- Email: [email protected]
The association between financial barriers and adverse clinical outcomes among patients with cardiovascular-related chronic diseases
Abstracts / Atherosclerosis 263 (2017) e29ee110
Methods: 119 females (mean age e 54 [51;60] years) with HT combined with RA were enrolled. The study was conducted according to norms of bioethics, all participants gave informed consent to participate. All patients received stable therapy for RA more than 6 months. Traditional cardiovascular risk was assessed, taking into account risk factors by SCORE scale and amended for patients with RA. The levels of total cholesterol, triglycerides, C-reactive protein, serum creatinine, body mass index, body area index were determined. Insulin resistance, endothelial-dependent flow mediated vasodilatation (EDVD) were measured. Results: 10-year cardiovascular risk matched by mSCORE in HT females with RA was 2.78 [2.06;3.11] %. The most frequently revealed traditional risk factors were dyslipidemia (83% pts) and obesity (78% pts). Subclinical manifestations of atherosclerosis were established in 88.2% HT females with RA and 40% control group pts with comparable risk factors. The majority HT females with RA have atherosclerotic plaques - 58.8%, including unstable plaques in 31.9% pts (p<0.05). The presence of atherosclerotic plaques in HT females with RA was associated with age (OR¼1.124, p¼0.024, 95% CI 1.07-1.23), RA disease activity (OR¼1.325, p¼0.004, 95% CI 1.12-1.45), endothelial dysfunction (OR¼1.578, p¼0.001, 95% CI 1.34-1.73), insulin resistance (OR¼1.678, p¼0.014, 95% CI 1.32-1.84), duration of steroid therapy (OR¼1.227, p¼0.028, 95% CI 1.17-1.43). Conclusions: Hypertensive patients with rheumatoid arthritis are characterized by high cardiometabolic risk profile and frequency of subclinical atherosclerosis do not fully reflected by a modified SCORE.
SAG173. THE COMBINED EFFECT OF DEPRESSION AND ANXIETY ON 10-YEAR CARDIOVASCULAR DISEASE INCIDENCE AMONG APPARENTLY HEALTHY GREEK ADULTS: THE ATTICA STUDY Demosthenes Panagiotakos1, Ekavi Natasa Kollia1, 1 2 Georgousopoulou , Christina Chrysohoou , Mary Giannakoulia1, George Georgiopoulos2, Christina Chatzinikolaou1, Ioannis Skoumas2, Dimitrios Christodoulos Stefanadis2, Charalabos Tousoulis2, Papageorgiou3, Christos Pitsavos2. 1 Department of Science of Dietetics and Nutrition, School of Health Science and Education, Harokopio University, Athens, Greece; 2 First Cardiology Clinic, School of Medicine, University of Athens, Athens, Greece; 3 Department of Psychiatry School of Medicine, University of Athens, Athens, Greece Aim: Background: Despite recent declines in mortality, cardiovascular disease (CVD) remains the leading cause of death in Europe today. Given the fact that many of the biological risk factors have already been identified, researchers still search for different modifiable factors that may influence CVD risk such as behavioral and psychological parameters. Aims: to prospectively explore the combined effect of depression and anxiety on 10-year CVD incidence. Methods: Methods: In the context of the ATTICA study (a populationbased prospective survey, 2002e2012), 853 adult participants without previous CVD history [453 men (45±13 years) and 400 women (44±18 years)] underwent psychological evaluations through validated, selfreporting depression and anxiety questionnaires. The sum of the z-scores of these two psychological instruments (DEPANX) was calculated. Results: Results: After adjusting for multiple established CVD risk factors, DEPANX was positively and independently associated with the 10-year CVD incidence but only among individuals with a total cholesterol-to-HDL ratio equal to or greater than 5 [adjusted odds ratio and 95% confidence interval: 1.8 (1.1, 2.9)], implying a potential synergistic interaction between chronic stress and lipidemic profile. Additionally, females with total cholesterol-to-HDL ratio equal to or greater than 5 at baseline, scored higher in DEPANX (p¼0.005) and so did women with low socioeconomic status (p¼0.022) or inactive women (p¼0.042). Among men, DEPANX was positively associated with obesity (p¼0.090), metabolic syndrome (p¼0.034) and inactivity (p¼0.029). Conclusions: Conclusions: There is evidence that the combination of increased anxiety with depressive symptomatology increases CVD risk and this relationship is enhanced in the presence of a disordered lipidemic profile.
