Atorvastatin in low-density lipoprotein apheresis-treated patients with homozygous and heterozygous familial hypercholesterolemia

To further reduce low-density lipoprotein-cholesterol (LDL-C), atorvastatin treatment was investigated in patients with homozygous (n = 4) and heterozygous (n = 10) familial hypercholesterolemia (FH) undergoing LDL-apheresis. After a wash-out period of 4 weeks, atorvastatin therapy was administered in escalating doses (10 up to 80 mg/d). LDL-apheresis was performed at weekly intervals during the entire study period. The LDL-C concentration decreased from 240 +/- 35 mg/dL after the wash-out period to 206 +/- 63 mg/dL during treatment with 10 mg atorvastatin. Four weeks of treatment with 80 mg atorvastatin resulted in an additional 24% (P <.05) reduction in LDL-C. LDL-C increased from 28.8 +/- 14.2 mg/dL immediately after apheresis to 156.6 +/- 25.5 mg/dL at day 7. LDL-C values remained below the recommended target range for an extended duration of 48 hours in atorvastatin-treated patients, but not in those without concomitant lipid-lowering drug therapy. The levels of high-density lipoprotein-cholesterol (HDL-C) and plasma fibrinogen were unchanged during the entire study period. No adverse events were observed with atorvastatin treatment. Finally, high-dose atorvastatin therapy resulted in a 40% reduction in LDL-apheresis sessions in these patients. Our results show that LDL-C reduction by atorvastatin is a safe and effective therapy in LDL-apheresis patients with severe heterozygous or homozygous FH.     

Rosiglitazone increases small dense low-density lipoprotein concentration and decreases high-density lipoprotein particle size in HIV-infected patients

After 12 weeks of rosiglitazone treatment, significant increases in total and small dense low-density lipoprotein, and the total: high-density lipoprotein (HDL)-cholesterol ratio were found. The large HDL concentration and HDL particle size decreased significantly with rosiglitazone compared with placebo. These data indicate the production of a more atherogenic lipid profile with rosiglitazone, a consideration when selecting treatment for the growing population of HIV-infected patients with type 2 diabetes and dyslipidemia.     

Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol.

OBJECTIVES: We sought to evaluate the significance of high-density lipoprotein cholesterol (HDL-C) in the context of low low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Earlier studies support an inverse correlation between circulating HDL-C and coronary risk in patients with normal or elevated LDL-C. METHODS: This study involved 4,188 patients attending the Palo Alto Veterans Administration Medical Center or affiliated clinics with LDL-C levels below 60 mg/dl. Outcomes were examined 1 year after the index LDL-C date. The combined primary end point was myocardial injury or hospitalization from ischemic heart disease. The secondary end point was all-cause mortality. RESULTS: Mean HDL-C levels (mg/dl) by quartile (Q) were: Q1 28 mg/dl, Q2 36 mg/dl, Q3 43 mg/dl, and Q4 63 mg/dl. The rate of myocardial injury or hospitalization for ischemic heart disease showed an inverse relationship to HDL-C (adjusted odds ratios: Q1 1.59 [95% confidence interval (CI) 1.16 to 2.19], Q2 1.39 [95% CI 1.01 to 1.92], Q3 1.33 [95% CI 0.96 to 1.84], and Q4 reference) that persisted regardless of statin use or recent myocardial injury. Analyzing HDL-C as a continuous variable revealed a 10% [95% CI 3% to 17%] increase in the combined end point of myocardial injury or hospitalization for ischemic heart disease for every 10-mg/dl decrease in HDL-C. The unadjusted and adjusted incidence of all-cause mortality demonstrated a U-shaped relationship to HDL-C (adjusted odds ratios: Q1 1.13 [95% CI 0.79 to 1.62], Q2 0.97 [95% CI 0.67 to 1.40], Q3 0.74 [95% CI 0.50 to 1.09], and Q4 reference). CONCLUSIONS: The inverse relationship between HDL-C and coronary risk persists even among patients with LDL-C below 60 mg/dl, although a U-shaped relationship is observed between HDL-C and all-cause mortality.     

Comparison of effects on low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with rosuvastatin versus atorvastatin in patients with type IIa or IIb hypercholesterolemia.

