Cholesterol Journal Articles

Record 8601 to 8620

Low-density lipoprotein cholesterol bulk is the pivotal determinant of atherosclerosis in familial hypercholesterolemia
Raal, F. J., G. J. Pilcher, et al. (1999), Am J Cardiol 83(9): 1330-3.
Abstract: This study's aim was to determine whether biochemical risk factors such as lipoprotein(a), fibrinogen, homocysteine, and insulin, as well as low-density lipoprotein (LDL) particle size, were predictive of carotid intimamedia thickness (IMT), an early marker of atherosclerosis, in subjects with familial hypercholesterolemia (FH). We also determined whether plasma 8-isoprostane, as a marker of in vivo lipid oxidation, correlated with carotid IMT. Twenty-two homozygous and 20 heterozygous subjects with FH were compared with 20 normocholesterolemic controls. On univariate analysis, plasma total and LDL cholesterol, the cholesterol-years score (CYS), lipoprotein(a), and fibrinogen, but not homocysteine or insulin, were positively related, and high-density lipoprotein (HDL) cholesterol was negatively related to carotid IMT. However, on multivariate analysis, only LDL cholesterol and the CYS predicted carotid IMT (multiple r = 0.82; r2 = 0.68; p <0.0001). The subjects with FH had large rather than small dense LDL particles, and plasma 8-isoprostane levels were not increased. LDL cholesterol and the CYS, or "cholesterol bulk" are the pivotal determinants of atherosclerosis and are the strongest predictors of carotid IMT in FH.

Low-density lipoprotein cholesterol can be chemically measured: a new superior method
Okada, M., H. Matsui, et al. (1998), J Lab Clin Med 132(3): 195-201.
Abstract: The association between elevated levels of low-density lipoprotein (LDL) cholesterol and an increased risk of premature coronary heart disease (CHD) is well documented. Most clinical laboratories estimate LDL cholesterol concentrations according to the Friedewald formula. It provides a relatively reliable estimate of LDL cholesterol concentration, provided the triglyceride concentration is <200 mg/dL. However, the reliability is considerably decreased if the triglyceride concentration is > or =400 mg/dL. The interactions between lipoproteins and surfactants, divalent cations, sugars, and lectins were investigated, and we developed a new assay protocol to chemically measure the LDL cholesterol level in serum that does not require immunoseparation or centrifugation. The assay protocol was evaluated by measuring serum samples obtained from 88 patients and 20 healthy volunteers. The triglyceride levels of the patient samples ranged from 66 to 2199 mg/dL, and the samples were classified as <200 mg/dL (n=36) and > or =400 mg/dL (n=52; 23, 3, and 26 patients had type IIb, type III, and type IV hyperlipoproteinemia, respectively) for comparative studies. The accuracy and precision of our assay protocol fulfilled the criteria of the NCEP Lipid Standardization Panel, and no matrix effect influenced the measurements. The assay protocol is less sensitive to LDL-I than to LDL-II and LDL-III. LDL cholesterol measurements correlated well with those obtained by the ultracentrifugal assay of normotriglyceridemic and hypertriglyceridemic samples. This evidence shows that the results obtained with our assay protocol are superior to those obtained with the Friedewald formula.

