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PubMed2005

Determinants of endothelial dysfunction and carotid intima-media thickness in combined hyperlipidemia.

BACKGROUND: Early functional and morphological changes in the course of the atherosclerotic process are manifested as endothelial dysfunction and increased intima-media thickness (IMT) of the arterial wall. These are both associated with various atherosclerotic risk factors. We investigated whether the same factors are associated with functional and morphological changes of the arterial wall in men with combined hyperlipidemia. METHODS: Flow-mediated dilatation (FMD) of the brachial artery and carotid IMT were measured in 72 male patients aged 46+/-5 years with combined hyperlipidemia. Serum lipoproteins, fibrinolytic and coagulation parameters, blood glucose, proinflammatory cytokines and C-reactive protein were also measured. RESULTS: Tumor necrosis factor-alpha, interleukin 6 and apolipoprotein (apo) B were found to be independent predictors of FMD, explaining 87% of FMD variability in multivariate analysis. On the other hand, total tissue factor pathway inhibitor and apo B were independent predictors of increased carotid IMT, explaining 82% of the variation in carotid IMT. CONCLUSIONS: Apo B, which is a marker for the presence of the atherogenic lipoproteins, is associated with both functional and morphological changes of the artery wall. In addition, in asymptomatic overweight middle-aged men with combined hyperlipidemia, functional changes are associated with proinflammatory cytokines, while morphological changes are associated with coagulation parameters.

Adult↗
PubMed1977

Cluster headache associated with primary hyperlipidemia.

Two brothers suffering from cluster headache of the chronic variant as well as hyperlipidemia are described. The mother very likely suffered from the same combination. Eleven consecutive cases of cluster headache were studied for lipid abnormalities. Among five patients of the intermittent type, one suffereed from xantelasmata but had normal blood lipids. Among six patients of the chronic variant two had essential hyperlipidemia type IV. An etiological relationship between some cases of cluster headache and hyperlipidemia is therefore suggested.

Adult↗
PubMedDate not supplied

Pravastatin treatment of very low density, intermediate density and low density lipoproteins in hypercholesterolemia and combined hyperlipidemia secondary to the nephrotic syndrome.

BACKGROUND/AIMS: In the current study pravastatin was used in nephrotic syndrome patients with hypercholesterolemia and combined hyperlipidemia to test whether the drug decreases production of LDL and reduces levels of VLDL and IDL. METHODS: Thirteen patients (7 with high LDL alone and 6 with high VLDL, IDL and LDL) were randomized in a placebo-controlled study that had a crossover design. Patients were treated 8 weeks with pravastatin (40 mg/day) (or placebo) and switched to the corresponding placebo/drug for another 8 weeks. During each phase of the trial, patients had measurement of plasma levels of lipoprotein lipids, and turnover rates of autologous LDL apo B. RESULTS: Pravastatin increased LDL clearance by 16.7% and reduced total cholesterol content per LDL particle in patients with hypercholesterolemia. In combined hyperlipidemia, LDL clearance increased by 19% and there was no significant change in the production of LDL-apo B. Levels of VLDL+IDL apo B were not reduced significantly, while the total cholesterol content of these particles was reduced by 31.7%. CONCLUSION: Pravastatin effectively reduced LDL levels in both types of dyslipidemia by increasing LDL clearance. Treatment had no effect on production of LDL or on levels of VLDL+IDL-apo B. Thus, pravastatin increases LDL clearance. Statins do not seem to affect production rates of apo B-containing lipoproteins. Treatment of combined hyperlipidemia may require pravastatin and an added drug targeted to normalize levels of VLDL and IDL.

Anticholesteremic Agents↗
PubMed2003

Hyperglycemia and hyperlipidemia act synergistically to induce renal disease in LDL receptor-deficient BALB mice.

