- Email: [email protected]
505 THE RELATIONSHIP BETWEEN HDL-CHOLESTEROL AND HDL FUNCTION
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
Methods and Results: The study population consisted of 127 consecutive patients with proven or suspected CAD, but without acute coronary syndrome, who underwent 64-slice CTA. CTA was used to assess 1. coronary calcification; 2. stenosis severity; 3. non-calcified plaque volume; 4. plaque composition. Sixty-eighth patients (age 59.9±12.5 years; 50% men) exhibited non-calcified plaques while 59 patients (age 65.8±10.4 years; 80% men) had calcified plaques and prevalence of stenotic plaques. Specification of plaque morphology revealed a significant inverse association between sRAGE levels and percent fibro-lipidic wall volume and a direct association between sRAGE and percent luminal volume in the patients with non-calcified plaques (r = −0.254, p = 0.0444 and r = 0.296, p = 0.014 respectively) but not in the patients with calcified plaques (r = −0.064, p = 0.637 and r = −0.101, p = 0.450 respectively). In a fully adjusted multivariate model sRAGE levels remained predictive of percent fibro-lipidic wall volume (b = −0.292, p = 0.0271). Conclusions and Significance: Decreased sRAGE levels were significantly associated with fibro-lipidic wall burden identified by CTA. Low levels of sRAGE can help identify those patients with subclinical atherosclerosis who are at risk for near-term atherothrombotic events. 502 ASSOCIATION OF BLOOD ACTIVE MATRIX METALLOPROTEINASE-3 WITH CAROTID PLAQUE SCORE IN MALE FROM A COMMUNITY POPULATION IN TAIWAN L.-M. Lien1 , Y.-C. Hsieh2 , C.-H. Bai2 , W.-H. Chen1 , H.-C. Chiu1 , F.-I. Hsieh2 , K.-G. Shyu3 , H.-Y. Chiou2 . 1 Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, 2 School of Public Health, Taipei Medical University, 3 Department of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan R.O.C. Objective: Blood levels of active matrix metalloproteinases-3 (MMP-3) are reported to be associated with the extent of carotid atherosclerosis based on carotid plaque score (PS) in a community population recently. However, the blood level of total MMP-3 is usually lower in female as compared with male. In this study, we assessed blood levels of active MMP-3 in relation to PS in male and female. Methods: In 433 subjects from a community primary stroke prevention program, blood levels of active MMP-3 and total MMP-3 were determined using enzymelinked immunosorbent assays and carotid plaque score (PS) by high-resolution B-mode ultrasonography. Results: The blood levels of active MMP-3 (8.4±4.1ng/ml vs. 4.0±2.4ng/ml, p < 0.0001) and total MMP-3 (13.1±5.6ng/ml vs. 6.6±3.3ng/ml, p < 0.0001) are both higher in male than in female, respectively. Study subjects were separated into 3 groups based on PS: group 1 (PS = 0), group 2 (PS = 1−2) and group 3 (PS 3). Blood levels of active MMP-3, but not total MMP-3, bear a highly significant relationship with PS in male, but not in female, (active MMP-3 level in group 1: 7.5±3.2ng/ml, group 2: 8.4±3.9ng/ml, and group 3: 10.7±5.5ng/ml; p for trend = 0.0004). A stepwise logistic regression analysis after adjustment of potential covariates including age, hypertension and cigarette smoking revealed blood levels of active MMP-3 are correlated with PS (OR, 1.5; 95% CI, 1.1 to 2.0; p = 0.006) in male. Conclusion: Blood levels of active MMP-3 are associated with the extent of carotid atherosclerosis in this community population in male but not in female in Taiwan. 503 ASSOCIATION OF COPY NUMBER VARIATIONS AND SINGLE NUCLEOTIDE POLYMORPHISMS IN METALLOTHIONEIN GENES WITH PATHOGENESIS OF DIABETES AND CORONARY ARTERY DISEASE R. Kozarova1 , A. Postadzhiyan2 , B. Finkov2 , M. Apostolova1 . 1 Institute of Molecular Biology, Bulgarian Academy of Sciences, 2 Clinic of Cardiology, St. Anna Hospital, Sofia, Bulgaria Introduction: Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) are widely distributed in the human genome. SNPs have allele frequency of 1%, while CNVs involve DNA fragment which is >1 kb. Methods: QPCR was used to detect the MT1X gene variations. SNPs +1245A/G in MT1A and −209A/G in MT2A gene were analyzed. Molecular analyses of CNVs and SNPs were done in 142 patients with coronary artery disease (CAD), 101 diabetic patients without clinical evidence for cardiovascular disease and 117 aged and sex matched controls. Results: 334 different CNVs were detected using 105K array CGH (Agilent Technologies). QPCR analyses for MT1X gene copy number variations confirmed the data from CGH array and showed significant association with developing of CAD (c2 = 21.036; OR = 4.787; 95% CI = 2.382–9.620; p < 0.001) and diabetes (c2 = 21.632; OR = 5.448; 95% CI = 2.565–11.570; p < 0.001). The polymorphism +1245A/G MT1A was significant associated with CAD (c2 = 9.492; p = 0.002). A binary logistic regression showed that +1245 AA
