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• W1978396895 abstract "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 Kaplan-Meyer 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 = 0.019), and this also remained stable in univariate (P = 0.027) and multivariate cox regression analyses (P = 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. 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 Kaplan-Meyer 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 = 0.019), and this also remained stable in univariate (P = 0.027) and multivariate cox regression analyses (P = 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. Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins with the arterial wall (1Williams K.J. Tabas I. The response-to-retention hypothesis of early atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar). Many processes have been implicated in early atherogenesis, including lipoprotein oxidation (2Witztum J.L. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Crossref PubMed Scopus (2468) Google Scholar), lipoprotein retention and aggregation, endothelial alteration, macrophage chemotaxis and foam cell formation, and smooth muscle cell migration and alteration (1Williams K.J. Tabas I. The response-to-retention hypothesis of early atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar, 3Nievelstein P.F. Fogelman A.M. Mottino G. Frank J.S. Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein.Arterioscler. Thromb. 1991; 11: 1795-1805Crossref PubMed Google Scholar). However, subendothelial retention and aggregation of LDL particles have emerged as the primary pathogenic processes (1Williams K.J. Tabas I. The response-to-retention hypothesis of early atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar, 4Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-808Crossref PubMed Scopus (9959) Google Scholar). 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 (5Maron D.J. Fazio S. Linton M.F. Current perspectives on statins.Circulation. 2000; 101: 207-213Crossref PubMed Scopus (1083) Google Scholar). Whether the benefit of statin therapy can completely explained by reducing LDL cholesterol (LDL-C) levels or whether other nonlipid- or lipid-associated effects may influence thrombus formation, inflammatory response, endothelial function, and plaque stability has been the subject of several publications (6Rosenson R.S. Tangney C.C. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.JAMA. 1998; 279: 1643-1650Crossref PubMed Scopus (977) Google Scholar, 7Libby P. Sasiela W. Plaque stabilization: Can we turn theory into evidence?.Am. J. Cardiol. 2006; 98: 26-33Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar–8Nicholls S.J. Tuzcu E.M. Sipahi I. Grasso A.W. Schoenhagen P. Hu T. Wolski K. Crowe T. Desai M.Y. Hazen S.L. et al.Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.JAMA. 2007; 297: 499-508Crossref PubMed Scopus (625) Google Scholar). Recent clinical trials have demonstrated that high-dose 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 (9Silber S. Albertsson P. Avilés F.F. Camici P.G. Colombo A. Hamm C. Jørgensen E. Marco J. Nordrehaug J.E. Ruzyllo W. Urban P. Stone G.W. Wijns W. Task Force for Percutaneous Coronary Interventions of the European Society of CardiologyGuidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology.Eur. Heart J. 2006; 26: 804-847Crossref Scopus (1602) Google Scholar, 10Cannon C.P. Braunwald E. McCabe C.H. Rader D.J. Rouleau J.L. Belder R. Joyal S.V. Hill K.A. Pfeffer M.A. Skene A.M. Intensive versus moderate lipid lowering with statins after acute coronary syndromes.N. Engl. J. Med. 2004; 350: 1495-1504Crossref PubMed Scopus (4297) Google Scholar, 11de Lemos J.A. Blazing M.A. Wiviott S.D. Lewis E.F. Fox K.A. White H.D. Rouleau J.L. Pedersen T.R. Gardner L.H. Mukherjee R. et al.Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.JAMA. 2004; 292: 1307-1316Crossref PubMed Scopus (1184) Google Scholar, 12LaRosa J.C. Grundy S.M. Waters D.D. Shear C. Barter P. Fruchart J.C. Gotto A.M. Greten H. Kastelein J.J. Shepherd J. et al.Intensive lipid lowering with atorvastatin in patients with stable coronary disease.N. Engl. J. Med. 2005; 352: 1425-1435Crossref PubMed Scopus (3000) Google Scholar–13Pedersen T.R. Faergeman O. Kastelein J.J. Olsson A.G. Tikkanen M.J. Holme I. Larsen M.L. Bendiksen F.S. Lindahl C. Szarek M. et al.High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.JAMA. 2005; 294: 2437-2445Crossref PubMed Scopus (1370) Google Scholar). The plasma phospholipid transfer protein (PLTP) is primarily involved in HDL metabolism. PLTP mediates net transfer and exchange of phospholipids between lipoproteins (14Tall A.R. Krumholz S. Olivecrona T. Deckelbaum R.J. Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis.J. Lipid Res. 1985; 26: 842-851Abstract Full Text PDF PubMed Google Scholar). PLTP can also cause convert HDL3 into larger and smaller particles in a time- and concentration-dependent fashion (15Tu A.Y. Nishida H.I. Nishida T. High density lipoprotein conversion mediated by human plasma phospholipid transfer protein.J. Biol. Chem. 1993; 268: 23098-23105Abstract Full Text PDF PubMed Google Scholar). 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 (16Huuskonen J. Ekstrom M. Tahvanainen E. Vainio A. Metso J. Pussinen P. Ehnholm C. Olkkonen V.M. Jauhiainen M. Quantification of human plasma phospholipid transfer protein (PLTP): relationship between PLTP mass and phospholipid transfer activity.Atherosclerosis. 2000; 151: 451-461Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 17Oka T. Kujiraoka T. Ito M. Egashira T. Takahashi S. Nanjee M.N. Miller N.E. Metso J. Olkkonen V.M. Ehnholm C. et al.Distribution of phospholipid transfer protein in human plasma: presence of two forms of phospholipid transfer protein, one catalytically active and the other inactive.J. Lipid Res. 2000; 41: 1651-1657Abstract Full Text Full Text PDF PubMed Google Scholar–18Karkkainen M. Oka T. Olkkonen V.M. Metso J. Hattori H. Jauhiainen M. Ehnholm C. Isolation and partial characterization of the inactive and active forms of human plasma phospholipid transfer protein (PLTP).J. Biol. Chem. 2002; 277: 15413-15418Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). 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-β-HDL particles (19Jiang X.C. Francone O.L. Bruce C. Milne R. Mar J. Walsh A. Breslow J.L. Tall A.R. Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.J. Clin. Invest. 1996; 98: 2373-2380Crossref PubMed Scopus (164) Google Scholar, 20Foger B. Santamarina-Fojo S. Shamburek R.D. Parrot C.L. Talley G.D. Brewer Jr., H.B. Plasma phospholipid transfer protein: adenovirusmediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL.J. Biol. Chem. 1997; 272: 27393-27400Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar–21Ehnholm S. van Dijk K.W. van't Hof B. van der Zee A. Olkkonen V.M. Jauhiainen M. Hofker M. Havekes L. Ehnholm C. Adenovirus mediated overexpression of human phospholipid transfer protein alters plasma HDL levels in mice.J. Lipid Res. 1998; 39: 1248-1253Abstract Full Text Full Text PDF PubMed Google Scholar). 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 (22Jiang X.C. Qin S. Min L. Schneider M. Tall A.R. Lagrost L. Phospholipid transfer protein (PLTP) deficiency represents an anti-oxidant state in mice.Circulation. 2001; 104: II-232Google Scholar, 23Qin S. Tall A.R. Jiang X.C. Phospholipid transfer protein deficiency reduces atherogenesis by inhibited LDL oxidation in LDL receptor knock out mice on western type diet.Circulation. 2001; 104: II-329Google Scholar). Moreover, PLTP’s 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 (24Jiang X.C. Qin S. Qiao C. Kawano K. Lin M. Skold A. Xiao X. Tall A.R. Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency.Nat. Med. 2001; 7: 847-852Crossref PubMed Scopus (231) Google Scholar) and increased bioavailability of vitamin E in atherogenic lipoproteins (25Jiang X.C. Tall A.R. Qin S. Lin M. Schneider M. Lalanne F. Deckert V. Desrumaux C. Athias A. Witztum J.L. et al.Phospholipid transfer protein deficiency protects circulating lipo- proteins from oxidation due to the enhanced accumulation of vitamin E.J. Biol. Chem. 2002; 277: 31850-31856Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). PLTP overexpression resulted in markedly increased atherosclerosis, due in part to decreased HDL levels (26van Haperen R. van Tol A. van Gent T. Scheek L. Visser P. van der Kamp A. Grosveld F. de Crom R. Increased risk of atherosclerosis by elevated plasma levels of phospholipid transfer protein.J. Biol. Chem. 2002; 277: 48938-48943Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar) and increased VLDL secretion (27Lie J. de Crom R. van Gent T. van Haperen R. Scheek L. Lankhuizen I. van Tol A. Elevation of plasma phospholipid transfer protein in transgenic mice increases VLDL secretion.J. Lipid Res. 2002; 43: 1875-1880Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). The role of PLTP in human atherosclerosis remains controversial. We have previously shown that high plasma PLTP activity is a risk marker for CAD (28Schlitt A. Bickel C. Thumma P. Blankenberg S. Rupprecht H.J. Meyer J. Jiang X.C. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1857-1862Crossref PubMed Scopus (115) Google Scholar). In contrast, a recently published study indicated that low PLTP activity was a risk factor for peripheral atherosclerosis (29Jauhiainen M. Metso J. Pahlman R. Blomqvist S. van Tol A. Ehnholm C. Human plasma phospholipid transfer protein causes high density lipoprotein conversion.J. Biol. Chem. 1993; 268: 4032-4036Abstract Full Text PDF PubMed Google Scholar). 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 (30Schgoer W. Mueller T. Jauhiainen M. Wehinger A. Gander R. Tancevski I. Salzmann K. Eller P. Ritsch A. Haltmayer M. et al.Low phospholipid transfer protein (PLTP) is a risk factor for peripheral atherosclerosis.Atherosclerosis. 2008; 196: 219-226Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). 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. Between November 1996 and July 2000, we recruited 1,085 patients suffering from symptoms of CAD (599 patients with stable angina [SAP]; 486 with acute coronary syndrome [ACS]) admitted to the II. Medical Department of the Johannes Gutenberg-University, Mainz, Germany, or the Hospital of the German Federal Armed Forces, Koblenz, Germany, for diagnostic coronary angiography. The sole inclusion criterion was the presence of a stenosis >30% in at least one major coronary artery. The study is described in detail elsewhere (31Schlitt A. Heine G.H. Jiang X.C. Messow M. Blankenberg S. Rupprecht H.J. Ulrich C. Buerke M. Werdan K. Lackner K.J. et al.Phospholipid transfer protein (PLTP) in hemodialysis patients.Am. J. Nephrol. 2007; 27: 138-143Crossref PubMed Scopus (10) Google Scholar). Exclusion criteria were lack of CAD as defined above and evidence of significant concomitant disease, in particular severe valvular heart disease, known cardiomyopathy, neoplastic disease, inflammatory disease, or a febrile condition. Patients completed a questionnaire about smoking habits, history of diabetes mellitus, hypertension, hyperlipoproteinemia, current drug use, and family history of premature CAD (documented in one first-degree relative before age 65). Diabetes mellitus was diagnosed in patients who had previously undergone dietary treatment or received additional oral antidiabetic or insulin medication or who had a current fasting blood sugar level >125 mg/dl. Patients who received antihypertensive treatment or had a blood pressure >160/90 mmHg in repeated measurements under standardized conditions were defined as hypertensive. Patients were followed up for a median of 5.1 years. The majority of the patients were invited for follow-up investigations and interviews and presented at our clinic. Patients that were not able or did not want to present at the clinic represents a small number. They were interviewed by telephone by trained medical staff. Approximately 2% of patients were lost to follow-up (lost to follow-up patients were found in all PLTP-quartiles). Totally, cardiovascular death or nonfatal myocardial infarction occurred in 156 patients. Information about the cause of death or clinical events was obtained from hospital or general practitioner charts. However, it was not possible in this subgroup of patients to get reliable information about medical treatment (statin intake) or other variables (active smoking) at the time of (fatal) events. In general, study patients were of German nationality and were inhabitants of the Rhein-Main Area. The study was approved by the ethics committee of the University of Mainz. Participation was voluntary, and each study subject gave written informed consent. Blood was drawn from all subjects under standardized conditions after a fasting period and before coronary angiography was performed. Plasma lipid levels [total cholesterol, Roche Diagnostics, Mannheim, Germany; HDL cholesterol (HDL-C), Rolf Greiner Biochemica, Flacht, Germany; LDL-C, calculated according to the Friedewald formula; triglycerides, Roche Diagnostics] were determined immediately. C-reactive protein (CRP) was determined by a highly sensitive, latex particle-enhanced immunoassay (detection range of 0–20 mg/l); the between-day imprecision of this assay (n = 21) was 2.14% and 1.44% at mean levels of 1.90 mg/l and 4.33 mg/l (Roche Diagnostics). PLTP activity was measured by using an assay kit (Cardiovascular Target, Inc., New York, NY), as described previously (28Schlitt A. Bickel C. Thumma P. Blankenberg S. Rupprecht H.J. Meyer J. Jiang X.C. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1857-1862Crossref PubMed Scopus (115) Google Scholar). Basically, the kit includes donor and acceptor particles. Incubation of donor and acceptor with 3 μl of human plasma results in the PLTP-mediated transfer of fluorescent phospholipid, which is present in a self-quenched state when associated with the donor. The transfer is determined by the increase in fluorescence intensity as the fluorescent lipid is removed from the donor and transferred to the acceptor. The interassay coefficient of variation of the PLTP activity was 3.3 ± 0.5%. The linear range of PLTP activity in this assay was between 1 μl and 7 μl of plasma. Three freeze-thaw cycles of plasma did not influence the assay. To validate this PLTP activity assay, we compared the results with those obtained by the classic method. The two methods were well correlated (r = 0.90, P < 0.01, n = 30) (14Tall A.R. Krumholz S. Olivecrona T. Deckelbaum R.J. Plasma phospholipid transfer protein enhances transfer and exchange of phospholipids between very low density lipoproteins and high density lipoproteins during lipolysis.J. Lipid Res. 1985; 26: 842-851Abstract Full Text PDF PubMed Google Scholar, 29Jauhiainen M. Metso J. Pahlman R. Blomqvist S. van Tol A. Ehnholm C. Human plasma phospholipid transfer protein causes high density lipoprotein conversion.J. Biol. Chem. 1993; 268: 4032-4036Abstract Full Text PDF PubMed Google Scholar). For detection of PLTP, samples were placed on ice immediately and within 30 min were centrifuged at 4,000 rpm for 10 min, divided into aliquots, and frozen at −80°C until analysis. Demographic and clinical variables of cases and controls were compared by the Chi-square test for categorical and t-test for continuous variables between patients receiving and not receiving statin therapy at baseline. Because of skewed distribution of triglyceride, HDL-C, and Hs-CRP levels, median values were presented and the Mann-Whitney test applied to assess these variables. We aimed to evaluate any evidence of an association between PLTP and CAD in models that assumed linear and nonlinear effects. We thus divided patients into quartiles. Survival was analyzed by the Kaplan-Meyer method and log-rank test. In all survival analyses, the endpoint comprised a combined endpoint of death of cardiovascular causes and nonfatal myocardial infarction. Data on patients who died of other causes were censored at the time of death. Hazard ratios and 95% confidence intervals (CIs) were reported with 2-tailed probability values. P < 0.05 was considered significant. All analyses were carried out using SPSS 11.5 software. Baseline data of our patients according to statin intake at baseline are specified in Table 1. Classical risk factors were not different; however, ACS was more frequently found in patients not under statin therapy at baseline. Hs-CRP and LDL-C were increased in these patients, whereas β-blocking agents, ACE inhibitors, and aspirin were used more often by patients who had been receiving statin therapy at baseline (Table 1).TABLE 1Patient baseline characteristicsVariableAll patientsStatins at baselineNo statins at baselinePPatients (n)1,085395690Age, years61.1 ± 10.160.3 ± 10.261.6 ± 10.00.683Sex, % male74.774.774.80.971BMI, kg/m227.2 ± 3.727.3 ± 3.827.1 ± 3.70.883Smoking (ever smoked), %37.236.237.80.603Diabetes, %21.719.522.90.190Hypertension, %71.174.969.90.074Family history of CAD, %38.240.536.80.228ACS, %44.835.949.9<0.001LVEF, %aLeft ventricular ejection fraction (LVEF) was determined in 902 patients.62.4 ± 14.763.5 ± 14.361.7 ± 14.90.494Beta blocking agents intake, %59.768.654.6<0.001ACE inhibitors intake, %48.154.244.60.002Aspirin intake, %87.693.284.5<0.001Total-cholesterol, mg/dl220 ± 46216 ± 49221 ± 440.164LDL-C, mg/dl142 ± 40138 ± 45144 ± 370.003HDL cholesterol, mg/dlbSkewed distributed variables are presented by median (25%/75%-interquartiles), statistical comparison by Mann-Whitney-test.47 (39/57)48 (38/58)46 (39/56)0.449Triglycerides, mg/dlbSkewed distributed variables are presented by