Three different LDL apheresis columns efficiently and equally reduce lipoprotein(a) concentrations in patients with familial hypercholesterolemia and small apolipoprotein(a) particles

Introduction

High levels of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] are associated with cardiovascular disease. In this study we determined apo(a) particle size and compared the Lp(a) reducing efficacy of three different LDL apheresis columns; DL-75, LA-15 and EC-50W in patients with familial hypercholesterolemia (FH).

Results

Average Lp(a) concentration was reduced by 70%, 74% and 75% (all p < 0.0001) for DL-75, LA-15 and EC-50W, respectively. No significant changes in the relative proportion of the isoforms of 14 and 32 K 4 domains were observed after apheresis.

Conclusion

Three different LDL apheresis columns reduced Lp(a) efficiently with preserved ratio between apo(a) isoforms.     

Comparison of different LDL apheresis methods

This article presents the generally accepted indications for LDL apheresis treatment. The available LDL apheresis methods differ with respect to acute relative reductions of LDL cholesterol; mean values after the LDL apheresis treatments are not different. Serum triglycerides, HDL-cholesterol, and lipoprotein(a) are also acutely reduced. Available LDL apheresis methods differ with respect to their impact on the coagulation system, on C-reactive protein and on leukocyte count. Cardiovascular events are clearly reduced by the LDL apheresis methods. There is an urgent need to prospectively compare the different LDL apheresis methods taking into account hard end points. The lower target values for LDL cholesterol suggested by international guidelines for high-risk patients will certainly require a more widespread use of LDL apheresis.     

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.     

Optimal therapy for reduction of lipoprotein(a)

What is known and Objective: There is a growing body of experimental and clinical evidence for the atherogenic and pro‐thrombotic potential of Lipoprotein(a) [Lp(a)], as well as for its causative role in coronary heart disease and stroke. We comment on novel strategies for reducing Lp(a) levels. Comment: Irrespective of the underlying biological mechanisms explaining the athero‐thrombotic potential of this lipoprotein, most work has focused on the identification of suitable therapies for hyperlipoproteinemia(a). These include apheresis techniques, nicotinic acid and statins. None of these strategies have been shown to be definitely effective or convenient for the patient and new strategies are being attempted. Promising results are emerging with therapeutic interventions targeting the ‘inflammatory pathways’ by inhibition of Interleukin‐6 (IL‐6) signalling with natural compounds (e.g., Ginko biloba) or the IL‐6 receptor antibody Tocilizumab. These may both lower Lp(a) and cardiovascular risk of the patients. Besides inhibiting platelet function, antiplatelet therapy with aspirin may also decrease the plasma concentration of Lp(a) and modulate its influence on platelets. What is new and Conclusion: We highlight the inadequacy of current approaches for lowering Lp(a) and draw attention to novel insights that may lead to better treatment.     

Long-term effects of LDL apheresis in patients with severe hypercholesterolemia

Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism involving mutations in the LDL receptor (LDL-R). Patients with mutation in one (heterozygous) or both (homozygous) genes have markedly elevated LDL cholesterol and are at increased risk for coronary heart disease (CHD). Aggressive lipid lowering is required for homozygous and many heterozygous FH patients. This often involves LDL-apheresis, where LDL and other apo-B containing lipoproteins are selectively removed from the plasma. We have retrospectively studied 34 patients treated with biweekly LDL-apheresis at the Hospital of the University of Pennsylvania. In our patient population, adverse events were uncommon and rarely resulted in shortened treatment time. There was a dramatic decrease in the relative risk of cardiovascular events and cardiovascular interventions in patients treated with LDL-apheresis for an average of 2.5 years. Some but not all patients had long-term reduction in their LDL levels as a result of LDL-apheresis, suggesting that time-averaged reduction in LDL and/or LDL:HDL ratios were responsible for clinical improvement. These data support the use of LDL-apheresis in patients with FH, as well as medication-intolerant patients that have elevated LDL cholesterol despite maximal pharmacological treatment.     

Lipoprotein apheresis reduces biomarkers of plaque destabilization and cardiovascular risk

Lipoprotein apheresis (LA) is believed to exert anti‐atherosclerotic effects beyond LDL‐cholesterol reduction. We investigated 22 patients undergoing regular LA on a weekly basis (group A) before (AP) and after LA procedure (EP), 15 healthy individuals (group B), and 22 hyperlipoproteinemic patients with concomitant cardiovascular end organ damage treated without LA therapy (group C). Biomarkers of endothelial inflammation (hsCRP), plaque destabilization, and rupture (sVCAM, MMP‐9, PAPP‐A, ADMA) were quantified. Intergroup comparison revealed a statistically significant lower MMP‐9 level in group A (AP and EP) compared with group C (P < 0.01), whereas PAPP‐A levels were lower in group B compared with group A and C (P = 0.04). EP ADMA‐levels and EP sVCAM levels in group A were statistically lower compared with group B and C. AP and EP values comparison revealed a significant reduction for hsCRP (mean 41.0 ± 16.7%, P < 0.01), sVCAM (mean 69.6 ± 14.0%, P < 0.01), PAPP‐A (mean 88.7 ± 20.4%, P < 0.01), ADMA (mean 69.7 ± 18.4% P < 0.01). In conclusion, we observed a transient decrease in the plasma concentrations of several biomarkers expressed during plaque destabilization and elevated cardiovascular risk after a single LA treatment. J. Clin. Apheresis 29:235–242, 2014. © 2013 Wiley Periodicals, Inc.     