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genotype (comparing to AG + GG-genotypes) was independent predictor only for CAD after adjustment for the conventional risk factors (adjusted OR = 6.712, 95% CI = 1.818–24.775; p = 0.004). The polymorphism −209 A/G MT2A showed significant association of −209 AG+GG genotypes compared to −209 AA genotypes (c2 = 3.825; OR = 4.130; 95% CI = 0.904–18.862; p = 0.050) only in patients with diabetes. Conclusion: Changes in copy numbers of MT1X gene possibly contribute to developing of CAD and Diabetes mellitus. SNP analyses showed that +1245 AA genotype is independently associated with an increased risk of CAD after adjusting for classical risk factors where the −209 AG+GG MT2A genotype is predominantly associated with diabetes. 504 SMALL ARTERIES DILATION AND ENDOTHELIAL MARKERS IN CARDIOVASCULAR RISK PATIENTS G. Aragones, ` R. Ferre, ´ J. Girona, N. Plana, J. Merino, M. Heras, L. Masana. Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Universitat Rovira i Virgili, Internal Medicine Department, Sant Joan University Hospital, IISPV. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Reus, Spain Background: The use of methods based on reactive hyperaemia of small distal arteries to assess endothelial function (EF) is increasing at the clinical level; however, the mechanisms regulating vascular function in large and small arteries are different and still not completely understood. We studied the correlations between hyperaemia reactivity of small peripheral arteries determined by peripheral artery tonometry (PAT) and the levels of serum biomarkers of EF, inflammation and oxidation in patients with cardiovascular (CV) risk factors. Methods: 407 patients without previous CV disease but at intermediate CV risk were recruited into a cross-sectional study to examine whether soluble endothelial, inflammatory and lipid oxidative biomarkers correlate with small arteries reactive hyperaemia index (saRHI) values, which were measured by PAT. Results: A significant correlation was found between saRHI values and the concentrations of soluble E-selectin (sE-selectin) (r = −0.184, P < 0.0001) and soluble VCAM-1 (sVCAM-1) (r = −0.119, P = 0.018). The correlation remained significant after adjustment for confounding variables. Patients with a lower saRHI (saRHI < 1.70) had higher concentrations of sE-selectin, sVCAM-1 and oxLDL/LDL (P < 0.0001, P = 0.023 and P = 0.048, respectively). Using a stepwise multivariable linear regression model, we found that sE-selectin was the only biomarker that significantly correlated with saRHI values (P < 0.0001). Conclusion: Elevated levels of sE-selectin, sVCAM-1 and oxLDL/LDL are associated with lower postischemic reactivity in the small distal arteries, which suggests that similar mechanisms are involved in the vascular function of large and small arteries. Therefore, methods based on the saRHI could be useful tools to assess EF at the clinical level. 505 THE RELATIONSHIP BETWEEN HDL-CHOLESTEROL AND HDL FUNCTION L. Wade1 , M. Widdowson2 , A. Mcgown2 , J. Gibney2 , F. Thies3 , A. Mcginty1 , I. Young1 , J. McEneny1 . 1 Centre for Public Health, Queen’s University Belfast, Belfast, UK , 2 Endocrinology and Diabetes, Adelaide and Meath Hospital, Dublin, Ireland, 3 School of Medicine and Dentistry, Aberdeen University, Aberdeen, UK Background: Epidemiological evidence has revealed that HDL protects against cardiovascular disease (CVD). However, CVD can be present in individuals with normal or even high HDL-cholesterol, suggesting that HDL-cholesterol levels may not predict its functionality. Objectives: To assess if HDL-cholesterol levels can predict the activity of HDL associated enzymes, and therefore, predict HDL function. Furthermore, the role of obesity and the adipocyte derived inflammatory molecule serum amyloid-A (SAA) on HDL function were also assessed. Design: Serum was collected from 118 overweight control subjects (48 males, 70 females, (mean±SEM) 50±0.07years: HDL-cholesterol, 1.54±0.00 mmol/l: BMI, 27.4±0.04 Kg/m2 ). HDL was subfractionated into HDL2&3 by rapid ultracentrifugation and the activity of paraoxonase-1 (PON-1; spectrophotometrically) and lecithin cholesteryl acyl transferase (LCAT) & cholesterol-ester transfer protein (CETP; fluorometrically) were assessed within HDL2&3 . SAA was measured within serum and HDL2&3 by an ELISA method. Results: As serum HDL-cholesterol levels increased there was a concomitant increase in PON-1 activity within HDL2&3 (HDL2 r = 0.290, p = 0.002; HDL3 r = 0.301, p = 0.001) and a decrease in CETP activity within HDL2 (r = −0.343, p = 0.000). Additionally, as BMI increased, serum HDL-cholesterol (r = −0.362, p = 0.000), HDL2 -protein (r = −0.199, p = 0.036) and HDL2&3 PON-1 activity (r = −0.222, p = 0.019; r = −0.263, p = 0.005, respectively) decreased, while HDL2 CETP activity increased (r = 0.215, p = 0.023). BMI positively correlated with serum-SAA (r = 0.270, p = 0.005) and SAA-associated with HDL2&3 (HDL2 r = 0.334, p = 0.002; HDL3 r = 0.240, p = 0.012).
