Hemodynamic unloading leads to regression of pulmonary vascular disease inrats

Objective: Treatment options for patients with advanced pulmonary vascular disease caused by a congenital heart defect are still mainly limited to hea rt-lung transplantation or lung transplantation with repair of the cardiac lesion. Because we have previously shown that the structural changes associ ated with pulmonary hypertension can be reversed by stress unloading in an organ culture model, we now investigate whether hemodynamic unloading will lead to regression of pulmonary vascular disease in the intact animal. Methods: Right middle and lower lobectomy and monocrotaline injection were performed in Lewis rats (n = 22) to cause pulmonary vascular disease from a combined hemodynamic and toxic injury. Twenty-eight days later the left lu ngs were examined (n = 10) or exposed to normal pulmonary artery pressure f or an additional 14 (n = 5) or 28 (n = 7) days by transplantation into: hea lthy recipients. Pulmonary artery pressure, ventricular weight, and pulmona ry artery morphology were evaluated in each group. Results: Pulmonary hypertension (50 vs 16 mm Hg; P < .001) and right ventri cular hypertrophy (right ventricular/left ventricular weight 0.69 vs 0.32; P < .001) associated with pulmonary artery medial hypertrophy (28.2% vs 7.2 % wall thickness; P < .001) and muscularization of small pulmonary arteries (92.3% vs 19.4%; P < .001) developed by day 28 (compared with untreated co ntrols). However, transplantation into healthy recipients effectively unloa ded the lungs (mean pulmonary artery pressure 17 and 24 mm Hg at 14 and 28 days after transplantation) and resulted in progressive normalization of me dial hypertrophy (15.6% and 12.1% at 14 and 28 days) and muscularization (6 5.1% and 42.2% at 14 and 28 days) relative to nontransplanted controls (P < .005 in each case). Conclusions: Hemodynamic unloading of lungs with pulmonary vascular disease results in progressive normalization of pulmonary artery structure. These results are the first to provide a rationale for attempting to induce regre ssion of pulmonary vascular disease by pressure unloading of the pulmonary circulation. Methods to mechanically unload the pulmonary circulation shoul d be critically evaluated as a strategy for staged surgical repair of conge nital heart defects despite presumed irreversible pulmonary hypertension.