Low-density lipoprotein cholesterol estimation by a new formula in Indian population
Anandaraja, S., R. Narang, et al. (2005), Int J Cardiol 102(1): 117-20.
Abstract: BACKGROUND: Estimation of low-density lipoprotein cholesterol is crucial in the management of ischemic heart disease patients. Low-density lipoprotein cholesterol is routinely calculated in laboratories world over by applying Friedewald formula for logistic reasons. We derived a new formula based on multiple regression approach. METHODS: Lipid profiles were done on blood samples of 2008 patients. In initial 1000 patients, low-density lipoprotein cholesterol was estimated by a direct method and also by Friedewald formula. By applying linear regression methods on the data of direct estimation method, a new formula was obtained and the accuracy of this new formula was validated in the next 1008 patients. RESULTS: The mean low-density lipoprotein cholesterol was 116+/-41.5 mg/dl (3.02+/-1.08 mmol/l) measured by direct low-density lipoprotein cholesterol assay and that calculated by Friedewald formula was 119+/-46 mg/dl (3.09+/-1.2 mmol/l) for the initial 1000 patients. Low-density lipoprotein cholesterol measured by direct low-density lipoprotein cholesterol assay and calculated from Friedewald formula showed good correlation (r = 0.88), however, there was minimal overestimation by the Friedewald formula. The correlation improved between direct low-density lipoprotein cholesterol and calculated low-density lipoprotein cholesterol after excluding the patients with triglycerides more than 350 mg/dl (r = 0.92). The mean low-density lipoprotein cholesterol measured by the direct assay and by new formula in the next 1008 patients was 117+/-40 mg/dl (3.04+/-1.04 mmol/l) and 113.7+/-37 mg/dl (2.96+/-0.96 mmol/l), respectively with very good correlation (r = 0.97) between them. CONCLUSIONS: The new formula derived from multiple linear regression analysis appears to be more accurate than Friedewald formula in Indian population.

Low-density lipoprotein cholesterol in patients with stable coronary heart disease--is it time to shift our goals?
Pitt, B. (2005), N Engl J Med 352(14): 1483-4.

Low-density lipoprotein cholesterol in subclinical hypothyroidism
Vierhapper, H., A. Nardi, et al. (2000), Thyroid 10(11): 981-4.
Abstract: The significance of subclinical hypothyroidism in regard to ensuing hyperlipidemia remains unclear. Because an unfavorable lipid profile would provide a possible explanation for the reported association of coronary-heart disease with this syndrome, we have evaluated the relationship of thyrotropin (TSH) with total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides in patients with normal thyroid function (n = 4886) as well as subclinical (n = 1055) and manifest (n = 92) hypothyroidism. Serum concentrations of LDL cholesterol were similar in euthyroid persons (134+/-39 mg/dL) and in patients with subclinical hypothyroidism (137+/-40 mg/dL) but were higher (178+/-70 mg/dL, p < 0.01) in overt hypothyroidism. Within the group of subjects with subclinical hypothyroidism there was no apparent relationship between serum concentrations of TSH ranging from 4.0 to 49.0 microU/mL and concentrations of LDL cholesterol. Thus, there is no "threshold value" of TSH in these patients per se necessitating substitution therapy with thyroxine.

Low-density lipoprotein cholesterol reduction and cardiovascular disease prevention: the search for superior treatment
Jones, P. H. (2004), Am J Med 116 Suppl 6A: 17S-25S.
Abstract: Current US lipid-lowering guidelines indicate that optimal plasma levels of low-density lipoprotein cholesterol (LDL-C) are <100 mg/dL, and targeting global risk assessment has significantly increased the number of individuals who are candidates for intensive plasma lipid-lowering therapy. There is accumulating evidence that reduction of plasma LDL-C concentrations to targets even lower than those currently recommended may provide additional benefit in coronary heart disease (CHD) prevention. For example, the Heart Protection Study (HPS) found that statin treatment initiated at a baseline LDL-C plasma level of <100 mg/dL in patients at high risk provided a relative benefit in reducing the incidence of cardiovascular events that was similar to when it was initiated at higher LDL-C plasma levels. In addition, it is becoming clear that CHD risk, and the need for intensive lipid-lowering treatment, may be underestimated in some populations, including individuals with the metabolic syndrome. In the overall primary prevention population, high-sensitivity C-reactive protein measurement has been shown to identify individuals at high risk of cardiovascular events who would not be considered at high risk on the basis of current systems of risk assessment. The increasing focus on intensive plasma lipid lowering to reduce CHD risk has placed a premium on the development of therapies with improved ability to reduce plasma levels of LDL-C.