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Discussion: These results demonstrate that HDL-cholesterol is weakly associated with HDL function, suggesting that complete compositional/functional analyses may be required to fully establish HDL’s anti-atherogenic properties. 506 BIOMARKERS OF INFLAMMATION AND OXIDATIVE STRESS INDEPENTLY PREDICT THE PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS D.J. Mulder1 , J.D. Lefrandt1 , E. Tremoli2,3 , D. Baldassarre2,3 , A.J. Smit1 , on behalf of the IMPROVE Study Group. 1 Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands, 2 Department of Pharmacological Sciences, University of Milan, 3 Monzino Cardiology Center, IRCCS, Milan, Italy Objectives: Prediction of cardiovascular events by inflammation and oxidative stress biomarkers reflects their pivotal role in development of atherosclerosis. However, it is unclear whether such biomarkers are associated with an accelerated progression of subclinical atherosclerosis. Methods: 151 asymptomatic subjects with 3 RFs participating in the IMPROVE observational study were included (median age 63; 67 male). Carotid IMT was measured at baseline and after 30 months. At baseline biomarkers were measured in blood samples, including WBC and CRP, neopterin, soluble receptor for advanced glycation end products (AGEs), tissue inhibitor of metalloproteinase-1 (TIMP1) and metalloproteinase-9 (MMP9), and diene concentration and antibodies against oxidized LDL (oxLDL), and autofluorescence, noninvasively measured in skin (SAF) as a marker for tissue accumulation of AGEs. Results: At baseline most conventional RFs correlated significantly with CIMT. Of the biomarkers, only SAF correlated with CIMT (r = 0.24, p = 0.001). At followup, a small increase was observed in the CIMT (0.020 (0.086) mm, p = 0.006). In contrast to RFs, the biomarkers, including CRP (r = 0.22, p = 0.007), oxLDL (r = 0.21, p = 0.012), TIMP1 (r = 0.29, p = 0.001), and WBC (r = 0.23, p = 0.004) correlated with CIMT progression. After stepwise, multiple regression, TIMP1 (b = 0.28, p = 0.001) and oxLDL (b = 0.25, p = 0.003) remained independently associated with CIMT. Conclusions: In asymptomatic subjects at high cardiovascular risk, conventional RF and SAF reflected the initial atherosclerosis profile, but several biomarkers independently predicted the 30 month progression of CIMT. These observational data strengthen the hypothesis that inflammation and oxidative stress promote the progression of subclinical atherosclerosis and thus are of clinical relevance in detecting high risk subjects. 507 PLASMA 1-DEOXYSPHINGOID BASES AS BIOMARKERS IN METABOLIC SYNDROME A. Othman1 , M.F. Rutti ¨ 2 , A. von Eckardstein1 , T. Hornemann1 . 1 Institute of Clinical Chemsitry, University Hopsital Zurich, Zurich, 2 Divison of Internal Medicine, Hospital Wil, Wil, Switzerland Metabolic syndrome represents a cluster of risk factors including; type 2 diabetes mellitus (T2DM), insulin resistance, hypertension, dyslipidemia and obesity. Sphingolipids are emerging as pathological agents in insulin resistance, diabetes and atherosclerosis. In the ‘atypical‘ do novo sphingolipid biosynthesis pathway; alanine, instead of serine, is conjugated with a palmitoylCoA 1-deoxysphingolipids. Elevation of plasma 1-deoxsphingolipids is well documented in patients with hereditary sensory neuropathy type I, where they are claimed to participate in the pathogenesis of the neuropathy. In a casecontrol study, we measured the sphingoid base backbones levels in healthy humans and in patients with metabolic syndrome. Sphingoid base backbones were liberated after subjecting the extracted plasma sphingolipids to acid and base hydrolysis and measured using LC/MS. ATP III guidelines were used to classify the subjects into controls, metabolic syndrome with and without T2DM. Univariate analysis revealed a significant elevation of plasma 1-deoxysphingoid base backbones levels in patients with metabolic syndrome with or without type2 diabetes mellitus (p = 1.1×10−5 ). Orthogonal partial least squares modeling showed that 1-deoxysphingoid bases contribute the second most to the metabolic syndrome state model, just next to triglycerides and above many of the traditional components of metabolic syndrome. Moreover, 1-deoxysphingoid bases correlated strongly with triglycerides (rho = 0.677, p = 2.6×10−11 ). ROC curve analysis showed the potential use of deoxysphingoid bases in diagnosing metabolic syndrome versus healthy controls (AUC = 0.875, p = 5.37×10−6 ). Taken together, our findings strongly argue for the potential use of 1-deoxysphingolipids as a new class of biomarkers for metabolic syndrome. 508 LIPOPROTEIN(A) IS AN INDEPENDENT RISK FACTOR FOR RECURRENT CORONARY EVENTS IN CHD PATIENTS M. Ezhov, M. Safarova, O. Afanasieva, A. Lyakishev, S. Pokrovsky. Russian Cardiology Research Center, Moscow, Russia Objective: To evaluate the association between high lipoprotein(a) [Lp(a)] levels and coronary events in patients with stable coronary heart disease (CHD). Methods: We prospectively enrolled 991 CHD patients (85% men, mean age 54.7±8.9 years). In accordance with angiography data they were divided into
