William P. Newman

Risk Factors and Atherosclerosis in Youth Autopsy Findings of the Bogalusa Heart Study

The Collaborative Pathology Study is one of the most impressive programs of the Bogalusa Heart Study. Attempts are made to obtain complete and uniform necropsy coverage of all decreased young people who may have been examined in the Bogalusa Heart Study. Since 1978, autopsy specimens have been collected from 190 deaths, representing 65% of all known deaths in the study age category. The relation of antemortem risk factors for cardiovascular disease to early atherosclerotic lesions in the aorta and coronary arteries was assessed in those individuals previously examined in the Bogalusa Heart Study (N = 59). Aortic fatty streaks were strongly related to both total and low-density lipoprotein (LDL) cholesterol (r = 0.62, P < 0.0001 for each association), and were inversely correlated with the ratio of high-density lipoprotein (HDL) cholesterol to LDL plus very-low-density lipoprotein (VLDL) cholesterol (r = -0.29, P < 0.01). Coronary artery fatty streaks were associated with elevated total cholesterol, LDL cholesterol, VLDL cholesterol, and systolic blood pressure. Higher levels of LDL and VLDL cholesterol, triglycerides, systolic and diastolic blood pressure, and a lower ratio of HDL to LDL plus VLDL were found in those people with coronary artery fibrous plaques. Microscopy offered additional information about the characteristics of the aortic and coronary arterial intimal disease. Histologic observations have confirmed some of the relationships indicated with gross observations and show the complexity of this disease process. These findings emphasize the importance of an approach to preventive cardiology early in life.

Coronary heart disease in young black and white males in New Orleans: Community Pathology Study☆

The biracial population of New Orleans has a high overall mortality rate, high coronary heart disease (CHD) mortality rate, and high autopsy rate. In the New Orleans Community Pathology Study we investigated atherosclerosis and CHD in all deceased males aged 25 to 44 years, with major focus on the 52% of subjects from whom heart and arterial specimens were collected and evaluated according to standardized procedures. Morphologic correlates of CHD are the same in young black and white males. CHD mortality and mortality from cerebral hemorrhage, hypertensive heart disease, chronic renal disease, and diabetes are greater in young black males than young white males. Age, serum cholesterol, and hypertension were identified as important associated factors in the atherosclerotic process, as well as in CHD. The extent of coronary lesions seems to have decreased between 1960-1964 and 1969-1978 in young white males but not in blacks. Racial differences in coronary lesion involvement in non-CHD deaths are smaller than in our earlier studies.

NATURALLY OCCURRING AND EXPERIMENTAL ATHEROSCLEROSIS IN PRIMATES

In the last two decades, investigators have increasingly turned toward nonhuman primates as experimental models for the study of atherosclerosis. Kawamural and Hueper2 were not able to produce arterial lesions in rhesus monkeys, but Mann and coworkers in 1953 reported the experimental production of hypercholesterolemia and sudanophilic aortic lesions in Cebus monkeys fed high-cholesterol diets containing protein that was deficient in sulphur amino acids.3 Since their report, lipid-containing arterial lesions have been reported in rhesus, Cehus, woolly, and squirrel monkeys and in baboons and chimpanzees that have been fed experimental diets high in fat and cholesterol but varying in other constituents. Taylor and associates were first to produce a complete model of human atherosclerotic disease in prim a t e ~ . ~ One of their rhesus monkeys developed atherosclerotic coronary artery lesions leading to stenosis, thrombosis, and myocardial infarction. Taylor reviewed experimental atherosclerosis in primates in 1%5.6 Since his review, Wissler and his coworker^,^.^ Portinan and Andrus,B-lO and workers from Albany Medical College,f1-*3 Bowman Gray School of Medicine,l4-lU University of Cambridge,17 and Louisiana State U n i v e r ~ i t y ~ ~ ~ ~ ~ have reported experiments in which they have produced arterial lesions of varying severity in primates with different dietary regimens. Dr. Wisslers experimental models are described in this symposium.20

Long-term induction and regression of diet-induced atherosclerotic lesions in rhesus monkeys. I. Morphological and chemical evidence for regression of lesions in the aorta and carotid and peripheral arteries.

