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J Thorac Cardiovasc Surg 2005;129:407-415
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation

Toronto General Hospital, University Health Network, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada

Read at the Eighty-fourth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 25-28, 2004.

Received for publication May 4, 2004; accepted for publication September 2, 2004.

^* Address for reprints: Vivek Rao, MD, PhD, FRCS, EN14-222, Toronto General Hospital, 200 Elizabeth St, Toronto, Ontario, M5G 2C4, Canada (E-mail: vivek.rao{at}uhn.on.ca).

BACKGROUND: Endothelin is a potent inflammatory peptide associated with myocardial dysfunction, coronary vasculopathy, and reduced survival after cardiac transplantation. We hypothesized that endothelin antagonism during cardiac allograft storage would limit early endothelial dysfunction and improve myocardial performance after transplantation.

METHODS: Porcine orthotopic transplantations (n = 16) were performed after 6 hours of ischemic storage. Intermittent donor blood perfusion (control, n = 8) was compared with donor blood perfusion enhanced with 100 µmol/L of an endothelin receptor blocker (n = 8). Left ventricular performance was assessed after caval occlusion with a Millar micromanometer and conductance catheter. Coronary endothelial function was assessed in vitro with a macrovascular tissue bath apparatus. Myocardial endothelin, tumor necrosis factor , and transforming growth factor ß protein expression were determined. Oxidative stress was inferred on the basis of 8-isoprostane levels, and myocardial metabolism was inferred on the basis of the extraction or production of oxygen, acid, and lactate by the heart.

RESULTS: Endothelial function was diminished 48 hours after transplantation but not earlier. Endothelin receptor blocker treatment during preservation limited coronary endothelial dysfunction 48 hours after reperfusion (P = .001). Weaning from cardiopulmonary bypass and left ventricular performance after transplantation was improved in endothelin receptor blocker–treated hearts (P = .02). Myocardial endothelin expression was equivalent in both groups and increased during reperfusion after transplantation (P = .001). Tumor necrosis factor levels decreased with endothelin receptor blocker treatment (P = .02), whereas transforming growth factor ß levels did not change (P = .86). 8-Isoprostane, oxygen, acid, and lactate levels were similar, suggesting that oxidative stress and metabolism were not important mechanisms of benefit.

CONCLUSIONS: Endothelin accumulates during allograft storage and contributes to endothelial and myocardial dysfunction after transplantation. Endothelin blockade during allograft preservation limits endothelial injury and enhances ventricular recovery after transplantation.

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