Poster presentations
conservative (n = 328), endovascular (n = 400) and surgical treatment groups (n = 263). All the participants were obliged to take statins and aspirin. We have measured lipids and Lp(a) levels. Primary outcomes were non-fatal myocardial infarction (MI) and cardiac death, combined coronary end-point also included myocardial revascularisation and hospitalisation for unstable angina. Results: Over a median of 60 month (1–120) follow-up, 74 non-fatal MIs and 77 coronary deaths occurred. Adjusting for age and sex high Lp(a) levels (30 mg/dl) were associated with a doubling of the primary outcome risk (RR 2.20, 95% CI 1.53–3.15, p < 0.01). In men risk of combined end-point adjusted for conventional risk factors was increased in presence of Lp(a) excess in three age groups (45 years, n = 132, 2.02; 1.17–3.49; 45−59 years, n = 418, 1.74; 1.30–2.32; 60 years, n = 286, 2.71; 1.89–3.89), p < 0.001, respectively. This relation was observed in women aged >55 years (n = 103, 2.83; 1.42–5.61, p < 0.01), not in younger ones (n = 52, 1.43; 0.59–3.49, p = 0.4). Elevated Lp(a) was associated with increasing risk of coronary events in all treatment groups: conservative (2.49; 1.73–3.59), endovascular (1.72; 1.10–1.99) and surgical strategy (3.24; 2.18–4.83), p < 0.01, respectively. Conclusion: Despite optimal treatment high Lp(a) level increases risk of recurrent coronary events in stable CHD patients, except women younger than 55 years. 509 ANEMIA AND IRON DEPLETION INDEPENDENTLY ASSOCIATED WITH ANGIOGRAPHIC CORONARY ARTERY DISEASE. (THE LUDWIGSHAFEN RISK AND CARDIOVASCULAR HEALTH STUDY) T. Grammer1 , G. Silbernagel2 , S. Pilz3 , M. Kleber1 , A. Tomaschitz3 , B. Boehm4 , B. Winkelmann5 , W. Maerz1 . 1 Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, 2 Department of Internal Medicine, Eberhard-Karls-University Tubingen, ¨ Tubingen, ¨ Germany, 3 Department of Internal Medicine, Medical University of Graz, Graz, Austria, 4 Department of Internal Medicine, Ulm University, Ulm, 5 Cardiology Group Frankfurt-Sachsenhausen, Frankfurt/Main, Germany Background: Anaemia and iron deficiency are common diseases, which are associated with poor prognosis and higher risk of mortality compared to nonanaemic conditions. We have investigated the association of anaemia and iron deficiency, using multiple markers in a large cohort of Caucasian patients undergoing coronary angiography. Methods and Results: Hemoglobin and iron status were determined in 2378 patients with angiographic CAD and in 579 individuals in whom CAD had been ruled out by angiography. The soluble transferrin receptor was only marginally associated with angiographic CAD. Compared to their highest genderspecific quartiles, crude odds ratios (OR) for CAD in the lowest quartiles of hemoglobin, iron, transferrin saturation, and ferritin were 2.53 (95% confidence interval, CI: 1.98–3.22), 3.00 (95% CI: 2.32–3.80, p < 0.001), 1.94 (95% CI: 1.53–2.46, p < 0.001), and 1.56 (95% CI: 1.22–1.98, p < 0.001), respectively. These findings were robust against adjustment for established cardiovascular risk factors including sensitive C-reactive protein; corresponding ORs were 1.79 (95% CI:1.36–2.35, p < 0.001), 2.11 (95% CI:1.58–2.81, p < 0.001), 1.77 (95% CI:1.34–2.34, p < 0.001), and 1.96 (95% CI: 1.48–2.58, p < 0.001). The association between anemia (haemoglobin in the lowest gender-specific quartile) and CAD appeared independent from the iron status. Conclusions: Both anemia and iron depletion are independently associated with angiographic CAD. 510 PERIPHERAL ARTERIAL DIASESE AND TYPE 2 DIABETES MELLITUS: ROLE OF INFLAMMATORY AND HEMATOLOGICAL PARAMETERS 3 ´ , T. Moreno3 , M.R. Sanchez´ J. Mancera1 , J. Rioja2 , M.A. Sanchez-Chaparro 1 3,4 Perez ´ , M.J. Ariza-Corbo2 , P. Gonzalez-Santos ´ , P. Valdivielso3,4 . 1 Centro 2 de Salud Ciudad Jard´ın, Servicio Andaluz de Salud, CIMES, Universidad de 3 ´ Malaga, Internal Medicine, Hospital Virgen de la Victoria, Malaga, 4 Medicine ´ ´ and Dermatology, Universidad de Malaga, Malaga, Spain In a previous study, we found a positive and strong association between the presence of peripheral arterial disease (PAD) in subjects with type 2 diabetes (T2D) and the platetet count. Iron stores and inflammatory background are major determinants of thrombopoeitin. Aim: To investigate whether this association is linked to inflammatory parameters (hsCRP) or ferritin levels. Patients and Methods: 456 ambulatory subjects with T2D were included. PAD was assessed by the ankle-brachial index <0.9 A full blood cell count was obtained in every participant. Ferritin and hsCRP was measured in plasma. Results: Among participants, 126 out of 456 had PAD; platelet count as well hsCRP but no neutrophils, haemoglobin, MCV, RDW were higher in the PAD group. Ferritin levels were found lower in PAD subjects. Using logistic regression analyses, only platelet count (OR 1.004, 95% CI 1.002–1.007), MCV (OR 1.046, 95% CI 1.000–1.094) and ferritin (OR 0.778, 95% CI 0.645–0.939) were associated to PAD, even including hsCRP, mean platelet volume and antiplatelet drugs use.
