The rebound of lipoproteins after LDL-apheresis. Kinetics and estimation of mean lipoprotein levels
Introduction
The performance of regular low density lipoprotein (LDL) apheresis permits the achievement of lower levels of LDL cholesterol which is usually not possible to attain with drug therapy alone [1], [2]. Consequently, the application of LDL-apheresis may offer opportunities in the arrest of progression or regression of coronary and peripheral vascular disease in selected hypercholesterolemic patient [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]. Only recently, two controlled LDL-apheresis regression studies were published, FH Regression Study and LAARS [10], [11]. Both studies showed angiographical arrest of progression of coronary artery disease in severe hypercholesterolemic subjects concomitantly treated with an HMG-CoA reductase inhibitor, whereas LAARS also showed reduction of the extent of peripheral vascular disease [14].
Treatment using selective LDL-apheresis removes large amounts of apolipoprotein B (apo B) containing lipoproteins from the body in a relatively short time, generally 2–4 h. Sawtooth-like alterations in lipoprotein concentrations are one of the most striking differences between patients undergoing repetitive LDL-apheresis and conventional therapy [15]. The efficacy of the treatment depends on the pre- and post-treatment lipid levels, and on the post-treatment return of lipids in plasma [16], [17], [18], [19], [20]. The combination therapy of LDL-apheresis and an HMG-CoA reductase inhibitor can be expected to decrease pre-treatment LDL cholesterol to lower levels and slow down the post-apheresis rebound, which permits prolongation of the intervals between the apheresis procedure [17], [20]. It has been shown that the increase of lipoprotein levels after the treatment can be explained by first order kinetics [16], [21]. Therefore, it is currently accepted that time-averaged concentrations provide the best estimate of the physiologically effective plasma levels of cholesterol during long-term treatment with LDL-apheresis [18].
There is no universal agreement whether the cholesterol synthesis is increased after a single apheresis or during regular treatments. An increased rate of cholesterol biosynthesis without any change in apo B synthesis has been reported after plasmapheresis [22], [23], [24], whereas both a transient increase and no change in cholesterol synthesis have been shown after LDL-apheresis [19], [20], [25], [26].
In this paper, we measured the rebound of lipids and lipoproteins in days following a treatment during long-term LDL-apheresis using dextran sulfate cellulose columns (DSC) [27]. Changes in the amounts of lipids and lipoproteins were measured, and the absolute and fractional recovery rates were calculated. Changes in cholesterol biosynthesis and in intestinal adsorption rate were quantitated indirectly by measurements of the sterol intermediate lathosterol and the plant sterol sitosterol in relation to serum cholesterol, respectively. The data were used for estimation of the mean effective lipid or lipoprotein concentrations with a formula during long-term biweekly treatment in the LDL-Apheresis Atherosclerosis Regression Study (LAARS) [11].
Section snippets
Subjects and treatment
The present study was carried out in subjects randomised to treatment with LDL-apheresis in the LDL-Apheresis Atherosclerosis Regression Study (LAARS) [11]. In this study the effect of 2 years of cholesterol lowering using biweekly LDL-apheresis plus simvastatin treatment was compared with the effect of conventional lipid lowering with simvastatin alone on coronary [11], [28] and peripheral vascular disease [14]. All eligible LAARS participants were men with a primary hypercholesterolemia and
Acute reductions in plasma lipids and lipoproteins
During biweekly treatment with LDL-apheresis and simvastatin lipid and lipoprotein concentrations were reduced to the pre-treatment levels (CMAX), as shown in Table 1. LDL-apheresis acutely reduced plasma total cholesterol and triglycerides to the same extent, 61 and 62%, respectively, whereas LDL cholesterol, apo B, and Lp(a) were lowered further and also to the same extent by an average of 77, 75, and 76%, respectively. HDL cholesterol levels were not influenced by LDL-apheresis. Immediate
Discussion
The aim of the present study was to examine acute changes induced by a single apheresis procedure during chronic treatment. It was demonstrated that LDL-apheresis induced substantial reductions in plasma lipids and lipoproteins, more than has been shown by others using DSC columns, immunoadsorption, or HELP (Heparin Extracorporeal LDL Precipitation) [7], [8], [9], [10], [11], [12], [13]. Dependent on the; initial levels, apheresis selectively removed large amounts of apo B-containing
Acknowledgements
This work was supported by the Dutch Heart Foundation (grant 90.065). We gratefully acknowledge the expert technical assistance of M. Hectors, P. van Heijst, and H. Hak-Lemmers.
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