title: Lipid overload and proteoglycan expression in chronic rejection of the human transplanted heart.
abstract: The degree to which transplant arteriopathy in solid organ allografts is an atheromatous process remains somewhat controversial. If atheromata develop as common and integral components of the arteriopathic lesions, then the process may be approached therapeutically in a manner analogous to native atheromatous diseases. Approaches to understanding the arteriopathic process may include not only the modulation of alloimmunity, but also the interruption of "storage" phenomena. We have examined the epicardial coronary arteries of nearly 50 explanted human heart allografts using biochemical, morphological, morphometrical, immunohistochemical, and molecular techniques in an effort to establish the degree, nature, and distribution of lipid accumulation in the vessel walls. Concomitantly, we studied the ascertainment of proteoglycan gene expression, represented by biglycan and decorin messenger RNA, and the localization of proteoglycan proteins in the vessels. The degree of lipid and proteoglycan buildup in both the intima and media of transplanted vessels is striking, and correlated strongly with intimal thickening, cross-sectional area reduction of the lumen, cumulative cyclosporine dose, corticosteroid dose, and serum cholesterol levels. Notably, lipid accumulation is not related to implant duration, this being true in an unselected series of "failed" allografts ranging from 4 to 1610 days post-transplant. The profound lipid accumulation in coronary walls of many grafts begins very early post-transplant and appears to contribute substantially to intimal thickening. Whether dysregulation of proteoglycan production leads to entrapment of lipids and lipoproteins remains an important and testable hypothesis.
authors.affiliation: St. Paul's Hospital, Cardiovascular Research Laboratory, University of British Columbia, Vancouver, Canada.
authors.forename: B M
authors.initials: BM
authors.lastname: McManus
authors.forename: G
authors.initials: G
authors.lastname: Malcom
authors.forename: T J
authors.initials: TJ
authors.lastname: Kendall
authors.forename: J M
authors.initials: JM
authors.lastname: Gulizia
authors.forename: J E
authors.initials: JE
authors.lastname: Wilson
authors.forename: G
authors.initials: G
authors.lastname: Winters
authors.forename: M R
authors.initials: MR
authors.lastname: Costanzo
authors.forename: S
authors.initials: S
authors.lastname: Thieszen
authors.forename: S J
authors.initials: SJ
authors.lastname: Radio
mesh_terms: D002908:Chronic Disease; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D003587:Cytomegalovirus / Q000302:isolation & purification; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006084:Graft Rejection / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D006801:Humans; D050356:Lipid Metabolism; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors
chemical_list: D011509:Proteoglycans