Enhanced Aortic Macrophage Lipid Accumulation and Inflammatory Response in LDL Receptor Null Mice Fed an Atherogenic Diet

The effect of an atherogenic diet on inflammatory response and elicited peritoneal macrophage (Mϕ) cholesterol accumulation in relation to aortic lesion formation was assessed in LDL receptor null (LDLr−/−) mice. Mice were fed an atherogenic or control diet for 32 weeks. The atherogenic relative to control diet resulted in significantly higher plasma monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) concentrations, more aortic wall Mϕ deposition, higher serum non HDL-cholesterol concentrations and total cholesterol to HDL-cholesterol ratios, and greater accumulation of both aortic free and esterified cholesterol. Elicited peritoneal Mϕ selectively accumulated longer chain unsaturated fatty acids in their membrane, independent of the dietary fatty acid profile. Elicited peritoneal Mϕ isolated from mice fed the atherogenic relative to control diet had significantly less arachidonic acid levels, accumulated significantly higher esterified cholesterol, had significantly higher mRNA levels and secretion of MCP-1, and mRNA and protein levels of ATP-binding cassette A1. Diet treatment had no significant effect in elicited peritoneal Mϕ on TNFα and IL-6 mRNA levels and secretion. These data suggest that the atherogenic relative to control diet resulted in higher plasma inflammatory factor concentrations, less favorable lipoprotein profile, higher elicited peritoneal Mϕ cholesterol accumulation and inflammatory factor secretion, and more aortic wall Mϕ deposition, which in turn were associated with greater aortic cholesterol accumulation.     

Plasma cholesterol turnover and esterification in the pigeon

The plasma cholesterol turnover and serum cholesterol esterifying system was studied in White Carneau pigeons. Eight pigeons received a single injection of 1,2-³H-cholesterol intravenously and the decline in plasma cholesterol specific activity was measured at intervals from 1–64 days. Kinetic analysis of the plasma cholesterol die-away curves indicates that plasma cholesterol turnover in the pigeon conforms to a 2 pool model. The mass of pool A (cholesterol in blood and those tissues which are rapidly equilibrated with blood) in pigeons maintaining consistently high serum cholesterol levels (≈900 mg/100 ml) was 988 mg and the daily fractional turnover of pool A was 19.7% compared with 676 mg and 12.2% found in pigeons maintaining consistently low (≈400 mg/100 ml) serum cholesterol levels. Serum cholesterol esterifying activity, in vitro, showed a positive correlation (rxy=0.806) with serum cholesterol concentration in the pigeon. The pigeon differs, in this regard, from the chicken, rat and rabbit in which a negative correlation has been reported.     

Atherosclerosis and plasma and liver lipids in nine inbred strains of mice

Nine inbred strains of mice, which are progenitors of recombinant inbred sets, were evaluated for aortic lesion formation and plasma and liver lipid levels. This survey was done to determine if a semi-synthetic high-fat diet could elicit the same extent of diet-induced atherosclerosis as that observed in mice fed a natural ingredient highfat diet and to discover strain-specific plasma and liver lipid variants for future genetic characterization. Evaluation of aortic lesions after 18 wk of diet consumption showed that strains C57BL/6J, C57L/J, SWR/J and SM/J were susceptible to atherosclerosis and that A/J, AKR/J, C3H/HeJ, DBA/2J and SJL/J were relatively resistant. High-density lipoprotein cholesterol (HDL-C) levels were negatively correlated to lesion formation. Susceptible strains had decreased HDL-C levels when switched from chow to the semi-synthetic high-fat, high cholesterol diet, whereas resistant strains either showed no change or a slight increase in HDL-C levels. The exception to this pattern was found in SM mice, which were susceptible to aortic lesion formation but maintained the same HDL-C level on both chow and high-fat diets. HDL size differed among the strains, and levels of plasma apolipoprotein A-I and A-II correlated with HDL-C levels. Liver damage was not correlated to HDL-C levels or to susceptibility to atherosclerosis. Mice from strain A, which are resistant to atherosclerosis, had evidence of liver damage as observed by elevated levels of plasma alanine aminotransferase activity, by liver histology, by increased liver weight and by exceptionally high hepatic cholesterol content. For all strains, the levels of liver cholesterol and triglycerides were inversely correlated with each other; phospholipids did not vary greatly among strains. No remarkable differences in hepatic fatty acid profile were noted among the strains fed the atherogenic diet, but the fatty acid profile did differ considerably from that found in the diet itself.     

