Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development.

Oxidative modification of LDL increases its atherogenicity, and 15-lipoxygenase (15-LO) has been implicated in the process. To address this issue, we generated transgenic rabbits that expressed 15-LO in a macrophage-specific manner and studied their susceptibility to atherosclerosis development when they were fed a high-fat, high-cholesterol (HFHC) diet (Teklad 0533 rabbit diet 7009 with 10% corn oil and 0.25% cholesterol) for 13.5 wk. Transgenic and nontransgenic rabbits developed similar degrees of hypercholesterolemia and had similar levels of triglyceride, VLDL, LDL, and HDL. Quantitative morphometric analysis of the aortic atherosclerosis indicated that the transgenic animals (n = 19) had significantly smaller lesion areas (9.8+/-6.5%, mean+/-SD) than their littermate controls (n = 14, 17.8+/-15.0%) (P < 0.05). In a subgroup (n = 9) of transgenic rabbits that received the HFHC diet plus the antioxidant N',N '-diphenyl-phenylenediamine (1%), the extent of lesion involvement (9.8+/-7.5%) did not differ from the subgroup (n = 10) that received the regular HFHC diet (9.7+/-5.9%). Since the results were unexpected, we repeated the experiments. Again, we found that the nontransgenic littermates (n = 12) had more extensive lesions (11.6+/-10.6%) than the transgenic rabbits (n = 13; 9.5+/-7.8%), although the difference was not significant. In a third set of experiments, we crossed 15-LO transgenic rabbits with Watanabe heritable hyperlipidemic (WHHL) rabbits and found that the lesion area in the 15-LO transgenic/heterozygous WHHL rabbits (n = 14) was only about one third (7.7+/-5.7%) that found in nontransgenic heterozygous WHHL littermate controls (n = 11, 20.7+/-19.4%) (P < 0.05). These data suggest that overexpression of 15-LO in monocytes/macrophages protects against lipid deposition in the vessel wall during early atherogenesis in these rabbit models of atherosclerosis.

Variability in subjective review of umbilical cord blood colony forming unit assay.

BACKGROUND: The goal of this study was to quantitatively evaluate the reproducibility of current manual counting methods of colony forming units (CFUs) from umbilical cord blood samples METHODS: Fresh and reconstituted frozen cells from 10 cord blood samples were cultured under standard conditions. The number of BFU-Es, CFU-GMs, and CFU-GEMMs were counted by three expert reviewers using the standard microscope method and manually traced CFUs on digital images of cell cultures. RESULTS: The mean colony count based on the traced digital images was 82 (22% CV) and 52 (15% CV) for the fresh and frozen samples, respectively. This was significantly greater than that observed using the microscope, 61 (13% CV) for fresh and 43 (16% CV) for frozen. The difference was mainly due to the reviewers observing more CFU-GMs in the digital images than through the microscope review. All three reviewers agreed on the presence of a colony 72% of the time based on the digital review in both fresh and frozen samples. Reviewer agreement with respect to colony type in the fresh samples was 38% (22%CV), 25% (51%CV), and 6% (115%CV) for BFU-Es, CFU-GMs, and CFU-GEMMs, respectively. Reviewer agreement increased for BFU-Es and CFU-GMs in the frozen samples where fewer colonies were present. CONCLUSIONS: Although this study showed marked variability between reviewers, the analysis of manually traced digital images has the potential to improve inter-observer variation when compared to current methods by identifying features that lead to discrepancies in colony counting and providing cases with consensus results. © 2016 International Clinical Cytometry Society.

Association of Coronary Heart Disease Risk Factors with microscopic qualities of coronary atherosclerosis in youth.

