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(Circulation. 2005;112:2446-2453.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Ability of Serum to Decrease Cellular AcylCoA:Cholesterol Acyl Transferase Activity Predicts Cardiovascular Outcomes

Julio A. Chirinos, MD; Juan P. Zambrano, MD; Simon Chakko, MD; Alan Schob, MD; Ronald B. Goldberg, MD; Guido Perez, MD; Armando J. Mendez, PhD

From the Miller School of Medicine, University of Miami (J.A.C., J.P.Z., S.C., A.S., R.B.G., G.P., A.J.M.), the Diabetes Research Institute (R.B.G., A.J.M.), and the Veterans Affairs Medical Center (S.C., A.S.), Miami, Fla.

Correspondence to Armando J. Mendez, PhD, Miller School of Medicine, University of Miami, Diabetes Research Institute (R-134), 1450 NW 10th Ave, Miami, FL 33138. E-mail amendez2{at}med.miami.edu

Received November 15, 2004; revision received April 27, 2005; accepted May 3, 2005.

Background— We evaluated whether cholesterol efflux activity of serum is associated with the presence of angiographic coronary artery disease (CAD) and the risk of major adverse cardiovascular events (MACE) and death.

Methods and Results— We studied 168 men undergoing coronary angiography. Cholesterol efflux activity was measured in vitro by incubation of patient serum with human skin fibroblasts and defined as the ability of serum to decrease the pool of cholesterol available for esterification by the acylCoA:cholesterol acyl transferase (ACAT) reaction. We evaluated whether this activity was associated with the presence of CAD and the risk of MACE and death during a 4.5-year follow-up. Serum-induced changes in ACAT activity did not correlate with HDL levels or the presence of CAD. Patients in the highest tertile of change in ACAT activity had a significantly higher risk for MACE (HR, 2.15; 95% CI, 1.36 to 3.39; P=0.001) and death (HR, 2.23; 95% CI, 1.17 to 4.26; P=0.01). These correlations were independent of other risk markers including LDL, HDL, and C-reactive protein levels.

Conclusions— Serum-induced depletion of cellular cholesterol available for esterification by ACAT was a strong, independent predictor of MACE and death. We speculate that the ability of serum to decrease ACAT activity depends on ATP binding cassette transporter A1 (ABCA1)–mediated efflux. Furthermore, serum samples that induce larger changes in ACAT activity contain increased levels of HDL particles that preferentially interact with ABCA1 and that these particles accumulate in the serum of patients because of low activity of ABCA1 in vivo preventing or limiting the extent of apoA-I lipidation.

Key Words: cardiovascular diseases • lipoproteins • cholesterol efflux • morbidity • risk factors