Vitamin E,cholesterol, and lipids during atherogenesis in rabbits

Rabbits were fed diets including cholesterol and 10% butterfat to determine whether polyunsaturated butter (9% 18∶2) would be less atherogenic than normal saturated butter (3% 18∶2) when fed for 12 weeks. The cholesterol diets alone, 0.5% or 2%, produced aortic plaque development, and plasma cholesterol increased 20 times, lipids increased 10 times, and vitamin E increased 5 times. The inclusion of both fat and cholesterol in the diet produced a synergistic effect, doubling these values to 40 times for cholesterol, 20 times for lipids, and 10 times for vitamin E. The higher circulating levels of cholesterol caused increased tissue levels of cholesterol. With 2% cholesterol and fat, liver and aorta cholesterol increased 10 times, heart 4 times, and muscle cholesterol 2 times. The lower 0.5% dietary cholesterol load was successful in limiting the amount of tissue cholesterol increase. Liver, aorta, heart, and muscle levels of cholesterol were only about half the concentration attained when 2% cholesterol was fed. It was concluded that there were no differences in plasma or tissue cholesterol, vitamin E, or atherosclerosis attributable to the polyunsaturated nature of the diet. The 10% butterfat diets alone, whether saturated or unsaturated, did not induce aortic plaques and did not increase blood or tissue cholesterol, lipids, or vitamin E. Our results suggest that the lipid mobilizing effect is mediated by cholesterol, probably by conversion to bile acids and a stimulation in intestinal absorption.     

Soluble fiber and soybean protein reduce atherosclerotic lesions in guinea pigs. Sex and hormonal status determine lesion extension

These studies were undertaken to assess guinea pigs as potential models for early atherosclerosis development. For that purpose, male, female, and ovariectomized (to mimic menopause) guinea pigs were fed a control or a TEST diet for 12 wk. Differences between diets were the type of protein (60% casein/40% soybean vs. 100% soybean) and the type of fiber (12.5% cellulose vs. 2.5% cellulose/5% pectin/5% psyllium) for control and TEST diets, respectively. Diet had no effect on plasma cholesterol or triacylglycerol (TAG) concentrations; however, there were significant effects related to sex/hormonal status. Ovariectomized guinea pigs had higher plasma cholesterol and TAG concentrations than males or females (P<0.01). In contrast to effects on plasma lipids, hepatic cholesterol and TAG were 50% lower in the TEST groups (P<0.01) compared to controls. Low density lipoproteins (LDL) from guinea pigs fed the TEST diet had a lower number of cholesteryl ester (CE) molecules and a smaller diameter than LDL from controls. Atherosclerotic lesions were modulated by both diet (P<0.0001) and sex (P<0.0001). Guinea pigs fed the TEST diet had 25% less lesion extension whereas males had 20% larger occlusion of the arteries compared to both female and ovariectomized guinea pigs. Significant positive correlations were found between LDL CE and atherosclerotic lesions (r=0.495, P<0.05) and LDL size and fatty streak area (r=0.56, P<0.01). In addition, females fed the TEST diet had the lowest plasma and hepatic cholesterol concentrations, the smallest LDL particles, and the least atherosclerosis involvement compared to the other groups. These data indicate that dietary factors and sex/hormonal status play a role in determining plasma lipids and atherosclerosis in guinea pigs.     

Effects of cholesterol oxidation derivatives on cholesterol esterifying and cholesteryl ester hydrolytic enzyme activity of cultured rabbit aortic smooth muscle cells

The effects of 5 μg/ml of 25-hydroxycholesterol; cholestane-3β, 5α,6β-triol; and cholesterol on acyl CoA cholesterol acyltransferase, acid cholesteryl ester hydrolase and neutral cholesteryl ester hydrolase was studied in cultured rabbit aortic smooth muscle cells. After 1 hour incubation, 25-hydroxycholesterol resulted in a fourfold stimulation of acyl CoA cholesterol acyltrans-ferase activity. No stimulation by 25-hydroxycholesterol was noted before 15 minutes or after 5 hours of incubation. Neither cholestane-3β,5α,6β-triol nor cholesterol influenced acyl CoA cholesterol acyltransferase activity at any time interval. No significant effects of any of the sterols were noted on acid cholesteryl ester hydrolase or neutral cholesteryl ester hydrolase activity. The imbalance between acyl CoA cholesterol acyl trans-ferase and hydrolase activities induced by 25-hydroxycholesterol could result in cholesteryl ester accumulation by arterial smooth muscle cells, which may be associated with atherosclerosis.     