Low-density lipoprotein cholesterol responsiveness to diet in normolipidemic subjects
Cobb, M. M. and N. Risch (1993), Metabolism 42(1): 7-13.
Abstract: Both apolipoprotein E genotype (apo E) and diet predict very-low-density (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) levels. In a retrospective pooled analysis of six studies, we sought to identify the predictors of VLDL-C and LDL-C change, or "responsiveness," to a diet crossover. "Response" to diet was studied in 67 normolipidemic subjects of common apo E genotype. Subjects were fed two contrasting, metabolically controlled diets: one had a low polyunsaturated to saturated fatty acid ratio (P:S), and the other had a high P:S ratio. Multiple blood samples were analyzed for VLDL-C and LDL-C levels at the end of each metabolic diet period, and values were averaged and differences were calculated. Despite adjustment for significant predictors across the component studies, a wide range of LDL-C responsiveness was found, with an average decrease of 28 mg/dL. Multivariate regression analysis was used to identify the most significant predictors of LDL-C response to the diet crossover. All dietary and clinical variables were entered by stepwise regression for potential inclusion in a "best-fit" model. The degree of change in saturated fat content and age were the most significant predictors of LDL-C responsiveness. Neither dietary cholesterol nor apo E phenotype were significant predictors of responsiveness. The most LDL-C-responsive subjects were older and required smaller reductions in dietary saturated fat levels than did less-responsive subjects to achieve a comparable reduction in LDL-C levels. Multiple regression analysis suggested a precursor-product relationship between VLDL-C and LDL-C responsiveness.

Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and apolipoprotein B: relationships among the different measurements
Franzini, C., C. Valente, et al. (2004), Scand J Clin Lab Invest 64(8): 703-7.
Abstract: Serum low-density lipoprotein cholesterol (LDLC) value is a recognized target for atherosclerotic risk management, and is generally calculated using the "Friedewald formula". Alternative risk markers include directly measured LDLC, non-high-density lipoprotein cholesterol (non-HDLC) and apolipoprotein B (ApoB). The relationships among such various measured or calculated quantities in medium-sized sets of patient results were investigated. Results from two sets of patients were retrieved from our laboratory information systems. One group (n=8436) included results of cholesterol, HDLC, triglyceride (TG) and glucose measurements. A second group (n = 902) included, in addition, results of ApoB measurement. The results confirmed the unreliability of the Friedewald formula at TG >350 mg/dL (3.96 mmol/L), but also indicated TG-linked underestimation of LDLC below such a TG level. By contrast, non-HDLC values were shown to be independent of TG, and better correlated to ApoB than LDLC values. Mathematically, the difference between non-HDLC and LDLC is TG x 0.458 (values in mmol/L): therefore, the latter cannot be compared to (or converted into) the former by simply adding a constant amount. The ratio LDLC/ApoB was shown continuously to decrease with increasing TG concentrations, while the ratio non-HDLC/ApoB did not. The TG-dependent underestimation of LDLC may be the reason for the reported better cardiovascular risk predictivity of non-HDLC in diseases associated with TG increase, such as in diabetes. Non-HDLC values are not influenced by TG levels, and are better correlated with ApoB.

Low-density lipoprotein cholesterol: association with mortality and hospitalization in hemodialysis patients
Chiang, C. K., T. I. Ho, et al. (2005), Blood Purif 23(2): 134-40.
Abstract: BACKGROUND/AIMS: Hypocholesterolemia is a common finding in hospitalized elderly people, critically ill surgical patients, septic patients and end-stage renal disease patients. The different effect of lipid subfractions on patients with end-stage renal disease has never been demonstrated. We aim to study the effect of lipid subfractions on hospitalization and mortality in maintenance hemodialysis (MHD) patients. METHODS: Lipid subfractions, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were measured in 210 patients with MHD in a single dialysis center. Patients were stratified into three groups based on the tertiles of lipid levels, and differences in patient characteristics and survival were evaluated. RESULTS: Of a total of 22 deceased patients in our MHD cohort, infection-related mortality (50%) was higher than cardiovascular-related mortality (18.2%). Significant differences (p < 0.05) in the duration and frequency of hospitalization and in mortality events were observed when patients were divided into different subgroups according to the tertiles of baseline TC and LDL-C levels. Patients with lower LDL had significantly lower levels of albumin, TC and TG. The LDL-C tertiles were similar in terms of age, hypertension, diabetes, biochemical results, hematocrit, adequacy of hemodialysis and normalized protein catabolism rate. Both TC and LDL-C predicted survival (p < 0.001), but not TG and HDL-C in the Kaplan-Meier model. The Cox proportional hazard model demonstrated that baseline serum LDL-C was the best lipid subfraction in predicting all-cause death with an adjusted hazard ratio (95% confidence interval) for each 10 mg/dl of 0.752 (0.631-0.898; p = 0.002). CONCLUSIONS: We firstly demonstrated that lipid subfractions, including TC and LDL-C, predict poor outcomes in a MHD cohort with high infection-related mortality.

Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men
Austin, M. A., B. L. Rodriguez, et al. (2000), Am J Cardiol 86(4): 412-6.
Abstract: Decreased low-density lipoprotein (LDL) particle size is associated with coronary heart disease (CHD) risk among middle-aged Caucasian populations, and has been consistently correlated with increased plasma levels of triglyceride and decreased levels of high-density lipoprotein (HDL) cholesterol. This study examines whether these risk factors predict CHD among older Japanese-American men. With use of the Honolulu Heart Program Lipoprotein Exam 3 (1980 to 1982) as baseline, and 12-year follow-up for CHD events, a nested, case-control study was designed. One hundred forty-five incident CHD cases were identified and matched to 2 controls each. LDL particle diameter (size) was determined by gradient gel electrophoresis. A 10-angstrom (A) decrease in LDL size at baseline was associated with increased risk of incident CHD (relative risk 1.28, 95% confidence interval 1.01 to 1.63). After adjustment for baseline risk factors, the LDL size association was no longer statistically significant (relative risk 1.13, 95% confidence interval 0.86 to 1.49). When principal components analysis was used to define a composite variable for LDL size, triglycerides, and HDL cholesterol, this component predicted CHD independent of smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, and beta-blocker use (p <0.01). Therefore, this prospective analysis of data from older, Japanese-American men demonstrated that decreased LDL size is a univariate predictor of incident CHD, and that a composite risk factor of LDL size, triglyceride, and HDL cholesterol was a risk factor for CHD independent of other risk factors.

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion
Fujino, T., H. Asaba, et al. (2003), Proc Natl Acad Sci U S A 100(1): 229-34.
Abstract: A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca(2+) in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-- islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-- islets. Furthermore, exposure of LRP5++ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that WntLRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Low-density lipoprotein turnover in inbred strains of rabbits hypo- or hyperresponsive to dietary cholesterol
Meijer, G. W., A. F. Stalenhoef, et al. (1992), Lipids 27(6): 474-7.
Abstract: In two inbred strains of rabbit with high or low response of plasma cholesterol to dietary cholesterol, low density lipoprotein (LDL) apolipoprotein (apoLDL) kinetics were determined with the use of a heterologous tracer isolated from a Watanabe heritable hyperlipidemic (WHHL) rabbit. On a diet without added cholesterol, the total clearance of apoLDL (which equals apoLDL production) did not differ significantly between rabbits of both strains. After the feeding of a diet containing 0.1% cholesterol for six weeks, plasma LDL cholesterol, plasma apoLDL and liver cholesterol concentrations rose significantly in the hyperresponsive but not in the hyporesponsive rabbits. Cholesterol feeding depressed the total fractional catabolic rate (FCR) of apoLDL in the hyper- but not in the hyporesponsive rabbits; this was attributed to a decrease of receptor-dependent FCR while receptor-independent FCR was similar in the two strains. On the diet containing cholesterol, the receptor-mediated absolute catabolic rate (ACR) of apoLDL did not differ between hyper- and hyporesponsive rabbits but receptor-independent ACR of apoLDL was higher in hyperresponders. It is concluded that the higher plasma apoLDL levels in hyperresponsive rabbits fed the 0.1% cholesterol diet are caused by a higher production of apoLDL and not by a lower flux of apoLDL through the receptor-mediated pathway.

