Direct Adsorption Of Lipoproteins Research Articles

#805 Successful application of DALI for extracorporeal hemocorrection in a patient with LDL cholesterol serum levels (case study)

Abstract Background and Aims Plasma lipoidosis type 4 (PLD4) is a rare hereditary disease characterized by disorders of fat metabolism in the body. PLD4 occurs rare in the general population. The exact frequency of occurrence is unknown, as it depends on hereditary factors in a particular population. The relevance of the disease lies in its rarity and potential association with various complications. Patients with PLD4 have decreased levels of low-density cholesterol (LDL) and increased levels of triglycerides in the blood, which can lead to the development of atherosclerosis and other cardiovascular diseases. Plasma lipoidosis type 4 requires further researches for better understanding of its epidemiology, mechanisms of development and possible treatment strategies. In this case, we describe the case of a patient with type 4 plasmatic lipoidosis who was treated with the DALI (Direct Adsorption of Lipoproteins) technique. Anticoagulation is initiated with heparin and maintained by ACT. This technique is accompanied by decreasing the level of LDL and Lp (a) without decreasing the level of HDL and fibrinogen. The pore sizes of the polyacrylamide bed are small enough to avoid the removal of red blood cells and platelets. Activation of leukocytes and complement is minimal and clinically insignificant. Depending on the initial level of lipidemia during this procedure, it is possible to select the appropriate adsorber (DALI-500, -750, -1000). Methods of extracorporeal correction of lipid metabolism disorders should be widely introduced into healthcare practice. It should be noted that during DALI apheresis, the fibrinogen level does not decrease so sharply and is not accompanied by changes in erythrocyte aggregation. (Richter W. O., 2003). Aim of study The purpose of our study was to evaluate the effectiveness of using DALI (Direct Adsorption of Lipoproteins) in a patient with type 4 plasmatic lipoidosis. Method Patient N., 67 years old, diagnosed with IHD. Angina pectoris FC 2. Plasma lipoidosis type 4, hyperbetalipoproteinemia by autosomal dominant type of inheritance. Cysts of both kidneys. In 1997, diagnosed with: plasma lipoidosis type 4, hyperbetalipoproteinemia by an autosomal dominant type of inheritance. The plasmapheresis sessions were recommended against the increased lipid metabolism indexes. The patient regularly receives antilipidemic therapy and plasmapheresis sessions up to 2 times a year. The patient is admitted with complaints of fatigue and general weakness. According to the patient's ambulatory card, discharge summaries: CREA - 147 µmol/l, UREA – 6.3 mmol/l. GFR – 34 ml/min/1.73 m2. Total bilirubin - 9 µmol/l, direct bilirubin - 3 µmol/l. Considering the severity of the condition and the activity of the main diagnosis, a procedure with the DALI technique was started. During the hospitalization period, 3 procedures were performed, the whole of them were tolerated satisfactorily. The general condition is of moderate severity. Consciousness is clear. Hemodynamics is stable. Urination is free and painless. Diuresis is adequate. Results Hemodynamics: when connected - blood pressure – 120/82 mm Hg, heart rate – 61 beats/min. When disconnected, the patient's condition is the same, hemodynamics - blood pressure – 119/59 mm Hg, heart rate – 65 beats / min. Conclusion The usage of the apheresis method with the DALI system can effectively reduce the level of low-density lipoprotein (LDL) and Lp (a), while maintaining the content of high-density lipoprotein (HDL) and fibrinogen at a constant level. This reduction in LDL concentrations has the potential to reduce patients' risk of developing cardiovascular disease and the mortality from it.

