patient-oriented and epidemiological research PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study

Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 patients who were on statins at baseline. In KaplanMeyer analyses serum PLTP activity was not associated with the combined endpoint in all patients. However, in the subgroup of patients receiving statins at baseline, PLTP was shown to be a significant predictor of cardiovascular outcome (P 5 0.019), and this also remained stable in univariate (P 5 0.027) and multivariate cox regression analyses (P 5 0.041) including potential confounders (classical risk factors, HDL cholesterol (HDL-C), and others). We showed in our study that, under statin treatment, high plasma PLTP activity was related to fatal and nonfatal cardiovascular events in CAD patients. —Schlitt, A. , S. Blankenberg, C. Bickel, K. J. Lackner, G. H. Heine, M. Buerke, K. Werdan, L. Maegdefessel, U. Raaz, H. J. Rupprecht, T. Munzel, and X-C. Jiang. PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene Study. J. Lipid Res. 2009. 50: 723–729. Supplementary key words lipid transfer proteins • atherosclerosis • 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors Atherogenesis is initiated by the interaction of cholesterolrich lipoproteins with the arterial wall (1). Many processes have been implicated in early atherogenesis, including lipoprotein oxidation (2), lipoprotein retention and aggregation, endothelial alteration, macrophage chemotaxis and foam cell formation, and smooth muscle cell migration and alteration (1, 3). However, subendothelial retention and aggregation of LDL particles have emerged as the primary pathogenic processes (1, 4). Primary and secondary intervention trials in patients with coronary atherosclerosis have shown that treatment with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (statins) reduces the relative risk of major coronary events by approximately 30%, demonstrating a greater benefit for patients with a higher baseline risk (5). Whether the benefit of statin therapy can completely explained by reducing LDL cholesterol (LDL-C) levels or whether other nonlipidor lipid-associated effects may influence thrombus formation, inflammatory response, endothelial function, and plaque stability has been the subject of several publications (6–8). Recent clinical trials have demonstrated that highdose statin therapy provides cardiovascular benefits beyond those of conventional statin therapy among patients with unstable and stable coronary artery disease (CAD). Thus, current guidelines recommend the use of high-dose statin therapy in patient populations at an increased risk for cardiovascular events with an optional therapeutic goal of LDL-C below 70 mg/dl (9–13). This work was partially supported by grants HL69817 and AHA Grant-in-Aid (0755922T). Competing interests: The authors declare that they have no competing interests. All authors have made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. All authors have been involved in drafting the manuscript or revising it critically for important intellectual content, and have given final approval of the version to be published. Manuscript received 5 August 2008 and in revised form 19 September 2008 and in re-revised form 20 October 2008. Published, JLR Papers in Press, November 10, 2008. DOI 10.1194/jlr.M800414-JLR200 1 To whom correspondence should be addressed. e-mail: axel.schlitt@medizin.uni-halle.de Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc. This article is available online at http://www.jlr. org Journal of Lipid Research Volume 50, 2009 723 The plasma phospholipid transfer protein (PLTP) is primarily involved in HDL metabolism. PLTP mediates net transfer and exchange of phospholipids between lipoproteins (14). PLTP can also cause convert HDL3 into larger and smaller particles in a timeand concentration-dependent fashion (15). Because there are two forms of PLTP in human plasma, one being catalytically active and the other not, activity measurement of PLTP is more relevant than its mass measurement (16–18). Genetic mouse models have played a crucial role in elucidating the role of PLTP. In PLTP transgenic mice, PLTP overexpression increases the influx of phospholipids and secondarily of cholesterol into HDL, leading to an increase in pre-b-HDL particles (19–21). PLTP gene knockout mice have provided the first in vivo evidence of a crucial role for PLTP-mediated lipid transfer in the maintenance of lipoprotein levels (22, 23). Moreover, PLTPʼs proatherogenic potency has been demonstrated in atherogenic mouse models: PLTP deficiency resulted in markedly decreased atherosclerosis, due in part to decreased production and lower levels of apoB-containing lipoproteins (24) and increased bioavailability of vitamin E in atherogenic lipoproteins (25). PLTP overexpression resulted in markedly increased atherosclerosis, due in part to decreased HDL levels (26) and increased VLDL secretion (27). The role of PLTP in human atherosclerosis remains controversial. We have previously shown that high plasma PLTP activity is a risk marker for CAD (28). In contrast, a recently published study indicated that low PLTP activity was a risk factor for peripheral atherosclerosis (29). Furthermore, we found that serum PLTP activity was higher in hemodialysis patients than in matched controls, presenting as a further aspect of uremic dyslipidemia in end-stage kidney disease. However, PLTP activity was not related to survival in this patient group (30). Thus, the significance of PLTP involvement in atherogenesis is still an open issue. In order to further investigate the role of PLTP in atherosclerosis, we measured plasma PLTP levels in 1,085 patients with angiographically proven CAD and its relationship to clinical outcome.