79th EAS Congress Atherosclerosis Supplements 12, no. 1 (2011) 13–184 55 251 DO MTTP MUTATIONS OVERCOME HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA? SEGREGATION ANALYSIS IN A FAMILY WITH BOTH LDLR AND MTTP MUTATIONS M. Di Filippo 1,2 , N. Peretti 2,3 , P. Moulin 2,4,5 , C. Jacobs 1 , S. Chebel 1 , A. Lachaux 3,5 , A. Sassolas 1,2 . 1 Dept of Biochemistry, Hospices Civils de Lyon, 2 INSERM U1060 CarMeN, 3 Dept of Pediatric Gastroenterology, 4 Dept of Endocrinology, Hospices Civils de Lyon, 5 University Lyon 1, Lyon, France Objectives: To investigate genetic and clinical abnormalities and treatment efficacy in a Turkish consanguineous family with combined inheritance of both familial hypercholesterolemia and abetalipoproteinemia. Methods: Lipid profiles and systematic sequencing of MTTP, LDLR, ApoE and ApoB genes were performed for both parents and the three children. Results: Abetalipoproteinemia (homozygous c.59del17 MTTP) was first diag- nosed in child 1 (1 year old, LDLC < 0.02 g/l); father (24 years) LDLC was 1.39 g/l and mother (19 years) was 2.09 g/l. Five years later, the third child (4 years) showed a severe hypercholesterolemia (LDLC 4.64 g/l, IMTc 0.52 mm), leading to the study of the LDLR gene: he was homozygous for p.V523M (12−25% residual LDLR activity) and was not carrier of the MTTP mutation. Both parents were found subsequently heterozygous for both mutations, child 2 was unaf- fected. Simultaneously, the father showed an increase in LDLC (2.21 g/l) and a recent corneal arc (IMTc 0.85 mm). Following statin treatment LDLC decreased to: 1.48 g/l for the father (atorvastatine 10 mg), 1.32 g/l for the mother (fluvas- tatine 80 mg) and 1.45 g/l for the child (atorvastatine 10 mg, ezetimibe 30 mg); interestingly, the child normalized IMTc (0.39 mm) after 2 years treatment. Conclusion: Weak residual LDLR activity could explain the excellent treatment responsiveness of the homozygous LDLR mutation carrier. Normal LDLC concentration in the father with delayed hypercholesterolemia suggests that partial inhibition of MTP may strongly alter the phenotype of heterozygous hypercholesterolemia. 252 PLAQUE OXYSTEROLS INDUCE IMBALANCED UP-REGULATION OF MMP-9 IN MACROPHAGIC CELLS THROUGH REDOX-SENSITIVE SIGNALING PATHWAYS S. Gargiulo, P. Gamba, B. Sottero, G. Poli, G. Leonarduzzi. Clinical and Biological Sciences, University of Turin, Orbassano (Torino), Italy The rupture of a vulnerable atherosclerotic plaque is a major cause of thrombus formation leading to acute coronary syndrome. Connective tissue integry depends on a balance between degradation and repair of the extracellular matrix (ECM). The degradation of ECM by MMPs contribute to fibrous cap thinning and plaque rupture. Macrophages are considered to be the major source of these enzyme in vulnerable regions of the atherosclerotic plaques. The MMPs are inhibited by forming 1:1 complexes with TIMPs. MMP-9 has a prominent role in plaque formation, destabilization and rupture. The oxidized LDL contain numerous lipid oxidation products and among them, oxysterols are able to modulate several biochemical effects in the pathogenesis of atherosclerosis. To clarify the role of these compounds, we have studied the effect of an oxysterol mixture, whose composition is similar to that found in the human carotid plaques, on the MMP-9 expression by promonocytic U937 cells. Our results indicate that the oxysterols induce a significantly increase of mRNA, protein and activity of MMP-9, whereas they don’t affect the expression of the endogenous inhibitors TIMP-1 and TIMP-2. The cell treatment with the pharmacological in- hibitors and siRNA demonstrate that this effect is mediated by NADPH oxidase- dependent ROS over-production and activation of the MAP kinases ERK and JNK which, in turn, may act on the transcription factors AP-1 and NF-kB. Our data show that oxysterols can contribute to the plaque instability through the upregulation of MMP-9, key enzyme in the degradation of fibrous cap of the advanced atherosclerotic plaques. 253 SAFETY PROFILE OF STATINS ALONE OR COMBINED WITH EZETIMIBE: A POOLED ANALYSIS OF OVER 21,000 PATIENTS P.P. Toth 1 , W. Weintraub 2 , D. Morrone 2 , M.E. Hanson 3 , R.S. Lowe 3 , J. Lin 3 , A. Shah 3 , A.M. Tershakovec 3 . 1 Preventive Cardiology, Sterling Rock Falls Clinic, Sterling, IL, 2 Christiana Care Center for Heart & Vascular Health, Christiana Care, Newark, DE, 3 Merck, Whitehouse Station, NJ, USA Objective: Assess the safety and tolerability profiles of various statins + ezetimibe vs statin monotherapy using a pooled analysis of data. Methods: Data were combined from 27 double-blind, placebo-controlled or active-comparator studies that randomized adult hypercholesterolemic patients to statin or statin+ezetimibe for 6−24 weeks. In the full cohort, percent patients with adverse events (AEs) within treatment groups (statin: N = 10,517; statin+ezetimibe N = 11,714) was assessed by a logistic regression model with terms for first-/second-line therapy (statin-na¨ ıve/ongoing statin at study entry), trial within first-/second-line