Diabetic nephropathy is the leading cause of end-stage renal disease in Western countries, but only a portion of diabetic patients develop diabetic nephropathy. Dyslipidemia represents an important aspect of the metabolic imbalance in diabetic patients. In this study, we addressed the impact of combined hyperlipidemia and hyperglycemia on renal pathology. Kidneys from wild-type (WT) or LDL receptor-deficient BALB/cBy mice (BALB.LDLR-/-) were examined at 22 weeks of age. Diabetes was induced by administration of streptozotocin and mice were randomly assigned to either standard chow or Western diet. Chow fed BALB.LDLR-/- mice did not demonstrate renal abnormalities, whereas BALB. LDLR-/- mice fed a Western diet showed occasional glomerular and tubulointerstitial foam cells. Diabetic WT mice had modestly increased glomerular cellularity and extracellular matrix. Hyperlipidemic and diabetic BALB.LDLR-/- mice exhibited an increase in glomerular cellularity and extracellular matrix, accumulation of glomerular and tubulointerstitial foam cells and mesangial lipid deposits. The tubular epithelium demonstrated pronounced lipid induced tubular degeneration with increased tubular epithelial cell turnover. Hyperlipidemia and hyperglycemia seem to act synergistically in inducing renal injury in the BALB.LDLR-/- mouse. This model of diabetic nephropathy is unique in its development of tubular lesions and may represent a good model for hyperlipidemia-exacerbated diabetic nephropathy.

Animals↗
PubMed1994

Hyperlipidemia after renal transplantation: treatment with gemfibrozil.

Thirty-eight renal allograft recipients who had persistent hyperlipidemia and stable renal function 27.8 +/- 18.2 months after renal transplantation were treated with gemfibrozil. Gemfibrozil therapy resulted in a decrease in the levels of total cholesterol (TC; 297.6 +/- 41.0 mg/dl to 249.2 +/- 43.7 mg/dl, -16.3%; p < 0.0001), triglyceride (TG; 231.9 +/- 116.8 to 125.7 +/- 58.4 mg/dl, -45.8%, p < 0.0005), and LDL-cholesterol (LDL-C; 203.8 +/- 37.4 to 174.5 +/- 42.5 mg/dl, -14.4%; p = 0.001), which were sustained for 29.1 +/- 16.0 months. Comparison of sequential lipid profiles between gemfibrozil-treated individuals and untreated hyperlipidemic controls matched for age, sex, time after transplantation, and the degree of hyperlipidemia, showed that gemfibrozil-treated patients had lower levels of TC (239.9 +/- 39.5 vs. 272.8 +/- 34.1 mg/dl; p < 0.005), TG (125.7 +/- 26.6 vs. 167.3 +/- 69.0 mg/dl; p < 0.05), and LDL-C (160.2 +/- 41.3 vs. 185.3 +/- 26.6 mg/dl; p < 0.05) on serial follow-up. No significant side-effect was observed with gemfibrozil therapy. Our data showed that gemfibrozil was a safe and effective drug for the treatment of hyperlipidemia in renal allograft recipients, which could reduce these patients's long-term cardiovascular risks.

Adult↗
PubMed1989

Plasma factor VII, triglyceride concentration and fibrin degradation products in primary hyperlipidemia: a clinical and laboratory study.

There is evidence that the increase in coagulation factor VII (FVII) represents a predictive risk factor of arterial thrombosis in coronary heart disease. Its relative contribution to this multifactorial process and its relationship to other risk factors, namely cholesterol and triglycerides, is yet a matter of investigation. In this study we aimed to clarify whether FVII synthesis or activation correlated with plasma lipid concentrations. For this, we assayed the plasma levels of FVII antigen (FVII:ag) and FVII coagulant activity (FVIIc) in types IIa, IIb and IV hyperlipidemic individuals, together with the levels of cholesterol, triglycerides, high-density lipoproteins and apolipoprotein B. FVII activation state (FVIIa) was then assessed by FVIIc/FVII:ag. In order to assess the possible correlation of FVII levels with the generation of thrombin and formation of fibrin, we also assayed the plasma concentration of fibrin degradation products (D-dimers) in these patients. Considering all the patients studied, there was a fair correlation between FVIIc and FVII:ag (r = 0.704; p less than 0.01). The mean levels of FVIIc and FVII:ag were significantly higher in type IV hyperlipidemia than in controls (t = 4.260; p less than 0.001 and t = 3.015; p less than 0.01, respectively) and other types of hyperlipidemia. We also found that FVIIc and FVII:ag significantly correlated to triglyceride concentration. We could not detect an evident activation of FVII in these patients since FVIIc/FVII:ag was not elevated in comparison with controls, nor did it correlate with any of the lipid determinations in any of the types of hyperlipidemia studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins B↗
PubMed2003

Hyperlipidemia promotes osteoclastic potential of bone marrow cells ex vivo.