e93
SAG174. CHILDHOOD SOCIOECONOMIC STATUS AND ARTERIAL STIFFNESS IN ADULTHOOD: THE CARDIOVASCULAR RISK IN YOUNG FINNS STUDY Markus Juonala1, Elina Puolakka1, Katja Pahkala1, Tomi Laitinen1, Costan €ki2, Jorma Viikari1, Olli Raitakari1. 1 University Magnussen1, Terho Lehtima of Turku, Turku, Finland; 2 University of Tampere, Tampere, Finland Aim: Increasing evidence supports the importance of socioeconomic factors in the development of atherosclerotic cardiovascular disease. However, the association of childhood socioeconomic status (SES) with arterial stiffness, a surrogate marker for cardiovascular disease, in adulthood has not been reported. We aimed to determine whether higher childhood family-level SES is associated with lower arterial stiffness in adulthood. Methods: Data from 2566 participants in the longitudinal Cardiovascular Risk in Young Finns Study was used. Participants had data on family-level SES in 1980 when aged 3 to 18 years who had arterial pulse wave velocity (PWV) and carotid artery distensibility (Cdist) measured 21 or 27 years later in adulthood. Results: Higher family SES in childhood was associated with lower arterial stiffness in adulthood; Cdist being higher (b-value ± SD 0.031 ± 0.0089, p<.001) and PWV lower (b-value ± SD -0.062±0.022, p¼.006) among those with higher family socioeconomic status in a multivariable analysis adjusted with age, sex, childhood cardiometabolic risk factors (lipids, systolic blood pressure, insulin, and body mass index), physical activity, and fruit and vegetable consumption. The association remained significant even after further adjustment for participant’s own SES in adulthood (bvalue ± SD 0.026 ± 0.010, p¼.009 for Cdist and b-value ± SD -0.048 ±0.023, p¼.04 for PWV). Conclusions: We observed an independent association between higher family SES in childhood and lower arterial stiffness in adulthood suggesting that special attention could be paid to children from low SES families to prevent atherosclerotic cardiovascular diseases.
SAG175. THE ASSOCIATION BETWEEN FINANCIAL BARRIERS AND ADVERSE CLINICAL OUTCOMES AMONG PATIENTS WITH CARDIOVASCULARRELATED CHRONIC DISEASES Braden Manns1, Robert Weaver1, Brenda David Campbell1, Hemmelgarn1, Kathryn King-Shier1, Claudia Sanmartin2. 1 University of Calgary, Calgary, Canada; 2 Statistics Canada, Ottawa, Canada Aim: Some patients with cardiovascular-related chronic diseases report financial barriers to achieving optimal health. Previous surveys report that the perception of having a financial barrier is associated with self-reported adverse clinical outcomes. We sought to confirm these findings using linked survey and administrative data to determine if there is an association between perceived financial barriers and the outcomes of: diseaserelated hospitalizations, all-cause mortality, and inpatient healthcare costs. Methods: We used 10 cycles of the Canadian Community Health Survey to identify a cohort of adults age 45 and older with hypertension, diabetes, heart disease or stroke. Financial barriers to various aspects of care were identified from the survey. The cohort was linked to administrative data sources for outcome ascertainment. We utilized Poisson regression, adjusting for potential confounding variables, to assess for associations between financial barriers and outcomes. We used gross costing methodology to assess the impact of financial barriers on hospital costs. Results: We identified 120,752 adults with hypertension, diabetes, heart disease or stroke. One in ten experienced financial barriers to at least one aspect of their care, the two most common being to medications and healthy food. Even after adjustment, those with financial barriers had an increased rate of disease-related hospitalization and mortality with incidence rate ratios of 1.36 (1.29-1.44) and 1.24 (1.16-1.32), respectively. Furthermore, having a financial barrier was associated with 30% higher inpatient costs.
e94
Abstracts / Atherosclerosis 263 (2017) e29ee110
Conclusions: Perceiving a financial barrier was associated with increased rates of hospitalization and mortality, and higher hospital costs, compared to those without financial barriers.