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Methods and Results: The study population consisted of 127 consecutive patients with proven or suspected CAD, but without acute coronary syndrome, who underwent 64-slice CTA. CTA was used to assess 1. coronary calcification; 2. stenosis severity; 3. non-calcified plaque volume; 4. plaque composition. Sixty-eighth patients (age 59.9±12.5 years; 50% men) exhibited non-calcified plaques while 59 patients (age 65.8±10.4 years; 80% men) had calcified plaques and prevalence of stenotic plaques. Specification of plaque morphology revealed a significant inverse association between sRAGE levels and percent fibro-lipidic wall volume and a direct association between sRAGE and percent luminal volume in the patients with non-calcified plaques (r = −0.254, p = 0.0444 and r = 0.296, p = 0.014 respectively) but not in the patients with calcified plaques (r = −0.064, p = 0.637 and r = −0.101, p = 0.450 respectively). In a fully adjusted multivariate model sRAGE levels remained predictive of percent fibro-lipidic wall volume (b = −0.292, p = 0.0271). Conclusions and Significance: Decreased sRAGE levels were significantly associated with fibro-lipidic wall burden identified by CTA. Low levels of sRAGE can help identify those patients with subclinical atherosclerosis who are at risk for near-term atherothrombotic events. 502 ASSOCIATION OF BLOOD ACTIVE MATRIX METALLOPROTEINASE-3 WITH CAROTID PLAQUE SCORE IN MALE FROM A COMMUNITY POPULATION IN TAIWAN L.-M. Lien1 , Y.-C. Hsieh2 , C.-H. Bai2 , W.-H. Chen1 , H.-C. Chiu1 , F.-I. Hsieh2 , K.-G. Shyu3 , H.-Y. Chiou2 . 1 Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, 2 School of Public Health, Taipei Medical University, 3 Department of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan R.O.C. Objective: Blood levels of active matrix metalloproteinases-3 (MMP-3) are reported to be associated with the extent of carotid atherosclerosis based on carotid plaque score (PS) in a community population recently. However, the blood level of total MMP-3 is usually lower in female as compared with male. In this study, we assessed blood levels of active MMP-3 in relation to PS in male and female. Methods: In 433 subjects from a community primary stroke prevention program, blood levels of active MMP-3 and total MMP-3 were determined using enzymelinked immunosorbent assays and carotid plaque score (PS) by high-resolution B-mode ultrasonography. Results: The blood levels of active MMP-3 (8.4±4.1ng/ml vs. 4.0±2.4ng/ml, p < 0.0001) and total MMP-3 (13.1±5.6ng/ml vs. 6.6±3.3ng/ml, p < 0.0001) are both higher in male than in female, respectively. Study subjects were separated into 3 groups based on PS: group 1 (PS = 0), group 2 (PS = 1−2) and group 3 (PS 3). Blood levels of active MMP-3, but not total MMP-3, bear a highly significant relationship with PS in male, but not in female, (active MMP-3 level in group 1: 7.5±3.2ng/ml, group 2: 8.4±3.9ng/ml, and group 3: 10.7±5.5ng/ml; p for trend = 0.0004). A stepwise logistic regression analysis after adjustment of potential covariates including age, hypertension and cigarette smoking revealed blood levels of active MMP-3 are correlated with PS (OR, 1.5; 95% CI, 1.1 to 2.0; p = 0.006) in male. Conclusion: Blood levels of active MMP-3 are associated with the extent of carotid atherosclerosis in this community population in male but not in female in Taiwan. 503 ASSOCIATION OF COPY NUMBER VARIATIONS AND SINGLE NUCLEOTIDE POLYMORPHISMS IN METALLOTHIONEIN GENES WITH PATHOGENESIS OF DIABETES AND CORONARY ARTERY DISEASE R. Kozarova1 , A. Postadzhiyan2 , B. Finkov2 , M. Apostolova1 . 1 Institute of Molecular Biology, Bulgarian Academy of Sciences, 2 Clinic of Cardiology, St. Anna Hospital, Sofia, Bulgaria Introduction: Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) are widely distributed in the human genome. SNPs have allele frequency of 1%, while CNVs involve DNA fragment which is >1 kb. Methods: QPCR was used to detect the MT1X gene variations. SNPs +1245A/G in MT1A and −209A/G in MT2A gene were analyzed. Molecular analyses of CNVs and SNPs were done in 142 patients with coronary artery disease (CAD), 101 diabetic patients without clinical evidence for cardiovascular disease and 117 aged and sex matched controls. Results: 334 different CNVs were detected using 105K array CGH (Agilent Technologies). QPCR analyses for MT1X gene copy number variations confirmed the data from CGH array and showed significant association with developing of CAD (c2 = 21.036; OR = 4.787; 95% CI = 2.382–9.620; p < 0.001) and diabetes (c2 = 21.632; OR = 5.448; 95% CI = 2.565–11.570; p < 0.001). The polymorphism +1245A/G MT1A was significant associated with CAD (c2 = 9.492; p = 0.002). A binary logistic regression showed that +1245 AA
