Influence of atorvastatin versus simvastatin on fibrinogen and other hemorheological parameters in patients with severe hypercholesterolemia treated with regular low-density lipoprotein immunoadsorption apheresis.

Low-density lipoprotein (LDL) apheresis is a treatment option in patients with coronary artery disease and elevated LDL cholesterol concentrations if maximal drug therapy fails to achieve adequate LDL cholesterol reduction. This therapy is more effective when combined with strong lipid-lowering drugs, such as atorvastatin. However, conflicting data have been published concerning the effect of atorvastatin on fibrinogen concentration. Therefore, we investigated the effect of atorvastatin compared to simvastatin on fibrinogen concentration and other hemorheological parameters in patients treated by weekly LDL apheresis. Hemorheological parameters were, studied twice in 9 patients (4 female, 5 male, 54.0+/-8.9 years) with coronary artery disease treated by weekly LDL immunoadsorption, once during concomitant simvastatin therapy (40 mg daily) and once during atorvastatin therapy (40 mg daily). Fibrinogen concentration, plasma and blood viscosity at different shear rates, parameters of red cell aggregation at stasis and shear rate 3/s, and erythrocyte filterability were determined 7 days after the last LDL apheresis after each drug had been given for a minimum for 8 weeks. Fibrinogen concentration did not show any statistically significant difference during therapy with atorvastatin (3.09+/-0.36 g/L) compared to simvastatin (3.13+/-0.77 g/L). Plasma and blood viscosity as well as erythrocyte filterability were also unchanged. The increase in red cell aggregation at stasis during atorvastatin treatment (5.82+/-1.00 U versus 4.89+/-0.48 U during simvastatin; p < 0.05) was inversely correlated with a lower high-density liprotein (HDL) cholesterol concentration (1.17+/-0.21 mmol/L versus 1.31+/-0.30 mmol/L during simvastatin; p < 0.05). LDL cholesterol showed a strong trend to lower concentrations during atorvastatin (4.14+/-0.61 mmol/L versus 4.56+/-0.66 mmol/L during simvastatin; p = 0.07), despite a reduced plasma volume treated (3,547+/-1,239 ml during atorvastatin versus 3,888+/-1,206 mL during simvastatin; p < 0.05). In conclusion, fibrinogen concentration and other hemorheological parameters were unchanged during atorvastatin compared to simvastatin therapy with the exception of a higher red cell aggregation at stasis. Therefore, with respect to hemorheology, we conclude that atorvastatin should not be withheld from hypercholesterolemic patients regularly treated with LDL immunoadsorption.     

Improvement of hemorheology by DALI apheresis: acute effects on plasma viscosity and erythrocyte aggregation in hypercholesterolemic patients.

Plasma viscosity (PV) and erythrocyte aggregation (EA) are determinants of microcirculation, especially under the compromised hemodynamic conditions resulting from atherosclerosis. Direct adsorption of lipoproteins (DALI) apheresis is the first method for direct adsorption of lipoproteins; it drastically reduces low-density lipoprotein (LDL)-cholesterol and lipoprotein (a) (Lp[a]), and may therefore improve PV and EA. The current study was performed to test the effect of DALI on hemorheology. Six hypercholesterolemic patients who had been on regular LDL apheresis for at least several months were treated on a weekly or biweekly basis, on average 5 times each by DALI. Before and after each session, PV was measured by a capillary tube plasma viscosimeter and EA by rotational aggregometry. Single DALI sessions (n = 31) acutely decreased PV from 1.18 +/- 0.04 to 1.06 +/- 0.3 mPa (-10%) while EA improved from 22.8 +/- 4.4 to 13.3 +/- 4.5 (arbitrary units) (-42%). LDL-cholesterol, Lp(a), and very-low-density lipoprotein (VLDL)-cholesterol were effectively reduced while the decrease of triglycerides and fibrinogen was only moderate. DALI apheresis exerted an acute positive effect on blood hemorheology which may have beneficial effects on microcirculation. This hypothesis is in accordance with the clinical observation that in some patients, improvement of angina and/or exercise tolerance can be observed after only a few DALI sessions where changes of coronary stenoses cannot be expected yet.     

Direct adsorption of lipoproteins from whole blood by DALI apheresis: technique and effects.

