Stoica, Serban Constantin; (2003) An analysis of the relationship between cellular and functional recovery in clinical heart transplantation. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Objective: Cardiac transplantation is faced with a decreasing number of donors and a higher proportion of borderline donor hearts. The main cause of early death is donor organ failure, which is more commonly right ventricular (RV) failure for incompletely understood reasons. We aimed to describe the high energy phosphate (HEP) metabolism and endothelial cell activation (ECA) after brain death and subsequently throughout transplantation and to make correlations with functional performance. Patients and methods: Sixty-nine donor hearts (including 6 domino) were studied. Transmural biopsies were taken from both ventricles at 2 time points during the donor operation and repeated 3 times during implantation, in addition, heart transplant patients had postoperative biopsies taken at 1 week, 1 month and 3 months postoperatively during rejection surveillance. HEP were measured by bioluminescence and ECA markers were assessed in situ by immunohistology. The following markers were studied; P-sel, E-sel, VC AM-1, thrombomodulin, iNOs, hsp70 and the apoptotic markers Bcl-2 and Bax. 17 donors and 5 recipients also had intraoperative measurements with a conductance catheter inserted in the RV. Results: Brain death does not affect HEP metabolism quantitatively but is associated with upregulation of adhesion molecules and thrombomodulin depletion, a phenomenon which occurs in domino hearts too. The 2 ventricles are not affected differently, however important time- dependent changes are seen. HEP levels fall significantly during warm ischaemia and recover partially after 10 minutes of reperfusion. HEP levels before reperfusion are poorly predictive of donor organ failure. Dysfunctional organs sustain the biggest injury at reperfusion and overall fail to replenish their energy stores. The expression of adhesion molecules is progressively upregulated during the procedure and remains high postoperatively in the absence of histological rejection. Bcl-2 and hsp70 are not expressed in the acute phase. Conversely, Bax and iNOs are uniformly present in all vessels and the intensity of staining in the surrounding myocytes increases in time-dependent fashion. None of the tissue markers studied was predictive of donor organ failure. A dissociation was observed between HEP metabolism and contractile performance by pressure-volume loops. Conclusion: Clinical transplantation is associated with cumulative injury to the myocardium and the endothelium. Despite this, most hearts perform well postoperatively. The pathophysiology of donor organ failure remains unclear, but the biggest insult seems to be sustained at reperfusion. This characterisation should assist in preservation and organ protection efforts for cardiac transplantation.

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