The rebound of lipoproteins after LDL-apheresis. Kinetics and estimation of mean lipoprotein levels

Abstract

We studied the rebound of lipoproteins in 20 hypercholesterolemic men [mean total cholesterol (TC) levels 9.6±1.8 mmol/l] after LDL-apheresis (LA) to determine the rate of recovery and the change in cholesterol synthesis, and to find a uniform estimation for time-averaged levels. After 10–20 months on biweekly LA using dextran sulfate cellulose columns and concomitant simvastatin administration, time-averaged levels (±SD) measured by integration of the area under the curve were as follows: TC 4.4±1.0 mmol/l, LDL cholesterol (LDL-C) 2.5±1.0 mmol/l, apolipoprotein B (apo B) 1.3±0.3 g/l, triglycerides (TG) 1.7±0.7 mmol/l, HDL-C 1.1±0.2 mmol/l, and lipoprotein(a) [Lp(a)] 53.7±49.4 mg/dl. Mean acute reductions in TC, LDL-C, apo B, Lp(a), and TG were 61, 77, 75, 76, and 62%, respectively. HDL-C levels were not influenced. Median recovery half times for TC, LDL-C, apo B, and Lp(a) were 3.0, 4.0, 2.3, and 3.5 days, respectively. The rebound of Lp(a) was identical to LDL-C, in 12 and 13 days post-treatment, respectively, whereas apo B and TC returned to pre-treatment levels in 7.5 and 10 days, respectively, due to the fast rebound of VLDL particles. Notwithstanding these differences, time-averaged levels (C_AVG) could be estimated uniformly for the four latter parameters with the formula: C_AVG=C_MIN+0.73(C_MAX−C_MIN), where C_MAX and C_MIN are the immediate pre- and post-treatment levels. During long-term treatment the whole-body cholesterol synthesis was increased as measured by the ratio lathosterol to cholesterol of 3.24±1.49 mmol/mmol, whereas no further transient increase in the recovery period after LA was found. In conclusion, long-term LA and simvastatin therapy induced acute and chronic changes in lipids and lipoproteins showing the feasibility of biweekly treatment. It was shown that time-averaged levels, as a measure for the effective plasma levels, can be accurately estimated from pre- and post-treatment levels only.

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].