Lipoprotein(a): Current Evidence for a Physiologic Role and the Effects of Nutraceutical Strategies

PurposeCardiovascular (CV) diseases account for most worldwide mortality, and a higher level of lipoprotein (Lp)-(a) is recognized as a prevalent contributing risk factor. However, there is no consensus regarding nutritional strategies for lowering Lp(a) concentration. Thus, the purposes of this literature review were to: (1) critically examine data concerning the effects of dietetic interventions and nutraceutical agents on Lp(a) level; and (2) review the feasibility and utility of their clinical use.MethodsA literature search was conducted for studies published between August 2018 and March 2019. The search was performed using the Cochrane, Medline, and Web of Science databases. In order to expand the research, there were no delimitations on the type or year of the studies. A total of 1932 articles were identified using this search procedure. After duplicates were eliminated, 740 abstracts of articles written in English were screened to identify those of highest relevance. In the final tally, a total of 152 full-text articles were included in this review.FindingsSeveral foods and decreases in saturated fat and ethanol intake, especially red wine intake, may lower Lp(a) concentration, but limits are necessary. Coffee and tea intake may decrease Lp(a) level; further investigation is crucial before they can be considered potent Lp(a)-lowering agents. Among supplementation strategies, only l-carnitine and coenzyme Q10 are promising clinical candidates to lower Lp(a) level. Since both l-carnitine and coenzyme Q10 supplementation are commonly used for CV support, they deserve further exploration regarding clinical applicability. In contrast, despite potential CV benefits, current research fails to justify use of higher intakes of vitamin C, soy isoflavones, garlic, and ω-3 for decreasing Lp(a) concentration.ImplicationsDefinitive long-term clinical trials are needed to confirm the effects of dietetic interventions and nutraceutical agents on Lp(a) concentration when anticipating improved CV outcomes.     

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.     

血浆中CRP、Hcy、LDL、HDL含量与动脉粥样硬化的相关性研究

目的通过检测动脉粥样硬化(AS)患者血浆中C反应蛋白(CRP)、同型半胱氨酸(Hcy)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)含量变化,探讨CRP、Hcy、LDL、HDL水平与不同程度冠状动脉粥样硬化的相关性及其在冠心病(CHD)发病机制中的作用。方法使用OLYMPUS 5400全自动生化分析仪和SIEMENS BN-Ⅱ特定蛋白分析仪分别检测211例AS(其中并发CHD患者156例)患者和59例健康人血浆中CRP、Hcy、LDL、HDL的含量,对检测结果进行统计学分析。结果与健康对照组相比,AS组CRP、Hcy、LDL水平均升高,而HDL水平低于健康对照组,差异有统计学意义(P<0.01)。并发CHD组与无CHD组对比,并发CHD组的CRP、Hcy、LDL水平均升高(P<0.01),而HDL低于健康对照组(P<0.01)。不同程度冠状动脉病变组间上述指标水平变化差异有统计学意义(P<0.01)。结论高CRP、Hcy、LDL是AS的危险因素,且与冠状动脉粥样硬化病变程度呈正相关,而HDL水平与冠状动脉粥样硬化病变程度呈负相关,这些指标为CHD患者病情程度的评估提供了重要的依据。并发CHD患者体内CRP、Hcy、LDL水平高于无冠心病患者,而HDL水平明显低于后者,因而这些指标也可用来监测AS患者出现CHD等并发症的危险性。     

Lipoprotein Lp(a) as predictor of myocardial infarction in comparison to fibrinogen,LDL cholesterol and other risk factors: results from the prospective Göttingen Risk Incidence and Prevalence Study (GRIPS)

Abstract. Based on pathophysiological findings Lp(a) is considered to be a cardiovascular risk factor. The Göttingen Risk Incidence and Prevalence Study (GRIPS) provides the possibility to evaluate this impact of Lp(a) on the basis of a large prospective cohort study. GRIPS included 6002 men, aged 40–59·9 years at baseline. Data of a 5 year follow-up period is now available for > 95% of the study participants. Multivariate logistic regression models for the estimation of MI risk confirm Lp(a) as an important risk factor, ranking fifth behind LDL cholesterol, family history of MI, plasma fibrinogen and HDL cholesterol (inversely related). The GRIPS data strongly support strategies for the identification and treatment of persons at increased MI risk which focus on LDL cholesterol. However, Lp(a) and fibrinogen have to be seriously considered as additional risk factors and should be included in diagnostic panels for the estimation of MI risk.     