Pravastatin Prevents Aortic Atherosclerosis via Modulation of Signal Transduction and Activation of Transcription 3 (STAT3) to Attenuate Interleukin-6 (IL-6) Action in ApoE Knockout Mice

The purpose of this study was to determine whether pravastatin’s prevention of aortic atherosclerosis via attenuation of IL-6 action depends on modulation of STAT3 activity. Male apoE knockout (apoE-/-) mice fed on a diet containing 1.25% cholesterol (wt/wt) were divided into pravastatin group provided with pravastatin (80 mg kg^-1 per day) and atherosclerosis group. After eight weeks, pravastatin significantly prevented atherosclerotic lesion and reduced levels of IL-6 in serum and lesion, and significantly decreased expressions of phosphorylated STAT3 (pSTAT3) and increased suppressor of cytokine signaling 3 (SOCS3) expressions in lesions. Our results suggested that pravastatin’s aortic atherosclerosis preventing action via attenuation of IL-6 action may partially depend on modulation of STAT3 activity.     

Perilla Oil Reduces Fatty Streak Formation at Aortic Sinus via Attenuation of Plasma Lipids and Regulation of Nitric Oxide Synthase in ApoE KO Mice

Consumption of n‐3 polyunsaturated fatty acids (PUFA) is associated with a reduced incidence of atherosclerosis. Perilla oil (PO) is a vegetable oil rich in α‐linolenic acid (ALA), an n‐3 PUFA. In this study, antiatherogenic effects and related mechanisms of PO were investigated in atherosclerotic mice. Apolipoprotein E knockout (ApoE KO) mice (male, n = 27) were fed high‐cholesterol and high‐fat diets containing 10 % w/w lard (LD), PO, or sunflower oil (SO) for 10 weeks. Plasma triglyceride, total cholesterol, and low‐density lipoprotein cholesterol concentrations reduced in the PO and SO groups compared to the concentrations in the LD group (P < 0.05). The PO group showed reduced fatty streak lesion size at the aortic sinus (P < 0.05) compared to the sizes in the LD and SO groups. A morphometric analysis showed enhancement of endothelial nitric oxide synthase expression and reduction of inducible nitric oxide synthase expression in the PO group compared to that in the LD group (P < 0.05). Furthermore, aortic protein expression of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1 was diminished in the PO group compared to that in the LD and SO groups (P < 0.05). These findings suggested that PO inhibited the development of aortic atherosclerosis by improving the plasma lipid profile, regulating nitric oxide synthase, and suppressing the vascular inflammatory response in the aorta of ApoE KO mice.     

Lipopolysaccharide and tyloxapol accelerate the development of atherosclerosis in mice

The occurrence of atherosclerosis is closely related to inflammation and lipid metabolism disorder. It has been found that lipopolysaccharide (LPS) could induce inflammation, and tyloxapol (Ty) could induce hyperlipidemia. However, the effects of LPS and Ty on the development and mechanism of atherosclerosis have not been investigated thoroughly. To answer this question, we used assay kits to detect total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) content to evaluate dyslipidemia. We used hematoxylin and eosin staining to evaluate the pathological structure of the aorta and liver, and then used Oil Red O staining to access lipid accumulation in the aortic wall. Subsequently, we used the alanine transaminase (ALT) kit to examine the liver injury. Finally, we used the Western blot experiment to measure proteins that regulate lipid metabolism. We found that the LPS + Ty group could increase the levels of TC, TG, and LDL in the serum and promote lipid accumulation in the aortic wall in mice. Moreover, our study showed that the LPS + Ty group induced pathological changes in hepatocytes and increased ALT content in mice. Significantly, we found that the LPS + Ty group could activate acetyl-CoA carboxylase, sterol regulatory element-binding protein-1c, and inhibit peroxisome proliferator-activated receptors α in mice. Therefore, we suppose that LPS and Ty aggravated the development of atherosclerosis by promoting hyperlipidemia and the disorder of lipid metabolism in mice. These findings are significant for the study of the pathogenesis of atherosclerosis and the selection of animal models.     

