Modulation of the regression of atherosclerosis in the hamster by dietary lipids: comparison of coconut oil and olive oil.The Golden Syrian hamster (Mesocricetus auratus) has been shown to be a useful model of both human lipoprotein metabolism and the development of atherosclerosis. We report the effects of dietary lipids on the progression and regression of atherosclerosis in this model. In the first study, hamsters fed on coconut oil (150 g/kg diet) and cholesterol (30 g/kg diet) developed lipid-rich lesions in the ascending aorta (0.28 (SD 0.14) mm2) and aortic arch (0.01 (SD 0.01) mm2) after 4 weeks that continued to progress over the next 8 weeks (0.75 (SD 0.41) mm2 and 0.12 (SD 0.11) mm2 for the ascending aorta and aortic arch respectively). Removal of cholesterol from the diet halted this progression. Furthermore, in animals fed on olive oil in the absence of added cholesterol, plasma LDL-cholesterol concentrations were lower (P < 0.05) and the extent of atherosclerotic lesions was reduced (P < 0.001 for both regions of the aorta) compared with animals fed on coconut oil (with no added cholesterol). In a second study, animals were fed on the atherogenic diet for 10 weeks, transferred to diets containing either coconut oil (150 g/kg diet) or olive oil (150 g/kg diet) without added cholesterol and monitored for up to 16 weeks. In the ascending aorta, lesion size doubled in animals fed on coconut oil but stabilized in those fed on olive oil. In the aortic arch, lesion size decreased linearly (P < 0.05, P < 0.001 for coconut oil and olive oil respectively) with the greatest reduction being seen in the olive-oil-fed animals (P < 0.05). Again, progression and regression of atherosclerosis appeared to reflect the relative concentrations of LDL-cholesterol and HDL-cholesterol in the plasma. We conclude that the male Golden Syrian hamster represents a useful model of dietary induced regression as well as progression of atherosclerosis.

Putative mechanisms of action of probucol on high-density lipoprotein apolipoprotein A-I and its isoproteins kinetics in rabbits.Probucol is a widely prescribed lipid-lowering agent, the major effects of which are to lower cholesterol in both low- and high-density lipoproteins (LDL and HDL, respectively). The mechanism of action of probucol on HDL apolipoprotein (apo) A-I kinetics was investigated in rabbits, with or without cholesterol feeding. 125I-labeled HDL was injected intravenously, and blood samples were taken periodically for 6 days. Kinetic parameters were calculated from the apo A-I-specific radioactivity decay curves. Fractional catabolic rate (FCR) and synthetic rate (SR) of apo A-I in rabbits fed a normal chow and normal chow with 1% probucol were similar. Apo A-I FCR of the rabbits fed 0.5% cholesterol was significantly increased but there were no changes in SR, compared to findings in the normal chow-fed group. Apo A-I FCR of the rabbits fed 1% probucol with 0.5% cholesterol (both 1 month and 2 months) was significantly increased compared to findings in rabbits fed the normal chow as well as 0.5% cholesterol diet group, while SR of apo A-I was significantly reduced in the former groups. Kinetics at 1 month after discontinuation of 1% probucol (under cholesterol feeding) showed a similar FCR of HDL-apo A-I to that of the rabbits fed 0.5% cholesterol, but the SR of apo A-I remained lower. Apo A-I isoproteins kinetics assessed by autoradiography of isoelectric focusing slab gels showed that the synthesis of proapo A-I was significantly reduced in the 1% probucol with 0.5% cholesterol administered, compared to the 0.5% cholesterol group. Thus, the action of probucol on HDL apo A-I kinetics was only prominent in case of higher serum cholesterol levels. The decreased HDL or apo A-I seen with probucol was apparently the result of an increase in FCR and a decrease in SR of HDL-apo A-I. A decreased synthesis of apo A-I remained evident even 1 month after discontinuing probucol. The action of probucol on the intracellular synthetic processes of apo A-I was revealed by the reduced synthesis of proapo A-I.