OBJECTIVE: Osteoporosis is associated epidemiologically with atherosclerosis and hyperlipidemia. We previously found that atherogenic lipids regulate bone formation. To determine whether hyperlipidemia also affects bone resorption, we compared osteoclastogenesis in marrow preosteoclasts derived from hyperlipidemic versus control mice. METHODS: Nonadherent marrow cells from low-density lipoprotein receptor-/- (LDLR-/-)and C57BL/6J mice were cultured with M-CSF and ligand for receptor activator of nuclear factor-kappaB (RANKL). Functional osteoclastic activity, measured as number of resorption pits, was significantly greater in 12-month-old LDLR-/-. Similar results were obtained in 5- and 10-month-old LDLR-/- versus C57BL/6J mice on a high-fat diet. Osteoclastic differentiation, indicated by tartrate resistant acid phosphatase (TRAP) activity, was significantly greater in the 12-month-old LDLR-/-, and there was a trend toward increased TRAP activity in LDLR-/- on a high-fat diet, at ages 5 and 10 months. Osteoclastic parameters correlated with total serum lipoproteins with a possible threshold effect. Osteoporotic human cortical bone stained positive for lipids in the perivascular space of Haversian canals by oil red O. The presence of lipid hydroperoxides was detected in bone marrow from hyperlipidemic mice. CONCLUSIONS: Hyperlipidemia may contribute to osteoporosis via increased osteoclastic bone resorption.

Animals↗
PubMed1996

Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia.

The effect of fenofibrate on plasma cholesteryl ester transfer protein (CETP) activity in relation to the quantitative and qualitative features of apoB- and apoA-I-containing lipoprotein subspecies was investigated in nine patients presenting with combined hyperlipidemia. Fenofibrate (200 mg/d for 8 weeks) induced significant reductions in plasma cholesterol (-16%; P < .01), triglyceride (-44%; P < .007), VLDL cholesterol (-52%; P = .01), LDL cholesterol (-14%; P < .001), and apoB (-15%; P < .009) levels and increased HDL cholesterol (19%; P = .0001) and apoA-I (12%; P = .003) levels. An exogenous cholesteryl ester transfer (CET) assay revealed a marked decrease (-26%; P < .002) in total plasma CETP-dependent CET activity after fenofibrate treatment. Concomitant with the pronounced reduction in VLDL levels (37%; P < .005), the rate of CET from HDL to VLDL was significantly reduced by 38% (P = .0001), whereas no modification in the rate of cholesteryl ester exchange between HDL and LDL occurred after fenofibrate therapy. Combined hyperlipidemia is characterized by an asymmetrical LDL profile in which small, dense LDL subspecies (LDL-4 and LDL-5, d = 1.039 to 1.063 g/mL) predominate. Fenofibrate quantitatively normalized the atherogenic LDL profile by reducing levels of dense LDL subspecies (-21%) and by inducing an elevation (26%; P < .05) in LDL subspecies of intermediate density (LDL-3, d = 1.029 to 1.039 g/mL), which possess optimal binding affinity for the cellular LDL receptor. However, no marked qualitative modifications in the chemical composition or size of LDL particles were observed after drug treatment. Interestingly, the HDL cholesterol concentration was increased by fenofibrate therapy, whereas no significant change was detected in total plasma HDL mass. In contrast, the HDL subspecies pattern was modified as the result of an increase in the total mass (11.7%) of HDL2a, HDL3a, and HDL3b (d = 1.091 to 1.156 g/mL) at the expense of reductions in the total mass (-23%) of HDL2b (d = 1.063 to 1.091 g/mL) and HDL3c (d = 1.156 to 1.179 g/mL). Such changes are consistent with a drug-induced reduction in CETP activity. In conclusion, the overall mechanism involved in the fenofibrate-induced modulation of the atherogenic dense LDL profile in combined hyperlipidemia primarily involves reduction in CET from HDL to VLDL together with normalization of the intravascular transformation of VLDL precursors to receptor-active LDLs of intermediate density.