Low-density lipoprotein (LDL) apheresis can drastically reduce atherogenic lipoproteins in coronary patients in whom LDL and lipoprotein (a) (Lp[a]) cannot be sufficiently reduced by conservative therapy. LDL and Lp(a) adsorption by polyacrylate/polyacrylamide (DALI) is the simplest procedure for clinical LDL apheresis to date. DALI was first applied in patients in 1994 and introduced into clinical routine in 1996. It is the first LDL-hemoperfusion system, i.e., it adsorbs LDL and Lp(a) directly from whole blood. This markedly simplifies the extracorporeal circuit, the handling of the system, and reduces significantly staff time and, especially at higher blood flow rates, treatment time. Its features are high selectivity and capacity of lipoprotein removal (maximum about 8 g low-density lipoprotein cholesterol per session). Using citrate anticoagulation, good biocompatibility is evidenced by the lack of cell losses, hemolysis, thrombotic events, and complement activation. Some clotting factors of the intrinsic system are also adsorbed. There is significant bradykinin activation that, however, does not cause problems in most patients if angiotensin converting enzyme inhibitor medication is avoided. In a first long-term study, 93% of sessions were uneventful. Major side effects were citrate-induced paresthesias (1.3%) and hypotension (0.8%). To date, more than 25,000 DALI sessions have been performed all over the world.     

Distinct effects of LDL apheresis by hemoperfusion (DALI) and heparin-induced extracorporeal precipitation (HELP) on leukocyte respiratory burst activity of patients with familial hypercholesterolemia

Hypercholesterolemia and oxidative stress are major risk factors in atherogenesis. In the last years, lipid apheresis has been established as an effective clinical therapy by lowering not only elevated plasma low-density lipoprotein (LDL) levels but also by reducing the incidence of cardiovascular events. The aim of the present study was to investigate peripheral leukocyte oxidant generation in patients with familial hypercholesterolemia (FH) undergoing regular LDL apheresis. The activity state of leukocytes was estimated prior to, immediately after, and 2 days after LDL apheresis carried out by two distinct techniques: hemoperfusion with the DALI system and heparin-induced extracorporeal LDL precipitation (HELP). Oxidant generating activity was measured by chemiluminescence (CL) in whole blood and isolated polymorphonuclear leukocytes (PMNL). The results of our study show increased baseline respiratory burst activities in FH patients as compared to healthy controls. Apheresis with the HELP system was followed by increases in leukocyte count, zymosan-induced whole blood CL, and plasma PMNL elastase levels. The DALI technique caused no changes in leukocyte count and elastase levels and decreased whole blood CL activity. Two days after lipid removal the observed changes returned to pre-apheresis levels. Leukocyte activity parameters before and after apheresis did not correlate with the corresponding plasma levels of triglycerides, total cholesterol, and LDL cholesterol, suggesting that different handling in the framework of both apheresis techniques rather than lipid profile changes during therapy accounted for leukocyte activity modulation.     

Low density lipoprotein hemoperfusion by direct adsorption of lipoproteins from whole blood (DALI apheresis): clinical experience from a single center.

The elimination of low density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) by conventional LDL apheresis techniques can only be achieved in a cell-free medium and thus requires the initial separation of plasma from the blood cells. The present paper describes the first LDL hemoperfusion system which is able to adsorb LDL and Lp(a) directly from whole blood. This simplifies the procedure substantially. The adsorber consists of polyacrylate ligands linked to a modified polyacrylamide matrix. These negatively charged polyacrylate ligands interact with the positively charged apoprotein B moiety of LDL and Lp(a), which results in selective adsorption of these lipoproteins onto the column. Three hypercholesterolemic patients suffering from overt atherosclerotic complications were treated weekly by direct adsorption of lipoproteins (DALI) (n = 20 sessions each). All patients were on the highest tolerated dose of cholesterol synthesis enzyme (CSE) inhibitors. About 1.3 patient blood volumes were treated per session. The anticoagulation was performed with acid citrate dextrose (ACD-A). The following acute reductions were achieved: LDL: 66%; Lp(a): 63%; and triglycerides: 29%. High density lipoprotein (HDL) (-13%) and fibrinogen (-16%) were not substantially reduced. The sessions were essentially uneventful. Due to a low ACD-A infusion rate, no hypocalcemic episodes were registered. One patient on enalapril was treated without complications when this angiotensin converting enzyme (ACE) inhibitor was withdrawn 2 days prior to apheresis. In summary, in our hands, DALI apheresis proved to be a simple, safe, and efficient method of lipid apheresis in hypercholesterolemic patients refractory to conservative lipid lowering therapy.     