Conjugated linoleic acid isomers reduce blood cholesterol levels but not aortic cholesterol accumulation in hypercholesterolemic hamsters

The aim of the present study was to characterize plasma lipids and lipoprotein cholesterol and glucose concentrations in hamsters fed either cis-9, trans-11 CLA (9c, 11t CLA); trans-10, cis-12 CLA (10t, 12c CLA); or linoleic acid (LA) on the accumulation of aortic cholesterol in hypercholesterolemic hamsters. One hundred male F₁B strain Syrian Golden Hamsters (Mesocricetus auratus) (BioBreeders Inc., Watertown, MA) approximately 9 wk of age were housed in individual stainless stel hanging cages at room temperature with a 12-h light/dark cycle. Hamsters were given food and water ad libitum. Following a 1-wk period of acclimation, the hamsters were fed a chow-based (nonpurified) hypercholesterolemic diet (HCD) contaning 10% coconut oil (92% saturated fat) and 0.1% cholesterol for 2 wk. After an overnight fast, the hamsters were bled and plasma cholesterol concentrations were measured. The hamsters were then divided into 4 groups of 25 based on similar mean plasma VLDL and LDL cholesterol (non HDL-C) concentrations. Group 1 remained on the HCD (control). Group 2 was fed the HCD plus 0.5% 9c, 11t CLA isomer. Group 3 was fed the HCD plus 0.5% 10t, 12c CLA isomer. Group 4 was fed the HCD plus 0.5% LA. Compared with the control, both CLA isomers and LA had significantly lower plasma total cholesterol and HDL cholesterol concentrations (P<0.001) after 12 but not 8 wk of treatment and were not significantly different from each other. Also, both CLA isomers had significantly lower plasma non HDL-C concentrations (P<0.01) compared with the control after 12 but not 8 wk of treatment and were not significantly different from each other or the LA-fed hamsters. Plasma TG concentrations were significantly higher (P<0.004) with the 10t, 12c CLA isomer compared with the other treatments at 8 but not at 12 wk of treatment. Plasma TG concentrations were also significantly lower (P<0.03) with the 9c, 11t CLA isomer compared with the control at 12 wk of treatment. Also, the 10t, 12c CLA isomer and LA had significantly higher plasma glucose concentrations compared with the control and 9c, 11t CLA isomer (P<0.008) at 12 wk of treatment whereas at 8 wk, only the LA treatment had significantly higher plasma glucose concentrations (P<0.001) compared with the 9c, 11t CLA isomer. Although liver weights were significantly higher in 10t, 12c CLA isomer-fed hamsters, liver total cholesterol, free cholesterol, cholesterol ester, and TG concentrations were significantly lower in these hamsters compared with hamsters fed the control, 9c, 11t CLA isomer, and LA diets (P<0.05). The 9c, 11t CLA isomer and LA diets tended to reduce cholesterol accumulation in the aortic arch, whereas the 10t, 12c CLA isomer diet tended to raise cholesterol accumulation compared with the control diet; however, neither was significant. In summary, no differences were observed between the CLA isomers for changes in plasma lipids or lipoprotein cholesterol concentrations. However, the 9c, 11t CLA isomer did appear to lower plasma TG and glucose concentrations compared with the 10t, 12c CLA isomer. Such differences may increase the risk of insulin resistance and type 2 diabetes in humans when the 10t, 12c CLA isomer is fed separately.     

Effect of Dietary Cholesterol and Fat on Cell Cholesterol Transfer to Postprandial Plasma in Hyperlipidemic Men

Postprandial chylomicrons are potent ultimate acceptors of cell membrane cholesterol and are believed to accelerate reverse cholesterol transport (RCT). We compared the effects of meals rich in polyunsaturated fat (PUFA) and either high (605 mg) or low (151 mg) in cholesterol and a meal rich in dairy fat (DF) in the form of cream on net in vitro transport of red blood cell (RBC) membrane cholesterol to 4 and 6 h postprandial plasma in eight normotriglyceridemic (NTG-H) and eight hypertriglyceridemic (HTG-H) men with mild to moderate hypercholesterolemia. In HTG-H men, cell cholesterol accumulation in 6-h postprandial plasma was significantly (P = 0.02) less after the PUFA-HC meal compared with the other meals. The significant (P < 0.001) increase in cell plus endogenous cholesterol accumulation in the triglyceride-rich lipoprotein (TRL) fraction of 4 h postprandial plasma incubated with RBC was significantly (P = 0.007) higher after the PUFA-HC meal compared with DF meal in HTG-H men. In NTG-H men, cholesterol accumulation in plasma and plasma lipoproteins in the presence and absence of RBC was not significantly affected by the type of meal ingested. These data suggest that addition of large amounts of cholesterol to a PUFA meal may impair diffusion-mediated transport of cell membrane cholesterol to postprandial plasma and that replacing DF with PUFA in a meal increases postprandial lipemia and may potentially increase cholesterol accumulation in atherogenic postprandial TRL in HTG-H men.     