Low-density lipoprotein uptake and cholesterol accumulation by cultured renal cells
Hashimoto, S. and G. T. Nagami (1991), J Am Soc Nephrol 2(6): 1101-7.
Abstract: The uptake of low-density lipoprotein (LDL) and the accumulation of cholesterol were assessed in opossum kidney (OK) and Madin-Darby canine kidney (MDCK) cells. OK and MDCK cells were grown to confluency on Millicell well inserts. The uptake of human LDL across the apical and basolateral surfaces of OK and MDCK cells was assessed by the degradation of internalized (125I)LDL to trichloroacetic acid-soluble products. LDL uptake via the apical surface of OK cells increased linearly with LDL concentration, indicating nonreceptor-mediated uptake. In contrast, LDL uptake via the basolateral surface of OK cells and both apical and basolateral surfaces of MDCK cells followed a saturable pattern. In addition, (125I)LDL bound to the apical membrane of MDCK cells, but not to the apical membrane of OK cells, was displaced by heparin and by excess of unlabeled LDL. Exposure to LDL (100 mg/mL) resulted in an increase in total cholesterol content of OK and MDCK cells (23 and 18%, respectively). Most of the increase in total cholesterol content with LDL exposure resulted from increased free cholesterol content in MDCK cells and esterified cholesterol in OK cells. The differences in cholesteryl ester formation were consistent with the slower rates of (14C) oleate incorporation into cholesteryl ester and lower cholesterol esterifying activity observed in MDCK cells compared with that in OK cells. These results demonstrate that LDL uptake can be receptor or nonreceptor mediated, depending upon the renal cell type and the surface exposed to LDL, and that LDL exposure leads to increased cholesterol content in OK and MDCK cells.

Low-density lipoprotein-cholesterol determines vascular responsiveness to angiotensin II in normocholesterolaemic humans
John, S., C. Delles, et al. (1999), J Hypertens 17(12 Pt 2): 1933-9.
Abstract: OBJECTIVE: Both LDL-cholesterol and angiotensin II have been shown to increase the risk for and severity of cardiovascular disease. In hypercholesterolaemia, experimental studies have demonstrated an increased angiotensin type 1 (AT1) receptor expression on vascular smooth muscle cells and an increased vascular responsiveness to vasopressors has been documented in humans. We investigated in a normocholesterolaemic young population whether vascular responsiveness to angiotensin II (Ang II) infusion depends on LDL-cholesterol serum levels in the systemic and renal circulation. DESIGN AND METHODS: Changes in systolic and diastolic blood pressure (deltaBP) to Ang II infusion (0.5 and 3.0 ng/kg per min) were investigated in 103 normocholesterolaemic (LDL-cholesterol < 160 mg/dl) young white men (26+/-3 years; 24 h BP: 128+/-10/75+/-7 mmHg) without cardiovascular disease. According to their LDL-cholesterol levels, participants were classified into tertiles (lower tertile < 85 mg/dl, middle tertile 85-111 mg/dl, upper tertile > 111 mg/dl). RESULTS: Blood pressure (BP) responses to Ang II infusion 3.0 ng/kg per min were enhanced in the group with the highest LDL-cholesterol levels (delta systolic BP: +12.8+/-6.7, +13.2+/-8.6, +17.9+/-9.6, P < 0.02; delta diastolic BP: +11.1+/-5.8, +11.5+/-6.5, +16.5+/-8.3, P < 0.01, for the lower, middle and upper tertiles, respectively). This holds true when baseline BP was taken into account as a confounding covariable (P < 0.015). BP responses to Ang II infusion were related to LDL-cholesterol serum levels (delta systolic BP: r = 0.26, P = 0.01; delta diastolic BP: r = 0.32, P = 0.001). In multiple stepwise regression analysis, LDL-cholesterol emerged as the strongest determinant of vascular responsiveness to Ang II (delta systolic BP: P < 0.01; delta diastolic BP: P < 0.001). CONCLUSION: In young male subjects, responsiveness to Ang II is determined by the LDL-cholesterol serum level even in the normal range of LDL-cholesterol, thereby potentially contributing to the cardiovascular risk of LDL-cholesterol even within the so-called normal range.

