Search

Thermofiltration, a system of membrane plasmapheresis for LDL apheresis, was applied to the treatment of hypercholesterolemic patients to assess its lipid lowering potential, clinical feasibility and post-treatment lipid recovery. Plasma separated by a membrane separator was warmed above physiologic temperature, filtered with a plasma filter and returned to the patient on-line without requiring supplemental plasma product infusion. One calculated plasma volume was treated. Treatment schedules were weekly, biweekly or monthly. Patients treated by thermofiltration in this study were diagnosed as type II hypercholesterolemia. Reductions and sievings of high density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol were evaluated. In addition, post-treatment solute recovery was assessed. The reduction ratios of HDL cholesterol and LDL cholesterol were 0.31 ± 0.08 and 0.58 ± 0.08, respectively (mean ± S.D. of 7 patients). Sieving coefficients of the plasma filter for HDL cholesterol and LDL cholesterol were 0.62 ± 0.12 and 0.03 ± 0.02, respectively (mean ± S.D. of 32 treatments). Cholesterol reduction fitted well to a single pool model. HDL cholesterol recovered significantly faster than LDL cholesterol and LDL cholesterol recovery differed among individuals. For some patients total cholesterol and LDL cholesterol levels were lowered by the biweekly treatment while for others the weekly treatment was required. Significant removal of LDL cholesterol with sparing of HDL cholesterol was achieved without the requirement for plasma products.

Changes in high density lipoprotein (HDL) subfraction structure and composition were analyzed during and after extracorporeal removal of apo B containing lipoproteins in seven familial hypercholesterolemic (FH) patients. After the apheretic procedure, carried out with dextran-sulfate-cellulose columns, the plasma levels of very low density lipoproteins (VLDL), low density lipoproteins (LDL), and HDL decreased by 72%, 50%, and 19%, respectively. The free cholesterol to esterified cholesterol ratio in plasma increased, with a 26% drop in the lecithin: cholesterol acyl transferase (LCAT) activity. In the ensuing 24 hours, VLDL, HDL, and LCAT activity approached the pretreatment levels. During this phase, possibly as a consequence of increased cholesterol esterification and exchange of cholesteryl esters for triglycerides between HDL and VLDL, HDL 2a particles were detected in plasma. However, these metabolic changes did not result in clearcut modifications in the HDL 2 -HDL 3 subfraction distribution. These findings clearly demonstrate that rapid changes in the plasma VLDL-LDL levels affect several processes involved in the HDL metabolism, but confirm that the HDL system, in spite of a considerable plasticity, displays a marked stability of the HDL 2 -HDL 3 subfraction distribution.

In addition to LDL, Lp(a) can be quantitatively eliminated from plasma in an extracorporeal LDL-apheresis procedure based on precipitation with heparin at pH 5.12. The rates of return of post-apheresis Lp(a) and LDL-cholesterol concentrations to baseline levels were investigated in six individuals with familial hypercholesterolaemia (one homozygote, five heterozygote) and one normolipaemic individual. The first-order disappearance constants (kappa) were derived for LDL and Lp(a) according to Apstein et al. The kappa values for LDL in the homozygous FH and the normolipaemic individual were 0.082 and 0.43 respectively while the heterozygous FH patients had kappa values intermediate between the two (median 0.231; range 0.116-0.261). The first-order disappearance constants of Lp(a) did not correlate with those of LDL. The homozygous FH and normolipaemic individuals had Lp(a) kappa values of 0.158 and 0.199 respectively; the corresponding values in the heterozygous FH patients were: median 0.142; range 0.045-0.179.

Plasma lipoproteins were selectively removed from familial hypercholesterolemic patients by using two types of plasmapheresis: double-membrane filtration and selective adsorption of very low density lipoproteins (VLDL) and low density lipoproteins (LDL). In both techniques, plasma was separated from blood cells by using hollow-fiber filters, and 100% of the VLDL and LDL was recovered in the filtrate. In double-membrane filtration, the second hollow-fiber filter trapped 84% of LDL + VLDL, 48% of high density lipoprotein (HDL), 24% of albumin, and 46% of the remaining plasma protein. By treating 3 liters of plasma from a patient weighing 60 kg, 60% of the LDL and 30% to 40% of the HDL were removed as a result of an exponential decay of each component with the respective trapping coefficients. When dextran sulfate-cellulose was used as a LDL sorbent, there was only loss of LDL and VLDL, and no loss of any other major plasma component or of HDL. The sorbent column (400 ml) was saturated with 7.5 g of LDL cholesterol by treatment with 3.5 liters of plasma; the maximum reduction of LDL cholesterol was thus about 300 mg/dl for the patient weighing 60 kg. No serious side effects were observed during the long-term trials (19 to 27 months for four patients on double-membrane filtration and 10 months for the two patients on dextran sulfate-cellulose treatment.

Comparison of the effects of plasma exchange using lipoprotein-deficient plasma with those of LDL apheresis using a dextran sulphate column was undertaken in two groups of Watanabe heritable hyperlipidemic rabbits pre-labelled with 3H-cholesterol. Total and HDL cholesterol were reduced more by plasma exchange but HDL cholesterol rebounded higher after LDL apheresis; rises in HDL cholesterol correlated with preceding decreases in both HDL and total cholesterol. An increase in the specific activity of HDL cholesterol occurred on the day after each procedure, being more marked after plasma exchange, and was accompanied by a decrease in the cholesterol/phospholipid ratio of HDL. These results suggest that an influx of extravascular HDL into plasma occurred after both procedures, resulting in mobilization of tissue cholesterol.

Objective Familial hypercholesterolemia (FH) is an autosomal dominant inherited disorder caused by mutations in the low density lipoprotein receptor (LDLR) gene. FH is characterized by elevated plasma LDL cholesterol, premature atherosclerosis, and a high risk of premature myocardial infarction. In general, mutations within LDLR gene can cause five different classes of defects, namely: class I defect: no LDLR synthesis; class II defect: no LDLR transport; class III defect: no low density lipoprotein (LDL) to LDLR binding; class IV defect: no LDLR/LDL internalization; and class V defect: no LDLR recycling. One might expect that both the class of LDLR defect as well as the precise mutation influences the severity of hypercholesterolemia on one hand and the response on drug treatment on the other. To clarify this question we studied the effect of the LDLR mutation p.W556R in two heterozygote subjects. Results We found that two heterozygote FH patients with the LDLR mutation p.W556R causing a class II LDLR defect (transport defective LDLR) respond exceedingly well to the treatment with simvastatin 40 mg/ezetimibe 10 mg. There was a LDL cholesterol decrease of 55 and 64%, respectively. In contrast, two affected homozygote p.W556R FH patients, in the mean time undergoing LDL apheresis, had no response to statin but a 15% LDL cholesterol decrease on ezetimibe monotherapy. Conclusions The LDLR mutation p.W556R is a frequent and severe class II defect for FH. The affected homozygote FH patients have a total loss of the functional LDLR and—as expected—do not respond on statin therapy and require LDL apheresis. In contrast, heterozygote FH patients with the same LDLR defect respond exceedingly well to standard lipid-lowering therapy, illustrating that the knowledge of the primary LDLR defect enables us to foresee the expected drug effects.

Low-density lipoprotein (LDL)-apheresis is a Food and Drug Administration–approved treatment for patients with homozygous familial hypercholesterolemia (FH) or severe heterozygous FH. Based on electrochemical principles, it selectively removes apolipoprotein B–containing lipoproteins through extracorporeal precipitation with either heparin (Heparin-induced Extracorporeal LDL Precipitation, ie, HELP) or dextran sulfate (Liposorber). LDL-apheresis can lead to an acute decrease in LDL cholesterol (LDL-C) of 70%–80%, but there is a rapid rebound to baseline levels within approximately 2 weeks. LDL-apheresis is typically performed once-a-week in patients with homozygous FH and every other week in those with heterozygous FH to produce time-average LDL-C reductions of ∼40%. Side effects associated with LDL-apheresis include hypotension (later found to be due to concomitant use of angiotensin-converting enzyme inhibitors), nausea/vomiting, flushing, angina, and fainting. Posttreatment bleeding can occur secondary to heparin used during the procedure. Challenges associated with LDL-apheresis include vascular access often requiring an arteriovenous fistula (fistulas may clot and require revision over time), the time associated with each treatment session (2–4 hours), the frequency of treatment, and the scarcity of medical centers which perform LDL-apheresis. Given the nature of LDL-apheresis, randomized placebo controlled trials are nearly impossible, and virtually all studies of clinical benefit have been non-randomized investigations of small numbers of subjects. Nonetheless, results from those studies support the benefits of LDL-C reduction for reducing coronary atherosclerosis and cardiovascular events.

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK.