This randomized, double-blind, placebo-controlled trial was conducted in 52 centers in North America to compare the effects of the new, highly effective statin, rosuvastatin, with atorvastatin and placebo in hypercholesterolemic patients. After a 6-week dietary run-in, 516 patients with low-density lipoprotein (LDL) cholesterol > or =4.14 mmol/L (160 mg/dl) and < 6.47 mmol/L (250 mg/dl) and triglycerides < or =4.52 mmol/L (400 mg/dl) were randomized to 12 weeks of once-daily placebo (n = 132), rosuvastatin 5 mg (n = 128), rosuvastatin 10 mg (n = 129), or atorvastatin 10 mg (n = 127). The primary efficacy end point was percent change in LDL cholesterol. Secondary efficacy variables were achievement of National Cholesterol Education Program (NCEP) Adult Treatment Panel II (ATP II), ATP III, and European Atherosclerosis Society LDL cholesterol goals and percent change from baseline in high-density lipoprotein (HDL) cholesterol, total cholesterol, triglycerides, non-HDL cholesterol, apolipoprotein B, and apolipoprotein A-I. Rosuvastatin 5 and 10 mg compared with atorvastatin 10 mg were associated with greater LDL cholesterol reductions (-40% and -43% vs 35%; p <0.01 and p <0.001, respectively) and HDL cholesterol increases (13% and 12% vs 8%, p <0.01 and p <0.05, respectively). Total cholesterol and apolipoprotein B reductions and apolipoprotein A-I increases were also greater with rosuvastatin; triglyceride reductions were similar. Rosuvastatin 5 and 10 mg were associated with improved achievement in ATP II (84% in both rosuvastatin groups vs 73%) and ATP III (84% and 82% vs 72%) LDL cholesterol goals, and rosuvastatin 10 mg was more effective than atorvastatin in achieving European Atherosclerosis Society LDL cholesterol goals. Both treatments were well tolerated.     

Effect of rosuvastatin on low-density lipoprotein cholesterol in patients with hypercholesterolemia

Rosuvastatin is a new, synthetic, orally active statin, with marked low-density lipoprotein (LDL) cholesterol-lowering activity. We conducted 2 dose-ranging studies. In the first study, after a 6-week dietary run-in, 142 moderately hypercholesterolemic patients were randomized equally to receive double-blind placebo or rosuvastatin 1, 2.5, 5, 10, 20, or 40 mg or open-label atorvastatin 10 or 80 mg once daily for 6 weeks; in the second study, conducted to extend the rosuvastatin dose range, 64 patients were randomized to double-blind, once-daily placebo or rosuvastatin 40 or 80 mg (1:1:2 ratio) for 6 weeks. Data from both studies were combined for analysis of lipid effects. No statistical comparison of atorvastatin arms with placebo or rosuvastatin was performed. Rosuvastatin was associated with highly significant dose-dependent reductions in LDL cholesterol compared with placebo (p <0.001); decreases ranged from 34% (1 mg) to 65% (80 mg). Linear regression analysis indicated an additional 4.5% LDL cholesterol reduction for each doubling of the rosuvastatin dose. Across the dose range, approximately 90% of LDL cholesterol reduction occurred within the first 2 weeks of treatment. Significant, dose-dependent reductions in total cholesterol and apolipoprotein B with rosuvastatin were also observed (p <0.001). High-density lipoprotein cholesterol increases and triglyceride reductions were consistently observed and statistically significant at some dose levels. All lipid ratios were significantly reduced at all rosuvastatin dose levels (p <0.001). Adverse events were similar across placebo and active treatments. No significant increases in alanine aminotransferase or creatine kinase were seen in any patient. Over 6 weeks, rosuvastatin produced large, rapid, dose-dependent LDL cholesterol reductions and was well tolerated in hypercholesterolemic patients.     

Reduction in plasma low-density lipoprotein cholesterol and urinary mevalonic acid by lovastatin in patients with heterozygous familial hypercholesterolemia