Adult↗
PubMed1999

Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism.

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158-->Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02). In the normoinsulinemic group, no such relation of the SstI polymorphism with hyperlipidemia was observed. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.

Adult↗
PubMedDate not supplied

Hyperlipidemia in the Pacific Northwest Bell Telephone Company Health Survey. Part 1. Lipoprotein cholesterol and triglyceride concentrations.

Lipoprotein triglyceride and cholesterol concentrations and characteristics are described in normolipidemic and in three categories of hyperlipidemic subjects participating in the Pacific Northwest Bell Telephone Company Health Survey. For this study, 350 white participants 20 to 59 years of age with cholesterol or triglyceride values exceeding the age, sex, and hormone-use specific, population-based 90th percentile values were defined as having hypercholesterolemia, hypertriglyceridemia, or combined hyperlipidemia; 722 participants were classified as normolipidemic. In hypercholesterolemia, very low density lipoprotein cholesterol and triglyceride and high density lipoprotein cholesterol concentrations were higher than in normolipidemia. In hypertriglyceridemia, high density lipoprotein cholesterol was significantly lower in men and women not using sex hormones and low density lipoprotein triglyceride was significantly higher in men and women using hormones compared to normolipidemia. In combined hyperlipidemia, high density lipoprotein cholesterol concentrations were lower than in normolipidemia, but higher than in pure hypertriglyceridemia. The presence of beta migrating very low density lipoprotein and chylomicrons was seen primarily in hypertriglyceridemic or combined hyperlipidemic men. Sinking prebeta lipoprotein was equally common (20%) among all normolipidemic and hypercholesterolemic subjects, but was less common (5% to 10%) in hypertriglyceridemic and combined hyperlipidemic men and female hormone users. Quantitative and qualitative lipoprotein abnormalities associated with hyperlipidemia were found to vary by gender and by sex hormone use in women and were often, but not always, more marked in men.

Adult↗
PubMed1979

Normal levels of fibrinopeptide A in patients with primary hyperlipidemia.

Fibrinopeptide A (FPA) levels were measured in a group of 130 controls and patients with various types of primary hyperlipidemia to investigate whether an increased steady state level of thrombin activity is present in hyperlipidemic patients. In a subset of 56 subjects, levels of clotting factors II, VII, and X were measured as well. FPA levels in hyperlipidemic patients were not significantly different from those of control subjects. Furthermore, on multiple regression analysis, no significant relationships were found between FPA levels and the concentrations of serum cholesterol or triglyceride, or log triglyceride levels. Statistically significant relationships were found between all three clotting factor levels and triglyceride concentration. The correlation coefficients for these relationships, however, were low, so that the correlations are of questionable pathophysiological significance. A weak relationship also was found between the plasma levels of cholesterol and of factor II. Thus, although small increases in various clotting factors may be found in patients with hyperlipidemia, plasma FPA levels are normal. These data indicate that hyperlipidemia is not associated with a steady state of increased thrombin activity in vivo in humans.

Cholesterol↗
PubMedDate not supplied

Familial hyperlipidemia in stroke in the young.

Serum cholesterol, low density lipoproteins (LDL), very low density lipoproteins (VLDL) and chylomicron levels were studied in 25 young patients (age 40 years or less) of non-embolic ischemic stroke of unknown aetiology. Fifteen patients were males and 10 were females. The prevalence of hyperlipidemia was found to be 60%. Frederickson's type IIb hyperlipoproteinemia was the commonest (32%) abnormal pattern observed, followed by type IIa (12%), type IV (12%) and type V (4%). Family studies were carried out in all the 25 index patients (15 hyperlipidemic and 10 normolipidemic). Familial hyperlipidemia (i.e. 2 or more hyperlipidemic members in the same family) was found in 9 of the 15 hyperlipidemic index patients and in none of the normolipidemic index patients. The common pattern was found to be that of familial combined hyperlipidemia. The study indicates that screening the family members of hyperlipidemic young patients of non-embolic ischemic stroke may delineate a group of high risk individuals for possible primary prevention before they develop the disease.

