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J Thorac Cardiovasc Surg 2001;122:746-752
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts

From the Departments of Medicine, Pathology, and Pharmacology, University of Alberta, Edmonton, Alberta, Canada, and the Departments of Medicine, Anaesthesia, and Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Supported by a grant from the Saskatchewan Heart and Stroke Foundation.

Received for publication Oct 23, 2000. Revisions requested Dec 21, 2000; revisions received March 23, 2001. Accepted for publication March 26, 2001. Address for reprints: Irvin Mayers, MD, Department of Medicine, Room 2E4.37, Walter C. Mackenzie Health Sciences Center, Edmonton, Alberta, Canada, T6G 2B7 (E-mail: imayers{at}ualberta.ca).

Objectives: Heart function is variably impaired after cardiopulmonary bypass. We hypothesized that, similar to other myocardial injury states, cardiopulmonary bypass leads to enhanced activity of nitric oxide synthase and matrix metalloproteinases.
Methods: We obtained right atrial biopsy specimens and plasma samples at the onset and termination of cardiopulmonary bypass in 10 patients. Biopsy specimens were analyzed for nitric oxide synthase activity by using a citrulline assay, whereas plasma and tissue were analyzed for matrix metalloproteinase-9 and matrix metalloproteinase-2 activity by using zymography. Tissue inhibitor of metalloproteinase-4 was analyzed by means of Western blotting. The cellular expression of inducible nitric oxide, endothelial nitric oxide synthase, matrix metalloproteinase-2, and matrix metalloproteinase-9 was determined in right atrial biopsy samples from 3 additional patients by using the appropriate conjugated antibodies.
Results: Nitric oxide synthase activity increased from the beginning to the end of bypass (4.46 ± 1.07 vs 16.77 ± 4.86 pmol citrulline/mg of protein per minute, respectively; P = .018). Pro-matrix metalloproteinase-9 activity increased in hearts (199 ± 41 vs 660 ± 177 density units/mg protein; P = .008) and plasma (14.1 ± 4.6 vs 52.2 ± 5.9 density units/mg protein; P = .008). Pro-matrix metalloproteinase-2 activity increased in the heart (201 ± 23 vs 310 ± 35 density units/mg protein, P < .05) but not in plasma. Tissue inhibitor of metalloproteinase-4 expression in the heart decreased (1574 ± 280 vs 864 ± 153 density units, P = .014).
Conclusions: Cardiopulmonary bypass activates enzymes mediating acute inflammation and organ injury (ie, nitric oxide synthase, matrix metalloproteinase-9, and matrix metalloproteinase-2). Decreased tissue inhibitor of metalloproteinase-4 expression allows relatively unopposed increases in matrix metalloproteinase tissue activity. We postulate that these changes play a role in the pathogenesis of heart dysfunction after bypass surgery.

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