Heparin extracorporeal LDL precipitation (HELP): an effective apheresis procedure for lowering Lp(a) levels

doi:10.1016/0009-3084(94)90152-X

Chemistry and Physics of Lipids

Volumes 67–68, January 1994, Pages 315-321

https://doi.org/10.1016/0009-3084(94)90152-X Get rights and content

Abstract

Heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) is based on the precipitation of apolipoprotein B (apo B) containing lipoproteins with heparin at low pH (4.85). In in vitro experiments we could show that Lp(a) is quantitatively (>99%) precipitated from plasma by heparin in the pH range 4.6–5.2. The acute changes in Lp(a) after a single HELP-LDL apheresis were investigated in twelve patients with Lp(a), concentrations > 30 mg/dl. A single treatment caused a highly significant decrease (62%) in the concentration of Lp(a), similar to the decrease (60%) observed for LDL-cholesterol. Analysis of the data from ten patients with different apo(a) phenotypes indicated that Lp(a) is eliminated with almost 100% efficiency in the extracorporeal circulation, irrespective of apo(a) phenotype and plasma concentration. The mean rate of recovery of Lp(a) following HELP-LDL apheresis was slightly slower than that of LDL-cholesterol. Plasma Lp(a) concentrations were monitored in seven patients over 2 years. Mean Lp(a) concentrations after 2 years were lower than pre-treatment levels, indicating that repeated elimination of the lipoprotein does not lead to an induction in its synthesis. HELP-LDL apheresis should be particularly suitable for treatment of patients with elevated LDL-cholesterol levels who are also at increased coronary risk because of high Lp(a) concentrations.

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Cited by (27)