Lipoprotein apheresis efficacy and challenges: single center experience

IntroductionLipoprotein apheresis (LA) is an extracorporeal therapy which removes apolipoprotein B-containing particles from the circulation. We evaluated techniques and efficiency of lipoprotein apheresis procedures applied to patients with familial and non-familial hypercholesterolemia (FH) at our center. MethodsWe retrospectively evaluated 250 LA procedures applied to 27 patients with dyslipidemia between March 2011 and August 2019. ResultsA total of 27 patients, of whom 19 (70.4%) were male and 8 (29.6%), female, were included. Eighteen (66.7%), 6 (22.2%) and 3 (11.1%) patients were diagnosed with non-FH, homozygous FH (HoFH) and heterozygous FH (HeFH), respectively. Two different apheresis techniques, direct adsorption of lipoproteins (DALI) (48.8%) and double filtration plasmapheresis (DFPP) (51.2%), were used. The change in the serum total cholesterol (TC) level was the median 302 mg/dl (171–604 mg/dl) (60.4%) in HoFH patients, 305 mg/dl (194–393 mg/dl) (60.8%) in HeFH patients and 227 mg/dl (75–749 mg/dl) (65.3%) in non-FH patients. The change in the serum low-density lipoprotein (LDL) level was the median 275 mg/dl (109–519 mg/dl) (64.2%), 232 mg/dl (207–291 mg/dl) (64.5%) and 325 mg/dl (22–735 mg/dl) (70.9%) in patients with HoFH, HeFH and non-FH, respectively. A significantly effective reduction in serum lipid levels, including TC, LDL and triglycerides, was achieved in all patients, regardless of the technique, p < .001. The decrease in the serum TC and LDL levels was significantly higher in the DFPP, compared to the DALI, being 220 mg/dl (−300 to 771) vs 184 mg/dl (64–415), p < .001 and 196 mg/dl (11–712) vs 157 mg/dl (54–340), p < .001, respectively. ConclusionsOur results showed that LA is a highly effective treatment in reducing serum lipid levels and safe, without any major adverse event.

Long-term lipoprotein apheresis in the treatment of severe familial hypercholesterolemia refractory to high intensity statin therapy: Three year experience at a lipoprotein apheresis centre.

Severe familial hypercholesterolemia (FH) individuals, refractory to conventional lipidlowering medications are at exceptionally high risk of cardiovascular events. The established therapeutic option of last choice is lipoprotein apheresis (LA). Herein, it was sought to investigate the clinical usefulness of LA in a highly selected group of severe heterozygous FH (HeFH), as recently described by the International Atherosclerosis Society (IAS), for their efficacy in lipid reduction and safety. Efficacy and safety of LA were investigated in 318 sessions of 7 severe HeFH females with cardiovascular disease, over a mean period of 26.9 ± 6.5 months. Relative reduction of low density lipoprotein cholesterol (LDL-C) ≥ 60%, clinical complications and vascular access problems were evaluated and compared between the direct adsorption of lipoproteins (DALI) and lipoprotein filtration (Membrane Filtration Optimized Novel Extracorporeal Treatment [MONET]). Additionally, lipoprotein (a) [Lp(a)], total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fibrinogen concentrations were investigated. The relative reduction of LDL-C, TC, TG and Lp(a) were 69.4 ± 12.9%, 59.7 ± 9.1, 51.5 ± ± 14.2% and 71.3 ± 14.4%, respectively. A similar efficacy was found in both systems in LDL-C removal. DALI system led to larger depletions of Lp(a) (80.0 [76-83]% vs. 73.0 [64.7-78.8]%; p < 0.001). The frequency of clinical side effects and vascular access problems were low (8.5%). Long-term LA in severe HeFH individuals is safe and efficiently reduces LDL-C and Lp(a). Higher efficacy of the DALI system than MONET in Lp(a) removal may indicate the need for individualized application of the LA system in severe HeFH individuals.

Lipoprotein apheresis in the management of severe hypercholesterolemia and hyperlipoproteinemia(a)—The Portuguese experience

BackgroundLow-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) are established causal risk factors for cardiovascular disease (CVD). Lipoprotein apheresis is often required for treatment of patients with a high risk for CVD due to hypercholesterolemia and/or hyperlipoproteinemia(a). AimTo describe our experience with lipoprotein apheresis in patients with severe hypercholesterolemia or with hyperlipoproteinemia(a). MethodsWe retrospectively investigated patients treated with Lipoprotein apheresis using direct adsorption of lipoproteins (DALI) technique, between December 2008 and March 2018, in our center. Adverse events, acute and long term reductions in lipid parameters were analyzed. ResultsBetween December 2008 and March 2018, a total of 950 treatments were performed in five patients, four with heterozygous familial hypercholesterolemia (HeFH), all on maximally tolerated cholesterol-lowering drug therapy and in one patient with hyperlipoproteinemia(a) and progressive CVD.In the four patients with HeFH we obtained mean acute reductions in LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) of 62.0 ± 7.8% and 60.4 ± 6.8%, respectively. Regarding long-term efficacy we achieved a mean reduction of 43.1% in LDL-C and of 41.2% in non-HDL-C. In the patient with hyperlipoproteinemia(a) we attained mean acute reductions of 60.4 ± 6.4% in Lp(a) and of 75.4 ± 7.3% in LDL-C per session and long term reductions in Lp(a) and LDL-C of 67.4% and 40.5%, respectively. Adverse events were recorded in only 1.2% of treatments. ConclusionLipoprotein apheresis is an efficient and safe treatment in severely hypercholesterolemic patients who are refractory to conservative lipid-lowering therapy or with hyperlipoproteinemia(a) and progressive CVD.