median (25%/75%-interquartiles), statistical comparison by Mann-Whitney-test.140 (102/192)145 (106/199)138 (99.5/189)0.121Hs-CRP, mg/lbSkewed distributed variables are presented by median (25%/75%-interquartiles), statistical comparison by Mann-Whitney-test.4.46 (1.94/12.51)3.50 (1.50/9.06)5.13 (2.25/14.09)<0.001ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CRP, C-reactive protein; LDL-C, LDL cholesterol. Categorical variables are presented as percentage of patients, and P values were obtained by Chi-square test; continuous, normally distributed variables are presented as mean ± SD, and P values were obtained by t-test.a Left ventricular ejection fraction (LVEF) was determined in 902 patients.b Skewed distributed variables are presented by median (25%/75%-interquartiles), statistical comparison by Mann-Whitney-test. Open table in a new tab ACS, acute coronary syndrome; BMI, body mass index; CAD, coronary artery disease; CRP, C-reactive protein; LDL-C, LDL cholesterol. Categorical variables are presented as percentage of patients, and P values were obtained by Chi-square test; continuous, normally distributed variables are presented as mean ± SD, and P values were obtained by t-test. In Table 2, patient characteristics are stratified in comparison to PLTP-quartiles. We found no significant differences for all variables (see Table 2), although there seemed to be a nonsignificant trend for less-ACS patients in the higher quartiles of PLTP (P = 0.209) and for a decrease of Hs-CRP also in the higher quartiles of PLTP (P = 0.389). Moreover, statin intake at baseline was also not different in comparison of PLTP-quartiles (P = 0.202, see Table 2).TABLE 2Patient characteristics stratified by quartiles of phospholipid transferprotein (PLTP)First quartile PLTPSecond quartile PLTPThird quartile PLTPFourth quartile PLTPPatients (n)271272271271PRange PLTP, pmol/μl/h<17.8≥17.840–24.9≥24.9–31.169≥31.169Age, years61.1 ± 9.962.1 ± 10.260.6 ± 10.160.8 ± 10.30.282Sex, % male71.277.274.576.00.408BMI, kg/m227.2 ± 3.727.1 ± 3.727.1 ± 3.727.3 ± 3.90.886Smoking (ever smoked), %39.333.837.638.10.584Diabetes, %22.124.619.220.70.460Hypertension, %70.872.470.872.70.941ACS, %49.146.742.141.30.209LVEF, %aLeft ventricular ejection fraction (LVEF) was determined in 902 patients.61.9 ± 15.161.8 ± 14.462.8 ± 14.563.0 ± 14.80.772Statins intake, %38.733.840.232.80.202Total-cholesterol, mg/dl220 ± 45218 ± 49220 ± 43221 ± 470.775LDL-C, mg/dl141 ± 39141 ± 43142 ± 37143 ± 420.951HDL cholesterol, mg/dlbBecause of skewed distribution, log transformation was applied and antilog values are presented.49 ± 1449 ± 1548 ± 1550 ± 160.524Triglycerides, mg/dlbBecause of skewed distribution, log transformation was applied and antilog values are presented.165 ± 107160 ± 103170 ± 100164 ± 910.689Hs-CRP, mg/lbBecause of skewed distribution, log transformation was applied and antilog values are presented.15.2 ± 28.914.7 ± 27.914.5 ± 28.610.9 ± 29.70.389ACS indicates acute coronary syndrome; BMI, body mass index. Categorical variables are presented as percentage of patients, and P values were obtained by Chi-square test; continuous variables are presented as mean ± SD, and P values were obtained by ANOVA.Cox regression analyses of serum PLTP activity stratified by quartiles in univariate (model 1) and multivariate models (model 2 included the classical risk factors: age, sex, BMI, smoking, diabetes mellitus, arterial hypertension, family history of CHD and left ventricular ejection fraction, HS-CRP, and HDL-C) in patients without statins at baseline (3A) and with statins at baseline (3B).a Left ventricular ejection fraction (LVEF) was determined in 902 patients.b Because of skewed distribution, log transformation was applied and antilog values are presented. Open table in a new tab ACS indicates acute coronary syndrome; BMI, body mass index. Categorical variables are presented as percentage of patients, and P values were obtained by Chi-square test; continuous variables are presented as mean ± SD, and P values were obtained by ANOVA. Cox regression analyses of serum PLTP activity stratified by quartiles in univariate (model 1) and multivariate models (model 2 included the classical risk factors: age, sex, BMI, smoking, diabetes mellitus, arterial hypertension, family history of CHD and left ventricular ejection fraction, HS-CRP, and HDL-C) in patients without statins at baseline (3A) and with statins at baseline (3B). Figure 