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Lipoprotein(a) (Lp(a)) is an internationally recognized atherogenic risk factor which is inherited and not changed by nutrition or physical activity. At present, only proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may modestly decrease its concentration (but not in all patients)-leading to a certain decrease in cardiovascular events (CVE) in controlled studies. However, at present an elevation of Lp(a) is not a generally accepted indication for their use. More effective is lipoprotein apheresis (LA) therapy with respect to both lowering Lp(a) levels and reduction of CVE. In the future, an antisense oligonucleotide against apolipoprotein(a) will probably be available. Atherosclerosis in patients with an elevation of Lp(a) may affect several vessel regions (carotids, aorta, coronaries, leg arteries). Thus, Lp(a) should be measured in high-risk patients. These patients are usually cared for by their family doctors and by other specialists who should closely cooperate. Lipidologists should decide whether costly therapies like PCSK9 inhibitors or LA should be started. The main aim of current therapy is to optimize all other risk factors (LDL cholesterol, hypertension, diabetes mellitus, body weight, renal insufficiency). Patients should be regularly monitored (lab data, heart, arteries). This paper describes the duties of physicians of different specialties when caring for patients with high Lp(a) concentrations.

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations.

Background: Despite advances in pharmacotherapy of lipid disorders, many dyslipidemic patients do not attain sufficient lipid lowering to mitigate risk of atherosclerotic cardiovascular disease. Several classes of novel lipid-lowering agents are being evaluated to reduce atherosclerotic cardiovascular disease risk. Lipoprotein apheresis (LA) is effective in acutely lowering the plasma concentrations of atherogenic lipoproteins including low-density lipoprotein cholesterol and lipoprotein(a), and novel lipid-lowering drugs may dampen the lipid rebound effect of LA, with the possibility that LA frequency may be decreased, in some cases even be discontinued. Sources of material: This document builds on current American Society for Apheresis guidelines and, for the first time, makes recommendations from summarized data of the emerging lipid-lowering drug classes (inhibitors of proprotein convertase subtilisin/kexin type 9 or microsomal triglyceride transfer protein, high-density lipoprotein mimetic), including the available evidence on combination therapy with LA with respect to the management of patients with dyslipidemia. Abstract of findings: Recommendations for different indications are given based on the latest evidence. However, except for lomitapide in homozygous familial hypercholesterolemia and alirocumab/evolocumab in heterozygous familial hypercholesterolemia subjects, limited data are available on the effectiveness and safety of combination therapy. More studies on combining LA with novel lipid-lowering drugs are needed. Conclusion: Novel lipid-lowering agents have potential to improve the performance of LA, but more evidence is needed. The Multidisciplinary International Group for Hemapheresis TherapY and Metabolic DIsturbances Contrast scientific society aims to establish an international registry of clinical experience on LA combination therapy to expand the evidence on this treatment in individuals at high cardiovascular disease risk.

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Aims: We wanted to study factors influencing the size of LDL particles. Material and methods: 752 persons (330 males, 422 females) have been studied. We performed an OGTT (plasma glucose, insulin, proinsulin). Triglycerides (TG), total cholesterol (TC) and protein (in whole plasma, in VLDL, in LDL) and HDL cholesterol have been measured. The size of the LDL particles has been estimated using a gel electrophoresis (in LDL subclasses 1 – 3, mean LDL particle diameter, affiliation to phenotypes A or B). Probands have been subdivided into those with normal glucose tolerance (n 540), with an impaired glucose tolerance (n 137), with a newly discovered or known diabetes (n 51), or with a diabetes mellitus which was treated by insulin (n 24). The Metabolic Syndrome (MS) has been defined according to the NCEP criteria. Results: In 29 % of all probands a MS was observed. These probands had a significantly smaller mean LDL particle diameter (25.5 nm) than those persons without a MS (26.2 nm). In univariate analysis (partially adjusted for fasting plasma glucose, proinsulin, insulin, gender, age, body mass index) the mean LDL diameter showed significant correlations with the VLDL TG, plasma TG, VLDL cholesterol, VLDL proteins and HDL cholesterol. In a linear stepwise regression analysis in the different groups of glucose tolerance different independent factors of influence were seen. Conclusions: The data obtained show the significance of TG levels, of glucose intolerance and the presence of the MS for the formation of atherogenic small dense LDL particles.

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Background: Small dense low-density lipoprotein (LDL) particles are known to be especially atherogenic. Several mechanisms are involved in this atherogenicity. Aims: We wanted to look for the presence of small dense LDL particles depending on gender, metabolic syndrome (MS) and different degrees of glucose intolerance. Moreover, we looked for anthropometric factors and factors of lipid and carbohydrate metabolism that are associated with changes in the LDL size. Results: We studied 752 persons (330 males, 422 females; age 40 ± 17 years). LDL particle size was estimated with polyacrylamide gel electrophoresis. Males had smaller LDL particles than females. Probands with the MS had smaller LDL particles than those without this syndrome. With rising plasma triglyceride (TG) levels more small dense LDL particles were seen. The highest proportion of these small dense LDL particles was observed in the subgroup of type 2 diabetic patients. In the whole material, the mean LDL diameter was correlated negatively with plasma TG and very low-density lipoprotein components (TG, cholesterol and proteins) and positively with high-density lipoprotein cholesterol. In a linear stepwise regression analysis different significant factors influencing the LDL size were found in the whole population, in normoglycaemic probands, in persons with impaired glucose tolerance, in type 2 diabetic patients and in type 2 diabetic patients injecting insulin. Conclusions: Our data point to different mechanisms of the formation of small dense LDL particles in dependence on the degree of glucose intolerance. Moreover, the target values for plasma TG should be set lower.

Aims/hypothesis: Glycoxidized low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis, one of the major diabetic complications. Since atherogenesis may occur early at the onset of diabetes, we investigated whether circulating LDL isolated from subjects with impaired glucose tolerance (n=20, IGT-LDL) showed an increased glycoxidation status and explored their proatherogenic effects on macrophages. Methods/Results: Using gas chromatography/mass spectrometry we could demonstrate a 3- to 5-fold higher oxidative apolipoprotein B-100 proline, arginine, lysine, and tyrosine modification as compared to LDL obtained from subjects with normal glucose tolerance (n=20, NGT-LDL). Moreover, LDL glycoxidation estimated by both N Epsilon-(carboxymethyl)lysine (CML) and N Epsilon-(carboxyethyl)lysine (CEL) residues was increased more than 9-fold in IGT-LDL when compared to NGT-LDL. After one hour incubation of murine macrophages with LDL mRNA expression rates of the scavenger receptors CD36 and SR-BI and transcription factor PPAR Gamma were quantified by reverse-transcription real-time PCR. In comparison to NGT-LDL, IGT-LDL elicited a significantly higher CD36 (p<0.05) and PPAR Gamma (p<0.05) gene expression, whereas SR-BI mRNA expression was not affected. Conclusion: These data suggest that impaired glucose tolerance is associated with increased glycoxidation of circulating LDL that might contribute to conversion of macrophages into a proatherogenic phenotype.

Background: Impaired glucose tolerance (IGT) is associated with an increased risk of atherosclerosis that may be due in part to dyslipidemia. The purpose of this study was to assess the regulatory role of lipid transfer proteins in the development of this dyslipidemia. Methods: Activities of cholesterol ester transfer protein (CETP) and phospholipid transfer protein (PLTP), as well as lipid and protein components of the major lipoprotein fractions, were evaluated in probands with IGT and were compared with those in subjects with normal glucose tolerance. The effect of a fat-rich meal on these variables was also investigated. Results: IGT probands had a higher triglyceride content in subfractions of low- (LDL) and high-density lipoprotein (HDL). IGT patients had higher fasting CETP activity. The latter was positively correlated with HDL2 triglycerides and negatively with HDL3 total cholesterol. PLTP activity and mass were not higher in IGT patients. However, PLTP activity correlated with components of VLDL and LDL and was influenced by the type of obesity. Neither CETP and PLTP activities nor PLTP mass were altered by a fat-rich meal. PLTP and CETP activities correlated in both fasting and postprandial conditions. Conclusions: Increased fasting CETP activity may contribute to increased risk of atherosclerosis in subjects with IGT.