Introduction Low density lipoprotein (LDL-C) apheresis is a last treatment option for hypercholesterolemic patientsresistant to conservative lipid-lowering therapy. In a retrospective analysis of 8,533 heparin-induced extra-corporeal LDL precipitation apheresis treatments (HELP), we evaluated the efficacy of LDL reduction, the rate of adverse events, and the progression of atherosclerosis. Methods Between July 1992 and April 2009, we performed 8,533 HELP apheresis therapies in patients with familial hypercholesterolemia (FH). Inclusion criteria were FH with insufficient lipidological status under optimal drug therapy and diet, and at least 50 HELP therapies. Left ventricular function and valvular status was checked prior to the first apheresis therapy and at the end of the individual HELP program. Blood samples were taken directly before and after each therapy. Blood count, electrolytes, total cholesterol, LDL–C, high density lipoprotein (HDL–C), triglycerides, lipoprotein (a) (Lp(a)), and fibrinogen were measured. Adverse events were documented weekly. Results We evaluated 27 patients (19 men) with FH (age 49.2 ± 12.5 years (range 10–67 years)). The number of HELP treatments once weekly was between 50 and 790 applications. Mean follow-up time was 7.0 ± 5.2 years (range 1.3–16.6 years). Prior to the individual apheresis program, 44.4% of the patients had a three vessel disease (VD; 25.9% two VD, 25.9% one VD) and 7.4% had a peripheral arterial occlusive disease. During the time of HELP treatment, none of the patients had a myocardial infarction; 3.7% had one percutaneous coronary intervention (PCI), 11.1% two PCI, 14.8% three PCI, 11.1% ³ four PCI. The patients received 1.2 ± 1.6 (range 0–5) PCI during follow-up time. Adverse events directly associated with HELP therapy were very rare (

1. (1) All types of columns used are effective for the reduction of total cholesterol and LDL levels with the procedures performed once in 7–10 days. HDL level remained unchanged, which had a favourable effect on TC HDL ratio. 2. (2) Prolonged treatment leads to the regression of xanthomata. 3. (3) Studies of coronary atherosclerosis regression after long-term LDL-apheresis are in progress.

A highly selective method for the removal of apolipoprotein-B-containing serum lipoproteins (low density lipoproteins [LDL] and very-low-density lipoproteins [VLDL]) from hypercholesterolaemic patients by immunoadsorption in an extracorporeal system consists of separation of plasma from the blood cells by a blood-separation centrifuge, followed by the selective adsorption of LDL from the plasma on anti-LDL- 'Sepharose'. The LDL-free plasma effluent, from which high-density lipoproteins (HDL) and other plasma proteins are not removed, is returned to the patient with the blood cells. Three patients with familial hypercholesterolaemia, one homozygous and two heterozygous, were treated repeatedly during a period of 9 months. No undesirable side-effects or changes in clinical, chemical, haematological, or immunological parameters have yet been observed. The new procedure has several advantages over treatments currently used; it is non-invasive, more specific, and less costly and lowers LDL to a greater degree.

Short-term organ culture and primary cell culture of human aorta were used to study the effect of selective removal of low-density lipoproteins (LDLs) from the surrounding medium (LDL apheresis) on the lipid content of cultured tissue and cells, respectively. LDL apheresis was performed by passing the culture medium through immunosorbent containing agarose-bound goat antibodies against human LDL. LDL apheresis promoted the decrease of lipids of all classes in the cultured atherosclerotic plaque. However, only the cholesteryl ester level, but not free cholesterol, triglyceride, or phospholipid levels, was lowered in the cells cultured from the plaque. One may thus assume that LDL apheresis facilitates regression of lipoidosis by reducing the content of lipids in atherosclerotic lesions.

Familial hypercholesterolaemia is characterized by an elevation of low density lipoprotein (LDL), related to the genetic expression of a membrane receptor defect. The patients suffer mainly from coronary heart disease, established at an early age, leading to longterm disability and early death. The majority of the heterozygous patients can be controlled with conventional therapy consisting of diet, exercise and cholesterol lowering drugs. However approximately 10% of the patients, including the homozygous group, cannot be suffiently treated this way and needs an additional elimination therapy.

Immune specific, on-line elimination of low-density lipoprotein (LDL) was originated by Stoffel, who between 1978 and 1981 experimentally investigated the therapeutic application of affinity chromatography [9]. This development led to its first application in patients in 1981 [10]. At that time the term LDL apheresis was introduced by the group at Koln, FRG, and since then has been reserved for immune-specific adsorption. The technical development led from a single, large apheresis column which was desorbed following therapeutic application (as were the subsequently introduced four small columns loaded sequentially) to the standardized application of two columns loaded and desorbed alternately during treatment under automated control [1]. Thus, the system became sufficiently practical to expand treatment to 10 patients at Koln during the following 5 years. The interest shown by foreign centers led to the introduction of this technique in the USA and the USSR. Starting in 1986 an additional multicenter trial was performed at five German universities, supported by the Federal Ministry for Research and Technology (Table 1).

The clinical application of a new extracorporeal procedure (HELP) for the selective elimination of low-density lipoproteins and fibrinogen by heparin precipitation at acid pH is described. Plasma, obtained by filtration of whole blood through a 0.2 micron filter is continuously mixed with an equal volume of an acetate buffer (pH 4.85) containing heparin. After removal of the precipitated heparin complex by filtration, excess heparin is adsorbed to a specially developed filter, and the clear plasma filtrate is subject to bicarbonate dialysis/ultrafiltration to restore physiologic pH and remove excess fluid. The calculated efficiency for the elimination of low-density lipoproteins and fibrinogen from plasma by HELP is 100% and is therefore comparable to conventional plasmapheresis. However, the HELP system shows a high degree of specificity, with over 80% of total protein being returned to the patient. A total of over 350 treatment procedures have now been performed. Patient compliance and acceptance have been excellent, and no major complications have been observed. The system is therefore suitable for the treatment of severe hyper-beta-lipoproteinemia; its use for the treatment of coronary heart disease is currently under investigation in a prospective multicenter study in which treatment efficiency will be controlled by coronary angiography on 45 patients treated with HELP over a period of 2 years.

