Effect of extracorporeal low-density lipoprotein elimination on circulating cell adhesion molecules in patients with hypercholesterolemia.

L of circulating cell adhesion molecules (cCAM) may be useful markers for stratifying cardiovascular disease severity or prognosis.1–4 Furthermore, cCAM levels are elevated in subjects with insulin resistance, type 2 diabetic patients, hypertensive patients, and in smokers.5–11 The reported effects of hypercholesterolemia on cCAM levels, however, has been controversial.12–15 Sampietro and colleagues12 reported that familial hypercholesterolemia was associated with elevated levels of cICAM-1 and cE-selectin. They found a decrease in the levels of these soluble CAMs immediately after extracorporeal low-density lipoprotein (LDL) elimination, which is capable of preventing the progression and initiating the regression of atherosclerosis in hypercholesterolemic patients by inducing functional improvement, which may precede anatomic changes.16,17 According to their hypothesis, plasma cholesterol regulates soluble CAM expression in familial hypercholesterolemia and soluble CAMs may serve as markers of efficacy in lipid-lowering trials. Futhermore, they concluded that the beneficial effects of LDL elimination on cardiovascular risk may be partially attributable to the downregulation of endothelial CAMs.12 Such an effect, if at least partially mediated by downregulation of endothelial CAM expression, would, however, presume a long-term effect. In contrast, a number of studies have shown that hypercholesterolemia is not correlated with increased cCAM levels.13,15 Therefore, the aim of the present study was to assess both the shortand long-term effects of LDL apheresis on the levels of circulating intercellular cell adhesion molecule (cICAM-1), circulating vascular cell adhesion molecule (cVCAM-1), and cE-selectin in patients with familial hypercholesterolemia. Eight hypercholesterolemic patients (4 men, 4 women; average age 52 6 15 years) were recruited at 3 LDL apheresis centers (Department of Internal Medicine IV of the University of Leipzig, Department of Metabolic Research of the Medical Faculty Carl Gustav Carus Dresden, and the Vogtland Clinic Plauen GmbH, Germany). The underlying hyperlipoproteinemia was heterozygous familial hypercholesterolemia. Patients had proved to be refractory to cholesterol-lowering drug therapy. A cholesterol-lowering diet equivalent to the American Heart Association step I diet and cholesterol-lowering drug therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and lovastatin was continued during the period of LDL apheresis treatment. All patients included in the study had various degrees of cardiovascular disease. The presence and severity of coronary artery disease was documented by coronary angiography. Patients with acute myocardial infarction, secondary hyperlipidemia, impaired hepatic or renal function, hypertension, diabetes mellitus, obesity, clinically manifest infections, connective tissue disease, malignancy, or who were on anti-inflammatory or cytotoxic drugs were excluded from the study. The Ethical Committee of the University of Leipzig approved the project plan and the patients gave informed consent. The method used for extracorporeal LDL elimination was DALI (Direct Adsorption of Lipids, Fresenius St. Wendel, Germany). In this LDL apheresis system, the elimination of LDL and lipoprotein(a) (Lp(a)) is performed not in plasma but in human whole blood by adsorption onto polyacrylatecoated polyacrylamide beads.18,19 LDL apheresis treatment was performed at weekly intervals. To test the long-term effects of extracorporeal LDL elimination, laboratory measurements were performed at baseline before the LDL apheresis procedure, 1 month after therapy, and 2, 3, and 6 months after LDL apheresis treatment. Furthermore, repeated measurement were performed immediately before and after each apheresis procedure in 10 patients. Blood samples, except those taken immediately after apheresis, were obtained after an overnight fast for measurement of serum lipids, apolipoproteins and lipoproteins, cCAMs, and other clinical chemistry parameters. Serum levels of ICAM-1, VCAM-1, and E-selectin were determined by monoclonal antibodybased enzyme-linked immunosorbent assays (R & D Systems, Europe Ltd., Abingdon, United Kingdom). All samples were tested twice. Cholesterol and triglyceride concentrations were determined using test kits from Roche Diagnostics Mannheim GmbH (Mannheim, Germany) (cholesteroloxidase–phenol, aminophenazone, peroxidase [CHOD-PAP] method). To determine serum high-density lipoprotein (HDL) cholesterol, we used the polyethylene glycol 20 000 precipitation method (Quantolip, Immuno GmbH, Heidelberg, Germany). LDL cholesterol was measured with the help of precipitation reagent polyvinyl From the Departments of Clinical Chemistry and Pathobiochemistry, Internal Medicine IV, and Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; the Department of Metabolic Research, Medical Faculty Carl-Gustav-Carus Dresden, Dresden; and the Vogtland Clinic Plauen GmbH, Plauen, Germany. Dr. Richter’s address is: Department of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Liebigstr. 27, 04103 Leipzig, Germany. E-mail: [email protected]. Manuscript received August 15, 2000; revised manuscript received and accepted December 1, 2000.