Cholesterol vehicle in experimental atherosclerosis. 23. Effects of specific synthetic triglycerides

Earlier work has shown that increasing concentration of palmitic acid at the sn-2 position of a fat enhances the atherogenic properties of that fat. This effect has been observed with lard, tallow, cottonseed oil, and palm oil. In the experiment reported here, we have studied the atherogenic effects of four synthetic fats fed to rabbits as 58% (w/w) of the total fat (15%) (w/w) of a semipurified diet containing 0.05% cholesterol. The fats being tested were: 1,3-stearoyl-2-oleoylglycerol (SOS); 1,2-stearoyl-3-oleoylglycerol (SSO); 1,3-palmitoyl-2-oleoylglycerol (POP); and 1,2-palmitoyl-3-oleoylglycerol (PPO). After 20 wk on diet there were no differences among the groups in weight gain, liver weight, serum, or liver lipids. These data are consistent with our previous findings. There were significant differences in atherosclerosis. The most severe atherosclerosis was observed in group PPO and the least in groups SSO and POP. Severity of atherosclerosis was graded visually on a 0–4 scale. The average atherosclerosis [(aortic arch and thoracic aorta)÷2] was: SOS-1.35; SSO-0.97; POP-0.83; and PPO-1.80. Fecal fat excretion (an indicator of fat absorption) was higher in the two groups fed the stearic acid-rich fats and lower in groups fed the palmitic acid-rich fats. There were no differences in low density lipoprotein particle size. The results confirm previous findings concerning the increased atherogenicity of fats bearing palmitic acid at the sn-2 position. The mechanism underlying these observations is moot but may, in part, reflect greater absorption of the atherogenic fat.     

Atherogenesis in swine fed several types of lipid-cholesterol diets

Eighteen-month-old Nebraska strain minipigs were fed diets containing 2% cholesterol and 20% corn oil, lard, or coconut oil for 12 to 18 months. Concentrations of serum total lipid, total cholesterol, and total phospholipid increased 200 to 300% with each diet. Changes in serum concentrations of S_f 20+ and S_f 0–20 lipoproteins varied with diets fed. Serum concentration of high density lipoprotein was increased in all cases. Intima concentration of S_f 0–20 lipoprotein fraction was elevated by feeding the corn oil diet. There was no development of atherosclerosis as a result of feeding the corn oil-cholesterol diet, but there was an increase in atherosclerosis as a result of feeding the lard or coconut oil diet. There were no correlations between fatty acid patterns of several lipid fractions from serum and corresponding lipid fractions from aortic intima of corn oil fed animals. Deceased.     

Reduction of atherogenicity of natural fats by small additions of ethyl linoleate in the diet of the rat

Ethyl linoleate was substituted in part for the 20% of butterfat, hydrogenated coconut oil, lard, or tallow in an atherogenic diet fed to rats throughout a 40-week experimental period. Aortic degeneration, evidenced by lipid infiltration of the intima, was observed in the control groups but not in the linoleate-fed groups. Groups that received butterfat or hydrogenated coconut oil showed reduced plasma and hepatic cholesterol levels when fed 2% of ethyl linoleate; groups that received lard or tallow showed no significant change in plasma and hepatic cholesterol levels when fed 2% of ethyl linoleate; and groups that received a fat-free diet with 2% of ethyl linoleate showed lower plasma and hepatic cholesterol levels and more complete aortic protection than groups that were fed 20% of corn oil or cottonseed oil. The data suggest that, in the cholesterol-fed rat, the kind and amount of dietary fatty esters may influence aortic condition via some route(s) other than control of plasma and hepatic cholesterol levels. Presented at the AOCS Meeting, Los Angeles, April 1966. Journal Paper No. 2952 of the Agricultural Experiment Station, Purdue University, Lafayette, Ind.     

