal range. In all four sheep histopathological study revealed significant pulmonary arteriolar lesions including narrowing of lumen, cellular proliferation of intima and thickening of media and adventitia and visible plexiform as well which were consistent with severe PH. Also, a remarkable increase in weight and thickness of the right ventricle was seen at necropsy, consistent with chronic PH.
CONCLUSION: 8 weeks of continuous pulmonary air-embolization produced a practical, reliable and clinically relevant severe chronic pulmonary hypertension large animal model.
CLINICAL IMPLICATIONS: Our large animal PH model will supply research platform for any new therapy strategy.
DISCLOSURE: Xiaoqin Zhou, None.