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genotype (comparing to AG + GG-genotypes) was independent predictor only for CAD after adjustment for the conventional risk factors (adjusted OR = 6.712, 95% CI = 1.818–24.775; p = 0.004). The polymorphism −209 A/G MT2A showed significant association of −209 AG+GG genotypes compared to −209 AA genotypes (c2 = 3.825; OR = 4.130; 95% CI = 0.904–18.862; p = 0.050) only in patients with diabetes. Conclusion: Changes in copy numbers of MT1X gene possibly contribute to developing of CAD and Diabetes mellitus. SNP analyses showed that +1245 AA genotype is independently associated with an increased risk of CAD after adjusting for classical risk factors where the −209 AG+GG MT2A genotype is predominantly associated with diabetes. 504 SMALL ARTERIES DILATION AND ENDOTHELIAL MARKERS IN CARDIOVASCULAR RISK PATIENTS G. Aragones, ` R. Ferre, ´ J. Girona, N. Plana, J. Merino, M. Heras, L. Masana. Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Universitat Rovira i Virgili, Internal Medicine Department, Sant Joan University Hospital, IISPV. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Reus, Spain Background: The use of methods based on reactive hyperaemia of small distal arteries to assess endothelial function (EF) is increasing at the clinical level; however, the mechanisms regulating vascular function in large and small arteries are different and still not completely understood. We studied the correlations between hyperaemia reactivity of small peripheral arteries determined by peripheral artery tonometry (PAT) and the levels of serum biomarkers of EF, inflammation and oxidation in patients with cardiovascular (CV) risk factors. Methods: 407 patients without previous CV disease but at intermediate CV risk were recruited into a cross-sectional study to examine whether soluble endothelial, inflammatory and lipid oxidative biomarkers correlate with small arteries reactive hyperaemia index (saRHI) values, which were measured by PAT. Results: A significant correlation was found between saRHI values and the concentrations of soluble E-selectin (sE-selectin) (r = −0.184, P < 0.0001) and soluble VCAM-1 (sVCAM-1) (r = −0.119, P = 0.018). The correlation remained significant after adjustment for confounding variables. Patients with a lower saRHI (saRHI < 1.70) had higher concentrations of sE-selectin, sVCAM-1 and oxLDL/LDL (P < 0.0001, P = 0.023 and P = 0.048, respectively). Using a stepwise multivariable linear regression model, we found that sE-selectin was the only biomarker that significantly correlated with saRHI values (P < 0.0001). Conclusion: Elevated levels of sE-selectin, sVCAM-1 and oxLDL/LDL are associated with lower postischemic reactivity in the small distal arteries, which suggests that similar mechanisms are involved in the vascular function of large and small arteries. Therefore, methods based on the saRHI could be useful tools to assess EF at the clinical level. 505 THE RELATIONSHIP BETWEEN HDL-CHOLESTEROL AND HDL FUNCTION L. Wade1 , M. Widdowson2 , A. Mcgown2 , J. Gibney2 , F. Thies3 , A. Mcginty1 , I. Young1 , J. McEneny1 . 1 Centre for Public Health, Queen’s University Belfast, Belfast, UK , 2 Endocrinology and Diabetes, Adelaide and Meath Hospital, Dublin, Ireland, 3 School of Medicine and Dentistry, Aberdeen University, Aberdeen, UK Background: Epidemiological evidence has revealed that HDL protects against cardiovascular disease (CVD). However, CVD can be present in individuals with normal or even high HDL-cholesterol, suggesting that HDL-cholesterol levels may not predict its functionality. Objectives: To assess if HDL-cholesterol levels can predict the activity of HDL associated enzymes, and therefore, predict HDL function. Furthermore, the role of obesity and the adipocyte derived inflammatory molecule serum amyloid-A (SAA) on HDL function were also assessed. Design: Serum was collected from 118 overweight control subjects (48 males, 70 females, (mean±SEM) 50±0.07years: HDL-cholesterol, 1.54±0.00 mmol/l: BMI, 27.4±0.04 Kg/m2 ). HDL was subfractionated into HDL2&3 by rapid ultracentrifugation and the activity of paraoxonase-1 (PON-1; spectrophotometrically) and lecithin cholesteryl acyl transferase (LCAT) & cholesterol-ester transfer protein (CETP; fluorometrically) were assessed within HDL2&3 . SAA was measured within serum and HDL2&3 by an ELISA method. Results: As serum HDL-cholesterol levels increased there was a concomitant increase in PON-1 activity within HDL2&3 (HDL2 r = 0.290, p = 0.002; HDL3 r = 0.301, p = 0.001) and a decrease in CETP activity within HDL2 (r = −0.343, p = 0.000). Additionally, as BMI increased, serum HDL-cholesterol (r = −0.362, p = 0.000), HDL2 -protein (r = −0.199, p = 0.036) and HDL2&3 PON-1 activity (r = −0.222, p = 0.019; r = −0.263, p = 0.005, respectively) decreased, while HDL2 CETP activity increased (r = 0.215, p = 0.023). BMI positively correlated with serum-SAA (r = 0.270, p = 0.005) and SAA-associated with HDL2&3 (HDL2 r = 0.334, p = 0.002; HDL3 r = 0.240, p = 0.012).