Atherosclerotic lesions were induced in rhesus monkeys by feeding a high-saturated fatty acid and high-cholesterol diet. After 5.4 years the extent of fatty streaks and raised lesions was evaluated in one group of animals (group P) by visual estimation in 10 arterial segments and chemically in four arterial segments. The remaining animals were switched to a basal regression diet low in cholesterol but high in saturated fatty acids for up to 3.7 years. Regression of lesions was evaluated in one group for 1.9 years (group R4) and in another for 3.7 years (group R5) after deleting cholesterol from the diet. The atherogenic diet increased serum cholesterol levels in all animals from a mean of 150 mg/dL to a mean of about 430 mg/dL. The atherogenic diet produced lesions in group P in all arterial segments (involving up to 50% of the arterial intimal surface) and increased cholesterol content in four arterial segments (varying between 443 and 506 micrograms/cm2). Switching to the basal regression diet decreased serum cholesterol levels to normal after 12 to 18 weeks. The switch to the basal diet significantly decreased the extent of fatty streaks in most arterial segments in both groups. Although differences in the mean extent of raised lesions among groups were not statistically significant, 7 of 10 arterial segments in group R4 and 9 of 10 segments in group R5 showed a lesser extent of raised lesions than in group P. Cholesterol content was lower (P < .05) in all four arterial segments in group R5 than in group P.(ABSTRACT TRUNCATED AT 250 WORDS)

Regression of experimental atherosclerotic lesions in rhesus monkeys consuming a high saturated fat diet.

Atherosclerotic lesions were induced in rhesus monkeys by feeding them a highfat, high-cholesterol diet for 2 years. Arteries were examined after autopsy of a subgroup of animals (group P) and cholesterol was removed from the diet of the remaining animals. Lesions were examined in other subgroups after 30 weeks (group R1) and after 52 weeks (group R2). A control group (group C) was fed the diet without cholesterol throughout the study. The mean total serum cholesterol concentration before, during, and after lesion induction was 151,390, and 157 mg/dl, respectively. The mean percent of surface area with fatty streak or fibrous plaque and the free and esterified cholesterol content of the artery increased in all six arterial segments examined in group P. The means for percent of surface with fatty streak and for arterial cholesterol content or concentration (but not for extent of surface with fibrous plaque) were consistently less in groups R1 and R2 than in group P, although they remained greater in groups R1 and R2 than in group C. The mean intimal thickness for coronary arteries was 10-fold greater in group P than in group C and 60 percent less in groups R1 and R2 than in group P; there was, however, much variability among animals and these differences among groups were not statistically significant. By using several measures in several arterial systems, we have shown that there was regression of dietinduced atherosclerotic lesions in rhesus monkeys while they were fed a diet high in saturated fat but without cholesterol for 30 or 52 weeks.

PATHOLOGY OF SUDDEN CORONARY DEATH

Sudden and unexpected death from coronary heart disease has been a major health problem throughout the world, especially in industrialized countries. Although progress has been made in determining the pathogenetic sequence of events leading to coronary heart disease and sudden death, many aspects of the process are still unknown. In our experience, most of these sudden deaths occur outside of the hospital or very shortly after the persons arrival. Autopsy materials from typical hospital-based studies do not include much of the information needed for a more complete description of the natural history of the disease. Our team of investigators has been studying atherosclerosis, coronary heart disease, and sudden death from a high percentage of all 25-44-year-old men dying in a well-delineated geographic location during a specified time period. This community-wide survey was designed to include men dying both inside and outside of hospitals. A large number of heart specimens, collected from young men dying of all causes, was examined by a team of pathologists according to a standardized protocol which required objective evaluation of findings and uniform application of definitions. This report focuses on the findings in sudden and not-sudden deaths from coronary heart disease in this 10-year study.

