Natural history of atherosclerosis and hyperlipidemia in heterozygous WHHL (WHHL-Hh) rabbits. II. Morphologic evaluation of spontaneously occurring aortic and coronary lesions.

This study evaluated the morphologic appearance of spontaneous aortic and coronary atherosclerotic lesions in 21 of the 28, 3-year old, heterozygous Watanabe heritable hyperlipidemic (WHHL-Hh) rabbits whose lipid profiles were presented in part I of this report. In situ perfusion fixation of the arteries showed 100% of the aortas involved with one or another type of intimal lesion. In male rabbits (n = 13), the abdominal aortas had more severe fibrosis and more diffuse intima thickening than the thoracic aortas, (p < 0.001). In female rabbits (n = 8), fatty streaks and fibrous lesions were more predominant in the thoracic than in the abdominal aorta (p < 0.05). Fatty aortic plaques in the female were more commonly found in the abdominal than in the thoracic aorta, but this finding was not statistically significant. In contrast, fatty aortic plaques were not found in the male aortas; however, larger areas of diffuse intimal thickening with fatty deposits were more common in the abdominal aortas of the males (p < 0.01). Annular arteriosclerotic lesions, exclusive to the thoracic aorta, occurred in three of 21 rabbits. Histologically, the aortas demonstrated subintimal fibrosis, fragmentation of the lamina elastica interna, focal medial degeneration, and cholesterol clefts. The coronary arteries were involved in 85% of the males and in 86% of the females. Lesions were more common in the left than in the right coronary artery and primarily consisted of mild nonobstructing intimal hyperplasia with fibrosis. Based on these observations, we consider older WHHL-Hh rabbits excellent models for studying atherosclerosis. Because of their genetic and age-related lesions, WHHL-Hh rabbits may be superior to the cholesterol-fed rabbit model with respect to comparability with human atherosclerotic lesions.

Multiple ex vivo organ preservation with warm whole blood.

To determine the feasibility of en bloc removal of the heart, lungs, liver, kidneys, and pancreas for preservation with warm blood autoperfusion, organs from 34 dogs were preserved ex vivo for periods of between 3 and 22 hours. The lungs were ventilated with a Bird Mark 7 respirator, and the heart served as the pump to perfuse all organs of the multiple organ block. In the first group of 28 animals, surgical and pharmacologic techniques were developed to permit management of the ex vivo model. The last six experiments were conducted in a standardized fashion for a period of 6 hours and evaluated on the basis of hemodynamic, biochemical, and pathologic measurements. In this group the pH level remained stable and blood gas levels remained within normal limits for inspired oxygen of 0.2. Serum and urine electrolyte levels were easily maintained within normal limits. Serum enzyme values were elevated initially after operation, and this increase persisted throughout the preservation period in most animals. Continuing refinements in surgical technique, pharmacologic management, and chamber development resulted in a dramatic reduction of the edema and organ damage seen on pathologic studies of the initial experiments. The presence of focal lymphatic congestion, however, was noted even in the animals in group II and may have been related to ligation of major lymphatic channels or to endothelial loss. These changes could contribute to the development of the pathologic changes seen in irreversible shock. Preservation of the multiple organ block by warm autoperfusion is an important step in understanding the physiology of organ preservation and has potential for permitting prolonged organ preservation. Studies are continuing to further analyze this model and prolong the time of preservation. Final assessment of the model will be transplantation of the preserved organs and evaluation of function after implantation.

Hyperplasia of pancreatic duct epithelium produced by exposure to sodium deoxycholate.

Severe epithelial hyperplasia was produced in a canine model by the perfusion of the main pancreatic duct with 15 mM of deoxycholate at rates as low as 1.5 ml/day in 6 to 14 days. At higher rates (5 ml/day) deoxycholate caused complete epithelial cell lysis in the duct closest to the tip of the cannula with hyperplastic changes downstream from this section. Perfusion with a buffer solution alone and cannulation alone produced none of these changes in similar duct segments. No hyperplasia was seen in the upstream cannula obstructed duct, even in the presence of severe atrophy. Long-term (81 days) perfusion with 3 mM of deoxycholate at 3 ml/day resulted in more severe hyperplasia that still appeared benign. When glycine-conjugated deoxycholate was perfused through the duct, hyperplasia but no cell lysis was seen. In vitro, deoxycholate caused epithelial cell lysis in pancreatic duct fragments at concentrations of 0.5 mM and above. The results of this study suggest that secondary bile salts or other similar surface-active cytotoxic agents present in the biliary tree or duodenum may play a more important role in the pathogenesis of pancreatic ductal epithelial hyperplasia associated with pancreatic cancer than ductal obstruction.

Erythropoietic protoporphyria. IV. Protection from sunlight.

Dihydroxyacetone and lawsone, in a vanishing cream base, applied to the skin was found to protect patients with erythropoietic protoporphyria against sunlight. The use of the same ingredients in a 50% isopropyl alcohol/water solution did not induce adequate light protection. The chemically induced ultraviolet light filter in the stratum corneum allowed these patients to change their lives from an "indoor" to an "outdoor" environment.