1demonstrates serum PLTP activity divided into quartiles in relation to the incidence of the combined endpoint (myocardial infarction and cardiovascular death) in the total cohort (Fig. 1A), in patients not receiving statins at baseline (Fig. 1B) and in patients receiving statins at baseline (Fig. 1C). The Kaplan-Meyer survival analyses showed that serum PLTP activity was not associated with the combined endpoint in the total cohort (P = 0.672 by log rank test, Fig. 1A) or in the subgroup of patients not receiving statins at baseline (P = 0.373 by log rank test, Fig. 1B). However, among the patients under statin treatment at baseline, a higher proportion of individuals who had suffered myocardial infarction and died of cardiovascular causes were found in the upper quartiles (P = 0.019 by log rank test, Fig. 1C). For further evaluation, univariate (model 1) and multivariate (model 2) Cox-regression analyses were performed in the subgroup of patients under statin therapy at baseline (Table 3). The univariate Cox regression analysis showed that PLTP activity was significantly related to the combined endpoint (P = 0.027 for all quartiles). This also remained significant in the multivariate Cox regression analyses including potential confounders (age, sex, body mass index, smoking, diabetes mellitus, arterial hypertension, family history of CHD, acute coronary syndrome, left ventricular ejection fraction, HDL-C, and HS-CRP, P = 0.041).TABLE 3.Model 1Model 2Events (%)Exp(B)Lower CIUpper CIPExp(B)Lower CIUpper CIPa. PLTP activity (pmol/μl/h)0.296aAll quartiles.0.460aAll quartiles.Q1 (<17.8)26 (24.3)Q2 (>17.8–24.9)29 (27.1)0.9900.5831.6810.970bFirst quartile.0.8910.4531.7500.737bFirst quartile.Q3 (>24.9–31.2)30 (29.0)1.1310.6721.9060.643bFirst quartile.1.3170.7062.4590.386bFirst quartile.Q4 (>31.2)21 (19.6)0.6670.3751.1850.167bFirst quartile.0.4080.4081.6680.592bFirst quartile.b. PLTP activity (pmol/μl/h)0.027aAll quartiles.0.041aAll quartiles.Q1 (<17.8)7 (14.9)Q2 (>17.8–24.9)9 (19.1)1.3840.4853.9450.543bFirst quartile.2.2070.5109.5550.290bFirst quartile.Q3 (>24.9–31.2)13 (27.7)1.8090.7304.4830.200bFirst quartile.3.0900.82211.6170.095bFirst quartile.Q4 (>31.2)18 (38.3)3.2981.3867.8460.007bFirst quartile.5.6631.54020.8270.009bFirst quartile.Cox regression analyses of serum PLTP activity stratified by quartiles in univariate (model 1) and multivariate models (model 2 included the classical risk factors: age, sex, BMI, smoking, diabetes mellitus, arterial hypertension, family history of CHD and left ventricular ejection fraction, HS-CRP, and HDL-C) in patients with statins at baseline. CI, confidence interval.a All quartiles.b First quartile. Open table in a new tab Cox regression analyses of serum PLTP activity stratified by quartiles in univariate (model 1) and multivariate models (model 2 included the classical risk factors: age, sex, BMI, smoking, diabetes mellitus, arterial hypertension, family history of CHD and left ventricular ejection fraction, HS-CRP, and HDL-C) in patients with statins at baseline. CI, confidence interval. Finally, we investigated the influence of statin treatment at baseline on cardiovascular outcome and found a nonsignificant increase of cardiovascular events in patients without statins at baseline (15.6% in patients without statins vs. 12.1% in patients with statins at baseline, P = 0.119, see Fig. 1D). In the present study, serum PLTP activity was not related to the combined endpoint in the patient group as a whole or in the subgroup of patients not receiving statins at baseline. However, we demonstrated that PLTP was a significant predictor for a combined endpoint including nonfatal myocardial infarction and death of cardiovascular causes in CAD patients under statin therapy according to Kaplan-Meyer and univariate Cox regression analyses. This remained stable in the multivariate Cox regression analysis including potential confounders related to outcome and/or related to PLTP activity, such as HDL-C, Hs-CRP, and left ventricular ejection fraction. Statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) are potent inhibitors of cholesterol biosynthesis. Large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might expect from changes in lipid profile alone, suggesting that the beneficial effects of statins might extend beyond those related to serum cholesterol levels. Indeed, experimental and clinical evidence indicates that some of the