Carlos Restrepo

Variations in human aortic fatty streaks among geographic locations

Histologic features of aortic fatty streaks were examined in male subjects aged 10-39 from Guatemala, Jamaica Negro, Durban Bantu, New Orleans Negro, New Orleans white, Lima and Santiago. These groups were selected from the 19 available in the IAP (International Atherosclerosis Project) because they represented the greatest contrasts between the exten of fatty streaks in the young and raised lesions in the elders. Among these seven groups the extent of raised lesions in the older subjects was significantly but weakly correlated with the type of fatty streaks in the young as measureed by lesion thickness, content of demonstrable lipid, numbers of foam and spindle cells. The severity of leukocytic infilitration and prevalence of foci of necrosis in fatty streaks however, correlated strongly with raised lesions (rank r equals 0.90). We interpret this to imply that the presence of leukocytes and of foci of necrosis in the fatty streak marks its propensity to progress into raised lesions. If this formulation is correct, then the presence of both features in the histology of fatty streaks could be used as a marker in future studies of factors bearing upon the emergence of raised lesions out of fatty streaks.

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.

Polyps in a low-risk colonic cancer population in Colombia, South America

Colonic polyps were systematically searched for in 508 specimens collected from unselected autopsies in individuals more than 10 years of age from Medillin, Colombia, a low-indicidence geographic region for colorectal cancer. Adenomatous polyps have a low prevalence rate in both sexes, comparable to that found in Cali, Colombia, and other populations with low risk for cancer. They were found more frequently in the right side of the colon and are rare in the sigmoid colon. They begin to appear in the third decade of life in both sexes. Prevalence rates for single and multiple polyps increase with age in both sexes, males showing higher rates than females at every age group. Adenomatous polyps in this population are usually less than 3 mm in diameter and do not show villous changes or epithelial atypia. Hyperplastic polyps were more frequently observed than adenomatous polyps and rates show a progressive increase with age in both sexes. Multiplicity also increases with age. Most polyps are located in the low rectum and sigmoid followed by the cecum and ascending colon. Usually hyperplastic polyps are smaller than 3 mm in diameter and do not show epithelial atypia. Juvenile polyps were infrequently found in this series because children less than 10 years old were excluded. Diverticular disease was also rare and, when found, was not associated with adenomatous polyps. The association between adenomatous polyps and colonic cancer is discussed based on findings in this report.

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.

Use of serum lipid and apolipoprotein concentrations to predict extent of diet-induced atherosclerotic lesions in aortas and coronary arteries and to demonstrate regression of lesions in individual rhesus monkeys.

In most studies, the assessment of lesion regression is based on comparisons of group means between the progression and regression groups. This comparison depends on the assumption that the extent and distribution of lesions produced by the end of the lesion-induction period in the regression animals are equal to those observed in the progression group. To determine whether significant regression of lesions occurs in an individual regression animal, it is necessary to obtain a measure of the lesions produced in these animals at the end of the lesion-induction period. We achieved this goal by developing models using multiple stepwise regression analysis that related steady-state serum cholesterol and apolipoprotein B and A-I concentrations measured during a lesion-induction period in 27 rhesus monkeys fed an atherogenic high-saturated-fat/high-cholesterol diet for 2 years. The models were developed to estimate the percent of intimal surface with lesions, the esterified cholesterol content (micrograms/cm2) for the artery segments, and three histomorphometric measures (mean intimal thickness, mean maximal intimal thickness, and mean percent stenosis) for the coronary arteries. In these models, multiple R2 ranged from 0.42 to 0.74 for the aortas and peripheral arteries, indicating that approximately one half to three fourths of the variance in lesions was accounted for. For the three histomorphometric measures in coronary arteries, however, the multiple R2 was 0.27 or 0.28, indicating that only approximately one fourth of the variance in lesions was accounted for.(ABSTRACT TRUNCATED AT 250 WORDS)