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Discussion: These results demonstrate that HDL-cholesterol is weakly associated with HDL function, suggesting that complete compositional/functional analyses may be required to fully establish HDL’s anti-atherogenic properties. 506 BIOMARKERS OF INFLAMMATION AND OXIDATIVE STRESS INDEPENTLY PREDICT THE PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS D.J. Mulder1 , J.D. Lefrandt1 , E. Tremoli2,3 , D. Baldassarre2,3 , A.J. Smit1 , on behalf of the IMPROVE Study Group. 1 Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands, 2 Department of Pharmacological Sciences, University of Milan, 3 Monzino Cardiology Center, IRCCS, Milan, Italy Objectives: Prediction of cardiovascular events by inflammation and oxidative stress biomarkers reflects their pivotal role in development of atherosclerosis. However, it is unclear whether such biomarkers are associated with an accelerated progression of subclinical atherosclerosis. Methods: 151 asymptomatic subjects with 3 RFs participating in the IMPROVE observational study were included (median age 63; 67 male). Carotid IMT was measured at baseline and after 30 months. At baseline biomarkers were measured in blood samples, including WBC and CRP, neopterin, soluble receptor for advanced glycation end products (AGEs), tissue inhibitor of metalloproteinase-1 (TIMP1) and metalloproteinase-9 (MMP9), and diene concentration and antibodies against oxidized LDL (oxLDL), and autofluorescence, noninvasively measured in skin (SAF) as a marker for tissue accumulation of AGEs. Results: At baseline most conventional RFs correlated significantly with CIMT. Of the biomarkers, only SAF correlated with CIMT (r = 0.24, p = 0.001). At followup, a small increase was observed in the CIMT (0.020 (0.086) mm, p = 0.006). In contrast to RFs, the biomarkers, including CRP (r = 0.22, p = 0.007), oxLDL (r = 0.21, p = 0.012), TIMP1 (r = 0.29, p = 0.001), and WBC (r = 0.23, p = 0.004) correlated with CIMT progression. After stepwise, multiple regression, TIMP1 (b = 0.28, p = 0.001) and oxLDL (b = 0.25, p = 0.003) remained independently associated with CIMT. Conclusions: In asymptomatic subjects at high cardiovascular risk, conventional RF and SAF reflected the initial atherosclerosis profile, but several biomarkers independently predicted the 30 month progression of CIMT. These observational data strengthen the hypothesis that inflammation and oxidative stress promote the progression of subclinical atherosclerosis and thus are of clinical relevance in detecting high risk subjects. 507 PLASMA 1-DEOXYSPHINGOID BASES AS BIOMARKERS IN METABOLIC SYNDROME A. Othman1 , M.F. Rutti ¨ 2 , A. von Eckardstein1 , T. Hornemann1 . 1 Institute of Clinical Chemsitry, University Hopsital Zurich, Zurich, 2 Divison of Internal Medicine, Hospital Wil, Wil, Switzerland Metabolic syndrome represents a cluster of risk factors including; type 2 diabetes mellitus (T2DM), insulin resistance, hypertension, dyslipidemia and obesity. Sphingolipids are emerging as pathological agents in insulin resistance, diabetes and atherosclerosis. In the ‘atypical‘ do novo sphingolipid biosynthesis pathway; alanine, instead of serine, is conjugated with a palmitoylCoA 1-deoxysphingolipids. Elevation of plasma 1-deoxsphingolipids is well documented in patients with hereditary sensory neuropathy type I, where they are claimed to participate in the pathogenesis of the neuropathy. In a casecontrol study, we measured the sphingoid base backbones levels in healthy humans and in patients with metabolic syndrome. Sphingoid base backbones were liberated after subjecting the extracted plasma sphingolipids to acid and base hydrolysis and measured using LC/MS. ATP III guidelines were used to classify the subjects into controls, metabolic syndrome with and without T2DM. Univariate analysis revealed a significant elevation of plasma 1-deoxysphingoid base backbones levels in patients with metabolic syndrome with or without type2 diabetes mellitus (p = 1.1×10−5 ). Orthogonal partial least squares modeling showed that 1-deoxysphingoid bases contribute the second most to the metabolic syndrome state model, just next to triglycerides and above many of the traditional components of metabolic syndrome. Moreover, 1-deoxysphingoid bases correlated strongly with triglycerides (rho = 0.677, p = 2.6×10−11 ). ROC curve analysis showed the potential use of deoxysphingoid bases in diagnosing metabolic syndrome versus healthy controls (AUC = 0.875, p = 5.37×10−6 ). Taken together, our findings strongly argue for the potential use of 1-deoxysphingolipids as a new class of biomarkers for metabolic syndrome. 508 LIPOPROTEIN(A) IS AN INDEPENDENT RISK FACTOR FOR RECURRENT CORONARY EVENTS IN CHD PATIENTS M. Ezhov, M. Safarova, O. Afanasieva, A. Lyakishev, S. Pokrovsky. Russian Cardiology Research Center, Moscow, Russia Objective: To evaluate the association between high lipoprotein(a) [Lp(a)] levels and coronary events in patients with stable coronary heart disease (CHD). Methods: We prospectively enrolled 991 CHD patients (85% men, mean age 54.7±8.9 years). In accordance with angiography data they were divided into
