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Background and aims Induction of low-density lipoprotein receptor (LDLR) plays a significant role in reduction of plasma LDL-cholesterol (LDL-C) levels. Therefore, strategies that enhance the protein level of LDLR provide an attractive therapeutic target for the treatment of hypercholesterolemia. With this aim in mind, we concentrated our effort on studying the role of AKT kinase in regulation of LDLR levels and proceeded to examine the effect of MK-2206, an allosteric and highly selective AKT inhibitor, on LDLR expression. Methods Cultured human hepatoma cells were used to examine the effect of MK-2206 on the proteolytic processing of sterol regulatory element-binding protein-2 (SREBP-2), the expression of LDLR and cellular internalization of LDL. We also examined the effect of MK-2206 on LDLR levels in primary human hepatocytes. Results MK-2206 induced the proteolytic processing of SREBP-2, upregulated LDLR expression and stimulated LDL uptake. In contrast to statins, induction of LDLR levels by MK-2206 did not rely on 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition. As a result, cotreatment of cells with MK-2206 and mevastatin potentiated the impact of mevastatin on LDLR. Importantly, MK-2206 stimulated the expression of LDLR by primary human hepatocytes. Conclusions MK-2206 is a novel LDLR-inducing agent that, either alone or in combination with statins, exerts a stimulating effect on cellular LDL uptake. [ABSTRACT FROM AUTHOR]

Background and aims Activation of brown adipose tissue (BAT) reduces both hyperlipidemia and atherosclerosis by increasing the uptake of triglyceride-derived fatty acids by BAT, accompanied by formation and clearance of lipoprotein remnants. We tested the hypothesis that the hepatic uptake of lipoprotein remnants generated by BAT activation would be accelerated by concomitant statin treatment, thereby further reducing hypercholesterolemia and atherosclerosis. Methods APOE*3-Leiden.CETP mice were fed a Western-type diet and treated without or with the selective β3-adrenergic receptor (AR) agonist CL316,243 that activates BAT, atorvastatin (statin) or both. Results β3-AR agonism increased energy expenditure as a result of an increased fat oxidation by activated BAT, which was not further enhanced by statin addition. Accordingly, statin treatment neither influenced the increased uptake of triglyceride-derived fatty acids from triglyceride-rich lipoprotein-like particles by BAT nor further lowered plasma triglyceride levels induced by β3-AR agonism. Statin treatment increased the hepatic uptake of the formed cholesterol-enriched remnants generated by β3-AR agonism. Consequently, statin treatment further lowered plasma cholesterol levels. Importantly, statin, in addition to β3-AR agonism, also further reduced the atherosclerotic lesion size as compared to β3-AR agonism alone, without altering lesion severity and composition. Conclusions Statin treatment accelerates the hepatic uptake of remnants generated by BAT activation, thereby increasing the lipid-lowering and anti-atherogenic effects of BAT activation in an additive fashion. We postulate that, in clinical practice, combining statin treatment with BAT activation is a promising new avenue to combat hyperlipidemia and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background and aims In this study, we evaluated the effect of mipomersen in patients with severe LDL-hypercholesterolaemia and atherosclerosis, treated by lipid lowering drugs and regular lipoprotein apheresis. Methods This prospective, randomized, controlled phase II single center trial enrolled 15 patients (9 males, 6 females; 59 ± 9 y, BMI 27 ± 4 kg/m 2 ) with established atherosclerosis, LDL-cholesterol ≥130 mg/dL (3.4 mmol/L) despite maximal possible drug therapy, and fulfilling German criteria for regular lipoprotein apheresis. All patients were on stable lipid lowering drug therapy and regular apheresis for >3 months. Patients randomized to treatment (n = 11) self-injected mipomersen 200 mg sc weekly, at day 4 after apheresis, for 26 weeks. Patients randomized to control (n = 4) continued apheresis without injection. The primary endpoint was the change in pre-apheresis LDL-cholesterol. Results Of the patients randomized to mipomersen, 3 discontinued the drug early (<12 weeks therapy) for side effects. For these, another 3 were recruited and randomized. Further, 4 patients discontinued mipomersen between 12 and 26 weeks for side effects (moderate to severe injection site reactions n = 3 and elevated liver enzymes n = 1). In those treated for >12 weeks, mipomersen reduced pre-apheresis LDL-cholesterol significantly by 22.6 ± 17.0%, from a baseline of 4.8 ± 1.2 mmol/L to 3.7 ± 0.9 mmol/L, while there was no significant change in the control group (+1.6 ± 9.3%), with the difference between the groups being significant ( p =0.02). Mipomersen also decreased pre-apheresis lipoprotein(a) (Lp(a)) concentration from a median baseline of 40.2 mg/dL (32.5,71) by 16% (−19.4,13.6), though without significance ( p= 0.21). Conclusions Mipomersen reduces LDL-cholesterol (significantly) and Lp(a) (non-significantly) in patients on maximal lipid-lowering drug therapy and regular apheresis, but is often associated with side effects. [ABSTRACT FROM AUTHOR]

Background and aims Homozygous familial hypercholesterolemia (hoFH) is a rare genetic disorder with potential severe atherosclerosis in the pediatric age. Methods We report on 9 patients with hoFH, who had been diagnosed within the last 30 years and who were consequently treated with apheresis and drugs. Results Two deaths occurred: one at age 36 years and the other at age four and a half years before effective treatment was commenced. All other patients are still in good clinical condition today, although four of them have proven aortic stenosis or arterial plaques. Conclusions Our case report highlights that adequate treatment should start as early as possible to delay the onset of clinical manifestations of atherosclerosis. It can be assumed that the introduction of new drugs can improve the outcome and possibly lengthen the life expectancy of patients affected by hoFH. [ABSTRACT FROM AUTHOR]

Background and aims Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited condition characterized by elevated plasma low-density lipoprotein-cholesterol (LDL-C) levels, severe, accelerated atherosclerosis and premature coronary heart disease. We evaluated cardiovascular complications in HoFH patients over extended follow-up and investigated their association with changes in cholesterol over time, as well as total cholesterol burden. Methods In this retrospective single-centre study, 53 patients (baseline mean ± standard deviation [SD], total cholesterol 15.5 ± 3.7 mmol/L and LDL-C 13.2 ± 2.6 mmol/L) were followed for up to 38 years (21.2 ± 10 years). The primary outcome was an adverse clinical event, defined as cardiovascular death, nonfatal myocardial infarction, or angina. Results Twenty-eight patients experienced an event, of whom 8 died due to complications of major surgery (4), myocardial infarction (3) or stroke (1). While total cholesterol levels were comparable in patients with and without an event at baseline (20 mmol/L), those who subsequently experienced an event showed a slower decline in total cholesterol. Cumulative total cholesterol (i.e. total-cholesterol year score) was highly associated with the incidence of an adverse clinical event in a linear dose-response relation. A 100 mmol/L increase in cumulative total cholesterol (i.e. an average exposure of 10 mmol/L per 10 years or 20 mmol/L per 5 years) was associated with a doubling of the risk of a cardiovascular event (age-adjusted incidence rate ratio: 1.99, 95% CI, 1.16–3.41). Conclusions Our findings reinforce the importance of early diagnosis and initiation of maximal treatment, including lipoprotein apheresis, to ensure long-term reduction in the cholesterol burden, expressed as the total-cholesterol year score, and risk of cardiovascular complications in HoFH. [ABSTRACT FROM AUTHOR]

Background and aims High plasma LDL-cholesterol (LDL-C) and platelet responses have major pathogenic roles in atherothrombosis. Thus, statins and anti-platelet drugs constitute mainstays in cardiovascular prevention/treatment. However, the role of platelet tissue factor-dependent procoagulant activity (TF-PCA) has remained unexplored in hypercholesterolemia. We aimed to study platelet TF-PCA and its relationship with membrane cholesterol in vitro and in 45 hypercholesterolemic patients (HC-patients) (LDL-C >3.37 mmol/L, 130 mg/dL) and 37 control subjects (LDL-C <3.37 mmol/L). The effect of 1-month administration of 80 mg/day atorvastatin (n = 21) and 20 mg/day rosuvastatin (n = 24) was compared. Methods Platelet TF-PCA was induced by GPIbα activation with VWF-ristocetin. Results Cholesterol-enriched platelets in vitro had augmented aggregation/secretion and platelet FXa generation (1.65-fold increase, p = 0.01). HC-patients had 1.5-, 2.3- and 2.5-fold increases in platelet cholesterol, TF protein and activity, respectively; their platelets had neither hyper-aggregation nor endogenous thrombin generation (ETP). Rosuvastatin, but not atorvastatin, normalized platelet cholesterol, TF protein and FXa generation. It also increased slightly the plasma HDL-C levels, which correlated negatively with TF-PCA. Conclusions Platelets from HC-patients were not hyper-responsive to low concentrations of classical agonists and had normal PRP-ETP, before and after statin administration. However, washed platelets from HC-patients had increased membrane cholesterol, TF protein and TF-PCA. The platelet TF-dependent PCA was specifically expressed after VWF-induced GPIbα activation. Rosuvastatin, but not atorvastatin treatment, normalized the membrane cholesterol, TF protein and TF-PCA in HC-patients, possibly unveiling a new pleiotropic effect of rosuvastatin. Modulation of platelet TF-PCA may become a novel target to prevent/treat atherothrombosis without increasing bleeding risks. [ABSTRACT FROM AUTHOR]

Background and aims For patients with homozygous familial hypercholesterolemia (HoFH), atherogenic lipoprotein changes and increased stress on cardiovascular system during pregnancy may pose substantial risk for both the mother and her fetus. Although lipoprotein apheresis (LA) is reported as the most effective therapy to control LDL-C levels during pregnancy in HoFH patients, only case reports have been published, and there is no guidance for management. Methods We report twelve pregnancies and ten deliveries in seven patients with HoFH, and compare the clinical outcomes between patients who received LA during pregnancy and those who did not. Results One patient who refused LA during pregnancy died from acute myocardial infarction after delivery. Another patient whose adherence to LA was poor also died of myocardial infarction during pregnancy. One patient who initiated LA at the age of 18 had to discontinue LA due to severe symptoms of angina pectoris during pregnancy. Another had symptoms of nausea, hypotension, and bradycardia with increased levels of serum bradykinin during a dextran sulfate cellulose absorption-based LA procedure. Although two of the other three patients had already had coronary artery disease by the time of pregnancy, early initiation of LA from childhood and good adherence to it during pregnancy resulted in the delivery of healthy infants without adverse effects. Conclusions LA is essential for managing pregnancy safely in patients with HoFH. Increasing numbers of documented cases, including ours, will be helpful to guide future therapeutic decisions. [ABSTRACT FROM AUTHOR]

Background and aims Familial hypercholesterolemia (FH) is a life-threatening disease, characterized by elevated LDL-C levels and a premature, increased risk of coronary heart disease (CHD) that is globally underdiagnosed. The percentage of patients with possible or probable FH in various countries was examined in the Dyslipidemia International Study (DYSIS). Methods DYSIS is a multinational, cross-sectional observational study of 54,811 adult outpatients treated with statin therapy. The percentages of patients with high levels of LDL-C, and with possible or probable FH, were assessed using the Dutch scoring method for FH across 29 countries, in age subgroups for the analysis population and among diabetes patients. Results Despite statin therapy, 16.1% (range 4.4–27.6%) of patients had LDL-C >3.6 mmol/L (140 mg/dL) across countries and the prevalence of possible FH was 15.0% (range 5.5–27.8%) and 1.1% (range 0.0–5.4%) for probable FH. The highest percentages of probable FH occurred in Egypt (5.4%), the Baltic states (4.2%), Russia (3.2%), and Slovenia (3.1%), with the lowest rates in Israel (0.0%), Canada (0.2%), and Sweden (0.3%). Rates of FH were the highest in younger patients (45–54 years) for secondary prevention, regardless of the presence/absence of diabetes. Conclusions Despite statin therapy, high LDL-C levels and rates of possible and probable FH were observed in some countries. The prevalence of FH was the highest in younger age patients, and >60% of patients with probable FH displayed CHD. Earlier diagnosis and treatment of patients with FH are needed to reduce CHD risk in these patients. [ABSTRACT FROM AUTHOR]

Background and aims Familial hypercholesterolaemia (FH) profoundly increases the risk of coronary artery disease (CAD). We investigated whether diet and a bile-acid sequestrant decrease coronary atherosclerosis in patients with FH. Methods We identified 26 men with FH and CAD, participating in the St Thomas' Atherosclerosis Regression Study, who had been randomized to receive a fat-modified diet plus cholestyramine (8 g twice daily) (DC, n = 12) or usual care (UC, n = 14), and investigated the relative effects of these treatments on the angiographic progression of coronary atherosclerosis over 39 months. FH was defined as probable/definite according to Dutch Lipid Clinic Network criteria; mean FH score was 8.7 (range 6–15) and mean baseline low-density lipoprotein cholesterol (LDL-Ch) concentration was 5.4 (SD 1.4) mmol/L. Coronary atherosclerosis was assessed by serial quantitative angiography as the global changes in mean and minimum absolute width of segments (MAWS and MinAWS, respectively). Results Mean plasma LDL-Ch concentration fell by 35% with DC and remained significantly ( p < 0.001) lower during the trial at 3.78 (SD 0.98) mmol/L compared with UC at 4.89 (1.04). MAWS decreased by 0.252 (SEM 0.072) mm in the UC group and by 0.001 (0.065) mm in the DC group ( p = 0.007), with corresponding reductions in MinAWS of 0.290 (0.087) mm and 0.013 (0.058) mm ( p = 0.009); these changes were significant after adjusting for baseline variables, including coronary luminal dimensions and lipoprotein(a). Progression was observed in 7 patients (50%) on UC and 3 (25%) on DC ( p = 0.19), with regression in no patients (0%) and 3 patients (25%) ( p < 0.05), respectively. Conclusions This investigation, carried out in the pre-statin era, demonstrates that a prudent diet and cholestyramine could improve the course of coronary atherosclerosis in men with phenotypic FH through sustained reductions in LDL-Ch. [ABSTRACT FROM AUTHOR]

Background and aims This multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). Methods Patients 18–80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. Results At Week 12, treatment with anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: −38.6 to −21.0; p < 0.001) favoring anacetrapib. Anacetrapib also reduced non-HDL-C (23. 6%; p < 0.001), ApoB (14.1%; p < 0.001) and Lp(a) (48.7%; p < 0.001), and increased HDL-C (110.0%; p < 0.001) and ApoA1 (48.2%; p < 0.001) versus placebo. Anacetrapib 100 mg added to ongoing therapy with statin ± other LMT for 12 weeks was generally well-tolerated. There were no differences between the groups in the proportion of patients who discontinued drug due to an adverse event or abnormalities in liver enzymes, creatinine kinase, blood pressure, electrolytes or adjudicated cardiovascular events. Conclusions In Japanese patients with HeFH, treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated. ( ClinicalTrials.gov NCT01824238 ) [ABSTRACT FROM AUTHOR]

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL-receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be grouped under “pleiotropic functions” of the protein. This includes PCSK9's role in: trafficking of epithelial sodium channel; hepatic regeneration; pancreatic integrity and glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signalling pathways; cortical neural differentiation; neuronal apoptosis and Alzheimer's disease. The question that needs to be investigated in depth is “How will the pleotropic functions of PCSK9, be affected by the therapeutic intervention of the protease's LDL-receptor lowering activity?” In this review, we appraise the different lipid lowering strategies targeting PCSK9 in light of the protein's different pleiotropic functions. Additionally, we delineate the key areas that require further examination, to ensure the long-term safety of the above lipid-lowering strategies. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia (FH) is a co-dominantly inherited disorder of plasma lipoprotein metabolism. The prevalence of heterozygous FH (HeFH) is between 1/500 and 1/200 whereas that of homozygous form (HoFH) is about 1/1,000,000. Diagnosis is based on cutaneous xanthomas and untreated levels of LDL-cholesterol over 500 mg/dl before 10 years of age. Life expectancy, without treatment, does not exceed 20 years of age. The aim of this study is to characterise in details a cohort of 8 HoFH paediatric patients in order to illustrate all the current therapeutic options and to add some clinical and genetic information about this rare disease. We collected demographic, clinical, biological, imaging and genotype details. Furthermore, clinical and biochemical response to different treatment methods was retrospectively evaluated. All patients had genetically proven HoFH. All patients were subject to a lipid-lowering diet and medical treatment (except one), three patients underwent a liver transplant and one an hepatocytes infusion. Medical treatment was well tolerated with a median reduction of 44% and 47% in LDL-Cholesterol and Total Cholesterol respectively. The hepatocytes transplant produced a further, though slight, decrease in cholesterol levels as opposed to medical therapy alone. Transplanted patients normalized their cholesterol levels. Since the very high cardiovascular risk, HoFH requires immediate diagnosis, treatment and monitoring. Nowadays, the use of statins remains the cornerstone of medical therapy and liver transplantation is the possibly curative therapy. Besides, high hopes are pinned in new drugs (antibody targeting PCSK9, Mipomersen and Lomitapide) and stem cells. [ABSTRACT FROM AUTHOR]

Background and aims Discontinuation of statin therapy by patients with hypercholesterolemia because of the onset of side-effects (statin-associated symptoms [SAS]) increases the risk of cardiovascular morbidity and mortality. We aimed to understand how patients with SAS, particularly those with statin-associated muscle symptoms (SAMS), are identified and managed in the outpatient setting. MethodsA web-based survey involving 60 clinicians in each of 12 countries and 90 clinicians in the US was conducted. Clinicians answered questions about the diagnostic criteria, estimated incidence of SAS, and choice of treatment for patients with SAS. ResultsOverall, 810 clinicians (78% cardiologists) completed the survey. An average of 72% of patients with potential SAS were reported to present with muscle-related symptoms (range across countries [RAC] 50–87%) that could be SAMS. Clinicians took a range of steps to confirm SAMS in these patients, including discontinuation of statin (average 59%; RAC 48–67%); re-challenge with ≥2 statins (average 74%; RAC 60–85%); modification of statin regimen (average 76%; RAC 65–85%); or a combination of these steps. Overall, 6% of patients with hypercholesterolemia were estimated to eventually have SAS (RAC 2–12%). In patients with SAS, on average 52% continued to receive a low-dose statin, usually with other lipid-lowering therapies (LLT). Of the remaining 49%, 38% received alternative LLT only; 11% did not receive any LLT. ConclusionThere is some consistency and stringency in clinical practice for identifying patients with SAS; however, a structured work-up for identification, followed by a defined therapeutic algorithm, may improve their management. [ABSTRACT FROM AUTHOR]

Background and aims There is a paucity of data concerning the influence of lipid-lowering therapy on cardiovascular (CV) outcomes in patients with homozygous familial hypercholesterolaemia (FH). To redress this a retrospective analysis was undertaken of the demographic features, lipid levels, low density lipoprotein receptor and Autosomal Recessive Hypercholesterolaemia gene mutations, CV outcomes and vital status of 44 FH homozygotes referred to a single centre in the UK between 1964 and 2014. Methods Data were obtained from past publications, case records and death certificates. Differences in categorical and continuous variables between living and dead patients were analysed using Fisher's exact test and an independent t-test respectively. Results During the 50 years covered by this survey 13 patients have died, 30 are still alive and 1 was lost to follow up. The mean age of Alive patients was 32.6 ± 11.5 versus 28.3 ± 14.9 years in Dead ones (P = 0.31) and they were born 18 years later (P = 0.0001). Pre-treatment serum total cholesterol (TC) was similar in Alive and Dead (20.2 ± 5.1 v 21.3 ± 4.4 mmol/l, P = 0.52) but on-treatment TC was lower in Alive than Dead (8.1 ± 2.8 v 14.5 ± 6.0 mmol/l, P = 0.0001) and CV adverse events were far less frequent (eg aortic stenosis, 33% v 77%, P = 0.02). Conclusions The lower on-treatment TC and fewer CV adverse events in FH homozygotes still living reflect advances in apheresis and drug therapy since the 1990s. Further improvements in prognosis can be expected with the impending introduction of novel lipid-lowering agents. [ABSTRACT FROM AUTHOR]

Objective Cholesterol analogs have been used to treat hypercholesterolemia. The present study was to examine the effect of dihydrocholesterol (DC) on plasma total cholesterol (TC) compared with that of β-sitosterol (SI) in hamsters fed a high cholesterol diet. Methods and Results Forty-five male hamsters were randomly divided into 6 groups, fed either a non-cholesterol diet (NCD) or one of five high-cholesterol diets without addition of DC and SI (HCD) or with addition of 0.2% DC (DA), 0.3% DC (DB), 0.2% SI (SA), and 0.3% SI (SB), respectively, for 6 weeks. Results showed that DC added into diet at a dose of 0.2% could reduce plasma TC by 21%, comparable to that of SI (19%). At a higher dose of 0.3%, DC reduced plasma TC by 15%, less effective than SI (32%). Both DC and SI could increase the excretion of fecal sterols, however, DC was more effective in increasing the excretion of neutral sterols but it was less effective in increasing the excretion of acidic sterols compared with SI. Results on the incorporation of sterols in micellar solutions clearly demonstrated both DC and SI could displace the cholesterol from micelles with the former being more effective than the latter. Conclusion DC was equally effective in reducing plasma cholesterol as SI at a low dose. Plasma TC-lowering activity of DC was mediated by inhibiting the cholesterol absorption and increasing the fecal sterol excretion. [ABSTRACT FROM AUTHOR]

Objective We compared the variability of LDL-C-lowering responses to treatment with ezetimibe + statins versus statins in hypercholesterolemic patients. Methods An analysis of patient-level data pooled from 27 double-blind, placebo and/or active-controlled studies in 21,671 patients treated with ezetimibe + statins versus statins on first-line (statin-naïve/wash-out) or second-line (on statin, randomized to ezetimibe versus placebo [add-on] or ezetimibe versus uptitrated statin [uptitrate]) for 6–24 wks. Variances (standard deviation [SD], coefficient of variation [CV], and root mean squared error [RMSE] adjusted for various factors) for % change from baseline in LDL-C were compared. Results In first-line and second-line add-on studies, the variability (SD, RMSE) of % change from baseline in LDL-C was lower in ezetimibe + statin-treated patients versus statin-treated patients, ±covariates. Differences were small but statistically significant due to the large sample size. In second-line uptitrate studies, ezetimibe + statin treatment resulted in greater unadjusted variability (SD) versus statin therapy, while the adjusted variability (RMSE) was significantly lower. Relative variability (CV = SD/mean) was lower for ezetimibe + statins versus statin therapy for all study types, being more pronounced in second-line add-on and uptitrate studies, attributed to larger mean LDL-C reductions for ezetimibe + statins versus statin groups. When assessed by individual study/type, statin brand, potency or dose, the CVs remained lower for ezetimibe + statins versus statins in second-line studies. The SDs showed no consistent trend for either therapy. Conclusion In hypercholesterolemic patients, the absolute variability of LDL-C-lowering responses to ezetimibe + statins was not greater versus statins alone and appeared lower when adjusted for other factors. Relative variability was lower in patients treated with statins + ezetimibe. A better understanding of the variability of the LDL-C lowering response may help guide clinicians in making therapeutic decisions. [ABSTRACT FROM AUTHOR]

Objective : This study aimed to investigate the exact prevalence of familial hypercholesterolemia (FH) in the general population, taking advantage of the fact that five low-density lipoprotein receptor ( LDLR ) founder mutations account for 78% of FH cases in Finland. Methods : Five LDLR founder mutations, FH-North Karelia, FH-Helsinki, FH-Pogosta, FH-Turku, and FH-Pori, were genotyped and serum lipid levels were measured in a large collection of Finnish population cohorts ( n = 28,465), including the National FINRISK Study and the Health 2000 Study. Follow-up data were obtained from national healthcare registries. Results : The combined prevalence of three of the five FH founder mutations (FH-North Karelia, FH-Helsinki, and FH-Pogosta) was 0.12% (95% CI 0.07–0.16%), while FH-Turku and FH-Pori were not identified in the present sample cohort. Our data suggest that the estimated total prevalence of FH in Finland is at least 0.17%. Approximately half of the 35 FH mutation carriers used lipid-lowering medication at the time of the baseline investigation. LDL cholesterol levels were on average 2 mmol/L higher in mutation carriers than in non-carriers ( p < 0.001) but did not differ between FH mutation carriers with and without lipid-lowering medication. During the follow-up for 13 years, one mutation carrier encountered a probable sudden cardiac death, two mutation carriers suffered from a stroke, and one from a myocardial infarction. Conclusions : In Finland, at least 1 in 600 individuals is estimated to have FH. A marked undertreatment of FH was observed in LDLR mutation carriers. [ABSTRACT FROM AUTHOR]

Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused mainly by LDLR mutations. This study assessed the influence of the presence and type of LDLR mutation on lipid profile and the response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Methods: For 14 ± 3 months, 156 patients with heterozygous FH receiving atorvastatin were followed. Coding sequences of the LDLR gene were bidirectionally sequenced, and the type of LDLR mutations were classified according to their probable functional class. Results: The frequencies of the types of LDLR mutations were: null-mutation (n = 40, 25.6%), defective-mutation (n = 59, 37.8%), and without an identified mutation (n = 57, 36.6%). Baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were higher in patients carrying a null mutation (9.9 ± 1.9 mmol/L, 7.9 ± 1.7 mmol/L), compared to those with a defective (8.9 ± 2.2 mmol/L, 7.0 ± 2.0 mmol/L), or no mutation (7.9 ± 1.9 mmol/L, 5.8 ± 1.9 mmol/L) (p < 0.001). After treatment, the proportion of patients attaining an LDL-C<3.4 mmol/L was significantly different among groups: null (22.5%), defective (27.1%), and without mutations (47.4%) (p = 0.02). The presence of LDLR mutations was independently associated with higher odds of not achieving the LDL-C cut-off (OR 9.07, 95% CI 1.41–58.16, p = 0.02). Conclusions: Our findings indicate that the presence and type of LDLR mutations influence lipid profile and response to lipid-lowering therapy in Brazilian patients with heterozygous FH. Thus, more intensive care with pharmacological therapeutics should be performed in patients who have a molecular analysis indicating the presence of a LDLR mutation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To analyze pomegranate extract (POMx) effects on serum and on human HMDM atherogenicity in simvastatin – treated hypercholesterolemic patients. Methods and results: Patients were randomly assigned to receive either simvastatin (20 mg/day) + vegan placebo pill (n = 11), or simvastatin (20 mg/day) + POMx pill (1g/day, n = 12). Fasting blood samples were collected at baseline and after 1 and 2 months of therapy. HMDM were collected from 3 patients in each group at baseline and after 2 months of therapy, as well as from 3 healthy subjects. After 2 months of therapy, serum LDL-cholesterol levels significantly decreased, by 23%, in the simvastatin + placebo group, and by 26% in the simvastatin + POMx group. Simvastatin + POMx therapy increased serum thiols concentration by 6%. Patients' HMDM reactive oxygen species (ROS) levels were significantly increased, by 69%, vs. healthy subjects HMDM. After 2 months of therapy, HMDM ROS levels decreased by 18% in the simvastatin + placebo group, whereas in the simvastatin + POMx group it decreased by up to 30%. A novel finding was the triglycerides levels in the patients' HMDM at baseline which were significantly higher, by 71%, vs. healthy subjects HMDM. The simvastatin + POMx, but not the simvastatin + placebo therapy, significantly reduced macrophage triglycerides content by 48%, vs. baseline levels. In addition, whereas the simvastatin + placebo therapy significantly decreased the patients' HMDM cholesterol biosynthesis rate by 33%, the simvastatin + POMx therapy further decreased it, by 44%. Conclusion: The addition of POMx to simvastatin therapy in hypercholesterolemic patients improved oxidative stress and lipid status in the patient's serum and in their HMDM. These anti-atherogenic effects could reduce the risk for atherosclerosis development. [Copyright &y& Elsevier]

Abstract: Objectives: Statins may exhibit anti-inflammatory and antioxidant effects. Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown. The aim of this study was to compare the effects of simvastatin, simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia. Methods: This was a pre-specified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study. We enrolled one hundred and fifty three (n = 153) hypercholesterolemic subjects who were randomized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily. Plasma 8-Epi prostaglandin F2 alpha (8-epiPGF2a), oxidized LDL (oxLDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass were measured at baseline and following 12 weeks of treatment. Results: A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [by 10%, 8% and 6% (p < 0.05 compared with baseline) and 41%, 40% and 39% (p < 0.001 compared with baseline) in simvastatin, simvastatin/ezetimibe and rosuvastatin groups, respectively]. In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed (by 36%, 31% and 38% and 36%, 32% and 32% for simvastatin, simvastatin/ezetimibe and rosuvastatin, respectively, p < 0.001 compared with baseline). No intergroup differences were observed. Conclusions: Simvastatin 40 mg, simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a, oxLDL and Lp-PLA2 activity and mass to a similar extent. [Copyright &y& Elsevier]

Abstract: Objective: Interruption of the enterohepatic circulation of bile acids induces hepatic bile acid synthesis, increases hepatic cholesterol demand, and increases clearance of apoB-containing lipoproteins in plasma. Based on these effects, bile acid sequestrants have been used for many years to treat hypercholesterolemia and the associated atherosclerosis. The objective of this study was to determine the effect of blocking ileal apical versus basolateral membrane bile acid transport on the development of hypercholesterolemia and atherosclerosis in mouse models. Methods and results: ApoE−/− and Ldlr−/− mice deficient in the apical sodium-dependent bile acid transporter (Asbt) or apoE−/− mice deficient in the basolateral bile acid transporter (Ostα) were fed an atherogenic diet for 16 weeks. Bile acid metabolism, cholesterol metabolism, gene expression, and development of atherosclerosis were examined. Mice deficient in Asbt exhibited the classic response to interruption of the enterohepatic circulation of bile acids, including significant reductions in hepatic and plasma cholesterol levels, and reduced aortic cholesteryl ester content. Ileal Fibroblast Growth Factor-15 (FGF15) expression was significantly reduced in Asbt−/−apoE−/− mice and was inversely correlated with expression of hepatic cholesterol 7-hydroxylase (Cyp7a1). Ileal FGF15 expression was directly correlated with plasma cholesterol levels and aortic cholesterol content. In contrast, plasma and hepatic cholesterol levels and atherosclerosis development were not reduced in apoE−/− mice deficient in Ostα. Conclusions: Decreases in ileal FGF15, with subsequent increases in hepatic Cyp7a1 expression and bile acid synthesis appear to be necessary for the plasma cholesterol-lowering and atheroprotective effects associated with blocking intestinal bile acid absorption. [Copyright &y& Elsevier]

Abstract: Objectives: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed to be a potential new therapeutic target for treatment of hypercholesterolaemia. However, little is known about the effects of PCSK9 inhibition on the lipidome. Methods: We performed molecular lipidomic analyses of plasma samples obtained from PCSK9-deficient mice, and serum of human carriers of a loss-of-function variant in the PCSK9 gene (R46L). Results: In both mouse and man, PCSK9 deficiency caused a decrease in several cholesteryl esters (CE) and short fatty acid chain containing sphingolipid species such as CE 16:0, glucosyl/galactosylceramide (Glc/GalCer) d18:1/16:0, and lactosylceramide (LacCer) d18:1/16:0. In mice, the changes in lipid concentrations were most prominent when animals were given regular chow diet. In man, a number of molecular lipid species was shown to decrease significantly even when LDL-cholesterol was non-significantly reduced by 10% only. Western diet attenuated the lipid lowering potency of PCSK9 deficiency in mice. Conclusions: Plasma molecular lipid species may be utilized for characterizing novel compounds inhibiting PCSK9 and as sensitive efficacy markers of the PCSK9 inhibition. [Copyright &y& Elsevier]

Objective: A low-fat, fiber-rich diet is the first step in the management for hypercholesterolemic children. Glucomannan (GM) is a natural fiber that has been demonstrated to lower total and LDL-cholesterol. The use of high-dose chromium-polynicotinate (CP) and policosanol (PC) has also shown cholesterol-lowering benefits. We aimed at investigating the effects of low-dose CP or PC and their GM combination in hypercholesterolemic children. Methods: A double-blind trial was conducted in 120 children (60 M, 60 F, 9 ± 4 years, median 9.6 years, range: 3–16 years) randomly assigned to 5 neutraceutical and 1 placebo (only resistant starch) 8-week treatment groups. Fasting blood glucose (FBG), total cholesterol (CholT), triglycerides (TG), HDL and LDL cholesterol were considered. Results: GM combination of low-dose CP or PC reduced CholT and LDL without changing HDL, TG and FBG. The highest post-treatment changes were seen after GM combination with CP (CholT 85 ± 3% and LDL 85 ± 5%, of pretreatment) which was significantly (p < 0.01) less than with low-dose CP or PC and starch. When GM was associated with starch, there was no lipid lowering effect, which was an unexpected finding as compared to previous data with GM and no starch. No adverse effects were reported. Conclusion: This is the first report to show the cholesterol-lowering efficacy of GM combined treatment with low-dose CP or PC. Further studies are needed to investigate the best combinations and doses of nutraceutics to be added to the standard GM treatment. The potential negative association of GM and nutraceutics with starch is clearly shown. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Bile acid sequestrants (BAS) and physical activity (RUN) decrease incidence of cardiovascular events. Both treatments are often prescribed, yet it is not known whether their beneficial effects are additive. We assessed the effects of BAS treatment alone and in combination with RUN on cholesterol metabolism, heart function and atherosclerotic lesion size in hypercholesterolemic mice. Methods: Male Ldlr-deficient mice remained either sedentary (CONTROL), were treated with Colesevelam HCl (BAS), had access to a running wheel (RUN), or were exposed to BAS and RUN (BAS RUN). All groups were fed a high cholesterol diet for 12 weeks. Then, feces, bile and plasma were collected. Atherosclerotic lesion size was determined in the aortic arch and heart function by echocardiography. Results: BAS RUN ran more than RUN (6.4 ± 1.4 vs. 3.5 ± 1.0 km/day, p < 0.05). BAS and BAS RUN displayed ∼3-fold reductions in plasma cholesterol levels (p < 0.001), ∼2.5-fold increases in fecal neutral sterol (p < 0.001) and bile acid (p = 0.01) outputs, decreases in biliary secretions of cholesterol (∼6-fold, p < 0.0001) and bile acids (∼2-fold, p < 0.001) vs. CONTROL while no significant effects were observed in RUN. Compared to CONTROL, lesion size decreased by 78% in both BAS and BAS RUN, (p < 0.0001). Conclusion: BAS reduce atherosclerosis in Ldlr-deficient mice, coinciding with a switch from body cholesterol accumulation to cholesterol loss. RUN slightly modulated atherosclerotic lesion formation but the combination of BAS and RUN had no clear additive effects in this respect. [Copyright &y& Elsevier]

Abstract: Objectives: In vitro and animal studies showed that statins could increase bilirubin levels by activation of haem oxygenase-1, whereas the effect of statins on serum bilirubin levels in humans remains controversial. The organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) play an important role in the disposition of bilirubin. This study investigated 1) whether common polymorphisms in UGT1A1 and SLCO1B1 influence bilirubin levels; 2) whether statin treatments affect bilirubin levels; and 3) whether the polymorphisms examined influence the drug effect. Methods: Associations between common polymorphisms in UGT1A1 and SLCO1B1 and the serum bilirubin levels on no lipid-lowering treatment were analyzed in 379 Chinese patients with hypercholesterolaemia. Effects of simvastatin 40 mg daily and rosuvastatin 10 mg daily on the bilirubin levels were compared in 236 subjects with good compliance to both statins. Results: The UGT1A1 polymorphisms associated with reduced enzyme activity were significantly associated with increased baseline bilirubin levels. The bilirubin levels were increased from a geometric mean (95% CI) of 10.9 (10.3–11.4) μmol/L at baseline to 11.6 (11.1–12.0) μmol/L with rosuvastatin and 12.5 (11.9–13.0) μmol/L with simvastatin and the increase was greater with simvastatin (P < 0.001). There was no relationship between polymorphisms in UGT1A1 or SLCO1B1 and changes in bilirubin levels with the two statins. Conclusions: This study showed that the polymorphisms in UGT1A1, but not SLCO1B1, were associated with serum bilirubin levels in Chinese patients. Statins increased bilirubin levels and this effect was independent of the polymorphisms in UGT1A1 and SLCO1B1. [Copyright &y& Elsevier]

Abstract: Homozygous familial hypercholesterolemia (HoFH) is an autosomal co-dominant disease resulting from mutations in both copies of the low-density lipoprotein receptor (LDLR) gene. Mutations in 3 other associated genes, proprotein convertase subtilisin/kexin type 9, apolipoprotein B (APOB), and, more rarely, the autosomal recessive hypercholesterolemia adaptor protein, may lead to a similar phenotype with varying severity. HoFH patients have aggressive cardiovascular disease that develops from birth due to severe LDLR defects, resulting, in turn, in excess production of Apo B-containing atherogenic lipoproteins (low-density lipoprotein [LDL] and lipoprotein(a)). The condition is characterized by exceptionally high LDL cholesterol levels, cutaneous and tendon xanthomas, and valvular and supravalvular stenosis, and accelerated atherosclerosis often manifests in the first 2 decades of life. Treatment typically involves lipid-modifying medical therapy as well as mechanical removal of plasma LDL by means of apheresis. Although statins have afforded survival into the third and fourth decades of life, further therapeutic advancements currently under investigation promise hope of further improvements in survival and improved quality of life. The purpose of this review is to provide current perspectives on diagnosis and therapy in an effort to encourage early recognition and treatment of this rare but severe disease. [Copyright &y& Elsevier]

Abstract: Objective: We investigated the effectiveness of statins in daily practice in reducing the arterial wall thicknesses by comparing the carotid intima-media thickness (cIMT) between statin-treated familial hypercholesterolemia (FH) patients and their unaffected spouses. Methods: FH subjects treated with LDL-c lowering medication for at least 5 years and their unaffected spouses were included in this observational study. Clinical data and carotid intima-media thickness (cIMT) as surrogate marker for atherosclerosis were acquired. Results: In total 40 FH patients, age 48.4±4.2 years, and their 40 unaffected spouses, age 47.4±3.9 years, were included. Pre-treatment total cholesterol levels of FH patients were on average 9.3±2.0mmol/L. Treated FH patients and unaffected spouses exhibited similar LDL-c (3.8±1.5 vs. 3.5±1.1mmol/L; p =0.25) and total cholesterol levels (5.8±1.6 vs. 5.6±1.1mmol/L; p =0.56). Also, in a multivariate model cIMT adjusted for age and sex did not differ between affecteds and spouses (95% CI: −0.032 to 0.092mm; p =0.34). Conclusion: Long-term statin treatment normalizes cIMT in severe FH patients and therefore it is likely that the extreme risk of cardiovascular disease in FH patients is significantly reduced by this therapy. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To determine whether lipid-lowering treatment with diet or statins would provide beneficial effects on visual field alterations associated with hypercholesterolemia. Methods: 180 subjects with hypercholesterolemia were randomly assigned to a low fat diet (diet group) or to a low fat diet plus 40mg/day of pravastatin (pravastatin group). At the beginning of the study and 6 months after the assigned treatment, all subjects underwent a computerized perimetry test and a determination of plasma concentration of glucose, total cholesterol, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglycerides. Results: At 6 months, both groups showed a significant decrease in total cholesterol, LDL-C and triglycerides compared to basal values, and a significant increase in the HDL-C. The pravastatin group had a significantly greater reduction in total cholesterol (−85±21mg/dl) and LDL-C (−86±23mg/dl) than the diet group (−28±9 and −28±10mg/dl, respectively). All perimetry parameters improved in both groups after the intervention period, although the improvement was greater in the pravastatin group. Using a general linear model, a significant effect of treatment with pravastatin compared to diet was observed in the improvement of all the perimetry parameters, whereas the change in LDL-C concentrations only had a significant effect on the improvement of one of them. Conclusion: In subjects with hypercholesterolemia, the decrease of blood lipids improves visual field parameters. The major beneficial effect noted with pravastatin, compared to diet, suggests that this effect could be due to the lipid-lowering and pleiotropic actions. [Copyright &y& Elsevier]

Abstract: Background: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels <2.5mmol/l. In the present study we evaluated the treatment of heFH patients in The Netherlands. Methods: A cross-sectional study was conducted in outpatient lipid clinics of three Academic Centers and two regional hospitals. Patient records of known heFH patients were retrieved and data were reviewed on the use of lipid-lowering medication, plasma lipids and lipoproteins, safety laboratory results and reasons for not achieving treatment goals. Results: The data of 1249 patients with heFH were available. Nearly all patients (96%) were on statin treatment. The treatment goal for LDL-c <2.5mmol/l was achieved in 261 (21%) patients. Among those who did not reach LDL-c goals, 261 (27%) were on combination therapy of maximum statin dose and ezetimibe. Main reason (32%) why patients did not use maximum therapy despite an LDL-c ≥2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c ≥2.5mmol/l and not using maximum therapy. Conclusion: Only a small proportion of patients with heFH reaches the LDL-c treatment target of <2.5mmol/l. These results emphasize the need for better monitoring, better utilization of available medication and for new treatment options in heFH to further decrease LDL-c levels. [Copyright &y& Elsevier]

Abstract: Low density lipoprotein (LDL) apheresis is now accepted as the treatment of choice for patients with homozygous familial hypercholesterolaemia and for heterozygotes with cardiovascular disease refractory to lipid-lowering drug therapy. However, a paucity of evidence has meant that detailed guidance on the extent of cholesterol reduction required to prevent the onset or progression of cardiovascular disease in these high risk patients is lacking. This review defines criteria for expressing the efficacy of apheresis, proposes target levels of total and LDL cholesterol for homozygotes and heterozygotes based on recent follow-up studies and suggests a scheme for monitoring cardiovascular disease in these patients. Establishing a uniform approach to data collection would facilitate the setting up of national or multi-national registers and might eventually provide the information needed to formulate evidence-based guidelines for LDL apheresis. [Copyright &y& Elsevier]

Abstract: Background: Ursodeoxycholic acid (UDCA) is a therapeutic bile acid used in dissolution of gallstones and treatment of several cholestatic liver diseases. Results obtained from primary biliary cirrhosis patients treated with UDCA suggested that this agent exerts significant cholesterol-lowering effects and justifies evaluation in primary hypercholesterolemic patients without liver disease. Purpose of this study was to determine whether UDCA had potential to be an effective, safe cholesterol-lowering agent in primary type IIa or IIb hypercholesterolemia. Methods: This was a multicenter randomized, double blind, placebo-controlled trial. After a 6-week placebo lead-in period during which two qualifying lipid profiles were obtained, patients with a mean serum LDL-cholesterol (LDL-C) between 130 and 190mg/dL, triglycerides <400mg/dL and HDL-cholesterol >30mg/dL were randomized to UDCA or matching placebo for 24 weeks. Results: Seven sites screened 200 patients with 134 patients meeting the entry criteria who were randomized to the two treatments. There were 125 patients meeting the efficacy evaluation criteria, 57 on UDCA and 68 on placebo. LDL-C change from weeks 0 to 24 showed no significant difference between groups. No significant differences in changes for total cholesterol, HDL-cholesterol and triglycerides were observed. Both groups had similar adverse event profiles. Conclusions: UDCA did not show intrinsic cholesterol-lowering properties and therefore is not a useful therapy in treating type IIa or type IIb hypercholesterolemic patients. UDCA was confirmed as a well tolerated and safe drug in this population. [Copyright &y& Elsevier]

Abstract: Various forms of atherogenic modified low-density lipoprotein (LDL) including oxidized LDL and small, dense LDL have increased negative charge as compared to normal LDL. Charge-modified LDL (electronegative LDL) and normal LDL subfractions in plasma are analyzed by capillary isotachophoresis (cITP) as fast-migrating LDL (fLDL) and slow-migrating LDL (sLDL). We examined the effects of pravastatin and simvastatin on charge-based LDL subfractions as determined by cITP in patients with hypercholesterolemia. Patients (n =72) with CHD or CHD risk factors and elevated LDL cholesterol (LDL-C) levels were randomly assigned to receive pravastatin or simvastatin. After treatment with statins for 3 and 6 months, both cITP fLDL and sLDL were reduced (p <0.05) from the baseline, but the effects did not differ between treatment with pravastatin and simvastatin. At baseline and after treatment for 3 months, cITP sLDL was correlated with LDL-C, but fLDL was correlated with inflammatory markers, high-sensitive C-reactive protein and LDL-associated platelet-activating factor acetylhydrolase, and atherogenic lipoproteins, remnant-like particle cholesterol and small, dense LDL cholesterol. In conclusion, cITP fLDL was related to inflammatory markers and atherogenic lipoproteins and was reduced by treatment with statins. Charge-modified LDL subfraction could be a potential marker for atherosclerosis and a target for therapy. [Copyright &y& Elsevier]

Low density lipoprotein (LDL) apheresis provides a safe and effective means of treating patients with homozygous familial hypercholesterolaemia (FH). It also has a role in preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs. Established methods involve either adsorption of apolipoprotein B-containing lipoproteins by affinity columns containing anti-apolipoprotein B antibodies or dextran sulphate, or their precipitation at low pH by heparin, in each instance after first separating plasma from blood cells with a cell separator. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate columns. All 4 methods have proved to be similarly efficient when used weekly or biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL cholesterol. Economic constraints restrict the use of LDL apheresis to the treatment of potentially fatal disorders such as FH, where there is clear evidence of benefit compared with conventional therapy. Widening the indications to include the treatment of other dyslipidaemic disorders such as steroid-resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and prevention of re-stenosis after coronary angioplasty requires evidence from controlled trials that is currently lacking. [Copyright &y& Elsevier]