Geographic comparisons of diffuse intimal thickening of the aorta

Aortic intimal thickness was measured microscopically in samples taken from areas grossly free of atherosclerotic lesions of 2,472 subjects aged 15 through 64 years collected during the first year of the International Atherosclerosis Project (IAP). Results indicate that there is progressive increase in aortic intimal thickness with increasing age in both sexes. No differences were observed between the upper thoracic and abdominal aorta. Mean intimal thickness does not appear to be consistently thicker in males than in females. Some differences were found in mean thickness among the 19 location--race groups included; however, such differences did not parallel those observed among the same location--race groups by the mean level of atherosclerosis. A few subjects with Coronary Heart Disease (CHD) and atherosclerosis-related cases had slightly thicker intimas. Diffuse Intimal Thickening (DIT) detected grossly correlates well with thicker means of intimal thickness in both sexes in the abdominal aorta and the thoracic aorta in females. DIT appears to be a universal phenomenon mainly age-dependent; it also appears to be increased in some (CHD) and atherosclerosis-related conditions.

Microscopic morphometry of abdominal aorta from men in New Orleans and Guatemala.

Morphometric light microscope measurements were made on 154 abdominal aortas from 77 Guatemalan Indian-white (ladinos) men and from 77 New Orleans white men, aged 15 to 54 years. In each case, means were derived from 12 points measured independently. A progressive increase in intimal lipid with increasing age was observed in men from both countries. Extracellular intimal lipid was consistently higher in men from New Orleans than in those from Guatemala, although not always significantly so. Intimal thickness followed a similar pattern to intimal lipid regarding age and geographic location. Foam cells and leukocytes (mainly monocytes) did not follow a consistent pattern. The smooth muscle cell count was the only variable that was significantly greater in New Orleans men than in Guatemalans aged 15 to 34 years. Morphometric microscopic measurements were significantly correlated with unaided visual estimates of atherosclerotic lesions and with chemical determinations of lipid fractions in the arterial intima. All three methods, gross grading, microscopy, and chemistry, agree in revealing little or no measureable difference between New Orleans men and Guatemalans younger than 35 years, but an accelerated divergence of the populations over age 35.

Pregnancy and atherosclerosis

Abstract We have compared the extent of atherosclerotic lesions in women dying while pregnant with those in women dying accidentally. For this study we used arteries from autopsied persons in geographically distinct human populations. These specimens were prepared and evaluated using standardized techniques and formed part of the material collected for the International Atherosclerosis Project. There were no consistent differences in mean extent of fatty streak involvement between pregnancy and accidental cases. In the pooled cases from geographic locations with high and medium levels of atherosclerotic lesion involvement, pregnant women aged 25–34 years had significantly more abdominal aortic fatty streaks than non-pregnant women who died in accidents. No significant differences in aortic fatty streaks were detected in the younger and older pregnant and non-pregnant women nor in those women from location-race groups with low levels of atherosclerosis. Pregnant women in the 35–44 year age group, on the average, had significantly less fatty streaks in the left anterior descending coronary than non-pregnant women. Significant differences in raised atherosclerotic lesions (fibrous plaques, complicated and calcified lesions) were neither expected nor found in either the abdominal aorta or left anterior descending coronary artery. Despite the paucity of significant differences and inconsistent differences, the results suggest that pregnancy may have some relation to the extent of fatty streak involvement in certain age groups, arterial segments, and selected populations.

Serum Cholesterol and Triglyceride Levels in Human Populations From Guatemala City and New Orleans

Abstract A real difference in serum cholesterol levels exists between male blood donors in New Orleans and Guatemala ( P Levels of serum cholesterol in donors parallel arterial atherosclerotic involvement in autopsied cases from the same geographic locations. The difference in cholesterol levels is not as much as might be expected considering the large difference in per cent surface involvement with atherosclerotic lesions. A real difference in mean serum triglyceride levels exists between male blood donors in New Orleans and Guatemala ( P Smoking habits are different among blood donors from New Orleans and Guatemala. The New Orleans men smoke at an average greater rate than Guatemalan men (17 vs 7 cigarettes per day). Systolic blood pressure is higher for New Orleans donors than for Guatemalan donors (135 vs 120 mm Hg; P Combined risk factors for CHD are found more frequently in the New Orleans donors than in the Guatemalan donors.