Serum alpha-tocopherol and retinol concentrations were followed in four heterozygous adults and one homozygous child with familial hypercholesterolemia being treated by regular low-density lipoprotein (LDL) apheresis. Approximately 50% of plasma alpha-tocopherol was eliminated during a single apheresis procedure in the heterozygous adults, while a complete elimination of this vitamin along with LDLs was observed in the homozygous child. Absolute losses of alpha-tocopherol amounted to 13.4-22.5 mg/apheresis and are equivalent to the recommended dietary intake for 1.5 to 2 days. Despite these losses, no changes were observed either in serum alpha-tocopherol levels or in the ratio of alpha-tocopherol/total serum lipids after 12 months regular apheresis treatment. Serum retinol concentrations only showed a small decrease on apheresis, there being apparently no specific elimination of this vitamin. The absolute losses ranged from 42-422 micrograms/apheresis and were, therefore, much lower than the recommended dietary intake of the equivalent of 1500 micrograms retinol/day. It is concluded that no extra supplementation of these vitamins is required during LDL-apheresis therapy, although it may be advisable to monitor vitamin E status in patients on long-term, intensive therapy.

Nine patients with familial hypercholesterolemia (FH), 6 with homozygotes and 3 with heterozygotes, were treated with long term repetitive LDL-apheresis. The techniques are simple plasma exchange with human albumin solution, double membrane filtration, and selective LDL-adsorption by dextran sulfate-cellulose gel. The average term was 3.5 years except for the two homozygotes for whom the treatment was only initiated in our facility. Plasma total cholesterol levels were controlled between pretreating level, 320 to 500 mg/dl, and posttreating level, 100 to 160 mg/dl, by biweekly treatments. All patients showed remarkable improvement of cutaneous and tendinous xanthomas. One homozygous patient died at 31 years old of myocardial infarction after 2 years of treatment. A homozygous patient who has been treated since 5 years old for 6 years was reexamined by angiography and was shown to have atheromatous lesions regressed in the aortic valve region and in the left renal artery.

Dextran sulfate (Mr 5,000) was covalently linked to porous cellulose beads, and the dissociation constant (Kd) and the maximum binding level (S) of the beads were calculated for the human plasma lipoproteins VLDL, LDL, and HDL. The S values for VLDL and LDL were 2 and 7 g cholesterol/liter of the wet beads and that for HDL was almost negligible, although the apparent Kd were all in the same order. In fact, LDL and VLDL were exclusively adsorbed by the beads from human plasma in vitro. Bound LDL was desorbed with 0.35 M NaCl. The beads were packed in a column (25-ml) and used with polysulfone hollow fibers in experimental LDL-apheresis for WHHL rabbits; LDL cholesterol was reduced from 500 to 200 mg/dl, while HDL, total plasma protein, and major blood cell counts did not change. For LDL apheresis of familial hypercholesterolemia, the sorbent column, 400-ml, was used with the polysulfone hollow fiber filter. The maximum removal of LDL + VLDL cholesterol was 6 to 8 g with a single column resulting in its reduction by 250 to 300 mg/dl after 3.5 liters plasma treatment. Adsorption was negligible with albumin, HDL, IgA, G, M, apoA-I, A-II, C-II, enzymes, and electrolytes. Activated complement fragments, C3a and C5a, were completely adsorbed. By periodic removal of LDL, an increase of HDL cholesterol was observed in some cases. In order to increase LDL removal in a single treatment and to reduce the extracorporeal circulation volume, two small columns (150 ml each) were used alternatively.(ABSTRACT TRUNCATED AT 250 WORDS)

We describe a new low density lipoprotein (LDL) apheresis system using dextran sulfate cellulose column in an automated column regenerating unit (LDL continuous apheresis). Two columns containing 150 ml of dextran sulfate cellulose were used, and the whole extracorporeal circulation was about 400 ml in volume. After 600 ml of plasma was adsorbed into the first column, the second column was used as an adsorbent and meanwhile the first column was regenerated. Thus, the 2 columns were used alternately without losing the potency of the columns. As the apparatus was automatically controlled by a computerized unit, no extra manipulation is necessary compared with the conventional single-column method. By treating 4–5 liters of plasma, non-high density lipoprotein (HDL)-cholesterol levels decreased by 63–71%, and HDL-cholesterol levels remained unchanged. Thus, this new method of LDL apheresis can safely reduce LDL-cholesterol to any desired level and will be applicable for the treatment of child and adult familial hypercholesterolemic patients with severe coronary heart disease.

