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Marc de Perrot
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J Thorac Cardiovasc Surg 2009;137:1538-1546
© 2009 The American Association for Thoracic Surgery

Cardiopulmonary Support

Regression of flow-induced pulmonary arterial vasculopathy after flow correction in piglets

Olaf Mercier, MD*, Edouard Sage, MD, Marc de Perrot, MD, Ly Tu, BSc, Elisabeth Marcos, BSc, Benoît Decante, MSc, Bruno Baudet, BSc, Philippe Hervé, MD, Philippe Dartevelle, MD, Saadia Eddahibi, PhD, Elie Fadel, MD

Laboratoire de Chirurgie Expérimentale UPRES-EA 2705, Uninersité Paris XI Hôpital Marie Lannelongue, Le Plessis-Robinson, France

Received for publication February 10, 2008; revisions received June 23, 2008; accepted for publication July 26, 2008.

* Address for reprints: Olaf Mercier, MD, Laboratoire de Chirurgie Expérimentale UPRES-EA 2705, Hôpital Marie Lannelongue, 133, Avenue de la Résistance, 92350 Le Plessis-Robinson, France. (Email: o.mercier{at}ccml.fr).

Objectives: Chronic thromboembolic pulmonary hypertension is due to partial obstruction of the pulmonary arterial bed and may resolve after pulmonary thromboendarterectomy. Persistent pulmonary hypertension, the main complication after pulmonary thromboendarterectomy, may reflect vessel alterations induced by high flow in unobstructed lung territories. The aim of this study was to determine whether correcting high flow led to reversal of the vasculopathy in piglets.

Methods: The effects of high pulmonary blood flow were investigated 5 weeks after creation of an aortopulmonary shunt (n = 10), and reversibility of vessel disease was evaluated at 1 week (n = 10) and 5 weeks after shunt closure (n = 10), compared to sham-operated animals (n = 10). Hemodynamic variables, pulmonary artery reactivity, and morphometry were recorded. We also investigated the endothelin, angiopoietin, and nitric oxide synthase pathways.

Results: High flow increased medial thickness in distal pulmonary arteries (55.6% ± 1.2% vs 35.9% ± 0.8%; P < .0001) owing to an increase of smooth muscle cell proliferation (proliferating cell nuclear antigen labeling). The endothelium-dependent relaxation was altered (P < .05). This phenomenon was associated to an overexpression of endothelin-1, endothelin-A, angiopoietin 1, angiopoietin 2, and Tie-2 (P < .05). After 1 week of shunt closure, all overexpressed genes returned to control values, the proliferation of smooth muscle cells stopped, and smooth muscle cell apoptosis increased (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling), preceding the normalization of the wall thickness hypertrophy and the pulmonary artery vasoreactivity observed at 5 weeks after shunt closure.

Conclusion: These results demonstrate that endothelin-1 and angiopoietin pathways are involved in vasculopathy development and may be important therapeutic targets for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

Abbreviations and Acronyms CTEPH = chronic thromboembolic pulmonary hypertension; eNOS = endothelial nitric oxide synthase; ET = endothelin; iNOS = inducible nitric oxide synthase; NOS = nitric oxide synthase; PA = pulmonary artery; PBS = phosphate-buffered saline; PCNA = proliferating cell nuclear antigen; PH = pulmonary hypertension; PTE = pulmonary thromboendarterectomy; SMC = smooth muscle cell; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling






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