Adult↗
PubMed1999

Increased cerebral CO(2) reactivity after heparin-mediated extracorporal LDL precipitation (HELP) in patients with coronary heart disease and hyperlipidemia.

BACKGROUND AND PURPOSE: There is experimental and clinical evidence that hypercholesterolemia leads to an impairment of endothelial function in coronary and cerebral arteries. Using transcranial Doppler sonography, we examined CO(2) reactivity as a marker of cerebral vasoreactivity in patients with coronary heart disease and hyperlipidemia before and after drastic lowering of LDL cholesterol, lipoprotein(a) [Lp(a)], and fibrinogen levels by heparin-mediated extracorporal LDL precipitation (HELP). METHODS: CO(2) reactivity was determined in 13 patients with coronary artery disease and hyperlipidemia undergoing regular HELP therapy. Middle cerebral artery mean blood flow velocity (MFV) was detected by transcranial Doppler. CO(2) reactivity was calculated as the percent change of MFV during hypercapnia, induced by ventilation of carbogene (5% CO(2), 95% O(2)), to normocapnia. Patients with extracranial or intracranial stenoses were excluded. Other parameters such as blood viscosity, heart rate, and blood pressure were measured to control hemorheologic and systemic influences on CO(2) reactivity. RESULTS: A single HELP treatment reduced total cholesterol, LDL cholesterol, Lp(a), triglycerides, and fibrinogen levels by >50% (P<0.001). Blood viscosity significantly decreased from 1.24+/-0.04 to 1.07+/-0.02 mPa (P<0.001). Blood pressure, heart rate, and MFV did not change significantly. CO(2) reactivity increased from 22% +/- 21% to 36% +/- 18% (P<0.05). CONCLUSIONS: Fast and drastic removal of LDL cholesterol, Lp(a), and fibrinogen from plasma results in an improvement of cerebrovascular reactivity in patients with coronary heart disease and hyperlipidemia. The clinical use of HELP in patients with impaired cerebrovascular reactivity might be promising.

Aged↗
PubMedDate not supplied

Starting with rosuvastatin in primary hyperlipidemia--Is there more than lipid lowering?

The authors investigated the effects of rosuvastatin, beyond its lipid-lowering activity, on several nonlipid metabolic variables, along with its safety and tolerability, in patients treated for primary hyperlipidemia. Patients (n = 55) with primary hyperlipidemia were open-label assigned to the recommended starting dose of rosuvastatin 10 mg/day, and serum metabolic variables were measured at baseline and after 8 and 20 weeks. Treatment with rosuvastatin produced significant reductions in total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, nonhigh-density lipoprotein cholesterol (non HDL-C), and triglyceride concentrations, whereas HDL-C, apolipoprotein A-I, and lipoprotein(a) levels did not change significantly from baseline. The LDL-C treatment target was achieved in 71% of patients. No significant variations in renal function parameters (serum creatinine and creatinine clearance), insulin resistance estimates, and serum concentrations of uric acid, total homocysteine, vitamin B12, and folic acid were observed during the period of treatment. High-sensitivity C-reactive protein levels were significantly lowered by rosuvastatin therapy (median values, 3.1 vs 2.0 vs 1.9 mg/L, at 0, 8, and 20 weeks, respectively; p < 0.0001). In conclusion, rosuvastatin at 10 mg/day is a highly effective, safe, and well-tolerated monotherapy option for patients with primary hyperlipidemia, with a favorable antiinflammatory potential and nondeteriorating effects on renal function.

Adult↗
PubMed2005

Substituting abacavir for hyperlipidemia-associated protease inhibitors in HAART regimens improves fasting lipid profiles, maintains virologic suppression, and simplifies treatment.