BACKGROUND: This study examined whether atherosclerosis in young people is associated with the risk factors for clinical coronary heart disease (CHD). Methods and Results-Histological sections of left anterior descending coronary arteries (LADs) from 760 autopsied 15- to 34-year-old victims of accidents, homicides, and suicides were graded according to the American Heart Association (AHA) system and computerized morphometry. Risk factors (dyslipoproteinemia, smoking, hypertension, obesity, impaired glucose tolerance) were assessed by postmortem measurements. Approximately 2% of 15- to 19-year-old men and 20% of 30- to 34-year-old men had AHA grade 4 or 5 (advanced) lesions. No 15- to 19-year-old women had grade 4 or 5 lesions; 8% of 30- to 34-year-old women had such lesions. Approximately 19% of 30- to 34-year-old men and 8% of 30- to 34-year-old women had atherosclerotic stenosis > or =40% in the LAD. AHA grade 2 or 3 lesions (fatty streaks), grade 4 or 5 lesions, and stenosis > or =40% were associated with non-HDL cholesterol > or =4.14 mmol/L (160 mg/dL). AHA grade 2 or 3 lesions were associated with HDL cholesterol <0.91 mmol/L (35 mg/dL) and smoking. AHA grade 4 or 5 lesions were associated with obesity (body mass index > or =30 kg/m(2)) and hypertension (mean arterial pressure > or =110 mm Hg). CONCLUSIONS: -Young Americans have a high prevalence of advanced atherosclerotic coronary artery plaques with qualities indicating vulnerability to rupture. Early atherosclerosis is influenced by the risk factors for clinical CHD. Long-range prevention of CHD must begin in adolescence or young adulthood.

Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis.

Coronary vasospasm has been implicated as a cause of myocardial ischemia and sudden cardiac death in cocaine abusers. However, the mechanism or mechanisms remain unknown. Autopsy records (n = 5,871) from the medical examiner's files at Baltimore, Maryland and northern Virginia were examined and 495 persons (8.4%) were identified with positive toxicologic findings for cocaine. Of these, six subjects (1.2%) had total thrombotic occlusion, involving primarily the left anterior descending coronary artery. The mean number of adventitial mast cells per coronary segment and the degree of atherosclerosis were determined. These observations were compared with findings in age- and gender-matched subjects who died from cocaine overdose and in patients who had sudden cardiac death (acute thrombosis) without a history of illicit drug abuse. There were significantly more mast cells in subjects with cocaine-associated thrombosis than in the other groups. The number of mast cells showed a significant correlation with the degree of cross-sectional luminal narrowing (r = 0.68) in subjects with cocaine-associated thrombosis but not in subjects with sudden death due to thrombosis (r = 0.34, p less than 0.03). Subjects with cocaine-associated thrombosis also had significant coronary atherosclerosis without plaque hemorrhage (five had one or more vessels with greater than 75% cross-sectional area luminal narrowing) despite a mean age of 29 +/- 2 years. These findings suggest that adventitial mast cells may potentiate atherosclerosis and vasospasm, thrombosis and premature sudden death in long-term cocaine abusers.

Origin of atherosclerosis in childhood and adolescence.

Atherosclerosis begins in childhood as deposits of cholesterol and its esters, referred to as fatty streaks, in the intima of large muscular arteries. In some persons and at certain arterial sites, more lipid accumulates and is covered by a fibromuscular cap to form a fibrous plaque. Further changes in fibrous plaques render them vulnerable to rupture, an event that precipitates occlusive thrombosis and clinically manifest disease (sudden cardiac death, myocardial infarction, stroke, or peripheral arterial disease). In adults, elevated non-HDL-cholesterol concentrations, low HDL-cholesterol concentrations, hypertension, smoking, diabetes, and obesity are associated with advanced atherosclerotic lesions and increased risk of clinically manifest atherosclerotic disease. Control of these risk factors is the major strategy for preventing atherosclerotic disease. To determine whether these risk factors also are associated with early atherosclerosis in young persons, we examined arteries and tissue from approximately 3000 autopsied persons aged 15-34 y who died of accidental injury, homicide, or suicide. The extent of both fatty streaks and raised lesions (fibrous plaques and other advanced lesions) in the right coronary artery and in the abdominal aorta was associated positively with non-HDL-cholesterol concentration, hypertension, impaired glucose tolerance, and obesity and associated negatively with HDL-cholesterol concentration. Atherosclerosis of the abdominal aorta also was associated positively with smoking. These observations indicate that long-range prevention of atherosclerosis and its sequelae by control of the risk factors for adult coronary artery disease should begin in adolescence and young adulthood.

Cocaine: an independent risk factor for aortic sudanophilia. A preliminary report.

