LIPID OVERLOAD AND PROTEOGLYCAN EXPRESSION IN CHRONIC REJECTION OF THE HUMAN TRANSPLANTED HEART

The degree to which transplant arteriopathy in solid organ allografts is an atheromatous process remains somewhat controversial. If atheroma ta develop as common and integral components of the arteriopathic lesi ons, then the process may be approached therapeutically in a manner an alogous to native atheromatous diseases. Approaches to understanding t he arteriopathic process may include not only the modulation of alloim munity, but also the interruption of ''storage'' phenomena. We have ex amined the epicardial coronary arteries of nearly 50 explanted human h eart allografts using biochemical, morphological, morphometrical, immu nohistochemical, and molecular techniques in an effort to establish th e degree, nature, and distribution of lipid accumulation in the vessel walls. Concomitantly, we studied the ascertainment of proteoglycan ge ne expression, represented by biglycan and decorin messenger RNA, and the localization of proteoglycan proteins in the vessels. The degree o f lipid and proteoglycan buildup in both the intima and media of trans planted vessels is striking, and correlated strongly with intimal thic kening, cross-sectional area reduction of the lumen, cumulative cyclos porine dose, corticosteroid dose, and serum cholesterol levels. Notabl y, lipid accumulation is not related to implant duration, this being t rue in an unselected series of ''failed'' allografts ranging from 4 to 1610 days post-transplant. The profound lipid accumulation in coronar y walls of many grafts begins very early post-transplant and appears t o contribute substantially to intimal thickening. Whether dysregulatio n of proteoglycan production leads to entrapment of lipids and lipopro teins remains an important and testable hypothesis.