Effects of two whole blood systems (DALI and Liposorber D) for LDL apheresis on lipids and cardiovascular risk markers in severe hypercholesterolemia

LDL apheresis is an extracorporal modality to lower the concentration of atherogenic lipoproteins, e.g., LDL cholesterol. We compared two recently introduced whole-blood LDL apheresis systems inpatients with hypercholesterolemia in a randomized cross-over trial with respect to their effects on lipoproteins as well as on other cardiovascular risk markers. Six patients (4 women, 2 men, median age 62.5 years, median BMI 25.9 kg/m(2)) on regular LDL apheresis were randomly assigned to receive six weekly treatments with either DALI (Fresenius) or Liposorber D (Kaneka). After 6 weeks, the patients were switched to the other device (again six weekly treatments). Blood was drawn before and immediately after LDL apheresis at three time points (last regular apheresis before the study; after six treatments with DALI and after six treatments with Liposorber D). LDL cholesterol concentration before the sixth apheresis (DALI 129 mg/dL, Liposorber D 132 mg/dL) as well as LDL cholesterol reduction during the sixth apheresis (DALI 68.3% and Liposorber D 68.4%) were similar with the two systems. CRP and fibrinogen concentrations were lower but interleukin-6, myeloperoxidase, and resistin concentrations were higher after the last Liposorber treatment compared with DALI (P < 0.05, respectively). No differences were observed concerning adiponectin, ghrelin, and PYY levels. In conclusion, both devices were highly effective in eliminating atherogenic lipoproteins. CRP and fibrinogen were better eliminated with Liposorber D. However, following Liposorber D, interleukin-6 levels were higher than after DALI possibly indicating an increased inflammatory activation.     

Comparison of different treatment regimens in a case of homozygous familial hypercholesterolemia.

The laboratory results of five periods of different treatment regimens were compared in a 19-year-old girl with homozygous familial hypercholesterolemia (FH): weekly low-density lipoprotein (LDL) apheresis sessions with dextran sulfate columns (LA 15, Kaneka Corporation, Osaka, Japan) without statin administration; weekly LDL apheresis with polyacrylate columns (DALI, Fresenius Adsorber Technology, Bad Homburg, Germany) without statin; LDL apheresis as in Period 2 with 40 mg atorvastatin daily; LDL apheresis as in Period 2 with 80 mg atorvastatin daily; and fortnightly LDL apheresis sessions with polyacrilate and administration of 80 mg atorvastatin daily. The five treatments were given in the above order, and each lasted at least 2 months. To compare the effectiveness of the different methods, the blood levels of total cholesterol, LDL-cholesterol and high-density lipoprotein (HDL)-cholesterol were measured before each session, and the percentage decreases in the blood levels of total cholesterol and LDL-cholesterol were recorded during sessions in Periods 1 and 2. In Periods 1 and 2, the biological effectiveness of LDL apheresis was comparable. Atorvastatin (40 mg daily) improved the blood levels of total cholesterol and LDL-cholesterol, but lowered HDL-cholesterol values. Increasing the daily dose of atorvastatin from 40 mg to 80 mg did not significantly improve LDL-cholesterol levels. When the time between two sessions was longer (Period 5), the total cholesterol and LDL-cholesterol values worsened and were comparable to those of Period 2 during which there was no atorvastatin treatment. In this case of homozygous FH, weekly sessions of LDL apheresis in association with atorvastatin at dose of 40 mg per day gave the best results.     

Direct adsorption of lipoproteins (DALI) from whole blood: first long-term clinical experience with a new LDL-apheresis system for the treatment of familial hypercholesterolaemia

