Beta-adrenoceptor subtypes and catecholamines in the transplanted human heart.

The beta-adrenoceptor pathway is the best characterised of human receptors and the transplanted heart offered the opportunity to evaluate the effects of various pathological states on beta-adrenoceptor density in the absence of local presynaptic neuronal influences. The sympathoadrenal system plays an important role in both health and disease anda detailed understanding of the pathophysiological sequelae of cardiac transplantation is necessary if clinical management is to have a rational basis. Controversy surrounds the question of whether the human heart remains sympathetically denervated and whether beta-adrenoceptors upregulate following transplantation. In this thesis the effect of transplantation on the cardiac sympathoadrenergic system in humans was evaluated. The presence of both beta-adrenoceptor subtypes was demonstrated by radioligand binding and autoradiographic methods. The two subtypes appear behave differently, with beta1-adrenoceptors exhibiting significant variability during the first thirteen postoperative months and overall upregulation in the stable orthotopically transplanted heart compared to successfully transplanted donors. In the chronically failing transplanted heart beta1-adrenoceptors exhibit chamber specific right ventricular downregulation even though catecholamine analysis revealed that human hearts remain denervated for up to 30 months. In addition, there was no apparant relationship between receptor density and circulating levels of adrenaline, noradrenaline nor dopamine. An unexpected observation, was that apparantly "normal" donor hearts are nonhomogeneous and may have beta-adrenoceptor downregulation that is associated with the development of graft failure early following implantation. This has important implications for studies that use the unused donor heart as "normal controls" and suggests a potentially important area for future studies into methods of risk stratifying potential donors as well as research into mechanisms of neurogenic myocardial injury.