SAG176. GENETIC TESTING OF FAMILIAL HYPERCHOLESTEROLEMIA: MONOGENIC FORM AND POLYGENIC CONTRIBUTION TO CARDIOVASCULAR RISK rie Philippe Couvert1, 2,3, 4, Philippe Giral1, 2, 3, 5, Pierre -Yves Boelle6, 7, Vale liard8, Jean -Marc Lacorte1, 2, 3, 4, Philippe Carreau1, 2, 3, 5, Sophie Be Vale ro8, Annelies Rotthier10, Eric Lesnik1, 2, 3, Francois Paillard9, Rene 1, 2, 3, 4. 1 INSERM Unit e Mixte de Recherche_S Bruckert1, 2, 3, 5, Alain Carrie 1166, Paris, France; 2 Universit e Pierre et Marie Curie, Paris, France; 3 Institute of Cardiometabolism and Nutrition, Paris, France; 4 Assistance Publique-Hopitaux de Paris, Hopital Pitie-Salpetriere, Service Biochimie Endocrinienne et Oncologique, Paris, France; 5 Assistance Publique-Hopitaux de Paris, Hopital Pitie-Salpetriere, Service Endocrinologie-M etabolisme, Paris, France; 6 IPLESP - Institut Pierre Louis d Epidemiologie et de Sante Publique, INSERM U1136 - E1, Paris, France; 7 AP-HP, Hopital Saint-Antoine, Biostatistiques & Sante Publique, Paris, France; 8 UMR 1062 INSERM/1260 INRA, Aix-Marseille University, Faculty of Medicine, Marseille, France; 9 Centre de Pr evention Cardio-vasculaire, CHU Pontchaillou, Rennes, France; 10 Multiplicom N.V, Galileilaan, Niel, Belgium Aim: Cascade screening of Familial Hypercholesterolemia (FH) using genetic testing has been recommended but polygenic origin could reduce the efficiency of such approach. A polyGenic Score (GS) has been described helping to identify polygenic form of FH. We have developed a genetic test combining detection of monogenic form as well as polygenic contribution in FH. Methods: 716 patients with a diagnosis of “possible FH” (Dutch Lipid Clinic Network) were analyzed in routine genetic testing using massive parallel sequencing (ADH MASTR v2, Multiplicom NV) in order to (i) detect mutation in coding regions of LDLR, PCSK9, APOE, and a specific region of APOB and to (ii) genotype the 12 SNPs used for the GS calculation. Results: 353 patients (49,3%) were found to be mutated. The use of GS in non-mutated FH patients increased to more than 90% the probability of a polygenic diagnosis in 88 among 101 (87%) subjects presenting a mild phenotype (maximum Total Cholesterol, maxTC < 320mg/dl). In addition, the GS was correlated to maxTC in patients exhibiting defective mutation. Finally, we fitted a logistic regression to explain the percentage of patients with CAC score above 10 according to GS adjusted for age and found an Odds Ratio of 1.9 and 5 for GS above 1 and 1.25 respectively. Conclusions: We have developed an efficient genetic test allowing the detection of monogenic and polygenic forms of FH. In addition, calculation of the GS in mutated patients may be used to identify subjects at higher cardiovascular risk. HDL metabolism SAG177. IMPACT OF ENDOTHELIAL LIPASE MODIFIED HDL ON ENOS PHOSPHORYLATION, INTRACELLULAR LOCALIZATION AND ACTIVITY Snjezana Radulovic1, Benjamin Gottschalk1, Irene Schilcher1, Kurt Schmidt2, Sasa Frank1. 1 Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria; 2 Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria Aim: Endothelial lipase (EL) hydrolyses high density lipoprotein (HDL) phospholipids thereby changing HDL composition, size and functionality. EL plasma levels are elevated in patients with various pathologies including coronary artery disease. HDL exerts direct beneficial effects on the vascular endothelium by stimulation of nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS) activation.
We aimed to examine whether EL, by acting on the whole serum, alters the effect of subsequently isolated HDL, on endothelial eNOS phosphorylation, localisation and activity. Methods: Human serum was incubated with HepG2 cells transduced with EL- or LacZ-Adenovirus (Ad). LacZ HDL (control) and EL HDL were isolated by ultracentrifugation. Ea.hy926 cells were treated with 100mg/ml of LacZ or EL HDL for 5h or 16h and analysed by Western Blot, to obtain eNOS and PeNOS protein expressions. eNOS activity was examined by measuring intracellular conversion of L-[3H]arginine into L-[3H]citrulline. eNOS-GFP translocation to the perinuclear region and colocalisation to mitochondria in ECV 304 cells was measured by confocal spinning disk and structured illumination microscopy (SIM), respectively. Results: Our data show that EL modification increases the capacity of HDL to induce eNOS phosphorylation in Eahy 926 cells following 5h and 16h treatments, as well as eNOS activity after 16h-treatment. Furthermore, following 16h pretreatment with EL HDL, eNOS translocation to the perinuclear region and colocalisation to mitochondria are inhibited compared to LacZ HDL.