The effects of lovastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG CoA reductase), on 24-hour urinary excretion rates of mevalonic acid (an intermediate in cholesterol biosynthesis) and plasma low-density lipoprotein (LDL) cholesterol concentrations were evaluated in patients with heterozygous familial hypercholesterolemia (FH). The mean rates of urinary mevalonate excretion of 28 FH patients were initially higher (2.95 +/- 0.29 (+/- SEM) mumols/d) than in 17 control subjects (1.82 +/- 0.12 mumols/d). Patients with FH were treated with sequentially increasing doses of lovastatin (10, 20, 40, and 80 mg daily, taken as a twice daily dosage) for a period of 6 weeks on each dose. When compared to baseline, LDL cholesterol levels fell by 22%, 26%, 30%, and 35% respectively, on these different doses. The mean daily urinary mevalonate excretion decreased from baseline by 19% after 4 weeks on 10 mg daily of lovastatin, 35% on 20 mg, and 31% on 40 mg and 80 mg daily. Similar decreases in urinary mevalonate excretions were observed when patients with FH were treated directly with 40 mg (20 mg twice daily) or 80 mg (40 mg twice daily) mg of lovastatin daily. The magnitude of decrease in LDL cholesterol did not show any significant correlation with the changes in urinary excretion of mevalonic acid. Lovastatin therapy decreases rates of urinary mevalonate excretion (which has previously been shown to reflect rates of cholesterol synthesis) by up to 35% at doses of 20 to 80 mg/d; such a decrease seems unlikely to compromise other important cellular requirements for mevalonate.     

Long-term effect of low-density lipoprotein apheresis in patients with heterozygous familial hypercholesterolemia

Clinical efficacy and safety of the therapeutic tool which directly removes LDL particles from circulation (LDL apheresis) have already been established in the treatment for refractory hypercholesterolemia in patients with familial hypercholesterolemia (FH). Two clinical studies with event-based assessment have demonstrated remarkably beneficial outcomes of long-term LDL apheresis using dextran sulfate cellulose columns plus adjunctive cholesterol-lowering drug therapy in the prevention of cardiovascular events in heterozygous FH with coronary artery disease. The results of several studies with angiographic and ultrasound-based assessment indicate a possible role for LDL apheresis in restructuring and stabilization of atherosclerotic lesions. These clinical improvements caused by LDL apheresis in heterozygous FH support the efficacy and importance of aggressive cholesterol-lowering therapy for secondary prevention of atherosclerotic cardiovascular disease in hypercholesterolemic patients.     

Long-term effect of low-density lipoprotein apheresis in patients with homozygous familial hypercholesterolemia

Patients that are homozygous for familial hypercholesterolemia (FH) exhibit severe hypercholesterolemia, cutaneous and tendon xanthomas and premature atherosclerosis beginning in childhood. They are resistant to drug therapy and low-density lipoprotein (LDL) apheresis is the practical treatment. Here we review the technique of LDL apheresis treatment, the long-term effects of LDL apheresis, the effect of apheresis on pregnancy, and the drugs that have proven beneficial in patients with homozygous FH. We also record our experiences of treating eight homozygous FH patients using the LDL apheresis treatment. Among the eight patients, one has been free from cardiovascular disease and two patients have each regressed once. In two patients, aortic valve stenosis developed and the other two patients died for acute myocardial infarction. Furthermore, two patients delivered healthy babies in spite of coronary artery disease. Thus, LDL apheresis therapy has the possibility of preventing the progression of atherosclerosis, but the prognosis assessed by long-term observation is still not satisfactory. A recent clinical trial showed some efficacy of the combination therapy of LDL apheresis and atorvastatin for reducing serum cholesterol levels in homozygous FH, suggesting that this combination therapy may be useful for prevention of atherosclerosis in patients homozygous for FH.     

Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men

The chromosomal localization of adiponectin has been found to be mapped to human chromosome 1q21.4-1q23, a region that was identified as a susceptibility locus for familial combined hyperlipidemia and polygenic type 2 diabetes. As these 2 disorders are associated with low high-density lipoprotein (HDL)-cholesterol, high triglycerides, and insulin resistance (IR), we examined the relation of serum adiponectin concentrations to serum lipid and lipoprotein profiles as well as IR in young healthy men. Serum adiponectin levels were positively associated with HDL-cholesterol, apolipoprotein (apo) A1, and low-density lipoprotein (LDL) particle size, and negatively associated with triglycerides and apo B. Negative associations were also found between adiponectin and body mass index (BMI), percent body fat, and IR,as determined by homeostasis model assessment (HOMA). However, after adjustment for BMI, no significant associations were found between adiponectin and LDL particle size and apo B. In a multiple regression analysis including all variables that showed significant univariate associations with adiponectin, associations of adiponectin with HDL-cholesterol (beta = 0.079, P =.0009), percent body fat (beta = -0.165, P =.002), and serum leptin (beta = -0.291, P =.01) were statistically significant. HDL-cholesterol (beta = 0.077, P =.001), percent body fat (beta = -0.078, P =.03), and LDL size (beta = 0.092, P =.03) emerged as significant and independent determinants of adiponectin after HOMA IR, fasting glucose, triglycerides, and systolic blood pressure (BP) were taken into account. Together, these variables explained 19% of adiponectin variability in the 2 models. HOMA IR did not emerge as a determinant of adiponectin in both models. These findings suggest that in young healthy men hypoadiponectinemia is more closely related to adiposity and dyslipidemia than IR.     