Low-density-lipoprotein cholesterol goals for patients with coronary disease: treating between the lines
Waters, D. D. and P. Y. Hsue (2001), Circulation 104(22): 2635-7.

Low-dose alpha-tocopherol improves and high-dose alpha-tocopherol worsens endothelial vasodilator function in cholesterol-fed rabbits
Keaney, J. F., Jr., J. M. Gaziano, et al. (1994), J Clin Invest 93(2): 844-51.
Abstract: Abnormalities in endothelium-dependent arterial relaxation develop early in atherosclerosis and may, in part, result from the effects of modified low-density lipoprotein (LDL) on agonist-mediated endothelium-derived relaxing factor (EDRF) release and EDRF degradation. alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in human plasma and lipoproteins, therefore, we investigated the effects of AT on endothelium-dependent arterial relaxation in male New Zealand White rabbits fed diets containing (a) no additive (controls), (b) 1% cholesterol (cholesterol group), or 1% cholesterol with either (c) 1,000 IU/kg chow AT (low-dose AT group) or (d) 10,000 IU/kg chow AT (high-dose AT group). After 28 d, we assayed endothelial function and LDL susceptibility to ex vivo copper-mediated oxidation. Acetylcholine-and A23187-mediated endothelium-dependent relaxations were significantly impaired in the cholesterol group (P < 0.001 vs. control), but preserved in the low-dose AT group (P = NS vs. control). Compared to the control and cholesterol groups, vessels from the high-dose AT group demonstrated profound impairment of arterial relaxation (P < 0.05) and significantly more intimal proliferation than other groups (P < 0.05). In normal vessels, alpha-tocopherol had no effect on endothelial function. LDL derived from both the high- and low-dose AT groups was more resistant to oxidation than LDL from control animals (P < 0.05). These data indicate that modest dietary treatment with AT preserves endothelial vasodilator function in cholesterol-fed rabbits while a higher dose of AT is associated with endothelial dysfunction and enhanced intimal proliferation despite continued LDL resistance to ex vivo copper-mediated oxidation.

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia
Davidson, M. H., P. Toth, et al. (2001), Clin Cardiol 24(6): 467-74.
Abstract: BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.

Low-dose expression of a human apolipoprotein E transgene in macrophages restores cholesterol efflux capacity of apolipoprotein E-deficient mouse plasma
Zhu, Y., S. Bellosta, et al. (1998), Proc Natl Acad Sci U S A 95(13): 7585-90.
Abstract: Apolipoprotein E- (apoE) deficient (E-/-) mice develop severe hyperlipidemia and diffuse atherosclerosis. Low-dose expression of a human apoE3 transgene in macrophages of apoE-deficient mice (E-/-hTgE+/0), which results in about 5% of wild-type apoE plasma levels, did not correct hyperlipidemia but significantly reduced the extent of atherosclerotic lesions. To investigate the contribution of apoE to reverse cholesterol transport, we compared plasmas of wild-type (E+/+), E-/-, and E-/-hTgE+/0 mice for the appearance of apoE-containing lipoproteins by electrophoresis and their capacity to take up and esterify 3H-labeled cholesterol from radiolabeled fibroblasts or J774 macrophages. Wild-type plasma displayed lipoproteins containing apoE that were the size of high density lipoprotein and that had either electrophoretic alpha or gamma mobilities. Similar particles were also present in E-/-hTgE+/0 plasma. Depending on incubation time, E-/- plasma released 48-74% less 3H-labeled cholesterol from fibroblasts than E+/+ plasma, whereas cholesterol efflux into E-/-hTgE+/0 plasma was only 11-25% lower than into E+/+ plasma. E-/-hTgE+/0 plasma also released 10% more 3H-labeled cholesterol from radiolabeled J774 macrophages than E-/- plasma. E+/+ and E-/-hTgE+/0 plasma each esterified significantly more cell-derived 3H-labeled cholesterol than E-/- plasma. Moreover, E-/- plasma accumulated much smaller proportions of fibroblast-derived 3H-labeled cholesterol in fractions with electrophoretic gamma and alpha mobility than E+/+ and E-/-hTgE+/0 plasma. Thus, low-dose expression of apoE in macrophages nearly restored the cholesterol efflux capacity of apoE-deficient plasma through the formation of apoE-containing particles, which efficiently take up cell-derived cholesterol, and through the increase of cholesterol esterification activity. Thus, macrophage-derived apoE may protect against atherosclerosis by increasing cholesterol efflux from arterial wall cells.