SAG178. SECRETORY PHOSPHOLIPASE A2 MODIFIED HIGH-DENSITY LIPOPROTEIN POTENTLY SUPPRESSES PLATELET ACTIVATION Gunther Marsche, Michael Holzer, Sanja Curcic. Medical University of Graz, Austria, Graz, Austria Aim: Levels of secretory phospholipases A2 (sPLA2) highly increase under acute and chronic inflammatory conditions. sPLA2 is mainly associated with high-density lipoproteins (HDL) and generates bioactive lysophospholipids implicated in acute and chronic inflammatory processes. Unexpectedly, pharmacological inhibition of sPLA2 in patients with acute coronary syndrome was associated with an increased risk of myocardial infarction and stroke. Given that platelets are key players in thrombosis and inflammation, we hypothesized that sPLA2-induced hydrolysis of HDL-associated phospholipids (sPLA2-HDL) generates modified HDL particles that affect platelet function. Methods: HDL was isolated by density gradient ultracentrifugation and modified by human recombinant type V sPLA2. Platelet GPIIb/IIIa activation, P-selectin expression, superoxide production were assessed by flow cytometry. Analysis of phosphorylation profiles of kinases were assessed using a human Phospho-Kinase Array kit. Platelet aggregation was assessed using the four-channel platelet aggregometer APACT4004.HDL associatedl ysophosphatidylcholines were assessed by mass spectrometry. Results: We observed that sPLA2-HDL potently and rapidly inhibited platelet aggregation induced by several agonists, P-selectin expression, GPIIb/IIIa activation and superoxide production, whereas native HDL showed little effects. sPLA2-HDL suppressed the agonist-induced rise of intracellular Ca++ levels and phosphorylation of Akt and ERK1/2, which trigger key steps in promoting platelet activation. Importantly, sPLA2 in the absence of HDL showed no effects, whereas enrichment of HDL with lysophosphatidylcholines containing saturated fatty acids (the main sPLA2 products) mimicked sPLA2-HDL activities. Conclusions: Our findings suggest that sPLA2 generates lysophosphatidylcholine-enriched HDL particles that might potently modulate platelet function during inflammatory conditions.
SAG179. HIGH-DENSITY LIPOPROTEIN CHOLESTEROL AS A DETERMINANT OF CHANGE IN CORONARY PLAQUE LIPID BURDEN ASSESSED BY NEAR INFRARED SPECTROSCOPY Satoshi Honda1, Samuel Sidharta1, 2, 3, Daisuke Shishikura1, Kohei Takata1, Jordan Andrews1, Susan Kim1, Julie Butters1, Peter Psaltis1, Matthew Worthley1,2, 3, Stephen Nicholls1, 2, 3. 1 South Australian Health and Medical Research Institute, Adelaide, Australia; 2 Royal Adelaide Hospital, Adelaide, Australia; 3 University of Adelaide, Adelaide, Australia
Methods: 119 females (mean age e 54 [51;60] years) with HT combined with RA were enrolled. The study was conducted according to norms of bioethics, all participants gave informed consent to participate. All patients received stable therapy for RA more than 6 months. Traditional cardiovascular risk was assessed, taking into account risk factors by SCORE scale and amended for patients with RA. The levels of total cholesterol, triglycerides, C-reactive protein, serum creatinine, body mass index, body area index were determined. Insulin resistance, endothelial-dependent flow mediated vasodilatation (EDVD) were measured. Results: 10-year cardiovascular risk matched by mSCORE in HT females with RA was 2.78 [2.06;3.11] %. The most frequently revealed traditional risk factors were dyslipidemia (83% pts) and obesity (78% pts). Subclinical manifestations of atherosclerosis were established in 88.2% HT females with RA and 40% control group pts with comparable risk factors. The majority HT females with RA have atherosclerotic plaques - 58.8%, including unstable plaques in 31.9% pts (p<0.05). The presence of atherosclerotic plaques in HT females with RA was associated with age (OR¼1.124, p¼0.024, 95% CI 1.07-1.23), RA disease activity (OR¼1.325, p¼0.004, 95% CI 1.12-1.45), endothelial dysfunction (OR¼1.578, p¼0.001, 95% CI 1.34-1.73), insulin resistance (OR¼1.678, p¼0.014, 95% CI 1.32-1.84), duration of steroid therapy (OR¼1.227, p¼0.028, 95% CI 1.17-1.43). Conclusions: Hypertensive patients with rheumatoid arthritis are characterized by high cardiometabolic risk profile and frequency of subclinical atherosclerosis do not fully reflected by a modified SCORE.
