The Fate and Fibrogenic Potential of Subintimal Implants of Crystalline Lipid in the Canine Aorta

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 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.