Long-term induction and regression of diet-induced atherosclerotic lesions in rhesus monkeys. II. Morphometric evaluation of lesions by light microscopy in coronary and carotid arteries.

Atherosclerotic lesions were induced in rhesus monkeys (Macaca mulatta) by feeding them a high-saturated fatty acid and high-cholesterol diet. After 5.4 years the extent of lesions in three major coronary arteries and the right carotid artery was evaluated morphometrically by light microscopy in one group of animals (group P). The remaining animals were switched to a low-cholesterol diet that remained high in saturated fatty acids and provided the same percentage of total calories as did the atherogenic diet. Lesion regression was then evaluated in one group of monkeys 1.9 years (group R4) and in another group of monkeys 3.7 years (group R5) after withdrawal of cholesterol alone from the diet. In group P, the mean intimal thickness varied between 26 and 47 microns, maximum intimal thickness between 70 and 92 microns, and luminal reduction between 9% and 12% in the three major coronary arteries. Luminal reduction varied between 1% and 11% in right carotid artery segments. After 1.9 years of consuming the basal diet, group R4 animals were no different from group P animals with respect to morphometric measures. Total intimal and medial areas of the left anterior descending (LAD) coronary artery in groups P and R4 were also similar. In contrast, after 3.7 years of consuming the basal diet, group R5 animals showed consistently although not statistically significantly lower values than those in group P for the morphometric measures in coronary arteries and total intimal area in the LAD. Similar results were obtained for the common carotid and external carotid arteries. Thus, our study shows that long-term diet-induced lesions in coronary arteries and in common and external segments of the right carotid artery regressed only when the animals were fed the basal diet for 3.7 years. We conclude that atherosclerotic lesions induced in coronary and carotid arteries can regress toward normal to a certain extent, but they require a longer time for regression than do other arterial segments. These findings support the results of clinical trials in human subjects.

EXPERIMENTAL ATHEROSCLEROSIS IN PRIMATES: A COMPARISON OF SELECTED SPECIES*

The similarity of anatomy, physiology, and phylogeny of subhuman primates to man is the principle reason for the increasing use of primates in research on experimental atherosclerosis. Several different primate species have been used in such studies, and although there are many similarities among them, it has become clear that not all primates react the same when placed on an atherogenic diet. We will examine some results that have been obtained by us and by other investigators to illustrate similarities or differences between several of the primate species that have most commonly been employed. However, since the only practical source of primates is animals trapped from the wild state, we would first like to review, briefly, the present knowledge on the extent of lesions in freeranging animals. NATURAL ESIONS

Insight into a bad omen for white men: Coronary artery disease—The Bogalusa Heart Study

Clinical experience of diagnostic and interventional procedures, including cardiac surgery, indicates a greater prevalence of coronary heart disease in white men than in other race-gender groups. Studies of children and young adults in the Bogalusa Heart Study have provided evidence that might account for this race-gender contrast. A variety of anthropometric and metabolic parameters influencing serum lipid and lipoprotein levels places white boys and young white men selectively at high risk for the development of atherosclerotic coronary artery disease. Obesity and greater central body fat, subtle aberrations in carbohydrate-lipid metabolic relations and variability in sex hormone profiles appear to underlie a trend to adverse lipoprotein changes in white men. A lower high-density lipoprotein cholesterol level and apolipoprotein A-l at puberty and a dramatic increase of low-density lipoprotein cholesterol are seen in young white men; such adverse changes identify them to be at greater risk. It is noteworthy that children whose fathers had myocardial infarction tend to be white. These children also have relatively high ratios of apolipoprotein B/apolipoprotein A-l and apolipoprotein B/low-density lipoprotein cholesterol. Studies of risk factors in children emphasize their importance in the early natural history of coronary artery disease. These findings show the need for beginning prevention of adult heart disease in childhood.