This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Khan, T. A. Articles by Sellke, F. W. Search for Related Content PubMed PubMed Citation Articles by Khan, T. A. Articles by Sellke, F. W. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Cardiomyopathy Edema Related Collections CV surgery: other Endothelium/vascular type/nitric oxide Other Vascular biology

(Circulation. 2005;112:I-196 – I-201.)
© 2005 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Aprotinin Preserves Cellular Junctions and Reduces Myocardial Edema After Regional Ischemia and Cardioplegic Arrest

Tanveer A. Khan, MD; Cesario Bianchi, MD, PhD; Eugenio Araujo, DVM, PhD; Pierre Voisine, MD; Shu-Hua Xu, PhD; Jun Feng, MD, PhD; Jian Li, MD, PhD; Frank W. Sellke, MD

From the Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.

Correspondence to Frank W. Sellke, MD, Chief, Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, 110 Francis St, LMOB 2A, Boston, MA 02215. E-mail fsellke{at}caregroup.harvard.edu

Background— Cardiac surgery with cardiopulmonary bypass (CPB) and cardioplegic arrest has been associated with myocardial edema attributable to vascular permeability, which is regulated in part by thrombin-induced alterations in cellular junctions. Aprotinin has been demonstrated to prevent activation of the thrombin protease-activated receptor, and we hypothesized that aprotinin preserves myocardial cellular junctions and prevents myocardial edema in a porcine model of regional ischemia and cardioplegic arrest.

Methods and Results— Fourteen pigs were subjected to 30 minutes of regional ischemia, followed by 60 minutes of CPB, with 45 minutes of crystalloid cardioplegia, then 90 minutes of post-CPB reperfusion. The treatment group (n=7) was administered aprotinin (40 000 kallikrein inhibitor units [KIU]/kg loading dose, 40 000 KIU/kg pump prime, and 10 000 KIU/kg per hour continuous infusion). Control animals (n=7) received normal saline. Myocardial vascular endothelial (VE)-cadherin, ß-catenin and -catenin, and associated mitogen-activated protein kinase (MAPK) pathways were assessed by immunoblot and immunoprecipitation. Histologic analysis of the cellular junctions was done by immunofluorescence. Myocardial tissue water content was measured. VE-cadherin, ß-catenin, and -catenin levels were significantly greater in the aprotinin group (all P<0.05). Immunfluorescence confirmed that aprotinin prevented loss of coronary endothelial adherens junction continuity. Aprotinin reduced tyrosine phosphorylation in myocardial tissue sections. Phospho-p38 activity was 30% lower in the aprotinin group (P=0.007). The aprotinin group demonstrated decreased myocardial tissue water content (81.2±0.5% versus 83.5±0.3%; P=0.01) and reduced intravenous fluid requirements (2.9±0.2 L versus 4.0±0.4 L; P=0.03).

Conclusions— Aprotinin preserves adherens junctions after regional ischemia and cardioplegic arrest through a mechanism potentially involving the p38 MAPK pathway, resulting in preservation of the VE barrier and reduced myocardial tissue edema.

Key Words: cardioplegia • cardiopulmonary bypass • cell adhesion molecules • edema • endothelium • ischemia • signal transduction