Biology, pathophysiology and current therapies that affect lipoprotein (a) levels
2019, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
Lipid apheresis (LA) is a procedure involving the extracorporeal removal of excess atherogenic apoB-100-containing lipoproteins such as Lp(a), and LDL from whole blood or plasma by adsorption, precipitation, or differential filtration [90]. This procedure was initially used to treat patients with FH, however since then, specific techniques to lower Lp(a) have been developed, achieving significant reductions in plasma Lp(a) by ~60% [28,91,92]. Although the role of Lp(a) in atherosclerosis has been established, no randomised prospective clinical trials showing the benefits of lowering Lp(a) using LA have been performed.
Lipoprotein (a) [Lp(a)] has recently emerged as a causal, independent and genetic risk factor for cardiovascular disease and calcific aortic valve disease. Given the high incidence of elevated Lp(a) among the general population, significant gaps in the knowledge of Lp(a) biology, pathophysiology and current therapies affecting Lp(a) reduction exist. As plasma Lp(a) levels are genetically determined and insensible to diet, exercise and lifestyle changes, lipid-lowering therapies seem to be the solution to lower elevated Lp(a) levels.
This review summarises the current knowledge of Lp(a) structure, metabolism, catabolism, pathophysiology, and Lp(a) response to statins, lipid apheresis, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, cholesterol esterase transferase protein (CETP) inhibitors and antisense oligonucleotides (ASOs).
Effects of Lipoprotein apheresis on the Lipoprotein(a) levels in the long run
2015, Atherosclerosis Supplements
Citation Excerpt :
Parhofer et al. reported that Lp(a) levels were more effectively reduced by HELP, immunoadsorption and dextran-sulfate apheresis compared with cascade filtration [17]. Evidently different LA methods have different effects on Lp(a) levels per session [18–20]. In the present study, no determining effect of the applied LA methods on the course of the pre-apheresis Lp(a) levels was seen.
Lipoprotein(a) (Lp(a)) is a low density lipoprotein-like particle to which apolipoprotein(a) is bound. It is recognized as an atherosclerosis-inducing risk factor. Up to now a detailed description of the effect of Lipoprotein apheresis (LA) on Lp(a) levels in the long run is lacking.
We studied 59 patients with elevated Lp(a) levels who were treated with LA at the Lipoprotein Apheresis Center at the University Hospital Dresden. We analyzed Lp(a) concentrations before the start of the LA treatment and during this extracorporeal therapy.
Comparing the Lp(a) levels before the start of LA therapy and pre-apheresis (measured before the LA sessions) Lp(a) levels, we observed a reduction of the Lp(a) levels of about 22.8% in all patients. Lp(a) levels were acutely (comparing post-apheresis with pre-apheresis concentrations) reduced by all 6 available LA methods (by about 70%). A linear regression analysis was performed to differentiate the long term course of pre-apheresis Lp(a) levels. In 30 patients we saw an increase of the pre-apheresis Lp(a) levels over the time, in 15 patients a constancy and in 14 patients a decrease. Patients with a decrease of pre-apheresis Lp(a) levels over the time had significantly higher initial (before the start of the extracorporeal treatment) and pre-apheresis values and they were significantly older. These patients had significantly more severe peripheral arterial disease as well as cardiac valve and carotid stenosis. The patients with the lowest initial Lp(a) levels and an increase of the pre-apheresis Lp(a) levels over the time had the highest percentage of intake of Tredaptive^®/Niaspan^® though after stopping the intake of these nicotinic acid preparations no clear increase of Lp(a) concentrations was observed. The applied LA systems did not seem to have a significant influence on the course of pre-apheresis Lp(a) levels. In all patients there was a high variability of Lp(a) concentrations between LA sessions which may in part be due to the inaccuracy of the method used to measure Lp(a) concentrations.
Pre-apheresis Lp(a) levels (before the LA sessions) are lower than those before the start of a LA treatment but they behave differently among patients during LA treatment.
Lipoprotein apheresis: State of the art and novelties
2013, Atherosclerosis Supplements
Citation Excerpt :
Furthermore, nicotinic acid is known to induce often serious side effects even at low dosage, independently of being associated to laropiprant. Several LA methods effectively lower the Lp(a) concentrations [26,53–58]. According to the experience at the Dresden Apheresis center, the Liposorber D method appears to be the most effective with a mean acute reduction rate of more than 80% [58].
Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10–20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia.
Current situation of lipoprotein apheresis in Saxony
2013, Atherosclerosis Supplements
Citation Excerpt :
Additionally, it compares the efficiency of the LA treatment at the UHD with that at other centers. Six lipoprotein apheresis methods were used, for details about these methods see the literature [4–10] (Table 1). In 2010, 119 patients were treated with lipoprotein apheresis in Saxony (Table 2), more than half of them at the UHD Apheresis Center.
This paper summarizes the situation pertinent to treatment via lipoprotein apheresis in the federal state of Saxony, Germany in 2010. In total, 119 predominately male patients were treated in 10 centers; the majority of the patients was older than the mean age of the general population. Several risk factors were present, particularly a familial predisposition and hypertension. All patients had experienced cardiovascular events and the majority was taking statins. Patient data from the University Hospital Carl Gustav Carus in Dresden concurred with data derived from patients treated at nephrological practices. In the mean, patients attended the centers for about 6 years, the majority weekly. LDL cholesterol concentrations prior to apheresis were clearly higher than target levels; apheresis sessions decreased LDL cholesterol by 69%. Lipoprotein(a) levels could be measured in 75 patients and were effectively reduced by lipoprotein apheresis. In Saxony, 29 patients per 1 million inhabitants received lipoprotein apheresis, which is higher than the proportion of patients treated in Germany as a whole. The need for this extracorporeal treatment seems to be much greater than its current utilization. Among the patients only one homozygous patient with familial hypercholesterolemia was observed. Physicians should be actively informed about this therapeutic possibility to reduce the cardiovascular risk efficiently. The introduction of new drugs may alter the position of lipoprotein apheresis within the therapeutic spectrum.
Elevated lipoprotein(a) - A genetic risk factor for premature vascular disease in people with and without standard risk factors: A review
2006, Disease-a-Month
LDL apheresis
2003, Atherosclerosis
Low density lipoprotein (LDL) apheresis provides a safe and effective means of treating patients with homozygous familial hypercholesterolaemia (FH). It also has a role in preventing the progression of coronary artery disease in heterozygotes and others with severe dyslipidaemia who are refractory to or intolerant of high doses of lipid-lowering drugs. Established methods involve either adsorption of apolipoprotein B-containing lipoproteins by affinity columns containing anti-apolipoprotein B antibodies or dextran sulphate, or their precipitation at low pH by heparin, in each instance after first separating plasma from blood cells with a cell separator. The most recently developed method enables lipoproteins to be adsorbed directly from whole blood, using polyacrylate columns. All 4 methods have proved to be similarly efficient when used weekly or biweekly to lower LDL cholesterol and Lp(a) without unduly reducing HDL cholesterol. Economic constraints restrict the use of LDL apheresis to the treatment of potentially fatal disorders such as FH, where there is clear evidence of benefit compared with conventional therapy. Widening the indications to include the treatment of other dyslipidaemic disorders such as steroid-resistant nephrotic syndrome, post-transplant donor vessel disease, stroke and prevention of re-stenosis after coronary angioplasty requires evidence from controlled trials that is currently lacking.

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Heparin extracorporeal LDL precipitation (HELP): an effective apheresis procedure for lowering Lp(a) levels

Abstract

Biochim. Biophys. Acta

Atherosclerosis

Atherosclerosis

Adv. Lipid Res.

Atherosclerosis

Clin. Chim. Acta

Lancet

Atherosclerosis

J. Lipid Res.

Atherosclerosis

Atherosclerosis

Atherosclerosis