BACKGROUND: Hyperlipidemia secondary to protease inhibitors (PI) may abate by switching to anti-HIV medications without lipid effects. METHOD: An open-label, randomized pilot study compared changes in fasting lipids and HIV-1 RNA in 104 HIV-infected adults with PI-associated hyperlipidemia (fasting serum total cholesterol >200 mg/dL) who were randomized either to a regimen in which their PI was replaced by abacavir 300 mg twice daily (n = 52) or a regimen in which their PI was continued (n = 52) for 28 weeks. All patients had undetectable viral loads (HIV-1 RNA <50 copies/mL) at baseline and were naive to abacavir and non-nucleoside reverse transcriptase inhibitors. RESULTS: At baseline, the mean total cholesterol was 243 mg/dL, low density lipoprotein (LDL)-cholesterol 149 mg/dL, high density lipoprotein (HDL)-cholesterol 41 mg/dL, and triglycerides 310 mg/dL. Mean CD4+ cell counts were 551 and 531 cells/mm3 in the abacavir-switch and PI-continuation arms, respectively. At week 28, the abacavir-switch arm had significantly greater least square mean reduction from baseline in total cholesterol (-42 vs -10 mg/dL, P < 0.001), LDL-cholesterol (-14 vs +5 mg/dL, P = 0.016), and triglycerides (-134 vs -36 mg/dL, P = 0.019) than the PI-continuation arm, with no differences in HDL-cholesterol (+0.2 vs +1.3 mg/dL, P = 0.583). A higher proportion of patients in the abacavir-switch arm had decreases in protocol-defined total cholesterol and triglyceride toxicity grades, whereas a smaller proportion had increases in these toxicity grades. At week 28, an intent-to treat: missing = failure analysis showed that the abacavir-switch and PI-continuation arms did not differ significantly with respect to proportion of patients maintaining HIV-1 RNA <400 or <50 copies/mL or adjusted mean change from baseline in CD4+ cell count. Two possible abacavir-related hypersensitivity reactions were reported. No significant changes in glucose, insulin, insulin resistance, C-peptide, or waist-to-hip ratios were observed in either treatment arm, nor were differences in these parameters noted between treatments. CONCLUSION: In hyperlipidemic, antiretroviral-experienced patients with HIV-1 RNA levels <50 copies/mL and CD4+ cell counts >500 cells/mm3, substituting abacavir for hyperlipidemia-associated PIs in combination antiretroviral regimens improves lipid profiles and maintains virologic suppression over a 28-week period, and it simplifies treatment.

Adult↗
PubMed2006

The lipoprotein lipase gene in combined hyperlipidemia: evidence of a protective allele depletion.

BACKGROUND: Lipoprotein Lipase (LPL), a key enzyme in lipid metabolism, catalyzes the hydrolysis of triglycerides (TG) from TG-rich lipoproteins, and serves a bridging function that enhances the cellular uptake of lipoproteins. Abnormalities in LPL function are associated with pathophysiological conditions, including familial combined hyperlipidemia (FCH). Whereas two LPL susceptibility alleles were found to co-segregate in a few FCH kindred, a role for common, protective alleles remains unexplored. The LPL Ser447Stop (S447X) allele is associated with anti-atherogenic lipid profiles and a modest reduction in risk for coronary disease. We hypothesize that significant depletion of the 447X allele exists in combined hyperlipidemia cases versus controls. A case-control design was employed. The polymorphism was assessed by restriction assay in 212 cases and 161 controls. Genotypic, allelic, and phenotypic associations were examined. RESULTS: We found evidence of significant allelic (447Xcontrol: 0.130 vs. 447Xcase: 0.031, chi2 = 29.085; 1df; p < 0.001) and genotypic association (SS: 0.745 vs. 0.939, and SX+XX: 0.255 vs. 0.061) in controls and cases, respectively (chi2 = 26.09; 1df; p < 0.001). In cases, depletion of the 447X allele is associated with a significant elevation in very-low-density lipoprotein cholesterol (VLDL-C, p = 0.045). Consonant with previous studies of this polymorphism, regression models predict that carriers of the 447X allele displayed significantly lower TG, low-density lipoprotein cholesterol (LDL-C) and TG/high-density lipoprotein cholesterol (HDL-C) ratio. CONCLUSION: These findings suggest a role for the S447X polymorphism in combined hyperlipidemia and demonstrate the importance of evaluating both susceptibility and protective genetic risk factors.