Low-density lipoprotein metabolism and its association to plasma lipoprotein(a) in the nephrotic syndrome

Patients with nephrotic syndrome have multiple abnormalities of lipoprotein metabolism, but the cause and exact nature of these abnormalities have not been established. In the present study we have determined the kinetics of plasma low-density lipoprotein (LDL) apoB in seven nephrotic patients demonstrating an elevated LDL apoB production rate (25.7 ± 6.4 vs. 13.1 ± 0.3 mg kg^–1 day^–1; P  < 0.001) but a normal LDL apoB fractional catabolic rate (FCR) (0.31 ± 0.04 vs. 0.33 ± 0.008 pools day^–1; NS) compared with 41 healthy control subjects. However, two out of the seven patients had a markedly low LDL apoB-FCR. Serum albumin was inversely correlated with the LDL apoB production rate ( R  = –0.82; P  < 0.05). Plasma lipoprotien (a) [Lp(a)] levels were significantly ( P  < 0.001) increased in the nephrotic patients compared with control subjects. Significant correlations were observed between log Lp(a) and LDL apoB production rate ( R  = 0.90; P  < 0.01), VLDL-cholesterol ( R  = 0.95; P  < 0.001) and VLDL-triglycerides ( R  = 0.80; P  < 0.05) respectively. In summary, the present study suggests that nephrotic hyperlipidaemia may be caused by at least two independent mechanisms. The elevated LDL apoB production rate is highly correlated with the prevailing levels of serum albumin, whereas some nephrotic patients seem to have a decreased LDL apoB clearance, suggesting impaired LDL receptor-mediated clearance. The present results also suggest that the elevated plasma Lp(a) levels in nephrosis are related to an increased hepatic synthesis rather than a decreased catabolism of lipoproteins.     

Decreased affinity of low density lipoprotein (LDL) particles for LDL receptors in patients with cholesteryl ester transfer protein deficiency

Abstract. We have reported that the disorder of lipoprotein metabolism in hyperalphalipoproteinae-mic patients with a deficiency of cholesteryl ester transfer protein (CETP) is characterized by the poly-disperse low density lipoprotein (LDL) particles and the accumulation of cholesteryl ester (CE) in high density lipoprotein (HDL) particles, forming cholesterol-induced HDL (HDLc)-like particles. In the present study we have investigated the interaction of these abnormal LDL with LDL receptors of normal human fibroblasts. Since the ultracentrifugally separated LDL fraction (1.019 < d < 1.063 gmL^-1) from the CETP-deficient patients contained HDLc-like particles, these particles were removed by anti-apolipoprotein (apo) A-I immunoaffinity column chromatography. The lipoproteins eluted in the unbound fraction of this column did not contain apo A-I, so this fraction was considered to be authentic LDL. The authentic LDL of the patients were deficient in CE and rich in triglycerides and apo B. The authentic LDL itself showed polydispersity, ranging in size from 23 nm to 30 nm. The affinity of these abnormal LDL particles for LDL receptors was analysed by a competitive assay in which cold LDL from the patients or control compete with ¹²⁵I-labelled LDL for fibroblast LDL receptors. The concentration of LDL particles at which 50% of ¹²⁵I-labelled normal LDL was replaced was two to three times higher for the patients than for the normal control. Therefore, the affinity of patient LDL was thought to be reduced compared to that of control LDL. These results demonstrate that CETP may play an important role in making LDL particles homogeneous and rich in CE. This modulation of LDL by CETP may enhance the affinity of LDL for LDL receptors to deliver cholesterol to peripheral tissues.     

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.     

Application of a new LDL apheresis system using two dextran sulfate cellulose columns in combination with an automatic column-regenerating unit and a blood cell separator

Extracorporeal procedures for selective removal of low-density lipoproteins have become a promising new approach for treatment of severe familial hypercholesterolemia. We tested efficacy and safety of a new LDL apheresis system by using two dextran sulfate cellulose adsorbents (Liposorber LA 15TM from Kanegafuchi) under the control of an automatic column-regenerating unit for continuous alternate adsorption and desorption. Plasma was taken from a continuous-flow blood cell separator (model IBM/Cobe 2997) allowing an extracorporeal circuit from one cubital vein to another. A 57-year-old male with drug-resistant heterozygous familial hypercholesterolemia accompanied by moderate hypertriglyceridemia and severe coronary artery disease has been treated every 2 weeks for 3 months so far. Treatment of 4-5 liters of plasma resulted in a mean decrease of total cholesterol from 355 to 111 mg/dl (9.20 to 2.88 mmol/l), of LDL cholesterol from 272 to 49 mg/dl (7.05 to 1.53 mmol/l), and of apolipoprotein B from 175 to 44 mg/dl. HDL cholesterol, apolipoprotein A-I, and other plasma proteins did not substantially change apart from hemodilution. No side effects were seen. This new technique of LDL apheresis represents a very effective and safe method for treatment of drug-resistant familial hypercholesterolemia without or with concomitant hypertriglyceridemia.