therapy, and treatment. The same model was fitted for age (<65, 65 years), gender, and race (white, black, other) subgroups with additional terms for subgroup and subgroup-by-treatment interaction. Results: In the full cohort, the only significant difference between treatments was in consecutive AST or ALT elevations 3× upper limit of normal (ULN), although the incidence was small (statin: 0.35%, statin+ezetimibe: 0.56%; p = 0.017). A significantly greater number of subjects reported 1 AE, drug- related, hepatitis-related and gastrointestinal-related AEs, and CK elevations 10×ULN (all p 0.008) in the first-line vs. second-line therapy studies in both treatment groups. AEs were generally similar between treatments in subgroups, and similar rates of AEs were reported between age and race subgroups; however, generally higher AE rates were reported for women. Conclusions: Statin+ezetimibe and statin monotherapy demonstrated gener- ally similar tolerability profiles. Ongoing statin treatment at study entry likely screened out participants for previous statin-related AEs and tolerability issues. Concerns regarding AEs should not limit lipid-altering therapy for subjects 65, though tolerability may be more of an issue for women. 254 PITAVASTATIN HAS PLEIOTROPIC ANTI-OXIDATIVE AND ANTI- INFLAMMATORY BENEFITS IN PATIENTS WITH DYSLIPIDAEMIA: RESULTS FROM A PHASE III STUDY PROGRAMME N. Hounslow. Kowa Research Europe, Wokingham, UK Aims: To determine the pleiotropic effects of pitavastatin by evaluating its anti- oxidative actions (reduction in pro-atherogenic oxidized low-density lipoprotein [Ox-LDL]) and anti-inflammatory effects (reductions in high sensitivity C-reactive protein [hs-CRP]) in patients at high risk of coronary heart disease (CHD). Methods: Evaluation of changes in Ox-LDL and hs-CRP (measured in a central research laboratory) in patients recruited to a 52-week open-label extension study of pitavastatin (NK-104–307), to two blinded active-controlled 44-week extension studies (NK-104–309 and NK-104–310) or to a 60-week open-label extension study (65 years of age; NK104–308). The daily dose of pitavastatin was 4 mg or 2 mg (NK-104–308). Patients had mixed (combined) dyslipidaemia or primary hypercholesterolaemia and a range of CHD risk factors, including type 2 diabetes and hypertension, and entered the extension studies from 12- week blinded core studies. Results: Pitavastatin 2−4 mg consistently decreased levels of Ox-LDL and hs- CRP during long-term treatment (Table). Table: Mean change (%) in Ox-LDL and hs-CRP Ox-LDL (U/L) hs-CRP (mg/L) Study Core study baseline* Change at end of core study Change at end of extension study Core study baseline Change at end of core study Change at end of extension study NK-104–307 (4 mg) 81.8 (n = 641) −30.8% −36.8% 3.19 (n = 1338) −13.5% −25.4% NK-104–309 (4 mg) 79.8 (n = 120) −33.4% −37.6% 3.53 (n = 120) −19.0% −11.9% NK104–310 (4 mg) 72.0 (n = 141) −30.0% −32.4% 3.38 (n = 141) N/A −9.5% NK-104–308 (2 mg) 79.1 (n = 511) −26.0% −38.4% 3.35 (n = 509) −0.6% −14.9% *Following a dietary and washout period of 6−8 weeks. Mean percentage changes are shown for individual patients from core study baseline. N/A, not available. Conclusions: Pitavastatin exerts beneficial anti-oxidative and anti-inflammatory effects in addition to its direct effects on cholesterol levels. 255 CORRELATION BETWEEN LP(A) AND PARAOXONASE IN PSORIASIS G. Ferretti 1 , T. Bacchetti 1 , A. Campanati 2 , O. Simonetti 2 , A. Offidani 2 . 1 Dipartimento di Biochimica, Biologia e Genetica, 2 Dipartimento di Medicina Clinica e Biotecnologie Applicate, Universit` a Politecnica delle Marche, Ancona, Italy Modifications of lipoprotein levels (LDL, HDL and VLDL) and composition play a role in inflammation and atherosclerosis. Recently, it has been demonstrated that also lipoprotein (a) [Lp(a)] is involved cardiovascular disease. Aim of the study was to investigate the relationship between Lp(a) levels, markers of oxidative stress and activity of paraoxonase (PON1), an antioxidant and antiinflammatory enzyme associated with HDL. The study was carried out in healthy subjects (n = 10) and patients affected by psoriasis (n = 23), an inflammatory disease associated with an increased risk of atherosclerosis. The results showed higher levels of Lp(a) in serum of psoriasis patients com- pared to controls (29.6±18.3 mg/dL vs 12.6±2.4 mg/dL; p < 0.001). Higher lev- els of lipid hydroperoxides (5.05±1.72 mmol/L vs 2.05±0.77 mmol/L, p < 0.001) and C-reactive protein (CRP) (0.69±0.56 mg/dL vs 0.32±0.15 mg/dL, p < 0.05) were observed in patients with respect to controls, confirming that psoriasis is associated with inflammation and oxidative stress. The mean value of serum PON1 activity, was lower in psoriasis patients (207.2±101.6 U/mL) with respect to controls (298.6±106.3 U/mL), but the differences were not statistically significant. Positive correlations were established between Lp(a) and lipid hydroperoxides (r = 0.71, n = 23, p < 0.001) or CRP levels (r = 0.56, n = 23;p < 0.01) in psoriasis subjects; in the same patients, a negative