Aims: We wanted to study factors influencing the size of LDL particles. Material and methods: 752 persons (330 males, 422 females) have been studied. We performed an OGTT (plasma glucose, insulin, proinsulin). Triglycerides (TG), total cholesterol (TC) and protein (in whole plasma, in VLDL, in LDL) and HDL cholesterol have been measured. The size of the LDL particles has been estimated using a gel electrophoresis (in LDL subclasses 1 – 3, mean LDL particle diameter, affiliation to phenotypes A or B). Probands have been subdivided into those with normal glucose tolerance (n 540), with an impaired glucose tolerance (n 137), with a newly discovered or known diabetes (n 51), or with a diabetes mellitus which was treated by insulin (n 24). The Metabolic Syndrome (MS) has been defined according to the NCEP criteria. Results: In 29 % of all probands a MS was observed. These probands had a significantly smaller mean LDL particle diameter (25.5 nm) than those persons without a MS (26.2 nm). In univariate analysis (partially adjusted for fasting plasma glucose, proinsulin, insulin, gender, age, body mass index) the mean LDL diameter showed significant correlations with the VLDL TG, plasma TG, VLDL cholesterol, VLDL proteins and HDL cholesterol. In a linear stepwise regression analysis in the different groups of glucose tolerance different independent factors of influence were seen. Conclusions: The data obtained show the significance of TG levels, of glucose intolerance and the presence of the MS for the formation of atherogenic small dense LDL particles.

Aims: We wanted to study factors influencing the size of LDL particles. Material and methods: 752 persons (330 males, 422 females) have been studied. We performed an OGTT (plasma glucose, insulin, proinsulin). Triglycerides (TG), total cholesterol (TC) and protein (in whole plasma, in VLDL, in LDL) and HDL cholesterol have been measured. The size of the LDL particles has been estimated using a gel electrophoresis (in LDL subclasses 1 – 3, mean LDL particle diameter, affiliation to phenotypes A or B). Probands have been subdivided into those with normal glucose tolerance (n 540), with an impaired glucose tolerance (n 137), with a newly discovered or known diabetes (n 51), or with a diabetes mellitus which was treated by insulin (n 24). The Metabolic Syndrome (MS) has been defined according to the NCEP criteria. Results: In 29 % of all probands a MS was observed. These probands had a significantly smaller mean LDL particle diameter (25.5 nm) than those persons without a MS (26.2 nm). In univariate analysis (partially adjusted for fasting plasma glucose, proinsulin, insulin, gender, age, body mass index) the mean LDL diameter showed significant correlations with the VLDL TG, plasma TG, VLDL cholesterol, VLDL proteins and HDL cholesterol. In a linear stepwise regression analysis in the different groups of glucose tolerance different independent factors of influence were seen. Conclusions: The data obtained show the significance of TG levels, of glucose intolerance and the presence of the MS for the formation of atherogenic small dense LDL particles.

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Growing evidence indicates that diabetes mellitus is accompanied by oxidative stress. In addition to lipids and nucleic acids, proteins also undergo oxidation. Diabetic patients have several groups of oxidatively modified proteins, i.e., advanced glycation end-products, carbonylated proteins, and advanced oxidation protein products, in the circulation. Oxidized proteins have also been detected in tissues of animals with experimental diabetes. Oxidative modifications of mitochondrial proteins are blunted in diabetic conditions. Of special interest is the oxidation of apolipoprotein B-100, the structural protein of low density lipoproteins. Oxidatively modified apolipoprotein B-100 molecules had been detected in atherosclerotic lesions as well as in the circulation. Oxidatively altered proteins lead to vascular damage. Increased oxidative stress was also observed in gestational diabetes. Protein oxidation plays a major role in the development of diabetes complications and has been implicated in the pathogenesis of diabetic nephropathy, neuropathy and retinopathy. In diabetic nephropathy which develops as a result of complex interplay of hemodynamic and metabolic factors, oxidative protein modifications contribute to albuminuria, mesangial expansion, glomerulosclerosis and tubulo-interstitial fibrosis. There is also strong experimental evidence that morphological abnormalities of diabetic retinopathy, such as pericyte dropout, formation of acellular capillaries, are associated with non-enzymatic glycosylation (glycation) and accumulation of advanced glycation end-products. Protein oxidation also takes place in the lens and plays a central role in the development of cataract. Growing evidence implicates advanced protein glycoxidation and lipoxidation in the pathogenesis of both somatic and autonomic diabetic neuropathy, and, in particular, motor and sensory nerve conduction deficits, neurovascular dysfunction, diabetic neuropathic pain and loss of sensory function, and

Growing evidence indicates that oxidative modification of low-density lipoprotein (LDL) is increased in diabetes mellitus; however, the mechanism(s) of this phenomenon is still unclear. Gamma-Glutamyl semialdehyde (gammaGSA) is a product of hemin (Fe3+-protoporphyrin IX)-catalyzed oxidation of apolipoprotein B-100 (apoB- 100) proline and arginine residues. On reduction, gammaGSA forms 5-hydroxy-2-aminovaleric acid (HAVA). This report describes the application of sensitive HAVA assay, to characterize gammaGSA formation in LDL under normo- and hyperglycemic conditions, both in vitro and in vivo. In vitro studies revealed that apoB-100 proline and arginine residues are not oxidized to HAVA by HOCl or the myeloperoxidase/hydrogen peroxide (H2O2) oxidation system. Cu2+, Cu2+/H2O2, and Fe2+ induced only minor HAVA formation. In contrast, the hemin oxidation system appeared reactive toward LDL apoB-100 proline and arginine residues. The resulting significant HAVA formation was specifically inhibited by a redox-inert ferric iron chelator. Glucose further enhanced hemin-induced increase in relative electrophoretic mobility of LDL and apoB-100 HAVAformation. In vivo we observed elevated concentrations of HAVA in LDL apoB-100 in patients with impaired glucose tolerance and with manifest diabetes mellitus. In conclusion, glucose promotes iron-mediated oxidation of apoB- 100 proline and arginine residues via a superoxide-dependent mechanism, thus rendering the LDL particles more atherogenic. The findings (a) identify a potential mechanism of enhanced atherogenesis in subjects with diabetes mellitus and (b) support the value of HAVA as a specific marker of LDL apoB-100 oxidation.

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Low density lipoprotein (LDL) apheresis is an effective treatment option for patients with severe hypercholesterolemia not adequately responding to diet and drug therapy. Membrane differential filtration (MDF), synonymous with double filtration plasmapheresis (DFPP), here named Lipidfiltration, and heparin-induced extracorporeal LDL-precipitation (HELP) are two of the five methods available for extracorporeal LDL apheresis. In this prospective investigation 6 patients with severe LDL-hypercholesterolemia and CAD were treated in a cross-over design with Lipidfiltration at two stages of technical development and HELP to compare the efficacy of these two LDL apheresis methods with respect to lowering and modifying plasma lipids and rheologically relevant plasma proteins, especially fibrinogen. In total, 44 LDL apheresis sessions were investigated. In weekly intervals, patients were treated with consecutive LDL apheresis sessions with either Lipidfiltration and HELP, treating identical plasma volumes. In one part of the investigation Lipidfiltration was performed with the novel Lipidfilter EC-50, combined with a newly developed blood and plasma therapy machine allowing optimized plasma heating. The results showed that the reduction rates of LDL-cholesterol, lipoprotein(a) and triglycerides were essentially identical for both methods. Also pretreatment levels of total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol were not significantly different in both treatment groups. Both methods lead to a significant reduction of serum lipoproteins, especially for LDL-cholesterol, which was decreased by 61.4% with Lipidfiltration (treated plasma volume: 2998 ml) and 61.3% with HELP (treated plasma volume: 3013 ml). With respect to Lipidfiltration LDL-cholesterol reduction was more efficient with the novel Lipidfilter EC-50. Mean pretreatment HDL cholesterol concentrations remained unchanged. Comparing Cascadeflo AC-1770 with the novel Lipidfilter EC-50 reduction ra

Oxidized LDL (oxLDL) is a key mediator in atherogenesis and a marker of coronary artery disease (CAD). Type 2 diabetes is associated with excessive cardiovascular morbidity and mortality. Because atherogenesis starts before diabetes is diagnosed, we investigated whether circulating oxLDL levels are increased in impaired glucose tolerance (IGT). OxLDL levels were measured in 376 subjects with normal glucose tolerance (NGT), 113 patients with IGT, and 54 patients with newly diagnosed type 2 diabetes. After correction for age and BMI, serum levels of oxLDL were significantly increased in IGT versus NGT subjects (P = 0.002). OxLDL levels were not associated with the following parameters of the oxidative/antioxidative balance in the blood: total antioxidant capacity, urate-to-allantoin ratio, and circulating phagocyte oxygenation activity. In stepwise multivariate analysis, LDL cholesterol (P < 0.0005) and triglycerides (P < 0.0005) were the strongest predictors of circulating oxLDL levels, followed by HDL cholesterol (P = 0.003), 2-h postchallenge C-peptide (P = 0.011), fasting free fatty acids (P = 0.013), and serum paraoxonase activity (P = 0.035). The strong correlation of oxLDL with LDL cholesterol and triglycerides indicates that LDL oxidation in IGT is preferentially associated with dyslipidemia. OxLDL increase may explain the high atherogenic potency of dyslipidemia in the prediabetic