Adult↗
PubMed2002

Effect of atorvastatin on plasma apoE metabolism in patients with combined hyperlipidemia.

Atorvastatin, a synthetic HMG-CoA reductase inhibitor used for the treatment of hyperlipidemia and the prevention of coronary artery disease, significantly lowers plasma cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. It also reduces total plasma triglyceride and apoE concentrations. In view of the direct involvement of apoE in the pathogenesis of atherosclerosis, we have investigated the effect of atorvastatin treatment (40 mg/day) on in vivo rates of plasma apoE production and catabolism in six patients with combined hyperlipidemia using a primed constant infusion of deuterated leucine. Atorvastatin treatment resulted in a significant decrease (i.e., 30-37%) in levels of total triglyceride, cholesterol, LDL-C, and apoB in all six patients. Total plasma apoE concentration was reduced from 7.4 +/- 0.9 to 4.3 +/- 0.2 mg/dl (-38 +/- 8%, P < 0.05), predominantly due to a decrease in VLDL apoE (3.4 +/- 0.8 vs. 1.7 +/- 0.2 mg/dl; -42 +/- 11%) and IDL/LDL apoE (1.9 +/- 0.3 vs. 0.8 +/- 0.1 mg/dl; -57 +/- 6%). Total plasma lipoprotein apoE transport (i.e., production) was significantly reduced from 4.67 +/- 0.39 to 3.04 +/- 0.51 mg/kg/day (-34 +/- 10%, P < 0.05) and VLDL apoE transport was reduced from 3.82 +/- 0.67 to 2.26 +/- 0.42 mg/kg/day (-36 +/- 10%, P = 0.057). Plasma and VLDL apoE residence times and HDL apoE kinetic parameters were not significantly affected by drug treatment. Percentage decreases in VLDL apoE concentration and VLDL apoE production were significantly correlated with drug-induced reductions in VLDL triglyceride concentration (r = 0.99, P < 0.001; r = 0.88, P < 0.05, respectively, n = 6). Our results demonstrate that atorvastatin causes a pronounced decrease in total plasma and VLDL apoE concentrations and a significant decrease in plasma and VLDL apoE rates of production in patients with combined hyperlipidemia.

Adult↗
PubMed2005

Alteration of the copy number of mitochondrial DNA in leukocytes of patients with hyperlipidemia.

Lipid metabolism in leukocytes may be disturbed by mitochondrial dysfunction caused by depletion of mitochondrial DNA (mtDNA) in response to an increase of oxidative stress in blood circulation. It is possible that alteration in mtDNA copy number of the leukocyte is involved in the impairment of the scavenging of oxidatively modified plasma proteins such as oxidized low-density lipoprotein (oxLDL). To test this hypothesis, we recruited 91 healthy subjects and 63 patients with hyperlipidemia (LDL >130 mg/dL) for this study. The copy number of mtDNA in the leukocyte and the titer of oxLDL IgG autoantibody (oLAB) were determined as indices of the oxidative stress response of immune cells. The results revealed a significant higher level of plasma oxLDL, lower titer of oLAB, and decreased copy number of mtDNA in patients with hyperlipidemia (P <0.05). In the analysis of partial correlations under age control, we found that an increase in the copy number of mtDNA was positively correlated with an increase in the level of oLAB (P <0.005, r = 0.3002) and a decrease in the oxLDL level (P <0.05, r = -0.2654) in healthy subjects but not in patients. Based on the results obtained from this case-control study, we conclude that the increase of mtDNA copy number might provide the leukocyte an increased capability of scavenging oxLDL, possibly by enhanced generation of oLAB in healthy subjects, but not in hyperlipidemic patients who had lower mtDNA copy numbers in their leukocytes. Taken together, these findings suggest that an alteration of mtDNA copy number in the leukocyte may be one of the risk factors for hyperlipidemia.

DNA, Mitochondrial↗