Several recent autopsy reports indicate an increased prevalence of coronary atherosclerosis in ischemic heart disease temporally associated with cocaine abuse. The objective of this study was to conduct a retrospective analysis of sudanophilic lesions in young asymptomatic individuals who abused cocaine. Twenty-six cases (15-34-year-old black males) were examined from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Sixteen subjects (mean age 25 +/- 1 years) had a positive toxicologic screen for cocaine and/or its major metabolites at autopsy and were confirmed habitual cocaine abusers. The remaining 10 cases (mean age 24 +/- 2 years) were subjects with a negative toxicologic screen at autopsy and no history of illicit drug abuse. Post-mortem blood was collected for lipoprotein analysis and determination of smoking status. The aorta and right coronary arteries were stained with Sudan IV and the degree and extent of sudanophilia was quantitated by image analysis. Multiple linear regression analysis of cocaine, age, smoking status, VLDL+LDL-C/HDL-C ratio and HDL-C as predictor variables of percentage intimal surface involvement, revealed an association between cocaine abuse and the extent of sudanophilia in both the thoracic and abdominal aorta (P = 0.002 and 0.049, respectively). Analysis of risk factors or of cocaine abuse as predictors of sudanophilia did not achieve statistical significance in the right coronary artery. These preliminary results suggest that habitual use of cocaine, through unknown mechanism(s), increases aortic sudanophilia independent of traditional risk factors.

Effect of age, race, body surface area, heart weight and atherosclerosis on coronary artery dimensions in young males.

Compensatory arterial enlargement in response to atherosclerosis has been demonstrated for the left main coronary artery. Only limited data is available on the interaction of patient characteristics and atherosclerosis with coronary artery dimensions. The purpose of the present study was to evaluate the influence of age, race, body habitus, heart weight and atherosclerosis on coronary artery dimensions of young males. Hearts from 137 young men (age 32 +/- 8 years; 78 black, 59 white) with unnatural deaths (homicide, suicide, accident, drug overdose) were perfusion-fixed, and histologic sections were obtained from the left main, proximal left anterior descending and left circumflex coronary arteries. Computerized planimetry was performed on Movat stained sections. Multiple regression analysis was used to evaluate the relative contribution of plaque size, age, race, heart weight and body surface area on coronary dimensions and compensatory enlargement in response to atherosclerosis. In the left anterior descending and left main coronary arteries, black race, body surface area and age were independent predictors of increased lumen area. In the left circumflex, age was a predictor of lumen area. Plaque area, black race and body surface area independently predicted increased area enclosed by the internal elastic lamina area. There was compensatory enlargement of internal elastic lamina with increasing plaque size in both races in the three arteries, but the percent luminal stenosis was greater in whites due to smaller artery size. Luminal narrowing did not develop until plaques occupied 30% of internal elastic lamina area. Among a population of young men with non-cardiac deaths, blacks have larger lumen and area enclosed by internal elastic lamina than whites. Age and body surface area are major determinants of lumen areas, and compensatory arterial enlargement was seen in all examined arteries in the present study.

Quantitative study of the rabbit aortic endothelium using vascular casts.

A quantitative study of the en face size and shape of rabbit endothelial cells from the ventral mid-thoracic and ventral infrarenal abdominal aorta has been carried out in 6 rabbits. Photomicrographs were taken from vascular casts of the rabbit aorta and the endothelial cell outlines were analyzed quantitatively using a digitizer and digital computer. The morphology of the endothelial cells was described using 8 calculated parameters (area, perimeter, length, width, angle of orientation, width:length ratio, axis intersection ratio and shape index). The endothelial cells in both locations had the same surface area (P greater than 0.30); however, the cells in the abdominal aorta were longer (P less than 0.01) and narrower (P less than 0.01) than those in the thoracic aorta. This fact is reflected by the smaller value for the shape index and width : length ratio in the abdominal aorta (P less than 0.01). Cells in both the thoracic and abdominal aorta were aligned with the flow direction.

Intersession repeatability of macular thickness measurements with the Humphrey 2000 OCT.

PURPOSE: This study was designed to determine intersession repeatability of measurements of macular thickness made with a commercially available optical coherence tomography (OCT) system. The images that can be routinely acquired with the commercial instrument differ significantly in quality from the images in the literature, which have mostly been acquired on prototype systems. METHODS: Multiple OCT images of the nasal macula were obtained from the right eye during three independent measuring sessions, using the Humphrey 2000 OCT system (Humphrey, San Leandro, CA). Twenty-six volunteers with no history of ocular disease participated in this investigation. Eyes in all subjects were undilated during scan acquisition. Scans were horizontal, 3 mm long, and through the fovea. Five scans were used from each session, for a total of 15 scans per subject. Retinal boundaries were automatically detected using custom software. Statistical software was used to calculate intersession and intrasession repeatability. Manual correction was performed on the automatically detected boundaries, and a second analysis was performed using these boundaries. RESULTS: When no manual correction of boundaries was performed, there were no significant effects between different sessions (P = 0.529) or between different scans within the same session (P = 0.509). Average retinal thickness was found to be 274 +/- 17 microm for a 1-mm long region 0.75 mm from the fovea. Individual scan averages differed from overall patient averages by 0 +/- 4.3 microm (99% confidence interval, 11.2 microm). CONCLUSIONS: OCT measurements of macular thickness made with the Humphrey 2000 OCT system are repeatable over different sessions with an expected variation of less than 11 microm (99% confidence interval).