SAG173. THE COMBINED EFFECT OF DEPRESSION AND ANXIETY ON 10-YEAR CARDIOVASCULAR DISEASE INCIDENCE AMONG APPARENTLY HEALTHY GREEK ADULTS: THE ATTICA STUDY Demosthenes Panagiotakos1, Ekavi Natasa Kollia1, 1 2 Georgousopoulou , Christina Chrysohoou , Mary Giannakoulia1, George Georgiopoulos2, Christina Chatzinikolaou1, Ioannis Skoumas2, Dimitrios Christodoulos Stefanadis2, Charalabos Tousoulis2, Papageorgiou3, Christos Pitsavos2. 1 Department of Science of Dietetics and Nutrition, School of Health Science and Education, Harokopio University, Athens, Greece; 2 First Cardiology Clinic, School of Medicine, University of Athens, Athens, Greece; 3 Department of Psychiatry School of Medicine, University of Athens, Athens, Greece Aim: Background: Despite recent declines in mortality, cardiovascular disease (CVD) remains the leading cause of death in Europe today. Given the fact that many of the biological risk factors have already been identified, researchers still search for different modifiable factors that may influence CVD risk such as behavioral and psychological parameters. Aims: to prospectively explore the combined effect of depression and anxiety on 10-year CVD incidence. Methods: Methods: In the context of the ATTICA study (a populationbased prospective survey, 2002e2012), 853 adult participants without previous CVD history [453 men (45±13 years) and 400 women (44±18 years)] underwent psychological evaluations through validated, selfreporting depression and anxiety questionnaires. The sum of the z-scores of these two psychological instruments (DEPANX) was calculated. Results: Results: After adjusting for multiple established CVD risk factors, DEPANX was positively and independently associated with the 10-year CVD incidence but only among individuals with a total cholesterol-to-HDL ratio equal to or greater than 5 [adjusted odds ratio and 95% confidence interval: 1.8 (1.1, 2.9)], implying a potential synergistic interaction between chronic stress and lipidemic profile. Additionally, females with total cholesterol-to-HDL ratio equal to or greater than 5 at baseline, scored higher in DEPANX (p¼0.005) and so did women with low socioeconomic status (p¼0.022) or inactive women (p¼0.042). Among men, DEPANX was positively associated with obesity (p¼0.090), metabolic syndrome (p¼0.034) and inactivity (p¼0.029). Conclusions: Conclusions: There is evidence that the combination of increased anxiety with depressive symptomatology increases CVD risk and this relationship is enhanced in the presence of a disordered lipidemic profile.
e93
SAG174. CHILDHOOD SOCIOECONOMIC STATUS AND ARTERIAL STIFFNESS IN ADULTHOOD: THE CARDIOVASCULAR RISK IN YOUNG FINNS STUDY Markus Juonala1, Elina Puolakka1, Katja Pahkala1, Tomi Laitinen1, Costan €ki2, Jorma Viikari1, Olli Raitakari1. 1 University Magnussen1, Terho Lehtima of Turku, Turku, Finland; 2 University of Tampere, Tampere, Finland Aim: Increasing evidence supports the importance of socioeconomic factors in the development of atherosclerotic cardiovascular disease. However, the association of childhood socioeconomic status (SES) with arterial stiffness, a surrogate marker for cardiovascular disease, in adulthood has not been reported. We aimed to determine whether higher childhood family-level SES is associated with lower arterial stiffness in adulthood. Methods: Data from 2566 participants in the longitudinal Cardiovascular Risk in Young Finns Study was used. Participants had data on family-level SES in 1980 when aged 3 to 18 years who had arterial pulse wave velocity (PWV) and carotid artery distensibility (Cdist) measured 21 or 27 years later in adulthood. Results: Higher family SES in childhood was associated with lower arterial stiffness in adulthood; Cdist being higher (b-value ± SD 0.031 ± 0.0089, p<.001) and PWV lower (b-value ± SD -0.062±0.022, p¼.006) among those with higher family socioeconomic status in a multivariable analysis adjusted with age, sex, childhood cardiometabolic risk factors (lipids, systolic blood pressure, insulin, and body mass index), physical activity, and fruit and vegetable consumption. The association remained significant even after further adjustment for participant’s own SES in adulthood (bvalue ± SD 0.026 ± 0.010, p¼.009 for Cdist and b-value ± SD -0.048 ±0.023, p¼.04 for PWV). Conclusions: We observed an independent association between higher family SES in childhood and lower arterial stiffness in adulthood suggesting that special attention could be paid to children from low SES families to prevent atherosclerotic cardiovascular diseases.