Safety aspects of lipidapheresis using DALI and MONET – Multicenter observational study

BackgroundLipidapheresis was introduced for intractable hyperlipidemia as a more selective therapy than plasma exchange aiming to enhance efficacy and limit side-effects. Although this therapy is regarded safe, multicenter data from routine application are limited. We investigated direct adsorption of lipoproteins (DALI) and lipofiltration (MONET) regarding the short and the long-term safety aspects. MethodsThis multicenter observational study prospectively evaluated 2154 DALI and 1297 MONET sessions of 122 patients during a period of 2 years. Safety parameters included clinical side-effects (adverse device effects, ADEs), technical complications, blood pressure and pulse rate. Also routinely performed laboratory parameters were documented. Analysis of laboratory parameters was not corrected for blood dilution. ResultsOverall 0.4% DALI and 0.5% MONET treatments were affected by ADE. Technical complications occurred in 2.1% and in 0.8% DALI and MONET sessions, respectively. The most frequent ADE was hypotension, and the majority of technical problems were related to vascular access. Both types of treatments led to a drop of thrombocytes in the range of 7–8%. Hematocrit and erythrocytes decreased only during the DALI treatments by about 6%. Leucocytes decreased during the DALI therapy (∼15%), whereas they increased during the MONET application (∼11%). MONET treatment was associated with a higher reduction of proteins (fibrinogen: 58% vs. 23%, albumin: 12% vs. 7%, CRP: 33% vs. 19% for MONET and DALI, respectively). Apart from severe thrombocytopenia in two DALI patients, changes of other parameters were typically transient. ConclusionsUnder routine use the frequency of side-effects was low. Still, monitoring of blood count and proteins in chronic apheresis patients is recommended.

Efficacy of lipid reduction with DALI and MONET

BackgroundLipidapheresis techniques are increasingly used to treat drug-resistant hyperlipidemia but few efficacy studies under routine application are available. In this multicenter observational study we investigated direct adsorption of lipoproteins (DALI) and lipoprotein filtration (MONET) for the short and the long-term effects on lipid-lowering effects. MethodsData of 122 apheresis patients from 11 centers (DALI: n = 78, MONET: n = 44) were prospectively collected for a period of 2 years. Routine lipid measurements were evaluated (2154 DALI and 1297 MONET sessions). It was investigated whether the relative reduction of LDL-C during apheresis session achieves at least 60%. Also relative reduction of total cholesterol, HDL, triglyceride, and Lp(a) were analyzed. ResultsThe relative reduction of LDL-C was at least 60%: DALI: 70.62%, 95% CI = [69.34; 71.90] and MONET: 64.12%, 95% CI = [60.79; 67.46]. Also triglycerides were reduced with both systems: DALI 38.63%, 95% CI = [33.95; 43.30] vs. MONET 57.68%, 95% CI = [51.91; 63.45]. Relative reductions of total cholesterol were in the range of 50% (DALI 95% CI = [46.49; 49.65] MONET 95% CI = [48.93; 55.26]) and of Lp(a) in the range of 65% (DALI 95% CI = [61.92; 65.83] MONET 95% CI = [63.71; 70.30]. HDL reduction was: DALI 15.01%, 95% CI = [13.22; 16.79] and MONET 22.59%, 95% CI = [19.33; 25.84]. For both devices treated patient plasma/blood volume and in case of DALI the use of the larger adsorber configurations (DALI 1000 and DALI 1250) were independent positive predictors of the relative reduction of LDL-C and of Lp(a). ConclusionsBoth systems effectively improved lipid profile and reduced atherogenic lipids. The results point to the importance of the individualized application of these valuable therapies to achieve clinical targets.