ADMA/SDMA in Elderly Subjects with Asymptomatic Carotid Atherosclerosis: Values and Site-Specific Association

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor known as a mediator of endothelial dysfunction and atherosclerosis. Circulating ADMA levels are correlated with cardiovascular risk factors such as hypercholesterolemia, arterial hypertension, diabetes mellitus, hyperhomocysteinemia, age and smoking. We assessed the relationship between ADMA values and site-specific association of asymptomatic carotid atherosclerosis (intima-media thickness (CIMT) and plaque) in elderly subjects. One hundred and eighty subjects underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and carotid ultrasound investigation (CUI). All subjects had no acute or chronic symptoms of carotid atherosclerosis. Statistical analyses showed that high plasma levels of ADMA/SDMA were positively correlated to carotid atherosclerosis (CIMT and plaque) (p < 0.001), with significant site-specific association. Total cholesterol, low density lipoprotein cholesterol, triglycerides and C-reactive protein plasma concentrations were significantly associated with asymptomatic carotid atherosclerosis (p < 0.001). High serum concentrations of ADMA and SDMA were associated with carotid atherosclerotic lesions as measured by CIMT ad plaque and may represent a new marker of asymptomatic carotid atherosclerosis in elderly subjects.     

Lipids rich in phosphatidylethanolamine from natural gas-utilizing bacteria reduce plasma cholesterol and classes of phospholipids: A comparison with soybean oil

We compared the effects of three different high-lipid diets on plasma lipoproteins and phospholipids in mink (Mustela vison). The 18 mink studied were fed one of the three diets during a 25-d period in a parallel group design. The compared diets had 0,17, and 67% extracted lipids from natural gas-utilizing bacteria (LNGB), which were rich in PE. The group with 0% LNGB was fed a diet for which the lipid content was 100% soybean oil. The total cholesterol, LDL cholesterol, and HDL cholesterol of animals consuming a diet with 67% LNGB (67LNGB-diet), were significantly lowered by 35, 49, and 29%, respectively, and unesterified cholesterol increased by 17% compared with the animals fed a diet of 100% lipids from soybean oil (SB-diet). In addition, the ratio of LDL cholesterol to HDL cholesterol was 27% lower in mink fed the 67LNGB-diet than those fed the SB-diet. When the mink were fed the 67LNGB-diet, plasma PC, total phospholipids, lysoPC, and PI were lowered significantly compared with the mink fed a SB-diet. Plasma total cholesterol was correlated with total phospholipids as well as with PC (R=0.8, P<0.001). A significantly higher fecal excretion of unesterified cholesterol, cholesteryl ester, PC, lysoPC, and PE was observed in the 67LNGB-fed mink compared with the SB-fed mink. We conclude that phospholipids from the 67LNGB-diet decreased plasma lipoprotein levels, the LDL/HDL cholesterol ratio, and plasma phospholipid levels, especially lysoPC and PC, compared with the highly unsaturated soybean oil. Our findings indicate that the decrease of plasma cholesterol is mainly caused by a specific mixture of phospholipids containing a high level of PE, and not by the dietary FA composition. The lack of significant differences in the level of plasma PE due to the diets indicates that most of the PE from LNGB has been converted to PC in the liver. Thus, plasma cholesterol may at least be partly regulated by phospholipid methylation from PE to PC in the liver.     

Maximum lipid reduction by partial lleal bypass: A test of the lipid-atherosclerosis hypothesis

Atherosclerosis is the process responsible for our national epidemic of coronary heart disease. A primary and proven atherosclerotic risk factor is the plasma cholesterol concentration. Yet, proof that a reduction in plasma cholesterol level results in reduction in the incidence or severity of atherosclerosis and atherosclerotic cardiovascular disease stil requires conclusive documentation. The controversial methods of operation and inconclusive results of concluded first and second generation trials are reviewed. These data clearly demonstrate that a definitive test of the lipid hypothesis has not been reported. Evidence is presented to show that the partial ileal bypass operation most nearly fulfills the six features of an “ideal” lipid lowering trial modality: maximum effectiveness (∼50% cholesterol reduction); known mechanism of action; no response “escape” or “rebound”; obligatory effect without patient cooperation; minimal side effects; and relative safety. The basic design and protocol of the National Heart and Lung Institute Program on Surgical Control of the Hyperlipidemias, a secondary intervention trial using a combination of diet therapy and partial ileal bypass surgery, are outlined.     

Cholesteryl ester hydrolase activity in human symptomatic atherosclerosis

Acid cholesteryl ester hydrolase (CEH) activity was assayed in mononuclear cells of patients with symptomatic atherosclerosis (transient ischemic attacks, TIA) and in age-matched controls showing no evidence of atherosclerosis. The acid CEH level of TIA patients was significantly lower than that of controls (1074±128 vs 2113±255 pmol/mg P/hr, mean±SE). Neither mononuclear cell nor plasma cholesterol and cholesteryl ester concentrations differed significantly between atherosclerotic and control groups. TIA women had lower mononuclear cell concentrations of free sholesterol than men.