Atherosclerosis-induced coronary heart disease remains the major cause of death and disability in industrialized countries. Hypercholesterolemia is recognized as a causative factor in the development of atherosclerosis. While the lowering of cholesterol levels as a treatment goal has met with general agreement and acceptance, the preferred methods for doing so are still open to conjecture. This literature review discusses various factors in the hypercho-lesierolemia-atherosclerosis link and surveys a variety of treatment protocols including diet modification, drug therapy, surgical intervention, and plasmapheresis. Evidence is accumulating to prove that the ideal hypercholes-terolemia therapy is one that reduces LDL levels while maintaining or increasing HDL levels. Because LDL-apheresis has this potential, this paper also reviews the various LDL-apheresis methods, including immunoadsorp-tion, chemical affinity,' and double-membrane filtration.

The presence of apo E-containing HDL in familial hypercholesterolaemia was investigated and its removal by LDL-apheresis using a dextran sulphate cellulose column was demonstrated by measurement of the apo E/apo A-I molar ratio of serum and by nondenaturing polyacrylamide gel electrophoresis followed by immunoblotting. The molar ratios of apo E/apo A-I in the density greater than 1.063 kg/l fraction of serum obtained from two homozygous patients with familial hypercholesterolaemia were higher (0.021 and 0.030) than that from normal subjects (mean +/- SE 0.011 +/- 0.002) (P less than 0.05). Polyacrylamide gel electrophoresis and immunoblotting showed an increase in apo E-containing HDL similar to HDL2, in the plasma obtained from the homozygous patient with familial hypercholesterolaemia. The increased amounts of apo E-enriched HDL were removed from plasma by adsorption with a dextran-sulphate cellulose column. These results suggested that LDL-apheresis using the dextran-sulphate cellulose column, may cause an increase in the turnover rate of the apo E-containing HDL and thus facilitate cholesterol removal from the peripheral tissues.

Nine heterozygous patients with familial hypercholesterolemia (FH) were treated by low density lipoprotein (LDL)-apheresis using dextran sulfate cellulose columns. After more than 3 procedures of LDL-apheresis without drug therapy, combination therapy with LDL-apheresis and CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, at a dose of 10 mg twice daily was started. Pre- and post-apheresis serum cholesterol levels were decreased significantly by CS-514, from 289 +/- 24 mg/dl (mean +/- SEM) to 247 +/- 25 mg/dl and from 118 +/- 7 mg/dl to 106 +/- 9 mg/dl, respectively. Pre- and post-apheresis apolipoprotein B levels decreased significantly on CS-514 from 160 +/- 9 mg/dl to 138 +/- 8 mg/dl and from 58 +/- 6 mg/dl to 45 +/- 6 mg/dl, respectively. No adverse effects were observed during the combination therapy. Thus, the addition of an inhibitor of HMG-CoA reductase to LDL-apheresis is a useful method for further reducing serum cholesterol and apolipoprotein B levels in FH heterozygotes.

A novel system of low density lipoprotein (LDL) apheresis for familial hypercholesterolemia (FH) was developed, combining a centrifugal plasma separator (IBM-2997) with a new adsorption column specific to lipoproteins containing apolipoprotein B (apo-B), and its operation was compared to previous methods. The present system selectively removed LDL without the substantial reduction of high density lipoprotein that was seen with other methods using membrane filters. The capacity for LDL removal was slightly more reduced with the adsorption column than with the membrane filters when a single column was used. Since the ability to obtain plasma in the centrifugal system was much higher than in the system using membrane filters for plasma separation, efficient apheresis could be performed in a much shorter time, without making an arterio-venous shunt. Remixing of blood cells, such as platelets, with the separated plasma sometimes raises the pressure within the plasma component separator, but the problem could be avoided by withdrawing the buffy coat fraction, using the WBC pump of the IBM separator. In conclusion, the novel system, combining the centrifugal plasma separator with the adsorption column, has proved, in our hands, to be a more useful and more convenient method than those previously used for the treatment of severe FH.

Two young women with homozygous familial hypercholesterolaemia and coronary and aortic atheroma were treated by repeated plasma exchange, using a continuous-flow blood-cell separator, for 4 and 8 months. A pronounced reduction in plasma cholesterol and low-density lipoprotein (L.D.L.) concentrations was achieved by exchanging each patient's plasma with cholesterol-free plasma protein fraction (B.P.), at 3-weekly intervals on an outpatient basis. By pre-labelling the patients' cholesterol with 14-C and comparing the specific activity of the cholesterol in adipose tissue with that in plasma, evidence was obtained of an influx of tissue cholesterol into plasma after each exchange. There was no side-effects and both patients lost their angina. Plasma exchange offers a new and practical approach to the long-term management of this lethal disorder and may also provide information about the possible reversibility of human atheroma.

Lipoprotein(a) has been shown to be an independent risk factor for atherosclerosis. The effect of different forms of plasmapheresis therapy on the removal ofLp (a) is examined. Plasmapheresis is successfully administered in a small number of hypercholesteremic patients who fail to respond to conventional therapy. Comparison of four different methods of plasma exchange (albumin substitution, anti-apoB antibody column, LDL precipitation, filtration) reveals significant differences in effectiveness in the ability to lower plasma Lp(a): plasma exchange with albumin und LDL precipitation seem to be the most effective, plasma filtration the least.

Summary Lipid apheresis (extracorporeal lipoprotein elimination) is administered to patients with familial hypercholesterolemia who fail to respond to standard therapy. The nature of the treatment process raises the suspicion that it decreases not only cholesterol but also antioxidants. A group of 12 patients (average age 47617 y, 4 homozygous and 8 heterozygous individuals) with familial hypercholesterolemia treated by LDL-apheresis or rheohaemapheresis for 3–12 y was included in the study. In addition to cholesterol and triacylglycerol levels, vitamin E and vitamin A and also other markers of antioxidant activity were investigated. Nevertheless, the most important determined parameter was the vitamin E/cholesterol ratio in serum and lipoproteins. The results indicate that both extracorporeal elimination methods are effective and suitable ways to treat severe familial hypercholesterolemia, as the LDL fraction of cholesterol decreased by approximately 77% and 66% following LDL-apheresis and rheohaemapheresis, respectively. In addition, the serum vitamin E decreased by 54% and 57% and the decrease of the serum vitamin A was approximately 20%. However, the main marker of antioxidant capacity, vitamin E/cholesterol ratio, in the serum, VLDL and LDL significantly increased. The increase of vitamin E levels in the erythrocyte membranes of 2% following LDL-apheresis and a significant increase of 4% following rheohaemapheresis were confirmed. The presented results indicate that LDL-apheresis and rheohaemapheresis can be considered to be safe procedures according to the antioxidant capacity of the serum, VLDL and LDL lipoprotein fractions and the erythrocyte membrane.

In the Czech Republic the therapy of severe familial hypercholesterolemia (FH) by extracorporeal elimination using LDL-apheresis (immunoadsorption) and hemorheopheresis is concentrated into one center. The authors evaluate the long-term therapy (3-12 years, median 7,25) in 12 patients with FH – 3 homozygous, 9 heterozygous; Fredrickson type IIa, IIb (treated: 9 by LDL-apheresis and 3 by hemorheo-pheresis). Immunoapheretic interventions decrease LDL-cholesterol, ApoB and even Lp(a) by about 82 ± 1; 73 ± 13; 82 ± 19 %, respectively. Selected non-invasive methods are important for a long-term and repeated follow-up. Carotid intima-media thickness showed improvement or stagnation in 75% of the patients. The level of some adhesive molecules, cytokines, endoglin and some coagulation functions were measured, but no universally accepted biomarkers informing of the actual activity of the disease were found to predict and plan the therapy. A program for procedure planning with the use of Microsoft(®) Excel for Windows(®) was developed. In summary, LDL-apheresis and hemorheopheresis substantially lower LDL-cholesterol in FH. Our experience with long-term therapy also shows good tolerance and a small number of complications (5,6% of clinically irrelevant side-effects). Hemorheopheresis may improve blood flow in microcirculation in familial hypercholesterolemia and also in some other disorders of microcirculation.

The use of apheretic procedures in pediatric patients has always been restricted by technical difficulties and the low incidence of diseases requiring this kind of treatment. The aim of the present study was to describe the solutions adopted to solve technical difficulties related to priming, vascular access and monitoring and then to evaluate clinical results. Between 1982 and 2000, 51 consecutive children (28 male, 23 female) with a mean age of 4.9 ± 4.8 years (3 months – 14.8 years) and a mean weight of 19.7 ± 12.8 kg (5 – 52 kg), with renal and/or extra-renal diseases requiring apheretic procedures were selected for the study. The overall number of procedures performed were: 226 plasma-exchange (PE), 6 LDL-apheresis (LDL-A) and 8 protein A immunoadsorption (IAPA) sessions. Our therapeutic protocol involves hematic flux of 20 – 100 ml/min and ultrafiltration of 5–20 ml/min. In each 70–95 minute session we exchanged plasmatic volume with fresh frozen plasma or with a solution of 6% albumin in lactated Ringer's, using heparin (10–20 UI/kg/h). We used Paired Filtration Dialysis Monitor in PE and LDL-A; Citem 10 in IAPA. As plasma separator, we used a filter made of polypropylene, 0.2 m2 surface, 30 ml priming (Hemaplex BT 900). Hemolytic uremic syndrome was the most commonly treated disease (18/51 cases) with good results in 10/18 cases. We recorded, good results in vasculitis as well, in one girl with focal glomerulosclerosis in transplanted kidney and rapid improvement in all children with Guillaine-Barré Syndrome. PE treatment was effective in metabolic disorders such as tirosynemia and familiar hypercolesterolemia. Only 4/12 patients with acute liver failure due to viral hepatitis recovered. We had poor results in the remaining eight cases. Complications were rare and no viral infection was found in any patient. Our data show that it is possible to use these procedures in pediatric patients even though clinical indications and real effectiveness still need to be cleared up.