Low-dose lovastatin safely lowers cholesterol after cardiac transplantation
Kobashigawa, J. A., F. L. Murphy, et al. (1990), Circulation 82(5 Suppl): IV281-3.
Abstract: Hypercholesterolemia occurs in many cardiac transplant patients and may aggravate graft coronary arteriopathy as well as contributing to peripheral vascular disease. Lovastatin, which inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase, in doses of 40-80 mg/day effectively lowers cholesterol in the general cardiac population but has been associated with rhabdomyolysis in cardiac transplant recipients. To determine whether lower doses of lovastatin would be effective and safe for lowering cholesterol after cardiac transplantation, 44 patients with blood cholesterol greater than 200 mg/dl at least 6 months after cardiac transplantation received 10-20 mg lovastatin daily. In addition, lovastatin enzyme inhibitor level was assayed in six patients to determine whether metabolism of the drug was abnormal. Lovastatin decreased total cholesterol by 28% from 282 +/- 54 to 208 +/- 62 mg/dl (p less than 0.005), primarily because of reduction in the low-density lipoprotein fractions, and was well-tolerated without any symptoms or abnormal creatine phosphokinase levels in 43 of 44 patients. One patient developed rhabdomyolysis and reversible renal failure when lovastatin was increased to 40 mg daily. Enzyme inhibitor levels in the six transplant patients were 4.2-7.8 times higher than those measured in normal volunteers. Low-dose lovastatin effectively lowers cholesterol in patients after transplantation, but metabolism is altered, perhaps by cyclosporine. Monitoring of enzyme inhibitor levels may be required to allow safe administration of this drug to cardiac transplant recipients.

Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: Main results from the Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS)
Hedblad, B., J. Wikstrand, et al. (2001), Circulation 103(13): 1721-6.
Abstract: BACKGROUND: Statins reduce cardiovascular events and progression of carotid intima-media thickness (IMT). beta-Blockers are also known to reduce cardiovascular events, but less is known about their effects on carotid IMT. METHODS AND RESULTS: We conducted a randomized, double-blind, placebo-controlled, single-center trial to compare the effects of low-dose metoprolol CR/XL (25 mg once daily) and fluvastatin (40 mg once daily) on the progression of carotid IMT during 36 months of treatment in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. Changes in mean IMT in the common carotid artery and maximal IMT in the bulb were the main outcome variables. Death and cardiovascular events were monitored. Progression of IMT(max) in the carotid bulb at both 18 and 36 months was reduced by metoprolol CR/XL (-0.058 mm/y; 95% CI, -0.094 to -0.023; P=0.004; and -0.023 mm/y; 95% CI, -0.044 to -0.003; P=0.014, respectively). Incidence of cardiovascular events tended to be lower in metoprolol CR/XL-treated patients (5 versus 13 patients, P=0.055). Rate of IMT(mean) progression in the common carotid at 36 months was reduced by fluvastatin (-0.009 mm/y; 95% CI, -0.015 to -0.003; P=0.002). Women in the fluvastatin group had increased frequency of transiently high liver enzymes. CONCLUSIONS: This is the first randomized trial to show that a beta-blocker can reduce the rate of progression of carotid IMT in clinically healthy, symptom-free subjects with carotid plaque. This suggests that beta-blockers may have a favorable effect on atherosclerosis development.

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