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J Thorac Cardiovasc Surg 2004;128:602-608
© 2004 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Reduction of myocardial reperfusion injury by aprotinin after regional ischemia and cardioplegic arrest

^a Department of Surgery, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass, USA
^b Department of Anesthesiology, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass, USA

Received for publication October 21, 2003; revisions received February 9, 2004; accepted for publication March 17, 2004.

^* Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 2A, Boston, MA 02215, USA
fsellke{at}caregroup.harvard.edu

BACKGROUND: Surgical coronary revascularization with cardiopulmonary bypass and cardioplegia has been associated with reperfusion injury. The serine protease inhibitor aprotinin has been suggested to reduce reperfusion injury, yet a clinically relevant study examining regional ischemia under conditions of cardiopulmonary bypass and cardioplegia has not been performed.

METHODS: Pigs were subjected to 30 minutes of regional myocardial ischemia by distal left anterior descending coronary artery occlusion, followed by 60 minutes of cardiopulmonary bypass with 45 minutes of cardioplegic arrest and 90 minutes of post–cardiopulmonary bypass reperfusion. The treatment group (n = 6) was administered aprotinin systemically (40,000 kallikrein-inhibiting units [KIU]/kg intravenous loading dose, 40,000 KIU/kg pump prime, and 10,000 KIU · kg^–1 · h^–1 intravenous continuous infusion). Control animals (n = 6) received crystalloid solution. Global and regional myocardial functions were analyzed by the left ventricular+dP/dt and the percentage segment shortening, respectively. Left ventricular infarct size was measured by tetrazolium staining. Tissue myeloperoxidase activity was measured. Myocardial sections were immunohistochemically stained for nitrotyrosine. Coronary microvessel function was studied by videomicroscopy.

RESULTS: Myocardial infarct size was decreased with aprotinin treatment (27.0% ± 3.5% vs 45.3% ± 3.0%, aprotinin vs control; P < .05). Myocardium from the ischemic territory showed diminished nitrotyrosine staining in aprotinin-treated animals versus controls, and this was significant by grade (1.3 ± 0.2 vs 3.2 ± 0.2, aprotinin vs control; P < .01). In the aprotinin group, coronary microvessel relaxation improved most in response to the endothelium-dependent agonist adenosine diphosphate (44.7% ± 3.2% vs 19.7% ± 1.7%, aprotinin vs control; P < .01). No significant improvements in myocardial function were observed with aprotinin treatment.

CONCLUSIONS: Aprotinin reduces reperfusion injury after regional ischemia and cardioplegic arrest. Protease inhibition may represent a molecular strategy to prevent postoperative myocardial injury after surgical revascularization with cardiopulmonary bypass.

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