Poster presentations
conservative (n = 328), endovascular (n = 400) and surgical treatment groups (n = 263). All the participants were obliged to take statins and aspirin. We have measured lipids and Lp(a) levels. Primary outcomes were non-fatal myocardial infarction (MI) and cardiac death, combined coronary end-point also included myocardial revascularisation and hospitalisation for unstable angina. Results: Over a median of 60 month (1–120) follow-up, 74 non-fatal MIs and 77 coronary deaths occurred. Adjusting for age and sex high Lp(a) levels (30 mg/dl) were associated with a doubling of the primary outcome risk (RR 2.20, 95% CI 1.53–3.15, p < 0.01). In men risk of combined end-point adjusted for conventional risk factors was increased in presence of Lp(a) excess in three age groups (45 years, n = 132, 2.02; 1.17–3.49; 45−59 years, n = 418, 1.74; 1.30–2.32; 60 years, n = 286, 2.71; 1.89–3.89), p < 0.001, respectively. This relation was observed in women aged >55 years (n = 103, 2.83; 1.42–5.61, p < 0.01), not in younger ones (n = 52, 1.43; 0.59–3.49, p = 0.4). Elevated Lp(a) was associated with increasing risk of coronary events in all treatment groups: conservative (2.49; 1.73–3.59), endovascular (1.72; 1.10–1.99) and surgical strategy (3.24; 2.18–4.83), p < 0.01, respectively. Conclusion: Despite optimal treatment high Lp(a) level increases risk of recurrent coronary events in stable CHD patients, except women younger than 55 years. 509 ANEMIA AND IRON DEPLETION INDEPENDENTLY ASSOCIATED WITH ANGIOGRAPHIC CORONARY ARTERY DISEASE. (THE LUDWIGSHAFEN RISK AND CARDIOVASCULAR HEALTH STUDY) T. Grammer1 , G. Silbernagel2 , S. Pilz3 , M. Kleber1 , A. Tomaschitz3 , B. Boehm4 , B. Winkelmann5 , W. Maerz1 . 1 Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, University of Heidelberg, Mannheim, 2 Department of Internal Medicine, Eberhard-Karls-University Tubingen, ¨ Tubingen, ¨ Germany, 3 Department of Internal Medicine, Medical University of Graz, Graz, Austria, 4 Department of Internal Medicine, Ulm University, Ulm, 5 Cardiology Group Frankfurt-Sachsenhausen, Frankfurt/Main, Germany Background: Anaemia and iron deficiency are common diseases, which are associated with poor prognosis and higher risk of mortality compared to nonanaemic conditions. We have investigated the association of anaemia and iron deficiency, using multiple markers in a large cohort of Caucasian patients undergoing coronary angiography. Methods and Results: Hemoglobin and iron status were determined in 2378 patients with angiographic CAD and in 579 individuals in whom CAD had been ruled out by angiography. The soluble transferrin receptor was only marginally associated with angiographic CAD. Compared to their highest genderspecific quartiles, crude odds ratios (OR) for CAD in the lowest quartiles of hemoglobin, iron, transferrin saturation, and ferritin were 2.53 (95% confidence interval, CI: 1.98–3.22), 3.00 (95% CI: 2.32–3.80, p < 0.001), 1.94 (95% CI: 1.53–2.46, p < 0.001), and 1.56 (95% CI: 1.22–1.98, p < 0.001), respectively. These findings were robust against adjustment for established cardiovascular risk factors including sensitive C-reactive protein; corresponding ORs were 1.79 (95% CI:1.36–2.35, p < 0.001), 2.11 (95% CI:1.58–2.81, p < 0.001), 1.77 (95% CI:1.34–2.34, p < 0.001), and 1.96 (95% CI: 1.48–2.58, p < 0.001). The association between anemia (haemoglobin in the lowest gender-specific quartile) and CAD appeared independent from the iron status. Conclusions: Both anemia and iron depletion are independently associated with angiographic CAD. 510 PERIPHERAL ARTERIAL DIASESE AND TYPE 2 DIABETES MELLITUS: ROLE OF INFLAMMATORY AND HEMATOLOGICAL PARAMETERS 3 ´ , T. Moreno3 , M.R. Sanchez´ J. Mancera1 , J. Rioja2 , M.A. Sanchez-Chaparro 1 3,4 Perez ´ , M.J. Ariza-Corbo2 , P. Gonzalez-Santos ´ , P. Valdivielso3,4 . 1 Centro 2 de Salud Ciudad Jard´ın, Servicio Andaluz de Salud, CIMES, Universidad de 3 ´ Malaga, Internal Medicine, Hospital Virgen de la Victoria, Malaga, 4 Medicine ´ ´ and Dermatology, Universidad de Malaga, Malaga, Spain In a previous study, we found a positive and strong association between the presence of peripheral arterial disease (PAD) in subjects with type 2 diabetes (T2D) and the platetet count. Iron stores and inflammatory background are major determinants of thrombopoeitin. Aim: To investigate whether this association is linked to inflammatory parameters (hsCRP) or ferritin levels. Patients and Methods: 456 ambulatory subjects with T2D were included. PAD was assessed by the ankle-brachial index <0.9 A full blood cell count was obtained in every participant. Ferritin and hsCRP was measured in plasma. Results: Among participants, 126 out of 456 had PAD; platelet count as well hsCRP but no neutrophils, haemoglobin, MCV, RDW were higher in the PAD group. Ferritin levels were found lower in PAD subjects. Using logistic regression analyses, only platelet count (OR 1.004, 95% CI 1.002–1.007), MCV (OR 1.046, 95% CI 1.000–1.094) and ferritin (OR 0.778, 95% CI 0.645–0.939) were associated to PAD, even including hsCRP, mean platelet volume and antiplatelet drugs use.