Hemodynamic unloading leads to regression of pulmonary vascular disease in rats.
OBJECTIVE
Treatment options for patients with advanced pulmonary vascular disease caused by a congenital heart defect are still mainly limited to heart-lung transplantation or lung transplantation with repair of the cardiac lesion. Because we have previously shown that the structural changes associated 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 lungs were examined (n = 10) or exposed to normal pulmonary artery pressure for an additional 14 (n = 5) or 28 (n = 7) days by transplantation into healthy recipients. Pulmonary artery pressure, ventricular weight, and pulmonary artery morphology were evaluated in each group.


RESULTS
Pulmonary hypertension (50 vs 16 mm Hg; P <.001) and right ventricular 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 controls). However, transplantation into healthy recipients effectively unloaded the lungs (mean pulmonary artery pressure 17 and 24 mm Hg at 14 and 28 days after transplantation) and resulted in progressive normalization of medial hypertrophy (15.6% and 12.1% at 14 and 28 days) and muscularization (65.1% 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 regression of pulmonary vascular disease by pressure unloading of the pulmonary circulation. Methods to mechanically unload the pulmonary circulation should be critically evaluated as a strategy for staged surgical repair of congenital heart defects despite presumed irreversible pulmonary hypertension.
O'Blenes
S B
SB
Division of Cardiovascular Research, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Ontario, Canada M5G 1X8.
Fischer
S
S
McIntyre
B
B
Keshavjee
S
S
Rabinovitch
M
M
D000818:Animals; D002455:Cell Division; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D006984:Hypertrophy / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D008173:Lung Diseases, Obstructive / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D016040:Lung Transplantation; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D051381:Rats; D014655:Vascular Resistance