Pleiotropic effects of regular lipoprotein-apheresis

BackgroundLipoprotein(LP)-apheresis is the treatment of choice in patients suffering from severe familial hypercholesterolemia. A wide range of mechanisms has been claimed to be responsible for the known clinical benefit. MethodsPatients suffering from heterozygous familial hypercholesterolemia undergoing LP-apheresis either with direct adsorption of lipoproteins (DALI) or dextran sulfate (DS) were examined. A total volume of 10 l blood was exchanged. Non-lipid effects, mainly concerning endothelial function (circulating endothelial cells, circulating endothelial progenitor cells, flow-mediated vasodilation, microalbuminuria) as well as left ventricular ejection fraction and homocysteine were assessed. ResultsA single LP-apheresis session improves paradox contractile response in statin intolerant patients, but not in those on regular statin therapy. In contrast, over a 6-months follow-up after treatment initiation, all the examined parameters (circulating endothelial cells, circulating endothelial progenitor cells, flow mediated vasodilatation, homocysteine, microalbuminuria and left ventricular ejection fraction) improved. When available, a comparison between DS vs. DALI was performed. In none of the subgroups a significant difference was noted. DiscussionThese findings indicate that beyond the well known lipid/lipoprotein lowering action the broad spectrum of functional tests examined reflecting mainly endothelial function is significantly improved by LP-apheresis treatment on the long-term and seems to be a key underlying reason for the clinical improvement seen in these patients.

Impact of selective LDL apheresis on serum chemerin levels in patients with hypercholesterolemia.

BackgroundSelective 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.MethodsIn 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).ResultsThe 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.ConclusionWe conclude that LDL apheresis decreases the circulating level of chemerin by binding the protein to the column and thus improves lipoprotein subfraction pattern.

Successful Direct Adsorption of Lipoproteins (DALI) Apheresis During Pregnancy in an Omani Woman with Homozygous Familial Hypercholesterolemia.

We report our experience with Direct Adsorption of Lipoproteins (DALI) apheresis in an Omani pregnant woman affected by homozygous familial hypercholesterolemia. To the best of our knowledge this is the first successful pregnancy treated with DALI apheresis. The patient had a history of coronary artery disease, supra-aortic valvular stenosis and severe carotid artery disease with right carotid artery stenting. She was on a regular biweekly DALI apheresis since 2008. In May 2013, she became pregnant and rosuvastatin and ezetimibe were stopped while she continued on DALI apheresis biweekly. This treatment during pregnancy was successful with no major complications. The average low-density lipoprotein cholesterol reduction during therapy was 50%. She spontaneously delivered a healthy male infant (2,400 g) at 37 weeks. We showed that DALI apheresis therapy was safe during pregnancy with a good outcome for both mother and neonate.

LDL apheresis in the treatment of familial hypercholesterolemia: Experience of Hospital Santo António, Porto

IntroductionHigh plasma levels of low-density lipoprotein (LDL) cholesterol are a risk factor for the development of premature atherosclerosis. Direct adsorption of lipoproteins (DALI) is an apheresis technique by which LDL cholesterol is selectively removed from whole blood. ObjectiveThe present study describes our experience with DALI LDL apheresis in severely hypercholesterolemic patients. MethodsThree hypercholesterolemic patients suffering from atherosclerotic complications were treated fortnightly by DALI apheresis, in a total of 308 sessions between December 2008 and January 2013. All patients were on the highest tolerated dose of statins and other lipid-lowering drugs. ResultsThe sessions were essentially uneventful, adverse events being recorded in only 3.6% of them. A mean 63.3% acute reduction in LDL cholesterol was obtained. ConclusionsDALI apheresis proved to be a simple, safe and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid-lowering therapy.

Effects of lipoprotein apheresis (la) on serum pcsk9 levels

Objectives: PCSK9 plays an important role in the regulation of LDLcholesterol concentrations via its influence on catabolism of the LDL receptors. It is known that PCSK9 levels are higher in patients with familial hypercholesterolemia than in normolipidemic controls. We wanted to estimate PCSK9 levels in patients currently undergoing apheresis or eligible to be treated by LA and look into the acute effects of LA on PCSK9 concentrations. Methods: We measured total serum PCSK9 levels (using an ELISA-method) in 2 cohorts: Cohort I consisted of patients actively undergoing lipoprotein apheresis as part of their routine care (n 40; 21 males, 19 females; age 55.6 years (range 32-73 years)). Blood was drawn before and immediately after 3 apheresis sessions (paying attention to standardized conditions). The following LA methods were used: Dextran Sulfate cellulose Adsorption (DSA), Heparin Extracorporeal LDL Precipitation (HELP) system, Double filtration plasmapheresis (DFPP), Direct Adsorption of Lipoproteins (DALI), and “other” systems. Cohort II consisted of patients who were eligible for lipoprotein apheresis but not undergoing the procedure (n 10; 3 males, 7 females; age 61.1 years (range 50-78 years)). Results: Mean PCSK9 pre-apheresis levels were 253.70 ng/mL in Cohort I, were decreased by approximately 50 % by LA, but returned to the preapheresis levels on the second dayafter the apheresis. It appeared that when compared with the DSA method HELP showed a more pronounced decline in PCSK9 concentrations, whereas DALI was associated with a less pronounced reduction than DSA. In Cohort II mean PCSK9 levels were 287.00 ng/mL. Conclusion: LA treatment reduced PCSK9 by approximately 50%, with the extent of reduction being dependent upon the type of apheresis method used. The PCSK9 concentrations were slightly higher in subjects eligible for, but not undergoing, apheresis compared to patients that were actively undergoing apheresis.

Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia

We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(∼10 mg/dl; range 10-11 mg/dl), intermediate (∼50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins.

Changes in Lipids and Lipoproteins after Selective LDL Apheresis (7-Year Experience).

Background. The aim of the study was to investigate the changes in plasma lipids and lipoproteins and the cardiovascular events after selective LDL apheresis. Methods and Results. Two pediatric patients with familial hypercholesterolemia aged 11 and 13 years and 19 dyslipidemic adults aged 41 ± 14 years underwent direct adsorption of lipoproteins (DALI) sessions. The mean follow-up period was 47 ± 23 months. The total cholesterol (TC) values before and after treatment were 8.2 ± 2.2 and 3.1 ± 1.6 mmol/l (318 ± 86 and 122 ± 62 mg/dL), respectively. The interval mean of TC was 6.9 ± 1.9 mmol/l (268 ± 75 mg/dL). The LDL cholesterol concentrations before and after treatment were 6.6 ± 2.1 and 1.7 ± 1.1 mmol/l, (256 ± 82 mg/dL and 65 ± 41 mg/dL), respectively. The percentage of acute LDL cholesterol reduction was 75 ± 11%. Cardiovascular events were observed in seven patients. The average annual event rate was 5.51%. Conclusion. LDL apheresis is a very important therapeutic tool in managing patients at high risk for premature CAD or with aggressive CAD, despite adequate medical treatment.

Low‐Density Lipoprotein Apheresis Decreases Ferritin, Transferrin and Vitamin B12, Which May Cause Anemia in Serially Treated Patients

Clinical observations revealed an increased prevalence of iron deficiency anemia without chronic bleeding in patients treated with serial low-density lipoprotein (LDL) apheresis. Since several different proteins are adsorbed by LDL apheresis beside pro-atherogenic lipoproteins, we examined the modification of the full blood count, plasma iron, vitamin B12, folic acid, and hemolysis by LDL apheresis. Nineteen patients (55 (50-59) years, 4 female, 15 male) undergoing chronic LDL apheresis due to mixed dyslipidemia (N = 17), homozygous familiar hypercholesterolemia (N = 1) or isolated elevated lipoprotein(a) (N = 1) were included in this study. They were treated with direct adsorption of lipoproteins (DALI; N = 6), heparin-induced LDL-precipitation (HELP; N = 7) or double filtration plasmapheresis (DFPP; N = 6). The patients' full blood count, iron metabolism (plasma iron, ferritin, transferrin, transferrin saturation), vitamins involved in erythropoiesis (vitamin B12 and folic acid), and markers of hemolysis (haptoglobin and free hemoglobin) were analyzed directly before and after LDL apheresis. A single LDL apheresis session significantly decreased the levels (reduction in the median [25(th)-75(th) percentiles] of: ferritin 9.8 [1.3-18] %; P = 0.004), transferrin (12.1 [10.0-15.96] %; P = 0.0005), and vitamin B12 (17.8 [16.2-20.8] %; P = 0.0005). Thereby, transferrin and vitamin B12 were decreased in all (N = 19) and ferritin in 74% (N = 14) of the patients. Twelve out of 19 patients (63.2%) had mild anemia despite iron administration in 14 out of 19 patients (73.7%). LDL apheresis had no significant influence on full blood count, plasma iron, transferrin saturation, folic acid, or hemolysis. Similar changes were observed in all LDL apheresis methods used. LDL apheresis significantly decreases ferritin, transferrin, and vitamin B12, suggesting an influence of serial LDL apheresis on erythropoiesis.