Comparison of gemfibrozil and lovastatin in patients with high low-density lipoprotein and low high-density lipoprotein cholesterol levels.

BACKGROUND--The efficacy of gemfibrozil and lovastatin in the treatment of patients who have an elevated low-density lipoprotein cholesterol (LDL-C) level and a low high-density lipoprotein cholesterol (HDL-C) level was compared. METHODS--After at least 6 weeks of a cholestgerol-lowering diet, 17 patients who had a mean baseline LDL-C level above 4.14 mmol/L (160 mg/dL) and an HDL-C level below 1.03 mmol/L (40 mg/dL) received gemfibrozil 600 mg twice daily and lovastatin 20 mg twice daily each for 6 weeks according to a randomized, crossover, double-blind research design. RESULTS--Lovastatin and gemfibrozil reduced LDL-C levels 34% and 9% and raised HDL-C levels 15% and 18%, respectively. CONCLUSIONS--Lovastatin is more effective in lowering LDL-C levels and is as effective as gemfibrozil in increasing HDL-C levels in these patients.     

Selective and semiselective low-density lipoprotein apheresis in familial hypercholesterolemia

Seven patients with familial hypercholesterolemia were treated fortnightly for 3 months by selective low-density lipoprotein apheresis with dextran-sulfate cellulose column (DSC). Subsequently, 4 of them were treated with semiselective double filtration. No cholesterol-lowering drugs were given. Plasma processed ranged from 39 to 58 ml/kg body weight/procedure. Fractional removals from plasma filtrate at the secondary treatment (adsorption or fractionation) for total cholesterol, high-density lipoprotein cholesterol, and albumin, respectively, were 0.84, 0.06, and 0.03 with DSC and 0.74, 0.47 and 0.35 with double filtration. Postapheresis reductions of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were 57, 15, and 59% with DSC and 47,35, and 48% with double filtration. Both methods are suitable for clinical use, but with a 15-day treatment schedule, lowering circulating lipid fraction levels are maintained with DSC.     

Plasma triglycerides related decrease in high-density lipoprotein cholesterol and its association with myocardial infarction in heterozygous familial hypercholesterolemia

Recent studies suggest that decreased levels of high-density liopoprotein (HDL) may contribute to the risk of premature occlusive atherosclerosis in familial hypercholesterolemia (FH). To investigate further, we have analyzed the concentration as well as distribution of HDL cholesterol in relation to plasma triglycerides and their influence on ischaemic heart disease in FH subjects. The study was carried out in 71 men with heterozygous FH and 46 matched controls. FH subjects were relatively young with a mean age of 38 ± 11 years. Tendon xanthomatas were observed in 57% of the subjects, whereas ischemic heart disease was identified in 33%. Compared to normals, the mean value of HDL cholesterol is significantly reduced by 21% in FH heterozygotes (42 ± 12 v 33 ± 9 mg/dL, P < 0.001). The decrease in HDL cholesterol is highly correlated to the levels of plasma triglycerides (r = −0.50, P < 0.001) and VLDL cholesterol (r = −0.53, P < 0.001). Moreover, HDL cholesterol decrease is not associated with elevated levels of LDL cholesterol (r = −0.20, NS), which is the primary characteristic feature of FH subjects. However, HDL cholesterol decrease is weakly related to total plasma cholesterol concentration (r = −0.24, P < 0.05). The body weight is also contributory to the reduction of HDL cholesterol (r = −0.42, P < 0.01), probably due to its strong positive correlation to plasma triglycerides (r = +0.54, P < 0.001). Grouping of subjects on the basis of triglyceride levels of less than 200 mg/dL (IIa phenotype) and more than 200 mg/dL (IIb phenotype) shows that the concentration of HDL cholesterol undergoes a further significant decrease in the latter group (36 ± 9 v 30 ± 11 mg/dL, P < 0.001). Since the level of LDL cholesterol is similar in both groups (314 ± 68 v 316 ± 76 mg/dL, NS), a further reduction in HDL cholesterol concentration results in an increased LDL/HDL ratio in IIb phenotypes. Although HDL cholesterol is normally distributed in controls and type IIa phenotypes, its distribution is skewed to lower values in type IIb. In addition to similar levels of LDL cholesterol, the presence of tendon xanthomatas is equally observed in both type IIa and type IIb subjects (51.1% and 62.5%, respectively). Similarly, the incidence of angina pectoris (19.2% and 12.5% in type IIa and type IIb, respectively) is also approximately the same in both groups. However, the differences are striking in the incidence of myocardial infarction (MI), which is increased three-fold (25% v 8.5%) in type IIb subjects, as compared to type IIa. These findings indicate that in addition to LDL excess, HDL deficiency associated with elevated plasma triglycerides contributes to the severity of ischemic heart disease, as revealed from the manifestation of MI in some FH heterozygotes.     