Comparable proximal and distal severity of intimal thickening and size of epicardial coronary arteries in transplant arteriopathy of human cardiac allografts.

Previous angiographic observations have characterized transplant atherosclerosis as a generally diffuse and more distally severe disease with obliteration of secondary branches. However, it has not been firmly established that the disease is structurally and biologically more severe distally. We evaluated this hypothesis with computer-based digitization of subserial segments of the entire perfusion-fixed left anterior descending coronary artery (100 mm Hg for 1 hour with 10% formaldehyde solution) in 25 allografts at autopsy or explant (19 male and 6 female patients; mean age = 50 years, range 16 to 66; mean implant duration = 490 days, range 3 to 1610). The area, thickness, circumference of the intima and media, and the relative and absolute luminal narrowing were evaluated in a mean of 10 left anterior descending coronary artery sections per allograft. The percentage of luminal narrowing (intimal area/[intimal area + luminal area] x 100) was similar between proximal and distal segments of the left anterior descending coronary artery (45% versus 41%, p > 0.05), and the mean absolute intimal thicknesses (in millimeters) of proximal and distal segments of the left anterior descending coronary artery also were not different (0.32 versus 0.22, p > 0.05). In addition, the 95% confidence intervals for intimal thicknesses of proximal and distal segments were comparable. Because the absolute arterial size of proximal segments is naturally larger than that of distal segments (external diameter 9.37 versus 6.79, p < 0.0001), an appearance of progressive tapering may be visualized angiographically, even though the biologic severity of the disease is geographically uniform. Similarly, observations of obliterated secondary branches in distal segments may result from naturally smaller distal luminal areas which may be occluded by less intimal thickening than would be required proximally. These data emphasize that transplant atherosclerosis is biologically uniform from proximal to distal locations. Etiologic and pathogenetic studies on proximal or distal segments should be equally informative.

Gastric vascular ectasia in patients undergoing bone marrow transplantation.

The authors reviewed all gastric biopsy specimens from patients who had undergone bone marrow transplantation at our institution between 1986 and 1991. Ten of 28 patients had gastric vascular ectasia (GVE), a distinct lesion consisting of telangiectatic vessels within the superficial gastric mucosa. All patients undergoing bone marrow transplantation had received a standard chemotherapeutic transplantation regimen consisting of busulfan and cyclophosphamide without total-body irradiation. Eight of the 10 patients with GVE had evidence of upper gastrointestinal tract bleeding, as compared with 4 of 18 patients without GVE. In all 10 patients with GVE, the results of liver chemistry analyses were abnormal. Five patients had hepatic veno-occlusive disease, and 8 patients had graft-versus-host disease. Endoscopic biopsy samples of GVE showed markedly dilated vascular spaces similar to those seen in gastric antral vascular ectasia and diffuse antral vascular ectasia. However, no thrombi were identified in these enlarged vessels. Digital morphometry showed the mean cross-sectional area of GVE vessels was significantly greater (P < .001, Wilcoxon's rank-sum test) than the mean vessel areas of 10 chemical gastritis and 10 normal antral (control) biopsy samples. Gastric vascular ectasia may be a significant cause of gastrointestinal bleeding in patients undergoing bone marrow transplantation. The pathogenesis of GVE is unknown; transplantation regimen toxicity may play a role.

Age-related development of atherosclerotic plaque stress: a population-based finite-element analysis.

BACKGROUND: In order to identify those age-related factors in the development of coronary atherosclerosis that would affect the stability of the plaque system, we have developed idealized, finite-element, cross-sectional models of the arterial wall and associated lesions, derived from population-based data. METHODS: The physical development and morphology of coronary plaques was documented in the Pathobiological Determinants of Atherosclerosis in Youth histological study. Using this database, finite-element analysis models were created for five age groups (15-19, 20-24, 25-29 and 30-34 years) and for the 25 largest lesions. Cosmos (Structural Research, Inc., Los Angeles, California, USA) was used to create and analyze the models. RESULTS: The area of greatest stress shifted from the intima opposite the lesion in the 15-19 years age group to the edge of the cap and adjacent healthy tissue in the later age groups. Increasing age had a strong positive correlation with the shoulder stress level (r = 0.95) and the per cent stenosis correlated well with shoulder stress (r = 0.99, P < 0.002). Increasing the cap stiffness from a soft cap to a fibrous cap in the 30-34 year age group model resulted in a localized increase in shoulder surface stress by 10%. A calcified cap increased this shoulder surface stress by 30%. CONCLUSIONS: This finite-element analysis of the population-based data shows that the increase in stress appears to be closely related to the impaired load-bearing capability of the lipid pool that develops with age. The shoulder area of the lesion has been shown to be the location of most of the plaque fractures.

The clinical morphology of human atherosclerotic lesions. Lessons from the PDAY Study. Pathobiological Determinants of Atherosclerosis in Youth.

The PDAY study addresses the role traditional risk factors play in the development and progression of arterial lesions in youth (15 to 34 years of age). This autopsy based study indicates that in the aorta and in the right coronary artery, atherosclerosis is positively associated with cholesterol (LDL+VLDL), glucose intolerance, smoking, hypertension, and obesity and negatively associated with HDL-cholesterol. When a high cholesterol group (> 240 mg/dl) is compared to a low cholesterol group (< 200 mg/dl) early fatty sudanophilic lesions decrease in the aorta from 35% to 29% (p < 0.03) surface area, while raised atherosclerotic lesions are lowered (from 5%) in the high cholesterol group (to 3%) in the low cholesterol group; p < 0.02). Clearly, risk factors particularly cholesterol levels, directly affect the development of atherosclerosis in the coronary arteries and the aorta of young people. The data presented suggest that risk factor modification would be beneficial in young people as from 15 years of age.

Local intimal-medial uptakes of 125I-albumin, 125I-LDL, and parenteral Evans blue dye protein complex along the aortas of normocholesterolemic minipigs as predictors of subsequent hypercholesterolemic atherogenesis.

This report describes the normalized intimal-medial uptakes [uptake (M, mg.cm-2) divided serum concentration (c0, mg.cm-3)] of 125I-albumin, 125I-low-density lipoprotein (LDL), and in vivo Evans blue dye (EBD)-albumin complex as functions of pressure (P), time (t), molecular species (i), and location (z) along a ventral longitudinal z axis of the normal, intact, aortic endothelial surface in adult normocholesterolemic Sinclair Research Farm (SRF) minipigs and compares these uptake (M/c0) measurements with atherogenesis in hypercholesterolemic cohorts. Uptakes of porcine serum 125I-albumin (n = 21) and 125I-LDL (n = 10) were measured in freshly excised, metabolically supported aortas using a recently developed organ-support system. In vivo intimal-medial EBD uptake vs z data were measured photometrically on opened descending aortas from another group (n = 6) of normocholesterolemic, adult, SRF minipigs 18 hours after the intravenous administration of EBD. For comparison purposes, the corresponding incidence of atherosclerotic lesions along the aortic z axis was calculated using topographic data from hypercholesterolemic minipig cohorts (n = 39). The results showed that uptakes varied greatly with t, z, and macromolecule (i) but not with P. More specifically, the value of M/c0 at any location (z) rose with t, was insensitive to P, decreased with macromolecular (i) size, and varied with z in a pattern that "peaked" in the upstream region, decreased to a nadir in the downstream region, and then rose again as it approached the abdominal celiac orifice. The spatially z-averaged uptake rates for the three different labeled serum proteins were 0.31 x 10(-3) cm.h-1 for 125I-albumin, 0.42 x 10(-3) cm.h-1 for EBD-albumin, and 0.04 x 10(-3) cm.h-1 for 125I-LDL. Nondimensionalized analysis of the individual sets of uptake data indicated that the overall uptake relationship [M(t,P,z,i)/c(io), cm] could be characterized empirically by the simple product of two separate functions: one, a "scaling function" [m(z,i)], that described the uptake magnitude for a given i and z and appeared to be independent of t or P; the other, a "shape function" [s(t,P)], that described the shapes of the uptake vs t and P relationships and appeared to be independent of z or i. The "scaling function" [m(z,i)] vs z contour appeared to correlate well with the corresponding atherosclerotic lesion incidence vs z contour from the group of hypercholesterolemic minipig cohorts. Assuming passive transport, it was shown ("Appendix") that m(z,i) can be interpreted physically in terms of an endothelial diffusive permeability coefficient (P,cm.s-1).(ABSTRACT TRUNCATED AT 400 WORDS)

High resolution MR imaging and localization of laser-induced thermal injury in the vascular wall.

With the increasing use of lasers in surgical procedures, there is need for a noninvasive imaging modality to monitor laser-tissue interactions. MRI can be used readily for imaging human anatomy and holds the potential to map laser-induced thermal injury. This study investigates high resolution T1-weighted MR imaging of human aorta samples (in vitro) that have been damaged thermally using an argon ion laser and the corresponding histology. High resolution T1-weighted MR images (voxel size, .156 x .156 x .700 mm) clearly detected residual thermal injury as areas of bright signal intensity. Effective localization of thermal injury was achieved by subtraction of preinjury and postinjury slices with pseudocoloring of positive and negative differences. The results may serve as a basis from which to guide future in vivo studies.

Topography of human aortic sudanophilic lesions.

The topographic distribution of sudanophilic lesions in the human aorta has been defined using probability-of-occurrence maps for a population dying of trauma (male, black and white, 15-29 years, n = 109). The maps demonstrate that sudanophilic lesions are localized with a characteristic topography. Regions of high probability (greater than 60%) occurred in close proximity to regions of low probability (less than 10%). Although some high-probability areas are associated with expected low wall shear stress regions, many other high probability areas are not and thus no specific causal hemodynamic localizing factors could be identified. The probability maps do however form an important basis for the development of rational strategies of tissue sampling in studies concerned with the characterization of localizing factors (biochemical, cellular, hemodynamic, and structural) and their relationship to putative atherogenic mechanisms.

Bioequivalent or nonbioequivalent?

The current tests for bioequivalence are based on assumptions that are not valid in general; this paper shows why it is necessary to use a method that does not depend upon assumptions that cannot, and need not, be proved in general.

Statistical comparison of dissolution curves.

The purpose of this investigation was to develop statistical procedures to determine if two sets of dissolution curves could have come from the same population of curves. The f(2)statistic developed by the Food and Drug Administration, FDA, has been shown to have many limitations and is too liberal in concluding similarity between dissolution profiles. The procedure currently used by the FDA involves computing the mean amount dissolved at each time and then comparing the two mean curves. This approach ignores all of the variability within sets of profiles, which, from a statistical viewpoint, is a serious limitation. This investigation presents three different statistics for comparison of dissolution curves with associated decision rules and power functions. These three statistics are extensions of existing procedures: (1) an extension of the Mann--Whitney test which compares the variability within each set of profiles and between the two sets; (2) an extension of the Kolmogorov--Smirnov D statistic which compares three empirical cumulative distribution functions; and (3) an adaptation of the well known chi-squared test. A computer program, which includes the algorithm for each of the three statistics and varying sample sizes, is also available.

Cholesterol-fed and casein-fed rabbit models of atherosclerosis. Part 1: Differing lesion area and volume despite equal plasma cholesterol levels.

One-month-old male New Zealand White rabbits were fed either a cholesterol-free casein diet (CAS; n = 10); low-level cholesterol-supplemented (0.125% to 0.5% by weight) chow (CH; n = 10); or standard laboratory rabbit chow (n = 3) for 24 weeks, during which total plasma cholesterol (TPC) levels were matched for the two experimental groups (TPCCAS = 475 +/- 39 mg/dL; TPCCH = 515 +/- 70 mg/dL). The percentage of cholesterol partitioned into each of the lipoprotein fractions except high-density lipoprotein (HDL) was significantly different for the experimental groups: casein-fed rabbits had a primarily low-density lipoprotein (LDL) hypercholesterolemia while cholesterol-fed rabbits had approximately equal levels of very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL cholesterol. Despite matched TPC, lesions in CH animals covered twice the luminal surface area (as detected by oil red O staining; P < .05) and had three times the total volume compared with lesions in the CAS group (P < .05). Lesion volume was positively correlated with TPC and IDL and LDL cholesterol for the CAS group and with TPC and IDL cholesterol for the CH group. When the experimental groups were combined, TPC and VLDL and IDL cholesterol were positively correlated with the lesion volume. Probability of occurrence maps revealed, however, that both groups were virtually identical with respect to the topographic distribution of lesions in the thoracic and abdominal aortas. The data suggested that the differential partitioning of cholesterol into the lipoprotein fractions seen in CAS and CH rabbits influenced lesion area and volume but not topographic distribution.