This report traces the development of our knowledge about immune-complex arteritis from the early 20th Century to the present time. The emphasis is on the work which began with the seminal observations of serum sickness by Longcope, MacKenzie, and Rich, to the pathogenetic studies of serum sickness arteritis in rabbits by serveral groups including the outstanding contributions by Dixon and coworkers concerning the role of circulating immune complexes. This work was followed by investigations of the relationship to atherosclerosis revealed by the sustained studiesl by Minick et al. on serum sickness arteritis in hypercholesterolemic rabbits. This pioneering research work has more recently been of pivotal value in understanding the arteritis observed in certain primate species such as the cynomolgus and the nemestrina, in human lupus erythematosus, and in organ transplantion arteritis. More recently it has become apparent that one of the microscopic hallmarks of this type of immune complex injury is the concentic microarchitecture of the inflammatory arterial lesions, for which, when they are also lipid containing, we have coined the term artheroarteritis. The contributions of the neoantigens from glycosylated LDL and oxidized LDL to the development of this type of atheroarteritis are considered. New frontiers in this area of research are being opened by the PDAY study which offers new opportunities to link circulating immune complexes and new antigens to arheroarteritis with its accelerated stenotic arterial lesion development.

Smoking is considered a major risk factor for the development and progression of atherosclerosis. The effects of apolipoprotein E (apo E) and macrophages in the pathogenesis and progression of human atherosclerosis have not been adequately elucidated even though they are frequent components of the diseased arterial intima. Anatomically standardized samples of arteries from young people whose risk factor indices indicated them as "smokers" or "non-smokers" have been studied micromorphometrically. It was found that smokers have a greater area in which apo E is deposited in the early stages of the disease than do non-smokers. Smokers also demonstrated greater "macrophage foam cell populations" than did non-smokers. The study also demonstrates a positive correlation between the number of macrophage foam cells and the extent of apo E deposition in the developing lesions of the thoracic and abdominal aortas of white men aged 30-34 years who have evidence of recent cigarette smoking as determined by their postmortem blood thiocyanate levels.

Standardized postmortem samples of thoracic and abdominal aortas from traumatic death victims (aged 15-34 inclusive) were selected according to renal indices of estimated blood pressure. Half of the males had renal small-artery evidence of elevated blood pressure, and half did not. The group consisted of an approximately equal number of black and white males. All of the individuals were nonsmokers and had similar age, cholesterol, and HDL distribution. Lipid deposition in the thoracic and abdominal aorta sections was determined quantitatively by means of computer micromorphometry in sections stained with Oil Red O. Results showed that there is a marked increase in extracellular lipid deposition in the intima for those arteries studied with elevated renal indices of hypertension. In addition, there is significantly more extracellular lipid in the abdominal aortas in black males than in white males. Also notable was the finding that the thoracic aorta samples exhibited significantly thicker intimas and larger intimal areas in the high blood pressure index groups than in the low blood pressure index groups. These results suggest that the development of atherosclerotic lesions may be due to an increased deposition of extracellular lipid in the matrix of the arterial intima.

Elevated levels of low density lipoprotein (LDL) and smoking have long been recognized as risk factors for atherosclerosis and coronary heart disease (CHD). However, the mechanisms by which these factors contribute to the disease have not been fully elucidated. It has been postulated from in vitro studies using serum and LDL from smokers that smoking increases the oxidation of LDL, which in turn contributes to atherogenesis. We know of no direct evidence linking oxidized LDL (oxLDL) in human arteries to increased atherosclerosis in individuals who show elevated serum thiocyanate levels (HST) as an indicator of recent smoking. We have studied arterial samples from smokers micromorphometrically and found that 'smokers' have a greater area in which oxLDL can be identified in the early stages of the disease than do 'nonsmokers',i.e., individuals with low serum thiocyanate levels (LST). This study demonstrates a positive correlation between the extent of oxLDL in the fatty streaks as well as the fatty plaques of standardized core sample areas of the thoracic and abdominal aortas of a sample group of young people, aged 15-34, who have evidence of recent smoking based on their postmortem serum thiocyanate levels.

In a cooperative multicenter study (Pathobiological Determinants of Atherosclerosis in Youth, PDAY) of 1532 young persons 15 through 34 years of age who died of external causes and were autopsied in medical examiners' laboratories, we quantified atherosclerosis of the aorta and the right coronary artery. We analyzed postmortem blood cells for glycohemoglobin and postmortem serum for lipoprotein cholesterol and thiocyanate (as an indicator for smoking). We measured the thickness of the panniculus adiposus and the body mass index (weight per height squared) as indicators of adiposity. Glycohemoglobin levels exceeding 8% were associated with substantially more extensive fatty streaks and raised lesions in the right coronary artery in persons more than 25 years of age and with more extensive raised lesions in the aorta in persons more than 30 years of age. Both thickness of the panniculus adiposus and body mass index were associated with more extensive fatty streaks and raised lesions in the right coronary artery. The associations of atherosclerotic lesions with glycohemoglobin and adiposity were not explained by a less favorable lipoprotein profile or smoking. The results show that atherosclerosis in young adults is associated with the prediabetic or early diabetic state, as indicated by elevated glycohemoglobin levels, and with obesity.

A multi-institutional study, Pathobiological Determinants of Atherosclerosis in Youth (PDAY), was initiated to document the natural history of atherosclerosis, its relationship to risk factors, and the pathobiology of lesion development in young subjects. Pathology laboratories in nine centers collected arteries and tissues from >2000 persons, ages 15-34 years, whose deaths were attributed to homicides, accidents, or suicides. Arteries were evaluated for lesions, and risk factors were analyzed in a central laboratory. Postmortem risk factors include serum lipoproteins, serum thiocyanate (smoking), glycohemoglobin (diabetes), thickness of panniculus adiposus (obesity), changes in small renal arteries (hypertension), and apoprotein isoforms. This PDAY study documents the development of atherosclerosis at an early age and shows that the recognized risk factors for coronary heart disease are associated with lesion development in the arteries of these young subjects. The findings provide a strong justification for reducing risk factors in young persons.

In this progress report the major pathological results gained from the research program called The Pathological Determinants of Atherosclerosis in Youth (PDAY) are summarized. These results are made possible because of the many unique features of this multicenter study, which are also summarized. The following main accomplishments utilize special quantitative techniques to study cellular, chemical and molecular (genetic) features of the developing plaques in young people. These include for the first time:The greater incidence of early progressive lesions in selective apo E phenotypesThe greater incidence of progressive lesions in black youth with an apo B deletion genotypeThe much higher concentration of epitopes of oxidized LDL in smokers than non-smokersMore prevalent macrophages and lymphocytes in the standardized thoracic aortic samples, where lesions progress slowly, than in the abdominal aortic core samples, where lesions are much more likely to become severeA strong correlation between the mast cell population and the concentration of biogenic amines in the lesionsThe location of Lp(a) specific antigens in these developing lesions as compared to apo BThe accumulation of extracellular lipid where progression of lesions is most rapid, with special emphasis on the effects of smokingThe correlation of modulation of the intimal smooth muscle cells with the sites where progresion of the plaque is most frequentPreliminary ultrastructural evidence of intimal platelet and leukocyte adherence and entrance into the intima of the thoracic aorta, where there is likely to be lack of progression of lesionsA review of the recently published biochemical evidence of the correlation of increased lesion cholesterol and collagen content in the abdominal aortaThe continuing studies and their implications are also summarized.