Apolipoprotein B-containing lipoproteins in renal failure: the relation to mode of dialysis.BACKGROUND: The aim of this study was to establish whether there is a differential effect of mode of dialysis, hemodialysis (HD), or continuous ambulatory peritoneal dialysis (CAPD) on the dyslipidemia of renal failure. METHODS: The lipoprotein profile was determined in 61 non-diabetic patients on chronic HD (N = 30) and CAPD treatment (N = 31), and in a control group of 27 healthy subjects. The analysis included the measurement of individual apolipoprotein (apo) A- and apo B-containing lipoproteins (LPs) separated by sequential immunoaffinity chromatography. Apo A-containing lipoproteins include lipoprotein A-I with apo A-I and lipoprotein A-I:A-II with apo A-I and apo A-II as the main protein constituents, whereas apo B-containing lipoproteins comprise simple cholesterol-rich lipoprotein B (LP-B), with apo B as the only protein moiety and complex triglyceride (TG)-rich lipoprotein B complex (LP-Bc) particles with apo B, apo A-II, apo C, and/or apo E as the protein constituents. RESULTS: CAPD patients had significantly higher concentrations of total cholesterol (6.8 vs. 5.1 mmol/liter), low-density lipoprotein (LDL) cholesterol (4.6 vs. 3.2 mmol/liter), TG (2.3 vs. 1.5 mmol/liter), apo B (155.3 vs. 105.7 mg/dl), LP-B (136.0 vs. 91.9 mg/dl), and LP-Bc (19.3 vs. 13.8 mg/dl) than HD patients. Both HD and CAPD patients had significantly higher TG, VLDL cholesterol, apo C-III, and apo E and significantly lower high-density lipoprotein cholesterol, apo A-II, and lipoprotein A-I:A-II levels than control subjects. The distribution of apo C-III in high-density lipoprotein and VLDL-LDL was altered in CAPD patients in comparison with control subjects. This suggests that the removal of TG-rich lipoproteins is less efficient in patients on CAPD. Normotriglyceridemic (NTG; TG < or = 1.7 mmol/liter, 150 mg/dl) CAPD patients had significantly higher levels of TC, LDL cholesterol, apo B, and LP-B than NTG-HD patients. There was little difference in the LP-Bc levels between NTG-CAPD, NTG-HD, and controls. Similarly, hypertriglyceridemic (HTG) CAPD patients had significantly higher TC, LDL cholesterol, apo B, and LP-B levels than HTG-HD patients. The LP-Bc levels were significantly increased in HTG-HD and HTG-CAPD patients compared with controls, but the slightly higher levels in the CAPD patients did not differ significantly from the HD group. CONCLUSION: CAPD and HD patients have a lipoprotein profile characteristic of renal failure. Patients on long-term CAPD have higher levels of cholesterol-rich apo B-containing lipoproteins unrelated to TG levels. Many patients on CAPD also have a substantial elevation of the plasma concentrations of TG-rich LPs. The clinical significance of increased levels of potentially atherogenic LP-B during CAPD remains to be investigated.

Precision of blood cholesterol measurement and high blood cholesterol case-finding and treatment.Imprecise blood cholesterol measurement can be expected to adversely affect large scale efforts to detect and treat high blood cholesterol. Using protocols specified by the National Cholesterol Education Program (NCEP), we used computer simulation techniques to quantify the effects of blood cholesterol measurement variability on misclassification rates, costs, effectiveness, and cost-effectiveness of high blood cholesterol case-finding and treatment. At the time of initial case-finding, increased measurement variability was associated with a moderate decrease in the proportions assigned to a treatment state and in the positive predictive value of such an assignment. After 10 years of continual case-finding and treatment, measurement variability dramatically affected proportions assigned to drug treatment and diminished the percent on drugs with blood cholesterol levels truly above NCEP cutpoints. Extreme variability in blood cholesterol measurement increased per capita costs by 14-18% and diminished cost-effectiveness by at least 11-12%. The adverse effects of measurement variability on cost-effectiveness were much more pronounced if adjustments to life-expectancy were made to recognize the lower quality of life associated with drug treatment. Misclassification rates can be decreased and cost-effectiveness improved by performing repeated measurements of blood cholesterol before increasing intensity of treatment. Improvement in the precision of measurement are especially beneficial for low-risk individuals.

Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients.The serum concentration of 24S-hydroxycholesterol reflecting brain cholesterol turnover may be a possible marker for neurodegeneration and demyelination in multiple sclerosis. Serum was analyzed for cholesterol precursors and oxysterols in multiple sclerosis patients of different clinical subtypes (n=20 each subtype) and in 37 healthy controls. Serum 24S-hydroxycholesterol levels were lower in primary progressive and in older relapsing remitting multiple sclerosis patients. Furthermore, serum levels of lathosterol were decreased in all clinical subtypes. The results are important given recent interest in statin treatment in multiple sclerosis, which will further decrease the cholesterol precursor and oxysterol levels. The decreased levels of brain specific and peripheral sterols indicate a role for cholesterol homeostasis in relation to the pathology of multiple sclerosis, at least in the primary progressive clinical subtype.

Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein.Mice in which the gene for mdr2 P-glycoprotein has been disrupted have a severe deficiency in biliary phospholipid and cholesterol secretion. We studied the relation between mdr2 gene expression and biliary lipid secretion with emphasis on the role of bile salt hydrophobicity. Control mice (+/+), and mice with a homozygous (-/-) or heterozygous (+/-) disruption of the mdr2 gene, were infused with taurodeoxycholate (TDC) or tauroursodeoxycholate (TUDC). In mdr2 (-/-) mice, virtually no phospholipids were secreted into bile, irrespective of the type of bile salt infused. In contrast, cholesterol secretion in (-/-) mice increased upon TDC infusion from less than 0.1 to more than 2 nmol/min . 100 g, which was similar to controls under the same conditions. After infusion of TUDC in (-/-) mice. cholesterol secretion also rose (to 1.8 nmol/min . 100 g) but remained much lower than in controls (8 nmol/min x 100 g). In (+/-) mice, cholesterol secretion was equal to (+/+) mice during secretion of endogenous bile salts and during TDC infusion, but was 50% of control levels during maximal TUDC infusion. We conclude that biliary phospholipid secretion completely depends on mdr2 gene expression but cholesterol can, at least partially, be secreted in an mdr2 Pgp-independent mechanism. The extent to which cholesterol is secreted via this mechanism may depend on the hydrophobicity (i.e., cholesterol-solubilizing capacity) of the secreted bile salt.

Changes in population cholesterol levels and Coronary Heart Disease deaths in seven countries.BACKGROUND: Are trends in Coronary Heart Disease deaths based on risk factor changes? OBJECTIVE: To study the relationship between trends in coronary deaths and changes in blood cholesterol in the Seven Countries Study. MATERIAL AND METHODS: Sixteen cohorts of men aged 40-59 years from seven countries (U.S.A., Finland, the Netherlands, Italy, Croatia (former Yugoslavia), Serbia (former Yugoslavia), Greece, Japan) were units for the analyses of serum cholesterol measured at entry and after 5 and 10 years, and for mortality over 25 years. RESULTS: In the populations, the ecological relationship of mean serum cholesterol at entry to late Coronary Heart Disease death rates during the 10- to 25-year follow-up was weak, with an R-square of 0.31. Cholesterol measurements made at year 10, and an indicator of cholesterol change during the first 10 years, increased the association (R-square, 0.49). A negative and significant interaction was shown between baseline population cholesterol levels and their 10-year change. As an indicator of acceleration in mortality, cholesterol change over 10 years was also positively correlated (partial R-square 0.44) with the ratio of 25-year to 5-year deaths. CONCLUSIONS: In the Seven Countries Study, late Coronary Heart Disease death rates are largely "explained' by changes in blood cholesterol levels during the early phases of the study, mainly due to increases in lower cholesterol levels among some cohorts.

A community-wide survey of physician practices and attitudes toward cholesterol management in patients with recent acute myocardial infarction.BACKGROUND: Physicians' current attitudes and practices toward the management of high cholesterol levels in patients with recent acute myocardial infarction are not well defined. OBJECTIVE: To examine threshold levels of serum cholesterol and other factors that influence physicians' decision to prescribe lipid-lowering drugs and initiate dietary therapy in patients with recent acute myocardial infarction. METHODS: Community-wide questionnaire survey of general internists, cardiologists, and family physicians practicing in the Worcester, Mass, metropolitan area. RESULTS: Among the 257 responding physicians, lipid-lowering drug therapy was more likely to be initiated in younger patients at lower total serum and low-density lipoprotein (LDL) cholesterol levels than in older patients (P =.03). Younger physicians were more likely to initiate dietary and lipid-lowering drug therapy at lower total and LDL cholesterol levels than their older counterparts. Younger physicians also considered LDL cholesterol level the most important factor in initiating lipid-lowering drug therapy in contrast to older physicians who favored total cholesterol level (P =.001). General practice physicians were more likely to initiate dietary therapy at lower total cholesterol levels, but tended to initiate lipid-lowering drug therapy at higher total and LDL cholesterol levels compared with internists and cardiologists. Physicians reported that the most important factors that interfere with patients' use of lipid-lowering medication were concerns about medication costs, issues related to polypharmacy, and failure to recognize the importance of lipid-lowering drugs. Several physician-associated factors, including perceived importance of other cardiac drugs and provider responsibility, were associated with the nonuse of lipid-lowering medications. CONCLUSION: Educational and practice-based efforts remain necessary to remove potential barriers to the implementation of effective long-term cholesterol management in patients with recent acute myocardial infarction.