cholesterol-independent or pleiotropic effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation (32Takemoto M. Liao J.K. Pleiotropic effects of 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1712-1719Crossref PubMed Scopus (1221) Google Scholar). It is well known that plasma PLTP function involves much more than phospholipid transfer and exchange among the lipoproteins. PLTP deficiency contributes to reduced systemic inflammation in mice (33Yan D. Navab M. Bruce C. Fogelman A.M. Jiang X.C. PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity.J. Lipid Res. 2004; 45: 1852-1858Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 34Schlitt A. Liu J. Yan D. Mondragon-Escorpizo M. Norin A.J. Jiang X.C. Anti-inflammatory effects of phospholipid transfer protein (PLTP) deficiency in mice.Biochim. Biophys. Acta. 2005; 1733: 187-191Crossref PubMed Scopus (46) Google Scholar–35Liu R. Iqbal J. Yeang C. Wang D.Q. Hussain M.M. Jiang X.C. Phospholipid transfer protein-deficient mice absorb less cholesterol.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2014-2021Crossref PubMed Scopus (39) Google Scholar). Indeed, PLTP deficiency increased (25Jiang X.C. Tall A.R. Qin S. Lin M. Schneider M. Lalanne F. Deckert V. Desrumaux C. Athias A. Witztum J.L. et al.Phospholipid transfer protein deficiency protects circulating lipo- proteins from oxidation due to the enhanced accumulation of vitamin E.J. Biol. Chem. 2002; 277: 31850-31856Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar), while PLTP overexpression decreased the antioxidant potential in mouse models (36Yang X.P. Yan D. Qiao C. Liu R.J. Chen J.G. Li J. Schneider M. Lagrost L. Xiao X. Jiang X.C. Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein overexpression.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1601-1607Crossref PubMed Scopus (89) Google Scholar). Although PLTP seems to be involved in human atherogenesis, it is unclear under which circumstances high or low PLTP activity increases or decreases initiation or progression of atherosclerotic diseases (28Schlitt A. Bickel C. Thumma P. Blankenberg S. Rupprecht H.J. Meyer J. Jiang X.C. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1857-1862Crossref PubMed Scopus (115) Google Scholar, 30Schgoer W. Mueller T. Jauhiainen M. Wehinger A. Gander R. Tancevski I. Salzmann K. Eller P. Ritsch A. Haltmayer M. et al.Low phospholipid transfer protein (PLTP) is a risk factor for peripheral atherosclerosis.Atherosclerosis. 2008; 196: 219-226Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). The relationship between statin treatment and PLTP activity is unknown and published results are controversial. In a recent study in patients with type 2 diabetes, atorvastatin treatment resulted in a decrease in PLTP activity and an increase in PLTP mass, leading to a substantial change in mass-adjusted activity, which was related to apoE metabolism (37Dallinga-Thie G.M. van Tol A. Hattori H. Rensen P.C. Sijbrands E.J. Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atorvastatin: a role for apolipoprotein E?.Diabetes. 2006; 55: 1491-1496Crossref PubMed Scopus (22) Google Scholar). In contrast, serum PLTP activity showed no significant changes in patients with type IIb hyperlipidemia after simvastatin treatment compared with controls (38Lagrost L. Athias A. Lemort N. Richard J.L. Desrumaux C. Chatenet-Duchene L. Courtois M. Farnier M. Jacotot B. Braschi S. et al.Plasma lipoprotein distribution and lipid transfer activities in patients with type IIb hyperlipidemia treated with simvastatin.Atherosclerosis. 1999; 143: 415-425Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Moreover, combined treatment with simvastatin and niacin over 12 months did not alter PLTP activity in patients with low HDL and cardiovascular disease (39Cheung M.C. Wolfbauer G. Kennedy H. Brown B.G. Albers J.J. Plasma phospholipid transfer protein activity in patients with low HDL and cardiovascular disease treated with simvastatin and niacin.Biochim. Biophys. Acta. 2001; 1537: 117-124Crossref PubMed Scopus (17) Google Scholar). These differing results in humans may be explained by the different effects of statins on PLTP activity as shown in a study comparing the effect of pravastatin and simvastatin on PLTP activity in plasma and cerebrospinal fluid in mice (40Vuletic S. Riekse R.G. Marcovina S.M. Peskind E.R. Hazzard W.R. Albers J.J. Statins of different brain penetrability differentially affect CSF PLTP activity.Dement. Geriatr. Cogn. Disord. 2006; 22: 392-398Crossref PubMed Scopus (56) Google Scholar). We recently reported that PLTP activity was independent of current statin treatment (25.0 ± 9.6pmol/μl/h in patients receiving and 25.6 ± 9.9pmol/μl/h in patients not receiving statin therapy at baseline, P = 0.350) (28Schlitt A. Bickel C. Thumma P. Blankenberg S. Rupprecht H.J. Meyer J. Jiang X.C. High plasma phospholipid transfer protein levels as a risk factor for coronary artery disease.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1857-1862Crossref PubMed Scopus (115) Google Scholar). What could be the link between statin treatment and the prognostic value of plasma PLTP activity? PLTP activity and statin treatment are closely related to inflammation, lipoprotein oxidation, and reverse cholesterol transport (6Rosenson R.S. Tangney C.C. Antiatherothrombotic properties of statins: implications for cardiovascular event reduction.JAMA. 1998; 279: 1643-1650Crossref PubMed Scopus (977) Google Scholar, 7Libby P. Sasiela W. Plaque stabilization: Can we turn theory into evidence?.Am. J. Cardiol. 2006; 98: 26-33Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar–8Nicholls S.J. Tuzcu E.M. Sipahi I. Grasso A.W. Schoenhagen P. Hu T. Wolski K. Crowe T. Desai M.Y. Hazen S.L. et al.Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.JAMA. 2007; 297: 499-508Crossref PubMed Scopus (625) Google Scholar, 34Schlitt A. Liu J. Yan D. Mondragon-Escorpizo M. Norin A.J. Jiang X.C. Anti-inflammatory effects of phospholipid transfer protein (PLTP) deficiency in mice.Biochim. Biophys. Acta. 2005; 1733: 187-191Crossref PubMed Scopus (46) Google Scholar, 35Liu R. Iqbal J. Yeang C. Wang D.Q. Hussain M.M. Jiang X.C. Phospholipid transfer protein-deficient mice absorb less cholesterol.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 2014-2021Crossref PubMed Scopus (39) Google Scholar, 41Qin S. Kawano K. Bruce C. Lin M. Bisgaier C. Tall A.R. Jiang X. Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins.J. Lipid Res. 2000; 41: 269-276Abstract Full Text Full Text PDF PubMed Google Scholar). As these mechanisms are involved in progression of atherosclerotic diseases, they are related to clinical outcome of these patients (1Williams K.J. Tabas I. The response-to-retention hypothesis of early atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 551-561Crossref PubMed Google Scholar, 2Witztum J.L. Steinberg D. Role of oxidized low density lipoprotein in atherogenesis.J. Clin. Invest. 1991; 88: 1785-1792Crossref PubMed Scopus (2468) Google Scholar, 3Nievelstein P.F. Fogelman A.M. Mottino G. Frank J.S. Lipid accumulation in rabbit aortic intima 2 hours after bolus infusion of low density lipoprotein.Arterioscler. Thromb. 1991; 11: 1795-1805Crossref PubMed Google Scholar–4Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s.Nature. 1993; 362: 801-808Crossref PubMed Scopus (9959) Google Scholar). As a consequence, it is reasonable to find comparable effects of PLTP and statin treatment. We showed in our study that, under statin treatment, high plasma PLTP activity is related to fatal and nonfatal cardiovascular events in CAD patients, independent of other markers such as Hs-CRP or HDL-C. Thus, on one hand we hypothesize that in the statin-treated group, PLTP activity elevation may indicate that, except for lowering levels of cholesterol, statin treatment does not improve the anti-flammation and anti-oxidation properties or even affect reverse cholesterol transport (42Sviridov D. Hoang A. Ooi E. Watts G. Barrett P.H. Nestel P. Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin.Atherosclerosis. 2008; 197: 732-739Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). On the other hand, another interpretation of the results of our study is that the benefical effects of statins are blunted in patients with high PLTP activity, which means that high PLTP activity could be one confounder for less-beneficial effect of statin treatment. However, this analysis is descriptive and the interpretation and is limited by missing data about laboratory (e.g., PLTP activity) and clinical parameters (e.g., smoking) at follow-up especially in case of events. Our data are hypothesis generating; further prospective trials are warranted to elucidate the exact connection between statin treatment and PLTP activity." @default.
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