Prevalence of low high-density lipoprotein cholesterol in patients with documented coronary heart disease or risk equivalent and controlled low-density lipoprotein cholesterol

Current guidelines identify low-density lipoprotein (LDL) cholesterol as the primary target for cardiovascular prevention but also recognize low high-density lipoprotein (HDL) cholesterol as an important secondary target. This study was conducted to determine the prevalence of low HDL cholesterol in a contemporary ambulatory high-risk population across various LDL cholesterol levels, including patients taking statins. Screening of 44,052 electronic medical records from a primary care practice identified 1,512 high-risk patients with documented coronary heart disease (CHD) or CHD risk equivalents. Low HDL cholesterol (< or =40 mg/dl in men, < or =50 mg/dl in women) was present in 66% of the 1,512 patients. Low HDL cholesterol was prevalent across all LDL cholesterol levels but most prevalent in patients with LDL cholesterol < or =70 mg/dl (79% vs 66% in those with LDL cholesterol 71 to 100 mg/dl and 64% in patients with LDL cholesterol >100 mg/dl, p <0.01). Low HDL cholesterol was equally and highly prevalent in patients taking statins (67%) and those not taking statins (64%) (p = NS). HDL cholesterol and LDL cholesterol levels correlated poorly (R(2) = 0.01), and this was unaffected by gender or statin treatment. In conclusion, in high-risk patients with CHD or CHD risk equivalents, low HDL cholesterol levels remain prevalent despite statin treatment and the achievement of aggressive LDL cholesterol goals.     

Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia.

Most described modifications of low-density lipoprotein (LDL) cholesterol share an increase in its negative electric charge; in fact, an electronegative form of LDL can be identified and isolated from plasma. Although the exact nature of the chemical modification of electronegative LDL is still controversial, its toxicity on endothelial cells has been demonstrated. Statins have protective effects against cardiovascular disease that are independent of their lipid-lowering action and which could be due, at least in part, to the prevention of LDL modification. We evaluated the effect of 6 months of simvastatin therapy (40 mg/day) on electronegative LDL proportion and LDL susceptibility to in vitro induced oxidation in 21 patients with heterozygous familial hypercholesterolemia (FH). Eleven normolipemic subjects were analyzed as a control group. Total cholesterol as well as LDL and very low density lipoprotein cholesterol, triglycerides, and apoprotein B decreased 30% after the first month of therapy, with no further decreases thereafter. LDL susceptibility to oxidation was similar in FH patients and controls and did not change throughout the treatment. Electronegative LDL proportion was 35.1 +/- 9.9% in FH patients and 9.1 +/- 2.4% in control subjects (p <0.0001) but, in contrast to total LDL cholesterol and the rest of lipid parameters, it decreased to 28.6 +/- 9.1% in the third month and to 21.2 +/- 7.7% in the sixth month of therapy. The decrease in these cytotoxic particles may be a relevant mechanism by which simvastatin protects against cardiovascular disease.     

Impact of low-density lipoprotein receptor mutational class on carotid atherosclerosis in patients with familial hypercholesterolemia