BACKGROUND: The DALI (direct adsorption of lipoproteins) LDL-apheresis system is a novel device for the removal of lipoproteins from whole blood. METHODS: We report the first long-term treatment experience (16.7 +/- 12.6 months; 57 +/- 43 treatments/patient) using different DALI adsorber sizes (DALI-500, DALI-750, DALI-1000) in seven patients with homozygous (n = 1) and severe heterozygous familial hypercholesterolaemia. For each treatment, 1.6 fold of the calculated blood volume was processed. Treatments were scheduled at weekly or two-weekly intervals. RESULTS: The smallest DALI-500 configuration was unable to achieve sufficient removal of LDL cholesterol, with the adsorber being exhausted already at desorption of 65% of the calculated blood volume. In contrast, both larger adsorber systems effectively removed lipoproteins until the end of treatment. Therefore, the DALI-750 device was used for long-term treatment. LDL cholesterol (mean pretreatment value: 179 +/- 44 mg/dl) was reduced by 73.4 +/- 7.7% and Lp(a) levels (mean pretreatment value: 43 +/- 33 mg/dl) by 69.5 +/- 8.3%. HDL cholesterol (mean pretreatment value: 47 +/- 15 mg/dl) was reduced by 16.3 +/- 8.0% during the treatment. In the long term, LDL cholesterol was reduced by 54.0 +/- 10.5%--from 259 +/- 101 mg/dl to 119 +/- 19 mg/dl. No serious side effects occurred during the treatment. Long-term evaluation of other laboratory parameters showed a reduction in haemoglobin due to treatment-associated blood loss despite frequent iron supplementation. CONCLUSION: Sufficient reductions in LDL cholesterol and Lp(a) were achieved using the DALI-750 system and the treatment was well tolerated. The easy use and short period of 153 +/- 22 minutes required for each treatment are the major advantages of the DALI system as compared to other available LDL-apheresis devices. Potential particle release from the adsorber into the circulation must be ruled out before the system can be introduced in clinical routine.     

Direct adsorption of low-density lipoprotein and lipoprotein(a) from whole blood: results of the first clinical long-term multicenter study using DALI apheresis

Direct adsorption of lipoproteins (DALI) is the first low-density lipoprotein (LDL)-apheresis technique by which atherogenic LDL and lipoprotein(a) (Lp(a)) can be selectively removed from whole blood without plasma separation. The present study was performed to evaluate the efficacy, selectivity and safety of long-term DALI apheresis. Sixty-three hypercholesterolemic coronary patients were treated by weekly DALI sessions. Initial LDL-cholesterol (C) plasma levels averaged 238 +/- 87 mg/dl (range 130-681 mg/dl). On average, 34 sessions (1-45) were performed processing 1.5 patient blood volumes. The primary aim was to acutely reduce LDL-C by >or=60% per session. To this end, three different adsorber sizes could be employed, i.e., DALI 500, 750, and 1000, which were used in 4, 73, and 23% of the 2156 sessions, respectively. On average, 7387 ml of blood were processed in 116 min per session. This resulted in the following mean acute changes: LDL-C 198 --> 63 mg/dl (-69%), Lp(a) 86 --> 32 mg/dl (-64%), triglycerides 185 --> 136 mg/dl (-27%). HDL-C (-11%) and fibrinogen (-15%) were not significantly influenced. The mean long-term reduction of LDL-C was 42% compared to baseline while HDL-C slightly increased in the long run (+4%). The selectivity of LDL removal was good as recoveries of albumin, immunoglobulins, and other proteins exceeded 85%. Ninety-five percent of 2156 sessions were completely uneventful. The most frequent adverse effects were hypotension (1.2% of sessions) and paresthesia (1.1%), which were probably due to citrate anticoagulation. Access problems had to be overcome in 1.5%, adsorber and hardware problems in 0.5% of the sessions. In this multicenter long-term study, DALI apheresis proved to be an efficient, safe, and easy procedure for extracorporeal LDL and Lp(a) elimination.     

Biological variability of lipoproteins and apolipoproteins in patients referred to a lipid clinic.

We determined the physiological variability of total cholesterol, high- (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoproteins A-I and B in fasting blood samples from patients referred to the Johns Hopkins Lipid Referral Clinic. Samples were taken on each of three occasions during baseline evaluation visits before the patients were treated. The median physiological coefficients of variation (CVp) were as follows: total cholesterol, 5.0%; triglycerides, 17.8%; HDL cholesterol, 7.1%; LDL cholesterol, calculated from the previous three measurements, 7.8%; and apolipoproteins A-I and B, 7.1% and 6.4%, respectively. There were no significant differences in CVp between children (less than or equal to 18 years) and adults (greater than 18 years) for any of the measurements. On the basis of our findings, single measurements in serial samples taken on three occasions suffice to establish the patients' usual values with the following precisions (+/- 1 CV): total cholesterol, +/- 4%; triglycerides, +/- 11%; HDL cholesterol, +/- 8%; LDL cholesterol, +/- 6%; and apolipoproteins A-I and B, +/- 7%.     

Effects of atorvastatin and simvastatin on low-density lipoprotein subfraction profile, low-density lipoprotein oxidizability, and antibodies to oxidized low-density lipoprotein in relation to carotid intima media thickness in familial hypercholesterolemia.