Retrospective Analysis of Long‐term Lipid Apheresis at a Single Center

We retrospectively analyzed 10 906 lipid apheresis sessions (heparin-induced lipoprotein precipitation, direct adsorption of lipoproteins, double filtration plasmapheresis, dextran sulfate adsorption, and immunoadsorption) in 38 patients who were consecutively treated in our department during the last 20 years. The incidences of major cardiovascular events (MACE) (death, cerebrovascular accident, myocardial infarction, limb amputation, and renal vascular involvement) were taken separately as primary end-points or as a combined end-point. The time-course of secondary end-points (coronary and extracranial status of arteries, left ventricular function, occlusive artery disease, and calculated glomerular filtration rate [cGFR]) were also evaluated, as well as the extent of the reduction in plasma lipids and lipoproteins and the incidence of therapy associated side-effects. MACE decreased from 7.02% events per patient per year at the start of lipid apheresis to 1.17% during lipid apheresis and the rate of myocardial revascularization decreased from 22.8% to 3.8% per patient per year. Classical (diabetes mellitus, arterial hypertension, and smoking history), as well as novel risk factors (cGFR < 60 mL/min, statin withdrawal, mixed hyperlipoproteinemia, and elevated lipoprotein (a)) were associated with an elevated risk for MACE. All applied methods had comparable effects. All lipid apheresis methods proved to be safe and suitable for long-term treatment. The present data demonstrate that treatment with lipid apheresis is very effective and leads to long-term reduction in cardiovascular mortality and morbidity.

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.

Low‐density Lipoprotein Apheresis in Children With Familial Hypercholesterolemia: Follow‐up to 21 Years

Twenty-seven patients (14 girls, 13 boys) affected by familial hypercholesterolemia who had begun low-density lipoprotein (LDL) apheresis treatment before the age of 15 were studied. The median age at diagnosis was 4 years and the blood LDL cholesterol level was 704 +/- 163 mg/dL. Screening was performed for homozygous or double heterozygous mutations of the LDL cholesterol receptor gene and mutations were found in 24 of the patients. The mean age at the beginning of treatment was 8.5 years and the mean length of follow up was 12.6 years. The two main procedures used were direct adsorption of lipoproteins and dextran sulfate cellulose adsorption. Nine patients experienced anaphylactic reactions due to bradykinin and six had to have their treatment changed. The LDL cholesterol level before the session was lowered by 45 +/- 11% of the value at diagnosis. The LDL cholesterol reduction in a session was 72 +/- 10%. Tendinous xanthomas disappeared or diminished dramatically in 62% of the children. In 22 patients no cardiovascular event occurred during LDL apheresis treatment. Three had angina pectoris; two others had surgical management of aortic stenosis, but no clinical manifestations. Seven children had normal cardiovascular pictures while on treatment. Eleven had abnormalities of the aortic root or coronary arteries, which in six cases had appeared before treatment; the other five children did not undergo prior cardiac evaluation. In five children the abnormalities appeared during treatment. Based on these data, LDL-apheresis can be recommended for the treatment of homozygous familial hypercholesterolemia, even in young children, with good efficiency on biological parameters, cutaneous lesions and cardiovascular events.

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.

Direct Adsorption of Low‐Density Lipoprotein by DALI‐LDL‐Apheresis: Results of a Prospective Long‐term Multicenter Follow‐up Covering 12 291 Sessions

Direct adsorption of lipoproteins (DALI) is the first low density lipoprotein (LDL)-apheresis technology by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present follow-up was carried out to evaluate the clinical efficacy, selectivity and safety of long-term DALI apheresis. The follow-up was carried out in an open, prospective uncontrolled multicenter clinical design. Included were 158 drug-resistant hypercholesterolemic patients from 28 apheresis centers. These patients underwent 12 291 DALI sessions between January 1997 and March 2002. The patients suffered from severe atherosclerosis and their mean LDL-C was 188 mg/dL before the sessions. Mean follow-up was 25 +/- 16 (range 1-56) months during which 78 +/- 53 sessions were carried out. In most treatments, DALI 750 (63%) or DALI 1000 (30%) adsorbers were used. On average, 7423 +/- 1495 mL blood was processed at a flow rate of 84 +/- 16 mL/min in 102 +/- 25 min. Acute reductions by the single DALI sessions averaged 69 +/- 12% for LDL-C, 41 +/- 18% for TG, 15 +/- 10% for HDL-C, 19 +/- 11% for fibrinogen and 62 +/- 24% for Lp(a) (in patients with Lp(a) > 30 mg/dL). Adverse events were recorded in only 3.9% of the sessions. In this 5-year follow-up, long-term therapy with DALI was safe, effective and selective as LDL-C and Lp(a) could be reduced by >60% per session in approximately 100 min treatment time while HDL-C decrease and the incidence of AE were low.