Background and objectivesDefects in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a highly atherogenic condition. The effect of different LDLR mutations on coronary heart disease (CHD) risk is insufficiently defined. We assessed carotid intima-media thickness (IMT), a surrogate marker of CHD, in relation to LDLR mutational class in FH.MethodsIn 436 Spanish FH patients (223 men and 213 women, age 44 ± 14 years) with known LDLR mutations, alleles were classified by standard criteria as null (n = 269), defective (n = 162), or undetermined (n = 5). LDLR defects were detected using a microarray (Lipochip^®) designed to uncover prevalent mutations in Spain and gene sequencing when no mutations were detected. Carotid IMT and plaque were assessed in FH patients and 268 healthy subjects.ResultsAll carotid measurements were increased in FH patients versus controls (p < 0.05), irrespective of genotype. After adjustment for gender and age, patients with null alleles compared with defective alleles had similar mean and maximum common carotid artery (CCA) IMT, but higher maximum IMT at any carotid segment, with median values (95% confidence interval) of 1.25 mm (1.19–1.31) and 1.11 mm (1.05–1.18), respectively. Multivariate analysis showed that null alleles were independently associated with maximum CCA-IMT (β = 0.09, p = 0.033) with an impact similar to that of gender (β = 0.10, p = 0.035).ConclusionsFH patients show advanced carotid atherosclerosis in relation to LDLR mutational class. The findings support the utility of genetic testing in FH beyond providing a secure diagnosis.     

Three different schedules of low-density lipoprotein apheresis compared with plasmapheresis in patients with homozygous familial hypercholesterolemia

PURPOSE: To determine the biochemical and clinical response of two patients with homozygous familial hypercholesterolemia to three different schedules of low-density lipoprotein apheresis compared with plasmapheresis. PATIENTS AND METHODS: Two female patients aged 17 years, both affected by homozygous familial hypercholesterolemia, underwent low-density lipoprotein apheresis using a dextran-sulfate/cellulose affinity column on successive twice-weekly, weekly, and biweekly schedules. Plasmapheresis was carried out only at biweekly intervals. Plasma lipids and apolipoproteins A1 and B were assayed before and after each procedure. Cardiac status was assessed before and after the study. RESULTS: On schedule 1 of apheresis, the immediate post-procedure low-density lipoprotein cholesterol levels declined to 60 mg/100 dL plasma. Quasi-steady-state values of low-density lipoprotein cholesterol and apolipoprotein B were also markedly reduced, with levels approaching the upper limits of normal for age and sex. This response was attenuated as the intervals between procedures were prolonged. No advantage of low-density lipoprotein apheresis over plasmapheresis was observed during the biweekly protocol except that after plasmapheresis high-density lipoprotein cholesterol levels declined by 50% or more compared with less than 10% after apheresis. The latter procedure, especially on schedules 1 and 2, caused an increase in the quasi-steady-state concentrations of both high-density lipoprotein cholesterol and apolipoprotein A1. Thus, mean low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and apolipoprotein B/apo A1 ratios were reduced by more than three- to four-fold during twice-weekly apheresis. Other laboratory parameters remained stable throughout except for iron and hemoglobin levels, which were reduced with both plasmapheresis and apheresis. Xanthomas regressed significantly in the one patient who had not been treated prior to the current trial. Cardiac changes were minor in both patients. CONCLUSION: Low-density lipoprotein apheresis proved safe and effective on an accelerated protocol as well as during more conventional schedules. Owing to its simplicity, selectivity, and safety, apheresis using a dextran-sulfate/cellulose column is possibly the optimum means currently available for the extracorporeal removal of low-density lipoprotein cholesterol.     

Prolonged stimulation of the adrenals by corticotropin suppresses hepatic low-density lipoprotein and high-density lipoprotein receptors and increases plasma cholesterol

Pituitary ACTH has been shown to strongly stimulate adrenal receptors for low-density lipoprotein (LDL) and high-density lipoprotein (HDL) scavenger receptor class B type 1(SR-BI) to provide precursor cholesterol for glucocorticoid synthesis. The present study aimed to determine the effects of ACTH on hepatic cholesterol metabolism and plasma lipoproteins. Treatment of Sprague Dawley rats or normal C57BL/6J mice with ACTH for 3.5 d reduced hepatic SR-BI and LDL receptors. Simultaneously, cholesterol in plasma LDL and HDL was increased. None of these effects could be reproduced using glucocorticoids instead of ACTH, and they were abolished in adrenalectomized rats, indicating an obligate role of the adrenals for the effects of ACTH observed in the liver. When ACTH was given to LDL receptor-deficient mice, plasma LDL did not increase and the increase in HDL cholesterol remained, as did the suppression of hepatic SR-BI. Our data show that prolonged ACTH treatment suppresses hepatic SR-BI and LDL receptors in vivo in rodents, resulting in elevated plasma HDL and LDL. The adrenals are obligate for these effects, suggesting that ACTH releases some factor(s) that suppresses hepatic LDL and SR-BI receptors. Hypothetically, this novel mechanism would further promote channeling of cholesterol to the adrenals in situations of prolonged stress.