BACKGROUND: Little is known about the effects of statins on the quality of circulating low-density lipoprotein (LDL) in relation to atherosclerosis progression. METHODS: In a double-blind, randomized trial of 325 patients with familial hypercholesterolemia (FH), we assessed the effects of high-dose atorvastatin (80 mg) and conventional-dose simvastatin (40 mg) on LDL subfraction profile (n = 289), LDL oxidizability (n = 121), and circulating autoantibodies to oxidized LDL (n = 220). Progression of atherosclerosis was measured by carotid intima media thickness (IMT) (n = 325). RESULTS: At baseline, the patients showed an intermediate LDL subfraction profile composed of three LDL subfractions (LDL1, LDL2, LDL3), with LDL2 as the predominant subfraction. A strong negative correlation was found between plasma triglycerides and the LDL subfraction profile (r = -.64, p = .000). Both plasma levels of triglycerides and small dense LDL3 correlated weakly with baseline IMT (r = .11, p = .04 and r = .15, p = .01, respectively; n = 289). No association was found between baseline IMT and oxidation parameters or circulating antibodies to oxidized LDL. Atorvastatin reduced triglycerides, LDL cholesterol, and all LDL subfractions to a greater extent than did simvastatin and led to regression of carotid IMT. However, LDL subfraction pattern and plasma levels of autoantibodies to oxidized LDL remained unchanged in both treatment groups, and LDL oxidizability increased minimally to a similar extent in both groups. Significant treatment differences were found for the rate of in vitro oxidation of LDL and the amount of dienes formed during in vitro oxidation of LDL, which both decreased more following atorvastatin than after simvastatin. CONCLUSION: Change of IMT after statin treatment was associated with baseline IMT (r = .41), LDL cholesterol (r = -.20), and the amount of dienes formed during in vitro oxidation of LOL (r = .28) but not with plasma levels of antibodies to oxidized LDL, in vitro LDL oxidizability, and LDL subfraction profile.     

Short-term and long-term effects of low-density lipoprotein (LDL) apheresis on restenosis after percutaneous transluminal coronary angioplasty (PTCA): is lowering Lp(a) by LDL apheresis effective on restenosis after PTCA?

It has been reported that serum lipoprotein(a) (Lp[a]) levels in patients with restenosis after percutaneous transluminal coronary angioplasty (PTCA) were significantly higher than in patients without restenosis. In this study, we evaluated the preventive effect of LDL apheresis on restenosis after PTCA in patients with hypercholesterolemia. For 10 patients who had shown a serum cholesterol level of more than 220 mg/dl despite treatment with antihypercholesterolemic drugs, LDL apheresis was conducted every 2 weeks after a successful PTCA until restenosis could be checked. In 4 patients, LDL apheresis was conducted for 2 years. LDL apheresis significantly reduced serum cholesterol from 248 +/- 22 mg/dl to 135 +/- 26 mg/dl and Lp(a) from 42 +/- 34 mg/dl to 21 +/- 16 mg/dl. The average degree of stenosis in the 11 lesions undergoing PTCA was 92 +/- 6% before PTCA, 35 +/- 10% immediately after PTCA, and 38 +/- 19% at 3 to 4 months after PTCA. Restenosis was observed in only 1 lesion. In 4 patients who received LDL apheresis for 2 years, restenosis did not occur in any of the 4 lesions treated. We concluded that LDL apheresis was an efficacious therapy to prevent restenosis after PTCA in patients with hypercholesterolemia.     

Low density lipoprotein immunoapheresis does not increase plasma lipid peroxidation products in vivo.

Extracorporeal elimination of low density lipoprotein (LDL) is frequently used in drug-resistant hypercholesterolemia. LDL-immunoapheresis selectively removes LDL and lipoprotein(a) [Lp(a)] from plasma. Lipid peroxidation is one unwanted side effect, that occurs during extracorporeal plasma treatment. The purpose of this study was to investigate the effect of LDL immunoapheresis on lipid peroxidation. Before and after a single LDL-immunoapheresis treatment, plasma concentrations of lipid hydroperoxides, determined with two different spectophotometric assays, thiobarbituric acid-reacting substances (TBARS), determined spectrophotometrically and malondialdehyde (MDA), determined by an MDA-TBA/HPLC method, were measured in 13 hypercholesterolemic patients. In addition MDA was also determined in the eluate of the apheresis column. Before treatment, plasma cholesterol and LDL cholesterol concentrations were significantly higher in patients than in healthy control subjects, as were the lipid peroxidation products. LDL-immunoapheresis treatment of the patients led to significant decreases in total cholesterol (69+/-8%), LDL-cholesterol (79+/-7%), HDL-cholesterol (35+/-17%), triglycerides (38+/-21%), apolipoprotein-B (77+/-6%), apolipoprotein-A1 (25+/-5%) and Lp(a) concentrations (76+/-10%). Changes in plasma lipid peroxide concentrations (17+/-8 nmol/l before vs. 14+/-5 nmol/l after treatment) were not significant, neither were those in TBARS (3. 0+/-2.6 micromol/l vs. 2.3+/-1.3 micromol/l) or MDA concentrations (1.03+/-0.17 micromol/l vs. 1.0+/-0.20 micromol/l). Patients with high baseline values showed a decrease, whereas others did not. MDA was present (0.57+/-0.13 micromol/l) in the eluate of the apheresis column, suggesting that, along with LDL, lipid peroxidation products are also removed. From these results we conclude that a single LDL-immunoapheresis treatment effectively reduces LDL and Lp(a) in the absence of increases in plasma lipid peroxidation products.     

High-efficiency DALI apheresis using 1,250 ml adsorbers in a hypercholesterolemic obese patient: a case report.

Direct adsorption of lipoproteins (DALI) apheresis is the first method for direct adsorption of lipoproteins from whole blood and is therefore an easy and rapid procedure. The majority of patients reaches >60% acute low-density lipoprotein cholesterol (LDL-C) reduction using either the DALI 750 or 1000 configuration. However, in patients with extremely high LDL-C levels or very large blood volumes, these configurations may lead to suboptimal results. The current study was performed to test the safety and efficacy of DALI 1250. In a severely obese patient (185 cm, 133 kg, blood volume 7.2 L, LDL-C 239 mg/dl), 11 L of blood (1.53-fold patient blood volume) was processed at a flow rate of 80 ml/min in 2.5 h; a combined heparin-plus-citrate anticoagulation regimen was used. Commercially available DALI 1250 and DALI hardware and disposables were manufactured by Fresenius HemoCare Adsorber Technology, St. Wendel, Germany. Twenty weekly sessions were performed. Clinically and technically, the apheresis sessions were completely uneventful. As compared to DALI 1000 (n = 4 sessions), the reduction rates by DALI 1250 (n = 20) improved for LDL-C (from 52% to 66%), lipoprotein (a) (Lp[a]) (53% vs. 66%), and fibrinogen (11% vs. 16%). There was a slight increase in high-density lipoprotein cholesterol (HDL-C) loss (20% vs. 24%). Moreover, the absolute amount of LDL-C removed per session increased from 5.06 g to 5.94 g. Laboratory safety parameters remained within the normal range, the anticoagulation was well controlled, and the pressure gradients over the adsorber remained constant. In this case report, DALI 1250 was perfectly safe and significantly increased the efficacy of LDL-C and Lp(a) elimination compared to standard DALI. Thus, this high-efficiency version of DALI may be used in patients with extremely high LDL-C levels and/or large blood volumes.     

Effects of peritoneal dialysis with an overnight icodextrin dwell on parameters of glucose and lipid metabolism.

OBJECTIVE: To examine whether a reduced daily glucose load by overnight application of the less-absorbed glucose polymer icodextrin would have favorable effects on lipid profiles of continuous ambulatory peritoneal dialysis (CAPD) patients. STUDY DESIGN: Randomized crossover study with two subsequent periods of 6 weeks. SETTING: Home PD unit of a secondary-care hospital. PATIENTS: Twenty-one nondiabetic CAPD patients (15 male, 6 female; mean age 50.3+/-11.8 years). INTERVENTION: Participants were randomly assigned to receive an overnight dwell with either standard glucose solution or with a 7.5% icodextrin-containing solution. MAIN OUTCOME MEASURES: Relation between reduction in the total amount of intraperitoneal infused glucose and parameters of glucose (plasma glucose, insulin, and HbA1C) and lipid metabolism [free fatty acids, plasma lipids, lipoproteins, and low density lipoprotein (LDL) subfraction profile]. RESULTS: After the icodextrin dwells, a reduction of plasma total cholesterol (from 5.43+/-0.85 to 4.86+/-0.70 mmol/L, p < 0.001) and LDL cholesterol (from 3.38+/-0.87 to 2.93+/-0.73 mmol/L, p = 0.001) was observed. Also, high density lipoprotein (HDL) cholesterol (from 0.95+/-0.27 to 0.90+/-0.24 mmol/L, p = 0.029) was reduced, but the plasma total cholesterol-to-HDL ratio remained similar. Plasma free fatty acids and triglyceride levels tended to decrease (from 0.16+/-0.10 to 0.13+/-0.08 mmol/L, p= 0.06, and from 2.14+/-1.96 to 1.92+/-1.03 mmol/L, respectively). Evaluation of LDL subfraction profiles after ultracentrifugation showed a more buoyant LDL subfraction profile with fewer dense LDL particles in 6 patients and no changes in 14 patients after icodextrin.The effects on lipids were not accompanied by a decrease in fasting plasma glucose (from 5.76+/-1.29 to 5.86+/-0.80 mmol/L) or insulin levels (from 19.5+/-14.4 to 20.3+/-13.0 mU/L). CONCLUSION: These results suggest a beneficial effect on lipid profiles of CAPD patients with the use of an overnight dwell with icodextrin.     

Effect of different LDL-apheresis methods on parameters involved in atherosclerosis

LDL-apheresis lowers the LDL level in patients with severe hypercholesterolemia. The present study compared three apheresis methods--DSA, DALI, and plasma exchange--for effectiveness in removal of LDL and effect on various blood parameters involved in atherogenesis. The study group included 6 patients with primary hypercholesterolemia unresponsive to maximal drug therapy. All were treated first with 4 consecutive plasma exchange sessions followed by 4 DSA sessions; in four out of six, an additional 4 sessions of DALI were then performed. Levels of lipoproteins, apoproteins, CRP, homocysteine, fibrinogen, and blood count were determined before and after each session. All 3 procedures yielded a significant reduction in total cholesterol and ApoB-containing lipoproteins, with DALI being the most effective. Also, a significant reduction in triglycerides, HDL, and ApoA1 was observed with all the methods. The reduction in HDL-C with DSA and DALI was greater than previously reported. The LDL/HDL-cholesterol ratio decreased significantly with DSA and DALI and increased with plasma exchange. There was a significant decrease in CRP, fibrinogen, and platelets with all three methods, and a significant decrease in homocysteine only with DSA and DALI. All three procedures effectively reduced the concentration of various compounds involved in atherosclerosis. Plasma exchange is nonselective and cannot be recommended as the procedure of choice.     

LDL apheresis in clinical practice: long-term treatment of severe hyperlipidemia.

Thirty patients (13 males, 17 females) suffering from familial hypercholesterolemia resistant to diet and lipid-lowering drugs were treated for 48.7 +/- 19.2 months (range, 2-87 months) with low density lipoprotein (LDL) apheresis. Three different systems (dextran sulfate adsorption for 27 of 30 [Kaneka, Liposorber, Japan], immunoadsorption system for 2 of 30 [Baxter, Therasorb, Germany], immunoadsorption system with special lipoprotein a [Lp(a)] columns for 1 of 30 patients [Lipopak, Pocard, Russia]) were applied. Before LDL apheresis 24 of 30 patients suffered from coronary heart disease (CHD) with angina symptoms. With LDL apheresis, reductions of 46% for total cholesterol, 49% for LDL, 30% for Lp(a), and 38% for triglycerides were reached. Severe side effects such as shock or allergic reactions were very rare (0.5%). In the course of treatment, an improvement in general well-being and increased performance were experienced in 27 of 30 patients. A 60 to 100% reduction of nitrate medication was observed in 17 of 24 patients. Regarding the different apheresis systems used, at the end of the trial there were no significant differences with respect to the clinical outcome experienced by the patients and concerning total cholesterol, LDL, high density lipoprotein, and triglyceride concentrations. But to reduce high Lp(a) levels, the immunoadsorption method with special Lp(a) columns seems to be the most effective (-57% versus 25% [Kaneka] and 23% [Baxter]). The present data clearly demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia, resistant to maximum conservative therapy, is very effective and safe, even in long-term application.     

Efficacy and safety of DALI LDL-apheresis at high blood flow rates: a prospective multicenter study

Direct adsorption of lipids (DALI) is the first LDL-apheresis method compatible with whole blood. Usually, the blood flow rate is adjusted at 60-80 ml/min, which results in session times of about 2 hr. The present study was performed to test the safety and efficacy of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] removal by DALI at high blood flow rates in order to reduce treatment time. Thirteen chronic DALI patients in seven centers suffering from hypercholesterolemia (LDL-C 162 +/- 42 mg/dl at baseline) and coronary artery disease were treated on a weekly or biweekly basis by DALI apheresis. The blood flow rate QB was held constant for at least two sessions, respectively, and was increased from 60 to 80, 120, 160, 200, and 240 ml/min. All patients had pre-existing av-fistulas. The anticoagulation was performed by a heparin bolus plus ACD-A at a ratio of citrate:blood ranging from 1:20 to 1:90. Clinically, the sessions were well tolerated and only 26/201 sessions (12%) of the treatments were fraught with minor adverse events. Acute LDL-C reductions (derived from LDL-C levels determined by lipoprotein electrophoresis) averaged 72/66/60/53/50/48% for QB=60/80/120/160/200/240 ml/min. Lp(a) reductions were 68/67/62/60/58/56%, whereas HDL-C losses were < or =10%. Routine blood chemistries and blood cell counts remained in the normal range. Treatment times averaged 142/83/45 min at Qb=60/120/240 ml/min. On average, DALI LDL-apheresis could be performed safely and effectively at high blood flow rates up to at least 120 ml/min in patients with good blood access, which significantly reduced treatment time from 142 to 83 min (-42%).     

Improvement of endothelium-dependent coronary vasodilation after a single LDL apheresis in patients with hypercholesterolemia

The purpose of this study was to determine whether a single LDL apheresis would improve impaired endothelium-dependent dilation of the coronary artery in patients with hypercholesterolemia. Hypercholesterolemia is associated with impaired endothelial function, and human studies using cholesterol-lowering drugs indicate that endothelial function in the coronary arteries improves with reduction of serum LDL cholesterol over 6 to 12 months. The internal diameter of the left coronary artery and the coronary blood flow were measured by intracoronary Doppler-wire measurement and quantitative angiography before and immediately after a single LDL apheresis in a population of 15 patients with familial hypercholesterolemia. Endothelium-dependent vasodilation was assessed by intracoronary infusion of acetylcholine (1, 10, and 50 microg/min), and endothelium-independent vasodilation was assessed by intracoronary bolus infusion of isosorbide dinitrate (2.5 mg) or papaverine (10 mg). A single 3-hour LDL apheresis reduced serum LDL cholesterol by an average of 86.6 +/- 1.7%. After the LDL apheresis, the changes in the coronary artery diameter and coronary blood flow in response to an infusion of 50 microg/min of acetylcholine increased significantly compared to the pre-apheresis values (from -19.7 +/- 4.8 to -2.9 +/- 3.0% [P < 0.01] and from 80.7 +/- 27.6 to 155.3 +/- 23.5% [P < 0.01], respectively). The LDL apheresis did not significantly change the response of either parameter to infusion with isosorbide dinitrate or papaverine. The endothelial function of the epicardial coronary artery and the coronary microvasculature improved in hypercholesterolemic patients after only a single LDL apheresis, a procedure that markedly reduces the serum level of LDL cholesterol.     

Nonenzymatic glycosylation of proteins. II. Does glycosylation of low density lipoproteins affect lipid composition of erythrocyte membranes?

The degree of nonenzymatic glycosylation of low density lipoprotein (LDL) and lipid composition of LDL as well as of erythrocyte membrane ghosts was investigated in order to determine the possible relationship of LDL glycosylation and lipid metabolism disorders. Three groups of juveniles attending outpatient clinic: diabetics without associated conditions, diabetics with background retinopathy and control healthy subjects were selected for our study. Anisotropy measurements and chemical determinations revealed that enhanced LDL glycation in diabetics (20.6 +/- 1.5 in uncomplicated diabetic subjects and 21.4 +/- 1.0 in retinopathic patients versus 18.1 +/- 1.9 controls) corroborated significantly with membrane cholesterol: phospholipid ratio (r = 0.695), LDL cholesterol (r = 0.720) and membrane rigidization (r = 0.504). Moreover, the elevation of LDL glycation, significance of which was established by nonparametric variance analysis (p less than 0.01), was considerably correlated with total plasma cholesterol (r = 0.743). The possibility that chemical modification of LDL by glucose might induce the altered cholesterol metabolism and distribution was suggested.