Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation.
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 micromol/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 alpha, and transforming growth factor beta 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 alpha levels decreased with endothelin receptor blocker treatment (P = .02), whereas transforming growth factor beta 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.
Fedak
Paul W M
PW
Toronto General Hospital, University Health Network, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada.
Rao
Vivek
V
Verma
Subodh
S
Ramzy
Danny
D
Tumiati
Laura
L
Miriuka
Santiago
S
Boylen
Patty
P
Weisel
Richard D
RD
Feindel
Christopher M
CM
D000818:Animals; D015415:Biomarkers / Q000097:blood; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D016027:Heart Transplantation; D008955:Models, Cardiovascular; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009926:Organ Preservation; D018384:Oxidative Stress / Q000187:drug effects; D017466:Receptors, Endothelin / Q000378:metabolism; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013552:Swine; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D015415:Biomarkers; D016207:Cytokines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost