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Lipoprotein apheresis has been shown to improve the cardiovascular outcome in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). An elevated intake of omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been associated with a reduced cardiovascular risk. However, until now only little is known about the effect of apheresis treatment on the levels of omega-6 and omega-3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA) in patients. Using gas chromatography (GC) the present study analyzed the content of n-6 and n-3 PUFA as well as saturated fatty acids and monounsaturated fatty acids in the plasma of 20 patients with hyperlipidemia undergoing regular lipoprotein apheresis procedures in direct pre- and post-therapy measurements. Lipoprotein apheresis uniformly reduced the concentrations of arachidonic acid (AA), EPA and DHA fatty acids analyzed in the plasma. However, the three different apheresis methods analyzed (heparin precipitation, membrane filtration and direct absorption) had different effects on the fatty acid profile in the plasma. We found that heparin precipitation and direct absorption apheresis procedures led to a significant decrease of plasma n-3 and n-6 PUFA by 40-50%. In contrast, patients undergoing membrane filtration apheresis, levels pre- and post-apheresis did not change significantly, with AA and EPA being only reduced by approximately 10% while levels of DHA were maintained pre- and post-apheresis. In contrast, total triglyceride levels were lowered most potently by membrane filtration apheresis. In summary, heparin precipitation and direct absorption apheresis approaches significantly lowered polyunsaturated fatty acids in plasma, while membrane filtration did not. This might have implications for cardiovascular and inflammatory risk/benefit profiles associated with n-6 and n-3 PUFA levels in the body., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Aims: Dyslipidaemias are associated with cardiovascular mortality and morbidity, driven by unstable atherosclerotic plaques with inflammatory infiltrates. Levels of messenger RNA (mRNA) for pro-inflammatory cytokines have been positively correlated with atherosclerotic disease progression. Therapeutic lipoprotein apheresis (LA) reduces plasma lipid levels and reduces inflammation. We evaluated the effects of LA on expression of mRNA coding for key pro-inflammatory cytokines in patients with dyslipidaemia, homo-/hetero-zygous familial hypercholesterolaemia (HoFH, HeFH) or hyperlipoprotein(a)aemia [hyperLp(a)] and associated coronary artery disease (CAD)., Approach: Ten patients (five males and five females, mean age 47 ± 9.2 years) were enrolled, all with HyperLp(a) or confirmed genetic diagnoses of dyslipidaemia, HoFH, or HeFH; all had associated CAD. mRNA determinations were via reverse transcriptase polymer chain reaction (RT-qPCR)., Results: LA was associated with downregulation of mRNA expression for IL-1α, IL-6 and TNF-α, starting after the first LA session. The observed reduction was progressively enhanced during the interval between the first and second LA sessions to achieve a maximum decrease by the end of the second session (IL-1α: -49%, p < 0.001; IL-6: -35%, p < 0.001; TNF-α: -56%, p < 0.001)., Conclusions: LA suppresses the expression of IL-1α, IL-6 and TNF-α mRNA in patients with dyslipidaemias. This may contribute to the arterial anti-inflammatory effect of LA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Elevated levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are known risk factors for atherosclerosis and cardiovascular events. Although lipoprotein apheresis (LA) yields optimal outcomes for patients suffering from progressive cardiovascular disease (CVD; coronary, peripheral, and cerebrovascular arterial disease) in the presence of hyperlipoproteinemia (LDL-C > 100 mg/dL or Lp(a) > 60 mg/dL), LA primarily serves as a "last-resort therapy". Extant findings show that the incidence of new cardiovascular events can be reduced by regular LA. However, it remains unclear whether improvements to the quality of life (QOL) improvement produced by the positive impact on the course of cardiovascular disease outweighs the therapy's time consuming and invasive character. We surveyed 36 patients (32 men and 4 women; age 53 ± 13 years [mean + standard deviation]) undergoing regular LA therapy to assess the effects of apheresis on QOL., Methods: QOL was evaluated in 29 patients on regular lipoprotein apheresis treatment using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), the Beck Depression Inventory (BDI), and a newly developed questionnaire for assessing QOL in patients undergoing LA., Results: Patients treated with LA showed lower QOL scores regarding mental aspects and equal scores regarding physical aspects compared to the general population, analogue to the results of patients on hemodialysis (SF-36). Analysis of BDI scores showed apheresis patients did not meet criteria for depression diagnosis, although their depression scores were higher than the general population. Compared to the pre-apheresis period, patients described an improvement of their physical and mental fitness, less angina pectoris and no treatment related pain were reported (apheresis questionnaire)., Conclusions: Apheresis treatment appears to reduce the subjective physical complaints of patients. The partly impaired mental health in patients undergoing apheresis may be attributed to the underlying severe cardiovascular disease. The procedure itself is generally tolerated without major complaints, suggesting the benefits of apheresis exceed any negative effects on patient QOL., (Copyright © 2016 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: In recent years the Federal Joint Committee (G-BA), a paramount decision-making body of the German health care system challenged the approval of diagnostic and therapeutic procedures for regular reimbursement, including lipoprotein apheresis therapy. Years before an interdisciplinary German apheresis working group, established by members of both German Societies of Nephrology (Verband Deutsche Nierenzentren (VDN), Deutsche Gesellschaft für Nephrologie (DGfN)), initiated a revision of the indication of lipoprotein apheresis therapy according to current guidelines and recommendations for the treatment of lipid disorders. This working group was convinced, that data derived from a registry would support lipoprotein apheresis as a therapy for severe hyperlipidemic patients suffering from progressive cardiovascular diseases., Methods and Results: In 2009 the working group established the indication for lipoprotein apheresis with respect to current cardiovascular guidelines and scientific knowledge for the registry, which are in line with the reimbursement guidelines. In 2011 financing by sponsors was secured and an internet-based registry was created. A pilot project with 5 apheresis centers finished in 2012 - since then the registry is available to all German apheresis centers., Conclusions: There has been consensus between the medical societies and health care carriers regarding the need for a German Lipoprotein Apheresis Registry (GLAR). The launch of this registry complies with requirements of the Federal Joint Committee (G-BA). Complementing the Pro(a)LiFe-Study, first data from GLAR support the safety of the different apheresis treatment procedures. In addition these first data suggest, with respect to the results of Pro(a)LiFe-Study, effectiveness in preventing cardiovascular progression as well. Here, further data are needed to statistically substantiate these early findings., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aim: Lipoprotein apheresis (LA) is the elective therapy for homozygous and other forms of familial hypercholesterolemia (FH) and familial combined hypercholesterolemia (FCH), resistant/intolerant to lipid lowering drugs, and hyperlipoproteinemia(a) for which drugs are not available. To assess the effect of LA on the incidence of adverse cardiac or vascular events (ACVE) at the time period of pre-initiation of apheresis and during the LA treatment., Methods: We collected data of 30 patients (mean age 62 ± 8 years, males 73%), with FH, or FCH and cardiovascular disease on maximally tolerated lipid lowering therapy and LA treatment (median 5 years, interquartile range 3-8 years). Associated hyperlipoproteinemia(a) was present in 16/30 subjects. The LA treatment was performed biweekly as clinically indicated by dextran-sulfate or heparin-induced LDL precipitation apheresis. The ACVE incidence, before and after treatment, was evaluated by statistical analyses., Results: The ACVE incidence occurred before and after the LA treatment inception, were 86 and 15 events respectively. Notably, 6/15 of ACVE were secondary to stent restenosis and 7/15 follow-up events occurred during the first 5 years. The AVCE rates/year were 0.58 and 0.13 respectively (p < 0.001)., Conclusions: Our data confirm long-term efficacy and positive impact of LA on morbidity in patients with FH and FCH and atherosclerotic disease at maximally tolerated lipid lowering therapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Lipoprotein apheresis (LA) is an officially accepted therapeutic approach in Germany. Reliable population-based data on the patients are scarce. It is of special interest to learn what are the main indications for this extracorporeal treatment and how many new patients started over the last years., Methods: This paper is a summary of the situation of the treatment of high-risk patients via LA in the federal state of Saxony, Germany. The documentation of all patients who agreed to be included into this study have been evaluated. Patients were treated at the University Hospital Dresden (UHD) and in private practices of nephrologists. This evaluation aimed at the characterization of patients treated with LA in Saxony with respect to age, gender, lipid pattern, to the number of new patients per year and the development of the ratio of patients to the Saxon population between 2010 and 2013. The obtained data were compared with the official statistics published by the National Association of Statutory Health Insurance Physicians for whole Germany., Results: In 2013, 181 patients, primarily males, were treated in 15 LA centers by 32 doctors. Still, the number of apheresis doctors per 1 million inhabitants is under the average in Germany (Saxony: 7.7/1 million inhabitants, average: 12/1 million inhabitants). The usage of LA is 45 per 1 million inhabitants in Saxony; in comparison to 2010, this is an increase of 16 per 1 million inhabitants. The number of new patients in 2013 with an isolated elevation of Lipoprotein(a) (Lp(a)) is twice as high than it was in 2011. The mean duration of all patients being treated with LA, most on a weekly basis, was 5.75 years (UHD: 6.2 years, range: 1 month to 23.1 years; other centers: 5.3 years, range: 1 month to 19.2 years). About 19.3% of all patients suffered from elevated triglyceride (TG) levels (>5 mmol/L). Non-high- density lipoprotein cholesterol (Non-HDL-C) was calculated, which is also acutely reduced by LA sessions. The following data were reported for those patients who are treated outside the UHD: risk factors such as hypertension and familial predisposition could be seen in almost every patient, and several others such as type 2 diabetes mellitus, genetic defects and obesity were also present. Almost all patients had suffered from cardiovascular events (CVE) occurring before the start of apheresis treatment. LA therapy led to a reduction in occurrence of CVE during LA therapy. In particular, patients with an isolated increased Lp(a) had the highest reduction when comparing CVE before and during apheresis therapy. In the official statistics published by the National Association of Statutory Health Insurance Physicians the number of LA patients with homozygous familial hypercholesterolemia (HoFH) is clearly too high. Moreover, these statistics do not include patients who are treated at hospitals like the UHD., Conclusion: All in all it can be shown that the extracorporeal therapy is performed effectively in Saxony, and that more centers than 2010 (additional 5) were conducting this therapy when lipid-lowering medication was not sufficiently effective. It is certain that the number of patients requiring LA will increase in the future., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Lipoprotein apheresis and immunoadsorption methods have a firm place among therapeutic approaches in order to treat disorders of lipoprotein metabolism or anti-body induced diseases. The extracorporeal treatment is associated with adverse effects, we wanted to report the Dresden experience., Methods: In this study we retrospectively analyzed the adverse events of several lipoprotein apheresis and immunoadsorption methods at the Apheresis Center in Dresden (Germany). We carefully looked into all available documents. The first extracorporeal lipoprotein apheresis was performed in 1990 and the first extracorporeal immunoadsorption was executed in 1995. Throughout the 23 years study period, 10 different methods were employed in treating 268 patients for a total of 25,293 treatments., Results: Adverse events of varying severity occurred in 1948 of the treatments (7.7%). We subdivided them into mild (61.3% no treatment was necessary), moderate (37.0% oral medication or infusion was given) and severe (1.7% emergency hospitalization was necessary). Therapy had to be stopped prematurely in 1.5% of the treatments. We compared adverse events profiles among the different methods and evaluated for differences by gender. Females were found to have a significantly higher risk of adverse events than male patients. In males, the rate of adverse events ranged from 3.3% (Liposorber(®) D) to 11% (Therasorb™ Ig); in females the minimum rate was 7.8% (DALI) and the maximum 30% (rheopheresis). Adverse events were evenly distributed between the ages of 30-69, the age range at which most of the therapies were performed. We also found that all methods had a higher rate of adverse events during the first year of treatment. Puncture problems and hypotension were the most common adverse events., Conclusion: It can be stressed that in general the extracorporeal methods used can be regarded as safe., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Despite the fact that extracorporeal methods such as lipoprotein apheresis (LA) and hemodialysis (HD) are highly effective in improving the physical status of patients, these treatment options may possibly harm the psychological status and the health related quality of life (HRQL)., Methods: The occurrences of anxiety, depression and the HRQL of 111 study participants treated with LA (n = 41), HD (n = 41) or undergoing plateletpheresis (PD) (n = 29) were compared to the normal population (NP), using standardized questionnaires (anxiety and depression: Hospital Anxiety and Depression Scale (HADS), heart-focused anxiety: Cardiac Anxiety Questionnaire (CAQ) and HRQL: Short-Form Health Survey (SF-12)). Additionally, the subjective mental and physical stress of study participants was evaluated., Results: LA females had a significantly elevated HADS-A score compared to PD and NP. Additionally, there was a trend toward higher HADS-A scores in the LA group compared to the HD group in females. In HD males HADS-A and -D scores increased compared to PD and NP. The CAQ revealed a significant increase in the CAQ-Fear scale in LA compared to HD and PD participants. The CAQ-Avoidance score showed significantly increased scores in LA and HD patients compared to PD and NP. In the CAQ-Attention scale the LA patients also showed significantly increased scores compared to PD and NP. The increased psychological symptoms were associated with significantly lower levels of objective and subjective HRQL in LA and HD patients compared to PD and NP., Conclusions: LA and HD patients had similarly increased presence of psychological symptoms with concurrent decreased quality of life compared to PD and the normal population, which may affect the outcome of the LA patients. Therefore, early psychosomatic screening and probable psychosomatic treatment should be performed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Previously we found a highly significant increase of phosphatidylethanolamines (PE) in response to acute lipoprotein apheresis (LA) with whole blood dextran sulfate adsorption (DSA) in contrast to the overall tendency of reduction of lipid metabolites of all lipid classes in post-apheresis plasma. Therefore, the aim of the present study was to analyze long-term modifications of the plasma lipidomic profile in patients with repeated DSA apheresis., Methods: Nine patients weekly treated with DSA were followed for 40 weeks. Pre- and post-apheresis levels of routine lipid parameters and lipidomic profiles of five apheresis sessions were assessed., Results: The main finding of the present study was a progressive increase of pre- and post-apheresis plasma lysophosphatidylcholine (LPC) levels, which doubled in concentration at the end of the 40 week observation period. LPC metabolites which mainly contributed to this increase were LPC 20:4 > 18:0 > 18:1 > 16:0 > 20:3 > 18:2., Conclusion: These data indicate that long-term application of DSA technology may be associated with a continuous increase in LPC levels. Possible pro- or anti-atherogenic consequences should be elucidated in further studies., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Lipoprotein apheresis is indicated in patients at high risk for cardiovascular disease due to severe hyperlipoproteinemia, which is not adequately controlled by diet and medication. This extracorporeal therapy reduces the event rate, although it does not completely abolish new events. We compared atherogenic risk factors in patients who were treated in 2009 and 2010 with lipoprotein apheresis and who suffered events (n 20) with patients who did not (n 44). Among the 45 cardiovascular events that occurred four were strokes, one was myocardial infarction, and two were bypass operations (one coronary and one peripheral). The following risk factors were found to be associated with events: male gender, coexisting diabetes/glucose intolerance and elevation of Lp(a) concentrations. In addition, the history of previous cardiovascular events, the efficiency of the lipoprotein apheresis therapy as judged by the reduction rates of LDL-C and of Lp(a), and the duration of the extracorporeal treatment (patients with events had started treatment with lipoprotein apheresis more recently) may play a role. We did not observe any influence of family history, of the underlying lipid disorder or lipid levels, of arterial hypertension or of smoking habits. Evidently, apheresis therapy of longer duration (more than two years) stabilizes the cardiovascular situation of the patients. Patients on apheresis therapy should be regularly assessed with respect to their risk factor and vascular situation. Lipoprotein apheresis therapy is important for the reduction of cardiovascular events, but optimization of additional modifiable risk factors should also be undertaken., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

This paper summarizes the situation pertinent to treatment via lipoprotein apheresis in the federal state of Saxony, Germany in 2010. In total, 119 predominately male patients were treated in 10 centers; the majority of the patients was older than the mean age of the general population. Several risk factors were present, particularly a familial predisposition and hypertension. All patients had experienced cardiovascular events and the majority was taking statins. Patient data from the University Hospital Carl Gustav Carus in Dresden concurred with data derived from patients treated at nephrological practices. In the mean, patients attended the centers for about 6 years, the majority weekly. LDL cholesterol concentrations prior to apheresis were clearly higher than target levels; apheresis sessions decreased LDL cholesterol by 69%. Lipoprotein(a) levels could be measured in 75 patients and were effectively reduced by lipoprotein apheresis. In Saxony, 29 patients per 1 million inhabitants received lipoprotein apheresis, which is higher than the proportion of patients treated in Germany as a whole. The need for this extracorporeal treatment seems to be much greater than its current utilization. Among the patients only one homozygous patient with familial hypercholesterolemia was observed. Physicians should be actively informed about this therapeutic possibility to reduce the cardiovascular risk efficiently. The introduction of new drugs may alter the position of lipoprotein apheresis within the therapeutic spectrum., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

In high-risk patients who are already on a maximal lipid-lowering therapy, a lipoprotein apheresis is an important therapeutic option in preventing further progress of vascular complications as it may decrease both LDL-cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) levels. We looked at the occurrence of cardiovascular events before apheresis and during apheresis in three groups defined by their lipid patterns at the start of an apheresis treatment: Group 1 (LDL-C ≥ 3.4 mmol/l and Lp(a) ≤ 600 mg/l; n = 35), Group 2 (LDL-C ≤ 3.4 mmol/l and Lp(a) ≥ 600 mg/l n = 37) and Group 3 (LDL-C ≥ 3.4 mmol/l and Lp(a) ≥ 600 mg/l; n = 15). Group 2 shows a time period of about 10 years from the first event until the start of apheresis treatment (compared to 2-6 years in the other two groups). Before the start of apheresis treatment 2.1 events per patient had occurred in Group 1, 3.4 events per patient in Group 2 and 1.8 events per patient in Group 3. Under apheresis therapy just 0.9 events per patient occurred in Group 1, 0.5 in Group 2 and 0.5 in Group 3. When comparing the two years before the start of apheresis treatment with the first two years under apheresis we saw the following reduction rates of cardiovascular events: Group 1-54%; Group 2-83%; Group 3-83.5%. Our results show that the reduction of cardiovascular events due to lipoprotein apheresis is especially high in patients with elevated levels of Lp(a) compared to patients with elevated LDL-C only indicating that physicians should be more focused on the risk factor elevated Lp(a)., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10-20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

With several techniques of selective apheresis treatment, some of which have been established for over 30 years, severe and pharmacologically unmanageable dyslipidemia can be treated successfully. The long-term lowering of LDL cholesterol and lipoprotein(a) by 60-80 percent, together with pleiotropic effects, allow for significant risk reduction in otherwise progressive chronic atherosclerotic disease, i.e. chronic coronary artery disease in most apheresis patients, and improvement of quality of life. For various reasons, worldwide only an estimated 2500 patients, among them 1400 to 1500 in Germany, are regularly treated by apheresis. This relatively small number of apheresis patients in Germany is being cared for in more than 200 centers, by more than 750 physicians approved for extracorporeal treatment, resulting in unraveling of expertise and diversity of treatment strategies instead of the needed concentration. Here we present a comprehensive standard for competence centers in apheresis treatment, which is an updated synthesis and amendment to previously published standards, based on the experience from more than 30,000 apheresis treatments in our own center. The presented standard provides a guideline for apheresis treatments, comprising all procedures, indications, detailing the application procedure, as well as suggestions for supportive care in extracorporeal therapy. In the absence of large studies of sufficient quality, this standard represents our "good clinical practice" and refers the "best available evidence", providing the indispensable basis for working in an apheresis center. The apheresis standard also aims to contribute to quality assurance, another intention is to increase the acceptance of this valuable treatment, with a view to admitting more patients in need to apheresis programs, on the basis of reliable cost reimbursement., (Crown Copyright © 2012. Published by Elsevier Ireland Ltd. All rights reserved.)

Lipoprotein apheresis is a well-established extracorporeal treatment in modality of severe hyperlipoproteinemia. Besides the reduction of LDL cholesterol and modifications to physiology of lipoprotein and lipid metabolism, Lipoprotein apheresis may have crucial effects on many other atherogenic factors as vascular inflammation, rheology and gene expressions in blood cells. These different effects of lipoprotein apheresis treatments are reviewed with respect to oxidative stress in plasma, red and white blood cells and in consequence to progression of atherosclerosis. However, in consideration of these reviewed aspects as a factor of biocompatibility lipoprotein apheresis remains safe., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Raised lipid parameters, especially increased LDL-cholesterol and lipoprotein(a) (Lp(a)) levels, are severe risk factors for atherosclerosis. Targets in the therapy of hyperlipoproteinemia are dependent on other risk factors including diabetes mellitus and manifest cardiovascular disease. Fasting levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides are measured for diagnosis of this disease. Lp(a) should be evaluated in instances of positive family history for cardiovascular disease and/or severe progress of cardiovascular disease or premature cardiovascular events. The basis of therapy includes diet measures as well as weight reduction and lifestyle modifications (raised physical activity after excluding contraindications). Numerous patients require lipid-lowering drug therapy, including most importantly statins but also bile acid sequestrants, ezetimibe, fibrates, nicotinic acid or omega-3-fatty acids. Special forms of hyperlipoproteinemia such as chylomicronemia syndrome and raised Lp(a) are described herein., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

We previously demonstrated the role of a phospholipid transfer protein (PLTP) gene variation (rs2294213) in determining levels of high-density lipoprotein cholesterol (HDL-C) in hypoalphalipoproteinemia (HypoA). We have now explored the role of PLTP in hyperalphalipoproteinemia (HyperA). The human PLTP gene was screened for sequence anomalies by DNA melting in 107 subjects with HyperA. The association with plasma lipoprotein levels was evaluated. We detected 7 sequence variations: 1 previously reported variation (rs2294213) and 5 novel mutations including 1 missense mutation (L106F). The PLTP activity was unchanged in the p.L106F mutation. The frequency of the rs2294213 minor allele was markedly increased in the HyperA group (7.0%) in comparison with a control group (4.3%) and the hypoalphalipoproteinemia group (2.2%). Moreover, rs2294213 was strongly associated with HDL-C levels. Linear regression models predict that possession of the rs2294213 minor allele increases HDL-C independent of triglycerides. These findings extend the association of rs2294213 with HDL-C levels into the extremes of the HDL distribution.

Purpose: To study the effect of hyperlipoproteinemia on in vitro distribution of amiodarone (AM) and its prevalent metabolite desethylamiodarone (DEA) in human and rat plasma., Materials and Methods: Human and rat normolipidemic (NL) and hyperlipidemic (HL) plasma were spiked with AM and DEA. The fractions (high and low density lipoproteins, triglyceride rich lipoproteins and lipoprotein deficient plasma) were separated using ultracentrifugation., Results: Human and rat displayed similar patterns in terms of association of AM and DEA in NL plasma, in which the highest and lowest associations were observed in lipoprotein deficient (LPDP) and triglyceride (TRL) rich plasma fractions, respectively. In HL a substantial shift was observed in partitioning of AM and DEA mostly to TRL. The shift of AM and DEA into TRL fraction of HL plasma was more drastic for rat than human. In HL, association of AM with rat LPDP and HDL fractions were 10 and 26-fold lower than in the corresponding human fractions, respectively. The DEA:AM ratio in rat, but not human, was significantly affected by HL., Conclusion: HL caused a major shift of AM and DEA to TRL fraction in both species. The findings were consistent with the higher AM concentrations previously noted in HL rats given the drug.

Laboratory measurements of plasma lipids (principally cholesterol and triglycerides) and lipoprotein lipids (principally low-density lipoprotein [LDL] and low-density lipoprotein [HDL] cholesterol) are the cornerstone of the clinical assessment and management of atherosclerotic cardiovascular disease (CVD) risk. LDL particles, and to a lesser extent very-low-density lipoprotein [VLDL] particles, cause atherosclerosis, whereas HDL particles prevent or reverse this process through reverse cholesterol transport. The overall risk for CVD depends on the balance between the "bad" LDL (and VLDL) and "good" HDL particles. Direct assessment of lipoprotein particle numbers us now possible through nuclear magnetic resonance spectroscopic analysis.

The thiazolidinediones, acting through peroxisome proliferator-activated receptor chi (PPARchi), affect multiple areas of metabolism. Of increasing importance is the recognition that these agents affect lipoprotein metabolism and cause changes in serum lipid and lipoprotein levels. All three thiazolidinediones, including troglitazone (which was withdrawn in the year 2000), rosiglitazone, and pioglitazone, tend to increase high-density lipoprotein (HDL) cholesterol, increase the size/decrease the density of low-density lipoprotein (LDL) particles, and raise the level of lipoprotein(a). In addition, troglitazone and pioglitazone, but not rosiglitazone, lower triglyceride levels modestly, thereby further contributing to increases in LDL and HDL size. The mechanism for these effects is still being clarified, but may involve enhancement of triglyceride clearance (in the case of pioglitazone), alteration of apolipoprotein C-III levels, reduction of hepatic lipase, and increase in ATP binding cassette A1 (ABCA1) activity. The clinical implications of these effects need further exploration.

Background: In plasma, triglycerides (TG) are transported in lipoprotein particles (mainly chylomicrons, very low-density and low-density lipoprotein). Turbidimetry (bichromatically at 660 and 700 nm) allows measurement of the lipemic (L) index. We explored the use of this index, in combination with a TG assay, to detect errors due to non-fasting, to assess abnormalities in TG metabolism and to detect patients with glycerol kinase deficiency (GKD)., Methods: We collected 2441 patient samples. Normolipidemic (n=2347), type IV hyperlipidemic (n=80), postprandial samples (n=22) and serial dilutions of Intralipid with saline (n=6) were selected. One patient presenting with GKD was included, as well as two patients with type I and type V hyperlipoproteinemia, respectively., Results: We introduced the use of the ratio between the logarithm of serum triglycerides and that of the L-index (TG/L ratio)., Conclusion: Although the proposed TG/L-index ratio cannot be regarded as an alternative for the accurate diagnosis of lipid disorders, it provides additional information about TG-containing particles.

Bacterial endotoxin (i.e., lipopolysaccharide [LPS]) elicits dramatic responses in the host, including elevated plasma lipid levels due to increased synthesis and secretion of triglyceride-rich lipoproteins by the liver and inhibition of lipoprotein lipase. This cytokine-induced hyperlipoproteinemia, clinically termed the "lipemia of sepsis," was customarily thought to involve the mobilization of lipid stores to fuel the host response to infection. However, because lipoproteins can also bind and neutralize LPS, we have long postulated that triglyceride-rich lipoproteins (very-low-density lipoproteins and chylomicrons) are also components of an innate, nonadaptive host immune response to infection. Recent research demonstrates the capacity of lipoproteins to bind LPS, protect against LPS-induced toxicity, and modulate the overall host response to this bacterial toxin.

This study aimed to determine whether elevated levels of remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, might be associated with coronary artery disease (CAD) and endothelial vasomotor dysfunction in metabolic syndrome. The fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 210 patients with metabolic syndrome meeting ATP III criteria. Flow-mediated endothelium-dependent dilatation (FMD) in the brachial artery during reactive hyperemia was examined by high-resolution ultrasound technique. This study found that elevated RLP-C levels were a significant and independent risk factor for impaired FMD and angiographically proven coronary artery disease (CAD). Treatment with bezafibrate (n = 20) or atorvastatin (n = 20) for 4 weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. The % reduction in RLP-C levels from baseline after the treatment was independently correlated with the magnitude of improvement in FMD after adjustment for the % changes in levels of triglyceride, hsCRP, and IL-6, and HOMA index. Thus, elevated levels of RLP-C are a risk factor for CAD and endothelial vasomotor dysfunction, a predictor of coronary events, in metabolic syndrome. Measurement of RLP-C is useful for assessment of CAD risk and therapeutic effects in metabolic syndrome.

Atherogenic lipoproteins can cause endothelial dysfunction in the initial stage of atherogenesis. In our study we examined 134 patients with defined hyperlipoproteinemia (non-HDL cholesterol>4.1 mmol/l or triglycerides>2.5 mmol/l or taking any of lipid lowering drugs)--94 men and 40 women. The subgroup of controls of comparable age contained 54 normolipidemic individuals--30 men and 24 women. Patients with hyperlipoproteinemia revealed significantly lower ability of endothelium-dependent flow-mediated vasodilation (EDV) measured on brachial artery (4.13+/-3.07 vs. 5.41+/-3.82 %; p=0.032) and higher carotid intima media thickness than normolipidemic controls (0.68+/-0.22 vs. 0.58+/-0.15 mm; p=0.005). In regression analysis, EDV correlated significantly with plasma concentrations of oxLDL (p<0.05) HDL-cholesterol (p<0.05), Apo A1 (p<0.05), ATI (p<0.01) and non-HDL cholesterol (p<0.05). Patients with hyperlipoproteinemia showed higher plasma levels of oxLDL (65.77+/-9.54 vs. 56.49+/-7.80 U/l; p=0.015), malondialdehyde (0.89+/-0.09 vs. 0.73+/-0.08 micromol/l; p=0.010) and nitrites/nitrates (20.42+/-4.88 vs. 16.37+/-4.44 micromol/l; p=0.018) indicating possible higher long-term oxidative stress in these patients.

Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARalpha) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma high-density lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARalpha binds to a DNA sequence element termed PPAR response element (PPRE) present in regulatory regions of target genes. A PPRE has been identified in the proximal 5' flanking region of the gene encoding the liver fatty acid binding protein (LFABP). LFABP is a small cytosolic protein of 14 kDa present in the liver and the intestine and is a member of the superfamily of the fatty acid binding proteins (FABPs). FABPs play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-ester to various intracellular organelles. FABPs serves as intracellular acceptors of LCFAs, and they may also have an impact in ligand-dependent transactivation of PPARs in trafficking LCFAs to the nucleus. Since PPARs are known to regulate the transcription of many genes involved in lipid metabolism, the importance of LFABP in fatty acid uptake has to be considered. The aim of this study was to verify whether genetic variations in the LFABP gene may impact on plasma lipoprotein/lipid levels in the fasting state as well as on the response to a lipid-lowering therapy with fenofibrate on plasma lipids and obesity variables. We also wanted to verify whether the presence of the PPARalpha L162V mutation interacts with genetic variants in LFABP gene. To achieve this goal, we first determined the genomic structure of the human LFABP gene and then designed intronic primers to sequence the coding regions, all exon-intron splicing boundaries, and the promoter region of the gene in 24 patients showing divergent plasma lipoprotein/lipid response to fenofibrate. Sequence analysis revealed the presence of a T94A missense mutation in exon 3. Interspecies comparison revealed that threonine 94 is conserved among species. We subsequently screened another sample of 130 French Canadian subjects treated with fenofibrate for the presence of the LFABP T94A mutation. Carriers of the A94 allele were at increased risk to exhibit plasma TG levels above 2.00 mmol/l after treatment with fenofibrate [2.75 (1.03-7.34); OR 95% confidence interval (CI)]. In addition, carriers of the A94 allele were characterized by higher baseline plasma-free fatty acid levels (FFA) ( p=0.01) and by a lower body mass index (BMI) ( p=0.05) and waist circumference ( p=0.005) than T94 homozygotes. Moreover, PPARalpha L162V and LFABP T94A showed to have a synergistic effect on BMI ( p interaction = 0.03). These results suggest that the LFABP T94A missense mutation could influence obesity indices as well as the risk to exhibit residual hypertriglyceridmia following a lipid-lowering therapy with fenofibrate.

Postprandial lipemia, characterized by a rise in triglyceride-rich lipoproteins after eating, is a dynamic, nonsteady-state condition in which humans spend the majority of time. There are several lines of evidence suggesting that postprandial lipemia increases risk of atherogenesis. Clinical data show a correlation between postprandial lipoproteins and the presence/progression of coronary artery disease and carotid intimal thickness. Mechanistic studies demonstrate that triglyceride-rich lipoprotein remnants may have adverse effects on endothelium and can penetrate into the subendothelial space. Exchange of core lipids between postprandial lipoproteins and low-density lipoprotein (LDL)/high-density lipoprotein (HDL) is increased during prolonged lipemia, resulting in small, dense LDL particles and reduced HDL cholesterol levels. Hemostatic variables, including clotting factors, platelet reactivity, and monocyte cytokine expression, may be increased during postprandial lipemia. Collectively, these data suggest that assessment and treatment of atherosclerosis should include parameters related to postprandial lipemia.

An immunoassay procedure that quantifies remnant-like particle (RLP) cholesterol in human blood plasma has shown considerable promise as a clinically applicable risk marker for atherosclerotic disease. The lipoproteins included in this assay include not only certain TG-rich lipoproteins [all particles containing apolipoprotein B-48 (apoB-48) and a fraction of those containing apoB-100] but also a very small proportion of plasma cholesterol-rich lipoproteins. The TG-rich lipoprotein component of RLP has been partially characterized, but relatively little is known about the component cholesterol-rich lipoproteins. We have further characterized the properties of the TG-rich component that is included in RLP in which about 25% of the particles contain apoB-48 and the remainder apoB-100. We show that the cholesterol-rich component is comprised mainly of beta-migrating LDLs that contain predominantly apoB-100. ApoE found in the LDL fraction of RLP resides on pre-beta lipoproteins that lack apoA-I as well as apoB. The TG-rich component of RLP is responsible for increased RLP-cholesterol concentrations associated with hypertriglyceridemia. By contrast, the cholesterol-rich component is a major contributor to plasma RLP-cholesterol in individuals with low plasma TG. Our results suggest that particle heterogeneity in the RLP fraction is likely to affect the ability of RLP-cholesterol concentration to predict atherosclerotic risk. RLP-cholesterol concentrations in individuals with low plasma TG may not have the same clinical significance as they do in those with hypertriglyceridemia.

We investigated whether the apolipoprotein-E (apoE) phenotype and the basal activity of low-density lipoprotein (LDL) receptor, which were reported to be the major determinants for increase in plasma LDL levels by cholesterol ingestion, have the same role in Japanese subjects whose diet is low in fat and cholesterol. Cholesterol (750 mg/d) was added to the ordinary diet as a dried egg-yolk supplement for 4 wk to 110 subjects. Plasma levels of lipids, apolipoproteins, and cholesterol in lipoprotein subfractions were measured at the beginning and end of the test period. Phenotyping of apoE was determined by an isoelectric focusing-immunoblotting method, and LDL receptor activity in lymphocytes was determined by flow cytometry. Plasma levels of cholesterol in less-dense LDL (LDL(1)) and less-dense high-density lipoprotein (HDL(2)) were slightly but significantly increased, 3.4% and 4.1%, respectively, by cholesterol ingestion, but the increases were not statistically significant in any of E2, E3, and E4 groups. The distribution of the apoE phenotype was equivalent in all three LDL-cholesterol groups (no change, increase, and decrease by cholesterol ingestion). Plasma levels of LDL, LDL(1), and LDL(2) cholesterol were not significantly increased in the three groups of subjects with lymphocyte LDL-receptor activities (low, medium, and high). As with apoE phenotype, LDL-receptor activities were the same in all three LDL-cholesterol groups. In addition, there were no significant correlations between LDL-receptor activity and changes in plasma levels of lipids, apolipoproteins, and cholesterol in lipoprotein subfractions. Therefore, we concluded that cholesterol ingestion significantly increases plasma levels of less-dense LDL and HDL, but neither apoE phenotype nor basal LDL-receptor activity explain the variability in changes in plasma lipoprotein subfractions by cholesterol ingestion in Japanese subjects.

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P < .05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P < .05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P < .05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.

Remnant-Like Particles (RLP) isolated by an immunoseparation method are heterogeneous in their physical and biochemical properties. The objective of this study was to examine the relation between RLP-triglyceride (RLP-TG) to RLP-cholesterol (RLP-C) ratio and particle size distribution in RLP-C profiles from patients with hyperlipoproteinemia by HPLC. RLP were isolated from serum samples from 147 subjects. RLP-C and RLP-TG were quantified by respective enzymatic methods. Particle sizes of the RLP were measured using HPLC with 4 connected TSKgel LipopropakXL columns. Based on HPLC profiles of RLP-C from individual subjects, three different types were classified: predominantly LDL, predominantly VLDL, and mostly VLDL types. All patients with type III hyperlipidemia were mostly VLDL type but with smaller particle size of VLDL (32 nm) than other subjects. Severe hypertriglyceridemic (TG>4.52 mmoll(-1)) subjects were mostly VLDL type with large particle size (41 nm). As for all subjects (n=105) without predominantly LDL type, a significant correlation between RLP particle size and RLP-TG to RLP-C ratio (r=0. 432, P<0.001) was obtained, but not in case of serum TG to RLP-C ratio (r=0.062). It suggests that RLP-TG to RLP-C ratio might be used for discrimination of atherogenic smaller-sized lipoprotein from larger-sized TG-rich lipoprotein remnants.

For clarifying the role of plasma cholesterol ester transfer activity (CETA) in forming hyperlipoproteinemia (HLP) and determination of high density lipoproteins cholesterol (Ch HDL) level, lipoprotein metabolism indicators were compared for individuals with high and low CETA. 257 subjects were investigated: 195 patients with different forms of hereditary HLP and individuals without HLP: 34 healthy and 28 with coronary heart disease (CHD). Lipids were determined enzymatically, apoproteins content by immunoturbodimetric and immunodiffusion methods. CETA and cholesterol esterification rate (CER) were measured through autological methods. Selected groups of patients with high and low CETA were significantly distinguished only by plasma Ch level (average Ch > 6.2 mmol/l in both groups), free Ch HDL and CER. The groups were not significantly different by men-women ratio (chi 2 = 0.016, p = 0.9) and CHD patients share (chi 2 = 0.126, p = 0.723). The correlation between CETA and Ch levels was significant for healthy individuals only. The data does not correspond to assumption of exclusively atherogenic influence of high CETA: 1) no correlation between CETA and atherogenic parameters of LP metabolism among different HLP forms was found; 2) Ch HDL levels were not distinguished at high and low CETA; 3) no domination of CHD patients among the subjects with high CETA was found.

Objective: To report reference values for plasma lipids and lipoproteins in Canadian adults and the prevalence in the population of various levels of risk for coronary artery disease from dyslipoproteinemia., Design, Setting and Participants: Population- based provincial heart health cross-sectional surveys in 10 provinces between 1986 and 1992 invited 29,855 men and women aged 18 to 74 years to participate. During a clinic visit after a home interview a blood sample was obtained following a fast of 8 h or more from 18,555 people. Plasma lipid levels were determined at the J Alick Little Lipid Research Laboratory, Toronto, with standardization of the Centers for Disease Control Lipid Standardization Program, Atlanta., Outcome Measures: Fasting plasma total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and non-HDL-C levels., Main Results: Mean plasma total cholesterol, LDL-C, non-HDL-C and triglyceride levels increased with age in men to a peak at around age 54 years, while in women the increases were more gradual at a lower level until age 54 years, after which they increased appreciably eventually exceeding values for men. A high percentage of adults were at increased risk for coronary artery disease: 44% had elevated total cholesterol levels above 5.2 mmol/L; 14% had LDL-C levels above 4.1 mmol/L; 8% had HDL-C values below 0.9 mmol/L; and 14% had triglyceride levels above 2.3 mmol/L. Eleven per cent of adults had both total cholesterol level above 6.2 mmol/L and LDL-C level above 4.1 mmol/L., Conclusion: The high prevalence of Canadian adults at risk because of elevated plasma lipid levels strongly indicates the need for comprehensive public health programs to reduce plasma lipid levels in the population and the need to encourage physicians to treat those at high risk.

Background: Tocotrienols, lipid-soluble antioxidants with vitamin E activity, have been reported to lower LDL-cholesterol concentrations and platelet aggregation in men, but results are contradictory., Objective: To examine in detail the effects of a vitamin E concentrate rich in tocotrienols on serum lipoproteins and on platelet function in men at risk for cardiovascular disease., Design: In this randomized, double-blind, placebo-controlled parallel trial, 20 men received daily for 6 wk 4 capsules, each containing 35 mg tocotrienols and 20 mg alpha-tocopherol; 20 other men received 4 capsules daily, each providing 20 mg alpha-tocopherol. All men had concentrations of serum total cholesterol between 6.5 and 8.0 mmol/L or lipoprotein(a) concentrations > 150 mg/L., Results: Compliance was confirmed by changes in serum tocopherol and tocotrienol concentrations. Serum LDL cholesterol in the tocotrienol group was 4.80 mmol/L before and 4.79 mmol/L after intervention, and increased from 4.70 to 4.86 mmol/L in the placebo group (95% CI for the difference: -0.54, 0.19 mmol/L; P = 0.333). Also, changes in HDL cholesterol, triacylglycerol, lipoprotein(a), and lipid peroxide concentrations did not differ between the groups. After adjustment for differences in initial values, no effects were found on collagen-induced platelet aggregation velocity, maximum aggregation, or thromboxane B2 formation in citrated whole blood. ATP release, however, was lower in the tocotrienol group. Urinary thromboxane B2 and 11-keto-thromboxane B2 concentrations and coagulation and fibrinolytic measures did not change., Conclusion: The tocotrienol supplements used had no marked favorable effects on the serum lipoprotein profile or on platelet function in men with slightly elevated lipid concentrations.

The serum levels of lipids, apolipoproteins and lipoprotein ratios in 19 healthy persons and 20 patients with uraemia not dialyzed were determined. Based on creatinine level the patients were divided into two groups: L (serum creatinine 2-5 mg/dl) and H (serum creatinine 5-10 mg/dl). Dyslipoproteinaemia in uraemic patients is already manifested in the early stages of the disease through its abnormal apolipoproteins rather than lipid profile and it suggests a high risk of atherosclerosis.

Aims: Epidemiological data have shown that haemorheological disorders are associated with an increased risk of atherosclerosis. We evaluated the effect of the nicotinic acid derivative acipimox on haemorheological and lipid parameters in 18 patients with mixed hyperlipoproteinaemia using a randomized, double-blind, placebo-controlled, cross-over study protocol., Methods: Patients (7 women, 11 men, aged 49.3+/-3.0 years) were investigated with acipimox (dose adjusted to weight, 500 or 750 mg daily) compared with placebo treatment each for 12 weeks. Lipid parameters, whole blood viscosity, plasma viscosity, fibrinogen, and red cell aggregation at native and standardized (0.45) haematocrit as well as red cell filterability were measured at baseline, at week 12 (change of therapy), and at week 24., Results: Total cholesterol concentration (8.30+/-0.32 vs 8.72+/-0.36 mmol/l(-1)) and apolipoprotein B (198.5+/-9.9 vs 217+/-9.9 mg dl(-1)) were significantly lower (P<0.05) during acipimox therapy compared with placebo, no significant changes were observed for triglycerides and low-density lipoprotein [LDL] cholesterol. However, total high-density lipoprotein [HDL] cholesterol (1.24+/-0.05 vs 1.10+/-0.05 mmol l(-1), P<0.001) as well as HDL2 and HDL3 cholesterol (P<0.05) were significantly higher during acipimox therapy. The LDL cholesterol to HDL cholesterol ratio significantly improved during acipimox therapy (4.63+/-0.25 vs 5.49+/-0.26, P<0.001). Red cell aggregation at native and standardized haematocrit were the only haemorheological parameters which improved during acipimox therapy in comparison with placebo (shear rate 3 s(-1):10.69+/-0.40 vs 11.50+/-0.44 U, P<0.05, for native red cell aggregation; 10.40+/-0.36 vs 11.28+/-0.39 U, P<0.05, for standardized red cell aggregation)., Conclusions: We conclude, that the cardiovascular risk profile improves during acipimox therapy due to an elevation in HDL cholesterol and its subfractions as well as a decrease in red cell aggregation.

Diet-induced hyperlipidaemia in baboons is similar to that in humans. As in humans, the ratio between low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol is a major determinant of atherosclerosis. Baboons, like humans and other non-human primates, vary in their lipaemic responses to dietary lipids. By selective breeding based on variability in plasma and lipoprotein cholesterol response to diet, lines of baboons with high and low responses of various lipoproteins have been developed. Genetic analyses suggest that lipoprotein patterns in response to dietary cholesterol and fat are heritable. Metabolic and molecular studies of high and low LDL and HDL cholesterol responses to dietary lipids have suggested that different mechanisms regulate plasma LDL cholesterol on the chow and on the high cholesterol-high fat (HCHF) diet. On the chow diet, plasma LDL cholesterol levels are positively associated with cholesterol absorption and negatively associated with hepatic LDL receptor levels and, thus, cholesterol absorption and LDL receptors seem to regulate plasma LDL cholesterol levels. However, when the animals consume a human-like fat- and cholesterol-enriched diet, plasma LDL cholesterol levels are not associated with either cholesterol absorption or hepatic LDL receptor mRNA levels, but are negatively associated with plasma 27-hydroxycholesterol concentrations, hepatic sterol 27-hydroxylase activity, and mRNA levels. Hepatic sterol 27-hydroxylase activity and mRNA levels are induced by dietary cholesterol and fat in low responding baboons more than in high responding baboons. Thus, the ability to induce sterol 27-hydroxylase determines the LDL cholesterol response in baboons. High HDL response baboons often have high levels of HDL1 in their plasma. Our studies suggest that the N-terminal fragment of apo C-I with 38 amino acids and a molecular weight of approximately 4 kDa acts as a cholesteryl ester transfer inhibitor peptide in high HDL1 baboons. The inhibitor peptide associates with apo A-1 in HDL to produce a modified apo A-1 protein with a molecular weight of approximately 31 kDa. The inhibitor peptide is a gene product and the presence of this peptide produces an antiatherogenic high HDL1 phenotype.

Background: Epidemiological trials provided evidence that the cholesterol concentration in lipoproteins B, i.e. VDL, IDL and LDL, correlate significantly with the incidence of ischaemic heart disease (IHD). The objective of the present study was to assess how the fatty acid composition in plasma phosphatidyl choline affects the total and LDL cholesterol, triglyceride and apolipoprotein B concentrations in subjects with primary hyperlipoproteinaemia and dyslipidaemia., Methods and Results: In a group of 142 subjects with primary hyperlipoproteinaemia and dyslipidaemia the concentrations of plasma lipids, lipoproteins apolipoproteins and fatty acids in plasma phosphatidyl choline (PC) were assessed. The authors provided evidence by discriminant analysis where the dependent variables were the lower quintiles (Q1 + Q2) and the upper quintiles (Q4 + Q5) of concentrations of total cholesterol, triglycerides, LDL-cholesterol and apolipoprotein B and the independent variables were FA concentrations in plasma PC, that the total cholesterol concentration was inversely associated with the concentration of docosahexaenic acid (22:6n-3). The concentration of LDL-cholesterol correlated inversely with the concentration of palmitoleic acid (16:1n-7). Triglyceridaemia was inversely associated with the linoleic acid concentration (18:2n-6). The concentration of apolipoprotein B correlated positively with myristic acid (14:0) and negatively with concentrations of oleic acid (18:1n-9) and linoleic acid (18:2n-6)., Conclusions: The submitted results indicate that the fatty acid concentrations of PC in plasma are significantly and markedly correlated with concentrations of total cholesterol, triglycerides, LDL-cholesterol and apolipoprotein B. It is possible that atherogenic lipoproteins may be favourably influenced not only by the amount of fat but also by a suitable fatty acid composition.

Atherosclerosis as a key factor of cardiovascular morbidity and mortality is one of the most pressing problem of modern medicine. Most phenotypic deviations of serum cholesterol levels are genetically predetermined and the influence of environmental factors is much less. The vast majority of hereditary dyslipoproteinemia are polygenic. Monogenic disorders are seen in a small proportion of patients with atherosclerosis. However, they only emphasizes the carriage of alleles of the genes that determine various aspects of lipid genesis, transport, and predisposition to atherosclerosis. Virtually all primary dyslipoproteinemias appear as atherogenic types and they represent a special form of atherosclerosis. This fact affects the specific features of cardiovascular diseases in patients with hereditary hyperlipidemias. In these patients coronary heart disease as the most common manifestation of atherosclerosis occurs just in infancy, it is malignant and progressive and unresponsive to treatment. Furthermore, there is a drastic increase in the likelihood of a menacing and fatal complication, such as sudden death. For therapeutical and preventive purposes, these all factors make it necessary to perform a comprehensive early diagnosis of hereditary dyslipoproteinemias by using clinical, genealogical and routine studies, followed by correction of the disorders detected.

A new analytical procedure for determining the fraction composition (FC) of lipoproteins (LP) is developed on the basis of the physical method small-angle X-ray scattering (SAXS). This method quantitatively determines the levels of the basic fractions of LP and their subfractions in plasma or serum to analyze LP FC and to diagnose lipid metabolic disturbances. The results obtained by this procedure were compared with those of gel-electrophoresis, biochemistry, and medical diagnosis. There was a good agreement of SAXS and routine methods. The new procedure shows extremely rapid (1.0-1.5 hr) analysis, uses a single reagent (such as the saccharose type), has a high accuracy, and resolution. The analysis requires as high as 0.05 ml of plasma or serum. LP FC may be analyzed both in protein-free and whole native plasma and sera. The findings may be used in clinical care for diagnosis of dyslipidemias and for researches.

Aim: To specify characteristics of lipoproteins (LPs) metabolism in patients with diverse forms of hereditary hyperlipoproteinemia (HLP) and determine biochemical tests for their differential diagnosis., Materials and Methods: According to the criteria of polygenic hypercholesterolemia (PHCE), family combined hyperlipidemia (FCHL), family hypertriglyceridemia (FHTG) and family hypercholesterolemia (FHCE), 157 patients were selected aged 7 to 70 years of 192 examinees (76 patients with primary HLP and 116 their close relatives). Lipids were measured by enzyme methods, apoproteins (apo)--by immunoturbidimetry and immune diffusion., Results: Compared to healthy subjects, PHCE patients were characterized by higher apoB level and proportion cholesterol (CS)/apoB in very low and low density lipoproteins (VLDL and LDL). In unchanged level of high density lipoprotein (HDL) CS and proportion HDLP CS/apoA1 there were reduced quantities of free HDLP CS, HDLP2 CS and apoA1. In FHCE and FCHL there were also low levels of HDL CS in elevated ones of apoE in (VLDL + LDL). However, in FCHL, contrary to FHCE, the proportion SC (VLDP + LDL)/apoB was as in control group. FHTG patients differed from healthy subjects by diminished HDL parameters: lower HDL CS due to free CS and its esters, apoA1 and proportion HDL Cs/apoA. There were no differences with controls by content of apoB and proportion CS (VLDL + LDL)/apoB, apoE levels in different class lipoproteins., Conclusion: Biochemical parameters are proposed which can differentiate various forms of hereditary hyperlipoproteinemia.

Objective: Most reported mutations that affect lipoprotein metabolism are found within the coding sequences of genes. Recently, a few mutations that occur within promoter sequences have been detected. These promoter sequence variants are the topic of the present review., Methods: Some of these variants are fairly common genomic variants in the promoter regions for candidate genes in lipoprotein metabolism, such as APOA1, APOC3, LPA, and LPL. It is possible that such regulatory sequence variants can result in chronic, modestly altered levels of expression of qualitatively normal gene products. This might have a cumulative effect on quantitative phenotypes, such as plasma lipoprotein concentrations, over the long term. Such an effect might not be detected by existing clinical, biochemical, and/or physiological assays., Results: At present, the most consistent evidence from several lines of experiments indicates that genomic variation in the APOC3 promoter creates slightly elevated plasma triglyceride concentrations within the physiologic range. This altered expression appears to predispose to hypertriglyceridemia in the presence of secondary factors. Genetic variants that produce small effects on promoter function might thus be one component of the predisposition to complex diseases., Conclusion: The aggregate of many small effects may create or contribute to a background of susceptibility that, under appropriate conditions, leads to development of frank dyslipidemia and atherosclerosis.

This study examines the prevalence of abnormal low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels in young adults to determine the ability of National Cholesterol Education Program Adult Treatment Panel (ATP) guidelines to identify persons with elevated LDL cholesterol, to compare other algorithms with those of the ATP, and to determine the contributions of race, gender, and other coronary artery disease risk factors to identifying patients with elevated LDL and low HDL cholesterol. The cohort was population-based, aged 23 to 35 years, and included relatively equal numbers of blacks and whites, and men and women. The prevalence of LDL cholesterol > or = 160 mg/dl (> 4.1 mmol/L) was 5% in black women, 4% in white women, 10% in black men, and 9% in white men. ATP identified most participants with elevated LDL cholesterol (range: 58.8% of white men to 70.7% of black women). Lipoprotein panels would have been required in 6% to 7% of women and to 15% to 18% of men. Algorithms that used nonlipid risk factors required more lipoprotein panels and identified fewer additional participants at risk. The prevalence of HDL cholesterol < 35 mg/dl (0.9 mmol/L) was 3% in women, 7% in black men, and 13% in white men. Algorithms that used nonlipid risk factors before measuring HDL cholesterol would require HDL cholesterol measurements in 35% of whites and 56% of blacks, but reduced sensitivity for identifying low HDL cholesterol (range: 58% in white men to 93% in black women). In young adults, algorithms based on nonlipid risk factors and family history have lower sensitivity, and increase rather than decrease the number of fasting lipoprotein panels required when compared with ATP levels.

In 56 patients with HLP (40 with hypertriglyceridemia and mixed HLP respectively and 16 with hypercholesterolemia), changes in the lipid state and in the parameters of the antioxidative potential before and after a 4-week olive-oil phase, and after 8-, 20- and 32-week intakes of salmon-oil capsules were determined. The treatment with salmon-oil led to a decrease of triglycerides in patients with hypertriglyceridemia and mixed HLP respectively, on the other hand, it led to an increase of cholesterol in hypercholesterolemia. The increase of malondialdehyde as measure of lipid peroxidation in both patient groups underlines the necessity of a substitution of antioxidants. Further investigations are necessary before wide use of fish-oil capsules can be recommended, especially to avoid side-effects.

HyperapoB is the atherogenic dyslipoproteinemia characterized by increased numbers of LDL particles in plasma due to increased secretion of B100 lipoprotein particles by the liver. The lipid phenotype in affected patients is variable but an increased plasma apoB points to the increased LDL particle number. The adipocyte-hepatocyte fatty acid axis refers to the traffic in fatty acids from adipocytes to hepatocytes and back again. Our central thesis is that a reduced rate of adipocyte triglyceride synthesis leads to increased traffic to and fro along this axis. This article outlines the ways in which impaired adipose tissue function leads to increased flux of fatty acids to the liver which leads, in turn, to increased secretion of hepatic B100 particles. The Adipsin-ASP pathway is a newly described biological pathway which appears to play a critical role in regulating adipose tissue triglyceride synthesis. Impaired function of this pathway appears to be the commonest reason for the increased fatty acid traffic in the adipocyte-hepatocyte axis leading to HyperapoB.

Objective: To determine the relative efficacy in general practice of dietary advice given by a dietitian, a practice nurse, or a diet leaflet alone in reducing total and low density lipoprotein cholesterol concentration., Design: Randomised six month parallel trial., Setting: A general practice in Oxfordshire., Subjects: 2004 subjects aged 35-64 years were screened for hypercholesterolaemia; 163 men and 146 women with a repeat total cholesterol concentration of 6.0-8.5 mmol/l entered the trial., Interventions: Individual advice provided by a dietitian using a diet history, a practice nurse using a structured food frequency questionnaire, or a detailed diet leaflet sent by post. All three groups were advised to limit the energy provided by fat to 30% or less and to increase carbohydrate and dietary fibre., Main Outcome Measures: Concentrations of total cholesterol and low density and high density lipoprotein cholesterol after six months; antioxidant concentration and body mass index., Results: No significant differences were found at the end of the trial between groups in mean concentrations of lipids, lipoproteins, and antioxidants or body mass index. After data were pooled from the three groups, the mean total cholesterol concentration fell by 1.9% (0.13 mmol/l, 95% confidence interval 0.06 to 0.22, P < 0.001) to 7.00 mmol/l, and low density lipoprotein cholesterol also fell. The total carotenoid concentration increased by 53 nmol/l (95% confidence interval 3.0 to 103, P = 0.039)., Conclusions: Dietary advice is equally effective when given by a dietitian, a practice nurse, or a diet leaflet alone but results in only a small reduction in total and low density lipoprotein cholesterol. To obtain a better response more intensive intervention than is normally available in primary care is probably necessary.

Oxidative modification of low-density lipoprotein (LDL) cholesterol appears to contribute to atherogenesis. Probucol reduces LDL cholesterol oxidation susceptibility, but the consistency, dose, and time course are not well described. Twelve hyperlipidemic patients were given probucol for 4 weeks at the usual dose for cholesterol reduction (1,000 mg/day), or one half (500 mg/day) or one quarter (250 mg/day) the usual dose. Lipoprotein oxidation susceptibility of apolipoprotein B-containing lipoproteins was assessed using a rapid test in which LDL cholesterol and very-low-density lipoprotein are precipitated with dextran sulfate and magnesium ions, redissolved, incubated with copper ions for 3 hours, and tested for thiobarbituric acid-reactive substances. Results are expressed as nmoles of malonyldialdehyde (MDA) generated per mg (nmol MDA/mg) non-high-density lipoprotein cholesterol. Lipoproteins from probucol-treated patients become resistant to oxidation with a predrug value of 85 +/- 19, and decreasing to 3 +/- 1 nmol MDA/mg after drug administration (p < 0.001). Both "half" and "full" doses were effective in lowering lipoprotein oxidation susceptibility by 95%. The "quarter" dose was less effective. Oxidation inhibition was maximized within 2 weeks, returning to baseline 4 to 6 weeks after discontinuing probucol. Four patients were subsequently crossed over to vitamin E (1,200 IU/day). Vitamin E had a milder, less predictable antioxidant effect, lowering lipoprotein oxidation susceptibility by a mean of 24%. In conclusion, probucol treatment effectively and predictably reduces plasma lipoprotein susceptibility to ex vivo, copper-induced oxidation. This clinically applicable test may provide quantitation of antioxidant effects of probucol or other antioxidants and thus facilitate dose adjustments and correlation with antiatherosclerotic effects.