The fate and fibrogenic potential of subintimal implants of crystalline lipid in the canine aorta. Quantitative histological and autoradiographic studies.
Authors: B G Brown, D L Fry
Journal: Circulation Research (1978)

To determine the histological reaction to, and the rate of absorption of, different pure crystalline lipids from the aortic subintimal space, cholesterol (Ch), cholesteryl palmitate (ChP), glyceryl tripalmitate (TP), palmitic acid (PA), and dipalmitoyl lecithin (DPL) were implanted in the inner media of the thoracic aorta of 37 dogs.Tiny crystalline rods were fabricated averaging 0.29 mm in diameter and 2.0 mm in length.Twenty such rods were placed with a needle inserter 113 ± 52 (SD) /am beneath the exposed endothelial surface during two separate operations in each dog.In seven dogs, the lipids were 1 4C-labeled.The dogs were killed at intervals from 3 days to 20 months postoperatively and the implantation sites removed for quantitative histological and autoradiographic measurements.Ch, ChP, and TP were predicted to persist for 73, 50, and 2.4 years, respectively.PA and DPL were absorbed in 4 months.When compared to PA, DPL, and results of certain other control studies, Ch and ChP caused a significantly greater local fibrotic reaction and a marked fibromuscular proliferation of the overlying intima.Fibrotic encapsulation of the Ch and ChP implants was associated with a progressive decrease in their local medial and intimal tissue concentrations.When cholesterol was mixed with DPL, its absorption rate was increased 20-fold, and the anticipated local fibrogenic reaction, but not the intimal proliferative response, was abolished.Autoradiographic determinations of the distribution of tissue lipid concentrations support the concept that lipid transport from an implanted source occurs by the process of diffusion in the orthogonally anisotropic arterial media.Migration of phagocytic cells plays no significant role as a vehicle for lipid removal.The extraordinarily slow rate of absorption and the stimulus to connective tissue proliferation seen with crystalline cholesterol and its esters in this model are documented quantitatively.These observations provide one explanation for their observed persistence and their association with fibrosis and smooth muscle proliferation in the atherosclerotic plaque.THE ASSOCIATION among intimal lipid deposits in various states of aggregation, intimal collagen production, and smooth muscle proliferation is common to most models of atherosclerosis.The establishment of pathogenic relationships among these interacting components of the plaque continues to be one of the major investigational goals of studies of this disease. 1" 7 Abnormal transport of lipids or of various lipid-bearing substances in arterial tissue is thought to account for their progressive accumulation in atherogenesis.Intimal lipids appear in lipoprotein form, as coalescent droplets, and eventually as crystalline deposits.The latter are largely composed of cholesterol and certain of its esters. 8he crystalline configuration, referred to as the "cholesterol cleft," is one of high sterol density and is highly water insoluble.Much of the lipid in an advanced ather-