Prescription and adherence to statins of patients with coronary artery disease and hypercholesterolemia.OBJECTIVE: statins have proved to be safe and effective in the secondary prevention of coronary artery disease, but the level of prescription and the reasons for nonadherence to treatment in many coronary diseases treatment centers has not been determined. The purpose of this study was to identify reasons for nonadherence to statin therapy. METHODS: We analyzed 207 consecutive patients with coronary artery disease and hypercholesterolemia (total cholesterol > or = 200 mg/dL or LDL-cholesterol > or = 130 mg/dL). Patients' average age was 61.7 +/- 10 year; 111 (53.6 %) male were and 94 (46.6 %) were female. We analyzed the level of prescription and adherence to treatment with statins. RESULTS: statins were prescribed for 139 (67 %) patients, but only 85 (41 %) used the drug. In spite of being indicated, statins were not prescribed in 68 (33 %) patients. Of 54 (26 %) patients, nonadherent to statins, 67 % did not use the drug due to its high cost, 31 % due to the lack of instruction, and only 2 % due to side effects. Total cholesterol (260.3 +/- 42.2 vs 226.4 +/- 51.9; p < 0.0001) and LDL cholesterol (174.6 +/- 38.1 vs 149.6 +/- 36.1; p < 0.0001) were lower in patients on medication. HDL-cholesterol increased from 37.6 +/- 9.6 to 41.5 +/- 12.9 mg/dL (p = 0.02), and triglycerides were not modified in patients using statins. CONCLUSION: The prescription of statins in patients with coronary artery disease and dyslipidemia is high; however, its adherence is far from satisfactory, due to the high cost of the medication. Reduction in total cholesterol and LDL cholesterol levels did not reach the targets recommended by the Brazilian Consensus on Dyslipidemia.

Free and esterified fatty acid and cholesterol synthesis in adult males and its effect on the doubly-labelled water method.The purpose of the present study was to estimate whole-body fatty acid and cholesterol synthesis in weight-stable adults and to determine the likely effect on the doubly-labelled water (DLW) method for measuring energy expenditure. Synthesis was measured by 2H incorporation over 14 d in six adult males in approximate energy balance following noradrenaline infusion to maximize mobilization of free fatty acid from adipose tissue. The inter-individual variation in synthesis rates was large and in one subject the proportion of free fatty acid synthesized was ten times that of the mean of the rest of the group; the fasting concentration of esterified fatty acid in this subject was five times that of the rest of the group indicating likely violation of the assumptions underlying the calculation of whole-body synthesis. After 14 d of labelling in the other five subjects, 0.9 (SEM 0.3)% of the circulating free fatty acid, 9.3 (SEM 3.0)% of the esterified fatty acid, 14.6 (SEM 2.4)% of the free cholesterol and 28.3 (SEM 3.7)% of esterified cholesterol had been synthesized de novo. A high rate of synthesis correlated with a low pre-dose 2H abundance both within and between lipid classes suggesting that natural 2H abundance variations in some lipid classes may be used to determine their metabolic origin. Whole-body synthetic rates were 8 g/d for fatty acid and 0.3-0.5 g/d for cholesterol. These values correspond to very small errors on DLW-derived estimates of CO2 production; -2.5 litres/d for fatty acid and -0.1 to -0.2 litres/d for cholesterol. These results, obtained in subjects typically consuming a diet with a lower fat and cholesterol content that the typical Western diet, suggest that the DLW method is unlikely to be affected by fatty acid and cholesterol synthesis in subjects in energy balance consuming a typical Western diet.