SAG175. THE ASSOCIATION BETWEEN FINANCIAL BARRIERS AND ADVERSE CLINICAL OUTCOMES AMONG PATIENTS WITH CARDIOVASCULARRELATED CHRONIC DISEASES Braden Manns1, Robert Weaver1, Brenda David Campbell1, Hemmelgarn1, Kathryn King-Shier1, Claudia Sanmartin2. 1 University of Calgary, Calgary, Canada; 2 Statistics Canada, Ottawa, Canada Aim: Some patients with cardiovascular-related chronic diseases report financial barriers to achieving optimal health. Previous surveys report that the perception of having a financial barrier is associated with self-reported adverse clinical outcomes. We sought to confirm these findings using linked survey and administrative data to determine if there is an association between perceived financial barriers and the outcomes of: diseaserelated hospitalizations, all-cause mortality, and inpatient healthcare costs. Methods: We used 10 cycles of the Canadian Community Health Survey to identify a cohort of adults age 45 and older with hypertension, diabetes, heart disease or stroke. Financial barriers to various aspects of care were identified from the survey. The cohort was linked to administrative data sources for outcome ascertainment. We utilized Poisson regression, adjusting for potential confounding variables, to assess for associations between financial barriers and outcomes. We used gross costing methodology to assess the impact of financial barriers on hospital costs. Results: We identified 120,752 adults with hypertension, diabetes, heart disease or stroke. One in ten experienced financial barriers to at least one aspect of their care, the two most common being to medications and healthy food. Even after adjustment, those with financial barriers had an increased rate of disease-related hospitalization and mortality with incidence rate ratios of 1.36 (1.29-1.44) and 1.24 (1.16-1.32), respectively. Furthermore, having a financial barrier was associated with 30% higher inpatient costs.
e94
Abstracts / Atherosclerosis 263 (2017) e29ee110
Conclusions: Perceiving a financial barrier was associated with increased rates of hospitalization and mortality, and higher hospital costs, compared to those without financial barriers.
SAG176. GENETIC TESTING OF FAMILIAL HYPERCHOLESTEROLEMIA: MONOGENIC FORM AND POLYGENIC CONTRIBUTION TO CARDIOVASCULAR RISK rie Philippe Couvert1, 2,3, 4, Philippe Giral1, 2, 3, 5, Pierre -Yves Boelle6, 7, Vale liard8, Jean -Marc Lacorte1, 2, 3, 4, Philippe Carreau1, 2, 3, 5, Sophie Be Vale ro8, Annelies Rotthier10, Eric Lesnik1, 2, 3, Francois Paillard9, Rene 1, 2, 3, 4. 1 INSERM Unit e Mixte de Recherche_S Bruckert1, 2, 3, 5, Alain Carrie 1166, Paris, France; 2 Universit e Pierre et Marie Curie, Paris, France; 3 Institute of Cardiometabolism and Nutrition, Paris, France; 4 Assistance Publique-Hopitaux de Paris, Hopital Pitie-Salpetriere, Service Biochimie Endocrinienne et Oncologique, Paris, France; 5 Assistance Publique-Hopitaux de Paris, Hopital Pitie-Salpetriere, Service Endocrinologie-M etabolisme, Paris, France; 6 IPLESP - Institut Pierre Louis d Epidemiologie et de Sante Publique, INSERM U1136 - E1, Paris, France; 7 AP-HP, