Heparin-induced Extracorporeal LDL Precipitation Research Articles

HELP-(Heparin-induced Extracorporeal LDL Precipitation)-apheresis in heart recipients with cardiac allograft vasculopathy and concomitant hypercholesterolemia: Influence of long-term treatment on the microcirculation.

Hyperlipidemic heart transplant patients who develop cardiac allograft vasculopathy (CAV) benefit from HELP-apheresis (Heparin-induced Extracorporeal LDL Precipitation) which enables drastic lowering of plasma low-density lipoprotein, lipoprotein (a), and fibrinogen. There is evidence that HELP-apheresis also improves microcirculation by an immediate improvement of impaired endothelial-dependent vasodilatation and additive hemorheological effects.Therefore, cutaneous microcirculation was examined before, during, and after the first HELP-apheresis in eight hyperlipidemic cardiac transplant recipients with CAV. To study the long-term effect the intravital microscopy was repeated after three and 12 months of weekly apheresis treatment.In CAV patients the baseline mean erythrocyte velocity was pathologically reduced with 0.13±0.07 mm/s. During the first HELP-apheresis the erythrocyte velocity increased significantly (p = 0.0001) and remained increased until the end of the HELP procedure (p < 0.05). After three months of weekly apheresis treatment a decrease of temporary flow stops in the capillaries with a progressive homogenization (concordance) of the cutaneous microcirculation was observed. After one year of weekly treatment a markedly increase in mean erythrocyte velocity under resting conditions occurred. In addition, a reactive post-ischemic hyperemia could be established for the first time.Even the first single HELP-apheresis resulted in a significant improvement of the cutaneous microcirculation. The long-term treatment of these patients resulted in a marked improvement of the cutaneous microcirculation with the tendency to a normalization of the regulation of the capillary perfusion.

Activation of Lipid Mediator Formation Due to Lipoprotein Apheresis.

Lipoprotein apheresis reliably reduces low-density lipoprotein (LDL) cholesterol in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). Besides lowering lipoproteins and triglycerides, apheresis also decreases levels of essential omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) in blood plasma. In contrast, heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) lipid apheresis might increase the formation of potentially pro-inflammatory and pro-thrombotic lipid mediators derived from n-6 and n-3 PUFAs. The study presented here analyzed lipid mediator profiles in the plasma of patients with hyperlipidemia treated by one of three different apheresis methods, either HELP, direct absorption (DA), or membrane filtration (MDF), in a direct pre- and post-apheresis comparison. Using gas chromatography and liquid chromatography tandem mass spectrometry (LC-MS/MS) we were able to analyze fatty acid composition and the formation of lipid mediators called oxylipins. Our data illustrate—particularly in HELP-treated patients—significant decreases of essential omega-6 and omega-3 polyunsaturated fatty acids in blood plasma but significant increases of PUFA-derived lipoxygenase-, as well as cyclooxygenase- and cytochrome P450-derived lipid mediators. Given that n-3 PUFAs in particular are presumed to be cardioprotective and n-3 PUFA-derived lipid mediators might limit inflammatory reactions, these data indicate that n-3 PUFA supplementation in the context of lipid apheresis treatment might have additional benefits through apheresis-triggered protective n-3 PUFA-derived lipid mediators.

COMPARISON OF TWO LIPID APHERESIS SYSTEMS IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: A SINGLE CENTER 3-YEAR EXPERIENCE

Despite the improvements in the treatment of hyperlipidemia, Low-density lipoprotein (LDL) apheresis is still regarded as the gold standard therapeutic choice in homozygous familial hypercholesterolemia (HoFH). Heparin-induced extracorporeal LDL precipitation (HELP) and double filtration

High serum triglyceride concentrations in patients with homozygous familial hypercholesterolemia attenuate the efficacy of lipoprotein apheresis by dextran sulfate adsorption

Background and aimsMaximizing the acute reduction of LDL-cholesterol (C) and lipoprotein (a) (Lp(a)) concentrations in patients with homozygous familial hypercholesterolemia (HoFH) is the main goal of lipoprotein apheresis (LA). The objective of this study was to examine how the pre-LA serum TG concentrations influence the efficacy of LA to acutely reduce LDL-C and Lp(a) concentrations in HoFH patients. MethodsData from 1761 LA treatments of HoFH patients (n = 10) and compound heterozygous patients (n = 5) collected between 2008 and 2016 were analyzed. These data included the pre- and post-LA concentrations of LDL-C, TGs and Lp(a); volume of filtered plasma; type of LA system used (dextran sulfate adsorption (DSA) or heparin-induced extracorporeal LDL precipitation (HELP)); and interval between treatments. ResultsA significant association between the pre-LA TG concentrations and acute LA-induced reduction in LDL-C, modified by the type of LA system used, was observed (ppre-LA TG quartile*LA system = .04). Using the DSA system, the acute reduction of the LDL-C concentrations was attenuated by 3.9% when the pre-LA TG concentrations were >2.09 mmol/L vs. ≤0.93 mmol/L (highest vs. lowest quartiles: −59.4% vs. −63.3%, p = .007). Using the HELP system, no significant difference was observed in the reduction of LDL-C between the highest and the lowest quartiles of serum TGs (−65.8% vs. −66.4%, p = .9). No association was observed between pre-LA TG concentrations and acute LA-induced decrease in Lp(a) (p = .2). ConclusionsThe efficacy of LA is inversely associated with pre-LA TG concentrations in HoFH patients who used the DSA system instead of the HELP system.

H.E.L.P apheresis exerts long term effects on the capacity of circulating proangiogenic cells

BackgroundSevere forms of mono- and polygenetic hypercholesterolemia as well as elevated Lipoprotein (a) (LP(a)) with progressing cardiovascular (CV) disease are indication for lipoprotein apheresis (LA) in Germany. Many studies investigated pleiotropic effects of LA that might contribute to beneficial effects in advanced atherosclerosis. The present study aimed at investigating the potential role of Proangiogenic Cells (PAC) in patients with new onset or chronic LA using the heparin induced extracorporeal LDL-precipitation (H.E.L.P.) apheresis system. MethodsPatients (n = 10) new to LA and HELP treatment were investigated immediately before, shortly after, 24 h later and 4 weeks following LA. Peripheral blood was used to count PAC in circulation via flow cytometry. In a second step, blood cells from patients were cultured in endothelial selective medium and further evaluated for adhesion in fibronectin coated chamber slides and migratory capacity (stromal cell-derived factor-1 (SDF-1) induced migration). ResultsCells expressing typical EPC markers were rarely detected in blood samples. No differences occurred over time in CD34+; CD34+ CD133+ CD45−; CD34+/KDR+ and CXCR4+/CD14+ positive PAC. We found no differences in cell adhesion at the different time points, while significantly more cells migrated into the SDF-1 medium following four weeks of continuing apheresis therapy. ConclusionUsing well established systems, this study was not able to demonstrate relevant acute effects of LA on PAC in patients new to LA. The increased migratory capacity of PAC might be an indicator of chronic beneficial pleiotropic effects in patients undergoing H.E.L.P. apheresis.

Biphasic hemodynamic effects of LDL-apheresis in common carotid artery.

Heparin-induced Extracorporeal Low Density Lipoprotein Precipitation (HELP) Apheresis gives beneficial reductions in Low Density Lipoprotein (LDL) cholesterol levels; otherwise, extracorporeal circulation settings might elicit inflammation and platelet aggregation. The net effect of these variations on carotid hemodynamic has not been established. Aim of the present study was to investigate periprocedural variations of common carotid artery wall shear stress, circumferential wall tension, and Peterson's elastic modulus. Measurements were sequentially performed on 22 procedures: immediately before apheresis (T1), within one hour after (T2), after 24 (T3) and 48 hours (T4). In order to confirm acute effects, in additional 30 procedures measurements were performed at T1 and T2. Mean shear stress was decreased at T2, with an improvement at T4. Mean circumferential wall tension showed an improvement at T4; arterial stiffness showed the same trend, but only close to statistical significance. The following 30 procedures, where measurements were performed at T1 and T2 only, confirmed previous results, showing a deep wall shear stress decrease at T2 (-21%). LDL apheresis seems to have a biphasic effect on common carotid hemodynamics: the acute worsening of shear stress, probably mediated by extracorporeal circulation, was followed by its improvement, possibly driven by LDL cholesterol reduction.

Fibrinogen is not a prognostic factor for response to HELP-apheresis in sudden sensorineural hearing loss (SSHL).

Higher levels of fibrinogen or cholesterol were associated with improved hearing recovery in SSHL patients after treatment with HELP-apheresis (Heparin-induced extracorporeal LDL precipitation apheresis). The present trial was performed to demonstrate HELP-related effects on relevant metabolic and inflammatory parameters in the context of SSHL treatment. In the framework of a single arm non-controlled trial, we investigated the variation of metabolic and inflammatory parameters using HELP-apheresis for a defined group of 100 patients with SSHL. Based on cut off inclusion criteria (Serum LDL-cholesterol >1.6 g/l and/or fibrinogen >2.0 g/l, SSHL in minimum three frequencies more than 30 dB, time after event not longer than 6 days), the protocol followed a strict time line with one single shot HELP-apheresis and follow-up monitoring including laboratory parameters at six defined time points. If HELP-apheresis could not effect improvement of hearing on day 5, additional corticosteroid treatment was applied. Concentration of anti-inflammatory IL-10 increased while other proinflammatory parameters declined. Serum levels of all measured sterols and apolipoproteins decreased significantly. None of the investigated parameters were suitable to predict hearing improvement of the patients. Levels of fibrinogen and LDL-cholesterol were not prognostic for outcome after HELP-apheresis. A significant (p < 0.001) increase of anti-inflammatory IL-10 after apheresis was notable, while most of the proinflammatory parameters declined. Despite the limited validity of a single arm non-controlled trial, these alterations on immune modulating factors indicate possible secondary pleiotropic effects caused by HELP-apheresis.

Emerging low-density lipoprotein (LDL) therapies: Management of severely elevated LDL cholesterol—The role of LDL-apheresis

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.

HELP apheresis in hypercholesterolemia and cardiovascular disease: efficacy and adverse events after 8,500 procedures

IntroductionLow 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.MethodsBetween 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.ResultsWe 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 (< 3%). Mean elimination of LDL-C was 63.49 ± 7.1%.DiscussionThe HELP apheresis therapy was well accepted by the patients in our programs. Adverse events during HELP apheresis were rare. This data is in line with the experiences published by other authors who reported an adverse event rate of 3.6% in adults. The LDL-HDL ratio, one of the strongest predictors of premature CHD events, improved significantly during the apheresis program.ConclusionHELP is a safe, comfortable, and highly effective treatment in which adverse events are rare. It can reduce the burden of atherosclerosis, with no myocardial infarction and a low coronary intervention rate in our patients.

Lipid apheresis: oxidative stress, rheology, and vasodilatation

In the treatment of homozygous and therapy-resistant hypercholesterolemia, lipid apheresis enables not only low density lipoprotein (LDL) cholesterol to be lowered by approximately 60%, but also oxidative stress factors to be influenced and adhesion molecules reduced. This was investigated in a group of 12 patients using the heparin-induced extracorporeal LDL precipitation (H.E.L.P.) procedure.A significant lowering of LDL cholesterol and fibrinogen leads to an improvement in rheology and endothelial function, detectable and measurable within approximately 20 h by assessing minimum coronary resistance using positron emission tomography (PET) performed in 35 patients. This effect is detectable even after the first lipid apheresis session (H.E.L.P. procedure), documented in 12 patients.Lipid apheresis appears to be the most effective procedure in the treatment of elevated lipoprotein(a) [Lp(a)]. A chosen group of nine patients with selective elevated Lp(a) illustrated both the influence on endothelial dysfunction, in the shape of sharply increased minimum coronary resistance, and the reduction through lipid apheresis, indicating that Lp(a) seems to exert a similar effect on the vascular wall and vascular function as LDL cholesterol.

A Child With Night Blindness

Refsum disease is a genetic progressive neurological disorder caused by neurotoxic phytanic acid, a nutritional component patients are unable to metabolize. Symptoms include retinopathy, polyneuropathy, ataxia, and deafness. They are variable and rarely recognized before adulthood. The authors report the case of a 14-year-old girl diagnosed because of night blindness. They treated her with a phytanic acid-poor diet and extracorporeal lipid apheresis. They used different methods over a 30-month period. Thereafter, the patient was treated with diet only. Membrane filtration and heparin-induced extracorporeal low-density lipoprotein precipitation apheresis were well tolerated. Withdrawal of phytanic acid was studied quantitatively. During a 5-year period, blood phytanic acid levels decreased to a noncritical range. The patient remained free of ophthalmological and neurological progression for a total observation of 12 years. Early diagnosis and effective measures to keep the phytanic acid load low can probably prevent the serious sequelae of Refsum disease. Developing a method for newborn screening is desirable.

Beyond lowering circulating LDL: Apheresis-induced changes of systemic oxidative stress markers by four different techniques

Objective and methods Dyslipidemia and oxidative stress are causally related to atherogenesis and cardiovascular disease. We assessed acute changes of systemic oxidative stress biomarkers in thirty-two patients undergoing regular apheresis using four different techniques: heparin-induced extracorporeal LDL precipitation (HELP), direct adsorption of lipoproteins (DALI), lipidfiltration (LF), and immunoadsorption of lipoproteins (IA). Results All apheresis procedures were similarly effective in lowering LDL cholesterol (−2.5±0.2 mmoL/L), oxidized LDL (−52.4±4.4 U/L), and levels of antioxLDL antibodies (−59.5±15.1 U/L). Among the LDL-apheresis methods investigated, only the DALI technique without prior separation of blood plasma led to a decline in leukocyte count (p=0.01 vs. LF post apheresis) and to decreased phagocyte oxidant-generating activity as evaluated by chemiluminescence. Moreover, DALI was followed by a smaller decrease of blood total antioxidant capacity than the other techniques (p<0.01 vs. HELP post apheresis). Conclusion Together, our data suggest that compared with other common techniques, the DALI apheresis system is accompanied by the lowest systemic oxidative burden evoked by a single apheresis treatment.

A Case Report of the Cascade Filtration System: A Safe and Effective Method for Low‐density Lipoprotein Apheresis During Pregnancy

Women with familial hypercholesterolemia (FH) should be treated effectively during pregnancy, as elevated low-density lipoprotein cholesterol (LDL-C) levels may result in life-threatening consequences. Hydroxymethylglutaryl-coenzyme A reductase inhibitors are contraindicated during pregnancy, therefore LDL apheresis should be considered in the management of such pregnant cases. There are five different methods of selective LDL apheresis: heparin-induced extracorporeal LDL precipitation, double filtration plasmapheresis, direct adsorption of lipoproteins, dextran sulfate adsorption, and LDL immunoadsorption. The cascade filtration system is another modern and effective method for the extracorporeal elimination of LDL-C, although it is not as selective as the methods mentioned above. Herein, we present the case of a pregnant woman with heterozygous FH and extremely elevated LDL-C levels who has been successfully treated with the cascade filtration system until delivery. As far as we can ascertain, LDL apheresis with the cascade filtration system during pregnancy has not yet been reported in the literature.

Protein adsorption during LDL-apheresis: proteomic analysis

The aim of our study was to investigate the clearance of functional proteins by different low-density lipoprotein-apheresis (LDL-A) methods with the help of proteomic analyses. Proteins were eluated from the different LDL-A columns and investigated with 2D electrophoresis combined with mass spectrometry methods. In parallel, we quantified the plasma protein loss from patients treated with double-filtration plasmapheresis (DFPP; n = 9), direct adsorption of lipoproteins (DALI; n = 5) or heparin-induced extracorporeal LDL precipitation (HELP; n = 7) with routine laboratory methods and western blots. Proteomic analyses of the column-bound proteins revealed a column-type-dependent loss with the highest number of protein spots in DALI-treated patients (1001 +/- 36), followed by HELP (881 +/- 25) and DFPP (535 +/- 20). More than 70 functional proteins were identified. These proteins are involved in the coagulation pathway (e.g. kininogen1) and have adhesive (e.g. fibronectin), rheological (e.g. fibrinogen) and immunological/inflammatory properties (e.g. complement components). Quantification with western blot analyses demonstrated a significant depletion (P < 0.01) of these proteins comparing serum samples before and after the column with a systemic lowering in patients' serum. These data reveal strong interaction between column and serum proteins during LDL-A. The clearance of proteins with adhesive, rheological, and inflammatory characteristics may have beneficial effects on microcirculation and reduce chronic inflammation but may also concomitantly induce side effects such as an increased bleeding risk.

The long-term therapy of familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation

The long-term tolerance to and effectiveness of heparin-induced extracorporeal LDL precipitation (HELP) in combination with lipid reducing drugs and diet was tested in six patient (5 males, 1 female; mean age 48 +/- 4 years). Follow-up period was over 50 months, in one patient over 24 months, while one man had a sudden cardiac death 57 weeks after starting treatment. The study was divided into three phases. In phase I (24 months) treatment consisted of HELP and conventional lipid-reducing drugs; in phase II (12 months) of lovastatin (80 mg daily) and cholestyramine (12-24 g daily); and phase III (14 months) of HELP, lovastatin and cholestyramine. In phase I it was possible to lower the pre-treatment level of LDL-cholesterol from 306 +/- 18 mg/dl to 173 +/- 13 mg/dl (43.5%). A similar effect (from 307 +/- 21 mg/dl to 155 +/- 17 mg/dl [-49.5%]) was obtained in phase II. The resumption of HELP reduced the pre-treatment LDL concentration to 136 +/- 9 mg/dl (-55.7%). The various treatment regimens were well tolerated. Biochemical data remained unchanged except for iron loss requiring substitution. Thus combined HELP, lovastatin and ion exchange offer for the first time an effective and reliable means in familial hypercholesterolaemia of clearly reducing long-term the mean LDL cholesterol level below the atherosclerosis threshold of 120 mg/dl.

Improved Coronary Vasodilatatory Capacity by H.E.L.P. Apheresis: Comparing Initial and Chronic Treatment

Hypercholesterolemia impairs endothelial function and subsequently decreases coronary vasodilatatory capacity. We examined the quantitative effects of one single LDL apheresis on vasodilatatory capacity. Using N-13 ammonia as a tracer for dynamic quantitative positron emission tomography (PET), mean myocardial perfusion measurements were carried out before and 20 h later after LDL apheresis, both under resting conditions and after pharmacological vasodilatation with dipyridamole. LDL apheresis was carried out using the heparin induced extracorporeal LDL precipitation (H.E.L.P.) procedure. We examined 47 patients (12 women and 35 men), with angiographically-proven coronary artery disease. All of them suffered from hypercholesterolemia. Of the patients, 35 received a chronic weekly H.E.L.P. procedure (group A), while H.E.L.P. procedure treatment was started for the first time in 12 patients, who were subsequently enrolled in a chronic apheresis program (group B). H.E.L.P. apheresis was combined with cholesterol lowering drugs in all patients. Both groups underwent positron emission tomography twice (prior to LDL apheresis and 20 h later). In group A, LDL cholesterol levels decreased from 175 +/- 50 mg/dL to 60 +/- 21 mg/dL immediately after H.E.L.P. (77 +/- 25 mg/dL before the second PET). Corresponding values for fibrinogen levels were 287 +/- 75 mg/dL to 102 +/- 29 mg/dL (155 +/- 52 mg/dL), minimal coronary resistance dropped from 0.56 +/- 0.20 to 0.44 +/- 0.17 mm Hg x 100 g x min/mL (P < 0.0001). Plasma viscosity decreased by 7.8%. In group B, LDL cholesterol decreased from 187 +/- 45 mg/dL to 75 +/- 27 mg/dL (85 +/- 29 mg/dL) and fibrinogen from 348 +/- 65 mg/dL to 126 +/- 38 mg/dL (168 +/- 45 mg/dL). Minimal coronary resistance was reduced from 0.61 +/- 0.23 to 0.53 +/- 0.19 mm Hg x 100 g x min/mL (P < 0.01). Plasma viscosity was observed to decrease by 7.6%. The strong LDL drop in patients under chronic H.E.L.P. treatment has a significant impact on coronary vasodilatatory capacity within 20 h leading to an improved overall cardiac perfusion. Nearly the same effect can be seen in patients after their first H.E.L.P. treatment.

Overview on LDL‐apheresis in cardiovascular diseases

LDL apheresis has been widely accepted as an effective treatment for hypercholesterolemic patients who are resistant to drug and conventional therapy such as in case of familial hypercholesterolemia (FH). There are various techniques for performing LDL apheresis including heparin‐induced extracorporeal LDL precipitation (HELP), specific immunoadsorption, double membrane filtration, dextran sulphate adsorption (Liposorber), and direct adsorption of lipoproteins (DALI, Liposorber D). All these techniques remove atherogenic substances such as LDL and Lp(a) at a high rate, however, the degree of HDL removal is low. Homozygous FH is regarded as an absolute indication of LDL apheresis, and the administration of repeat LDL apheresis has been shown to allow long‐term survival by preventing cardiac events and retarding the progression of aortic stenosis. In heterozygous FH, angiographic trials revealed that the combination of LDL apheresis and drug therapy delayed the progression and induced a regression of coronary atherosclerosis (LARS, HELP Study, and L – CAPS). The clinical effects of LDL apheresis such as improvements in endothelial dysfunction, the coronary flow reserve, hemorheological factors together with decreases in oxidized LDL, hsCRP, and adhesion molecule have been reported. Furthermore, LDL apheresis increases HGF which has an angiogenic effect. The clinical efficacy produced by LDL apheresis is therefore able to prevent cardiovascular events. A Hokuriku study evaluated 130 Hetero FH patients and divided them into 2 groups; namely, the LDL apheresis treated patients and those receiving drug therapy. The study followed up these patients for 6 years. The findings showed LDL apheresis to reduce the number of cardiovascular events by (72%) in the LDL apheresis group. The regression of coronary plaque has also been reported (LACMART) using intracoronary ultrasound. Recent developments in non invasive vascular imaging technology, such as multi detector‐row CT, now enable us to evaluate the clinical effects of LDL apheresis in patients with cardiovascular disease. Recently, due to the advent of potent statins, the clinical use of LDL apheresis is liable to decrease. On the other hand, the clinical use of apheresis (rheopheresis) for peripheral artery occlusive disease is increasing. Beside these diseases, effectiveness of LDL apheresis for carotid atherosclerosis, cholesterol embolic disease, the prevention of restenosis in post PCI cases, post transplant donor vessel disease, cerebrovascular disorders, and nephrotic syndrome have also recognized. The efficacy of LDL apheresis for cardiovascular diseases is remarkable and therefore to promote the application of LDL apheresis as a treatment of intractable cardiovascular diseases, we need to reduce the present high cost of the treatment and more clearly elucidate its clinical effectiveness.

Does LDL contribute to Viscosity?

There is a large body of evidence that large plasma proteins such as fibrinogen, IgM and alpha2‐macroglobulin contribute to plasma viscosity. Although familial hypercholesterolemia (FH) is often associated with hyperfibrinogenemia, elevated viscosity in FH patients independent from fibrinogen plasma levels was communicated in the literature. Selective LDL‐apheresis such as Apo‐B‐100 immunoadsorption, dextran sulfate adsorption and heparin‐induced extracorporeal LDL‐precipitation (HELP) are effective tools for investigating the effect of selective elimination of LDL and/or fibrinogen on viscosity. The decrease in viscosity during selective LDL‐apheresis was correlated to the differences in LDL and/or fibrinogen concentrations. Regression analysis of data obtained from 12 FH patients shows a strong correlation between LDL‐cholesterol and viscosity (r = 0.6892; P &lt; 0.001). Fibrinogen is also correlated with viscosity (r = 0.5433; P &lt; 0.001). The slope of LDL/viscosity regression shows a 5‐fold difference (0.00097 vs. 0.00018) for LDL and fibrinogen, respectively, thus demonstrating a strong contribution LDL‐cholesterol on viscosity.

Contact Activation in Low‐density Lipoprotein Apheresis Systems

Anaphylactoid reactions due to contact activation have been observed in patients on ACE inhibitor therapy and hemodialysis with negatively charged dialysis membranes. Negatively charged surfaces are functional constituents of different LDL apheresis systems. Therefore, contact activation was investigated during LDL apheresis with three different systems: (i) heparin-induced extracorporeal LDL precipitation (HELP); (ii) dextran sulfate cellulose (DSC) columns; and (iii) modified polyacrylate gels (DALI) in a clinical setting. 24 prevalent patients on regular LDL apheresis treatment were included in the study. Bradykinin, prekallikrein, and HMW kininogen were measured during a single LDL apheresis at different sites of the systems. LDL apheresis with DSC and DALI was associated with an extreme release of bradykinin after the passage of plasma or blood through the LDL adsorbers as well as with a decrease of prekallikrein and HMW kininogen during the course of the treatment. Bradykinin release exceeded the degradation capacity of the kininase II, since markedly elevated bradykinin concentrations were observed in the arterial line of the extracorporeal circuits of both systems. This was not associated with anaphylactoid reactions. In contrast to the treatments with DSC and DALI, the HELP system did not lead to any activation of the kallikrein-kinin system. From our data we conclude that angiotensin converting enzyme (ACE) inhibitors are contraindicated in patients on LDL apheresis with the DSC and the DALI system. Because the HELP system does not activate the kallikrein-kinin system, patients who need ACE inhibitors are predisposed for this LDL apheresis procedure.

Recent advances in therapeutic apheresis.

Recent advances in therapeutic apheresis include technical improvements, new indications, and pathophysiological insights. A new device that adsorbs endotoxins onto immobilized human albumin from human whole blood was recently developed. In a prospective randomized controlled trial (endotoxin adsorber study EASY), apheresis-treated patients had more improved APACHE II scores than controls. In a prospective randomized trial, the Prosorba column containing immobilized staphylococcal protein A was tested against sham apheresis in patients with end-stage rheumatoid arthritis. A significant improvement occurred in 42% of the treated patients vs. 16% of the controls. Sudden hearing loss was treated in a prospective randomized trial by a single heparin-induced extracorporeal LDL precipitation (HELP) treatment in comparison with conservative therapy. In patients with elevated fibrinogen and/or low-density lipoprotein (LDL) cholesterol levels, HELP was significantly superior to 10 days of intravenous conventional treatment. Promising results were achieved in prospective randomized trials applying immunoadsorption in end-stage dilated cardiomyopathy and rheopheresis in age-related macular degeneration. In a noncontrolled trial, C4d-positive acute humoral rejection after kidney transplantation could be effectively treated by immunoadsorption. Finally, HELP apheresis was simplified by using new hardware (HELP-Futura). Direct adsorption of lipids (DALI)-LDL-apheresis was improved by testing DALI 1250 adsorbers with improved capacity. High-blood-flow DALI was shown to be safe and effective, with the advantage of reduced treatment time. Last but not least, a modification of dextran-sulfate cellulose LDL apheresis was developed for direct LDL hemoperfusion.