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Lipid overload and proteoglycan expression in chronic rejection of the human transplanted heart
B M McManus1, G Malcom, T J Kendall
1St. Paul's Hospital, Cardiovascular Research Laboratory, University of British Columbia, Vancouver, Canada.
Insights
Transplant arteriopathy in heart allografts involves significant lipid and proteoglycan buildup, contributing to intimal thickening. This process, crucial for understanding graft failure, occurs early and is linked to medication and cholesterol levels.
Area of Science:
- Cardiovascular Pathology
- Transplantation Immunology
- Biomedical Engineering
Background:
- Transplant arteriopathy (TA) in solid organ allografts is a major cause of graft loss.
- The extent to which TA is an atheromatous process is debated, impacting therapeutic strategies.
- Understanding TA's mechanisms may involve alloimmunity and lipid "storage" phenomena.
Purpose of the Study:
- To investigate the degree, nature, and distribution of lipid accumulation in human heart allograft coronary arteries.
- To assess proteoglycan gene expression and protein localization in these vessels.
- To correlate lipid and proteoglycan buildup with clinical factors and intimal thickening.
Main Methods:
- Examination of nearly 50 explanted human heart allografts.
- Utilized biochemical, morphological, morphometrical, immunohistochemical, and molecular techniques.
- Analyzed epicardial coronary arteries for lipid and proteoglycan content.
Main Results:
- Striking lipid and proteoglycan accumulation observed in the intima and media of transplanted vessels.
- Buildup strongly correlated with intimal thickening, lumen area reduction, and cumulative immunosuppressant doses (cyclosporine, corticosteroids), and serum cholesterol.
- Lipid accumulation was not related to implant duration, appearing early post-transplant.
Conclusions:
- Lipid and proteoglycan accumulation significantly contribute to intimal thickening in heart allografts.
- Early lipid deposition suggests a critical role in the pathogenesis of transplant arteriopathy.
- Dysregulation of proteoglycan production as a mechanism for lipid entrapment warrants further investigation.
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.