Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins Andrei C. Sposito a,b , Raul D. Santos a , Rosangela F. Ama ˆncio a , Jose A.F. Ramires a , M. John Chapman b , Raul C. Maranha ˜o a,c, * a Heart Institute (InCor), University of Sa ˜o Paulo Medical School, Sao Paulo, Brazil b INSERM Unite ´ 551, Ho ˆpital de la Pitie ´-Salpetriere, Paris, France c Faculty of Pharmaceutical Sciences, University of Sa ˜o Paulo, Sao Paulo, Brazil Received 8 March 2002; received in revised form 10 July 2002; accepted 9 August 2002 Abstract Delayed chylomicron clearance is a characteristic of patients with coronary artery disease. In vivo study of the clearance of labeled chylomicron-like emulsions constitutes a valid model system for evaluation of chylomicron catabolism. The effects of atorvastatin at low (10 mg) and high (40 mg) dose upon the intravascular metabolism and plasma kinetics of chylomicron-like emulsions were evaluated in fasting hyperlipidemic subjects (n /45). Subjects were randomized to a 6-week treatment period with placebo (n /15), low dose or high dose atorvastatin (10 mg/day, n /17 and 40 mg/day, n /13). The chylomicron-like emulsion, double-labeled with 14 C-Cholesteryl oleate ( 14 C-CE) and 3 H-triolein ( 3 H-TG), was injected in a bolus after a 12-h fast, and blood samples were collected up to 60 min. Plasma decay curves were determined for labeled emulsion CE and TG and residence times (RT) calculated by the occupancy principle. The 14 C-CE RT was decreased by 50% after low dose atorvastatin and by 73% after atorvastatin at high dose in comparison to placebo (P B/0.05). The 3 H-TG RT was significantly reduced ( /55%) after high dose atorvastatin, but in contrast was not significantly reduced after placebo or low dose statin. By compartmental analysis, both doses of atorvastatin led to marked elevation in the slow removal component of emulsion remnant particles (10 mg/day /107%; 40 mg/day /195%, P /0.01). Equally, the rapid removal component was increased ( /99%) at high dose (P /0.015). Recirculation of 3 H-fatty acids was significantly reduced at both statin doses (43 and 83%, respectively) in comparison to placebo (P /0.01). In conclusion, atorvastatin treatment accelerates the plasma clearance of chylomicron-like emulsions and reduces recirculation of fatty acids in subjects with atherogenic hyperlipidemia. Such effect might implicate in reduction of cardiovascular risk. # 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Chylomicrons; Remnants; HMG CoA reductase inhibitor; Triglyceride 1. Introduction Chylomicrons and their remnants are implicated in the pathophysiology of atherosclerosis. Normocholes- terolemic patients with coronary artery disease (CAD) exhibit delayed chylomicron catabolism as compared with normocholesterolemic subjects without CAD [1  /4]. In animal studies, it has been demonstrated that chylomicron remnants can rapidly penetrate and accu- mulate in the subendothelial space of the arterial wall, thereby leading to macrophage uptake and foam cell formation [5]. Therefore, it is likely that predisposition to chylomicron remnant retention in plasma could be an independent risk factor for genesis of CAD. The intravascular metabolism of chylomicrons con- sists of a three-step process: (i) triglyceride hydrolysis by lipoprotein lipase (LPL) with formation of remnants; (ii) transfer of surface fragments, such as phospholipids, free cholesterol and apolipoproteins, to HDL via the action of phospholipid transfer protein, and (iii) uptake * Corresponding author. Present address: Laborato ´rio de Metabolismo de Lı ´pı ´des, Instituto do Corac ¸a ˜o do Hospital das Clı ´nicas da F.M.U.S.P, Av. Dr. Eneas C. Aguiar, 44, Sao Paulo, SP, 05403 000, Brazil. Tel.:  /55-11-3082-3378; fax:  /55-11-3069-5574. E-mail address: ramarans@usp.br (R.C. Maranha ˜o). Atherosclerosis 166 (2003) 311  /321 www.elsevier.com/locate/atherosclerosis 0021-9150/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(02)00334-9