The efficiency and efficacy of low-density lipoprotein (LDL) apheresis performed with a dextran sulphate cellulose (DSC) regenerating unit were tested in five familial hypercholesterolaemic patients. LDL apheresis was repeated four times at both bi-weekly and weekly intervals, processing one plasma volume each time. The efficiency of the procedure (i.e., the extent of lipoprotein removal) was nearly identical with both schedules. Efficacy parameters, i.e., decreases of plasma total and LDL cholesterol (TC and LDL-C) and apo B, were highly correlated (r greater than 0.96) with preapheresis levels, allowing an accurate prediction of the absolute lipid removal in the single individual. Plasma triglycerides, high-density lipoprotein cholesterol, apo A-I and apo A-II recovered rather rapidly, reaching 91-96% of the pre-apheresis values in 48 hours; the recovery of TC, LDL-C and apo B was much slower, with a relatively rapid early phase (80% recovery after about 7 days) followed by a successive slower rise. This pattern was highly reproducible in the single patient, allowing the definition of a simple mathematical model for an accurate (error less than 20%) prediction of the individual process. Based on this model one can design the treatment schedule necessary to maintain lipid levels within the desired range in the single individual. The hypolipidaemic efficacy of DSC apheresis appears, otherwise, not to be dependent upon the procedure per se, but on other individual factors, e.g. the amount of removable lipoproteins and the rate of lipid recovery; both can be predicted with sufficient accuracy.

Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy (N = 18; men = 8, age 55.4 ± 13.1 years) and patients under combined long-term LDL apheresis/hypolipidemic therapy (N = 14; men = 7; age 58.0 ± 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p < 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p < 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation.

BackgroundHomozygous familial hypercholesterolaemia (FH) is an autosomal-dominant inherited disease presenting with highly elevated low-density lipoprotein cholesterol (LDL-C) levels. Untreated, the patient can develop atherosclerosis and cardiovascular disease already in adolescence. Treatment with statins and ezetimibe is usually not sufficient and LDL apheresis is often required. Lomitapide, an inhibitor of the microsomal triglyceride transfer protein, reduces LDL-C and triglyceride levels and can be used alone or in combination with other therapies in homozygous FH. However, experience with this agent is still limited.Case summaryWe present a young female who was diagnosed with homozygous FH at 6 years of age. She shows a complete lack of normal LDL receptor activity and no cholesterol-lowering effect from statins. The patient was treated with LDL apheresis from 7 years of age. When LDL apheresis treatment extended to twice a week, she began to experience adverse effects, including catheter-related complications, infections, and hospital admissions. When lomitapide treatment was initiated, the frequency of apheresis reduced, the LDL-C levels improved and she has not had any further hospital admissions since. Initially, she suffered from gastrointestinal disturbances. However, after 3 years of treatment with lomitapide 20 mg/day, the patient has not experienced any adverse effects.DiscussionIn this female with homozygous FH adding lomitapide treatment to LDL apheresis has contributed to improved LDL-C levels, a reduction in LDL apheresis sessions and enhanced quality of life. No adverse effects have been reported. These findings suggest that lomitapide can be a drug of choice in patients with homozygous FH.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by a lifelong elevation in the concentration of low-density lipoprotein (LDL) bound cholesterol in blood by cholesterol deposits and by early coronary artery disease. The LDL apheresis technique has been introduced with the goal of reducing LDL cholesterol levels, thereby preventing the development of atherosclerosis. The literature on LDL apheresis reports 2 different facets, the therapeutic aspect associated with the lessening of LDL concentration and the initiation of a peroxidation process associated with the biocompatibility of the artificial membrane. Lipid and protein peroxidation gives rise to toxic and atherogenic hydroperoxide, mostly lipid hydroperoxides, and derivative compounds, which may offset the benefit of the procedure. In this paper, plasma hydroperoxide levels are determined along with the elevation of the serum and LDL antioxidant status in hypercholesterolemic patients before and following repeated LDL apheresis sessions. Hydroperoxide concentration has been expressed both in terms of plasma volume and LDL concentration. A highly significant increase in LDL lipid hydroperoxides is demonstrated when expressed in terms of LDL concentration and is associated with the LDL apheresis procedure. The usefulness of antioxidant supplementation in LDL apheresis is discussed.

Acute anterior ischemic optic neuropathy (AION) is a disabling disease which impairs visual function. Standard treatment is unable to affect the outcome and the visual damage persists. We describe the case of a 64-year-old patient affected by AION, whose only known risk factor was hypercholesterolemia. After a first onset of involvement of the right eye (RE), the patient presented four weeks later with an analogous episode affecting the left eye (LE). Since standard treatment, started at involvement of the RE, had not yielded any beneficial effect, the patient underwent three sessions of LDL apheresis. The scotomatous portion of the visual field reduced even after the first session, there was further improvement after the third, and after six months the condition remained stable. Corrected vision improved from 2/10 to 6/10 after the third session. LDL cholesterol and fibrinogen decresade after the third session from 239 mg/dL to 31 mg/dL and from 289 mg/dL to 92 mg/dL, respectively. In conclusion, thanks to its effect of antagonizing hemorheologic disorders of the ocular microcirculation, LDL apheresis seems to be an efficacious treatment of AION, especially in patients suffering from hypercholesterolemia.

We studied effect of cascade plasma filtration on subfractions of low density lipoproteins (LDL) in 16 patients with ischemic heart disease (IHD) and hyperlipidemias refractory to drug therapy. The procedure caused 37.6 ± 1.4%, 43.1 ± 2.5%, and 50.9 ± 1.4% lowering of total, low density lipoprotein cholesterol, and apolipoprotein B-100, respectively. The use of filters led to removal of larger less atherogenic LDL-1 and LDL-2 subfractions with relative accumulation of small dense LDL-3, LDL-4, and LDL-5 subfractions. Lowering of concentrations of all LDL subfractions was caused by specific LDL apheresis by immunosorbtion in 4 patients with IHD. Removal of small dense LDL was more effective than that of large less atherogenic LDL-1 and LDL-2 subfraction. Thus we found differences in spectrum of LDL removed by cascade plasma filtration and immunosorbtion. The use of filters was associated with less effective removal of most atherogenic small dense LDL than of large LDL particles what led to redistribution of concentrations of various LDL subfractions towards atherogenic profile of lipoproteins. These results could constitute a basis for revision of methods of conduct of cascade plasma filtration procedures in patients with IHD.

Background Selective low-density lipoprotein (LDL) apheresis is commonly used to treat patients with familial hypercholesterolemia (FH). Chemerin is an adipokine with putative roles in the regulation of lipid metabolism. Methods In our pilot study, we measured serum chemerin levels by enzyme-linked immunosorbent assay in six severe heterozygous FH patients before and after their first LDL apheresis treatments using the technique of direct adsorption of lipoproteins (DALI). Results The first treatment sessions decreased serum chemerin levels by an average of 27.26 %. While following one patient, 12 months of regular LDL apheresis resulted in a permanent reduction in his serum chemerin level. Changes in the lipoprotein subfractions measured by gel electrophoresis (Lipoprint) correlated with the reduction of chemerin levels. Furthermore, we eluted and then measured chemerin bound to the DALI column. Conclusion We conclude that LDL apheresis decreases the circulating level of chemerin by binding the protein to the column and thus improves lipoprotein subfraction pattern.

Low-density lipoprotein (LDL)-apheresis is a method of extracorporeal elimination of LDL-cholesterol in patients with severe primary lipoprotein disorders. LDL-cholesterol activates macrophages, which play an important role in atheromatous plaque formation. In the present study, we have investigated urinary neopterin, a specific marker of macrophage activation and microalbuminuria, an indicator of generalized vascular dysfunction, after a single LDL-apheresis procedure in 10 patients with severe primary lipoprotein disorder. The urinary neopterin/creatinine ratio was increased in patients compared to controls. No significant changes of the neopterin/creatinine and albumin/creatinine ratios were observed after LDL-apheresis, except a significant (p < 0.006) decrease of urinary neopterin/creatinine ratio in the evening after the apheresis. This decrease showed significant negative correlation with the pre-apheretic levels of atherogenic cholesterol fractions (p < 0.05) and with cholesterol decrease during the apheresis (p < 0.05). Urinary albumin/creatinine ratio correlated positively with total and LDL-cholesterol levels before the apheresis and with the evening urinary neopterin/creatinine ratio after the apheresis, but did not correlate with glycemia and triacylglycerides. Elevated urinary neopterin in the patients with severe primary lipoprotein disorders reflects the presence of atherosclerosis. A single LDL-apheresis procedure did not significantly affect microalbuminuria. The decrease of urinary neopterin in the evening after the apheresis corresponds with the diurnal rhythm of neopterin excretion and was less pronounced in patients with more severe hypercholesterolemia. The correlations between microalbuminuria, neopterin and pre-apheretic cholesterol concentrations indicate a possible connection between microvascular dysfunction, macrophage activity and severity of hyperlipidemia, but these results should be interpreted with caution because of small number of subjects evaluated.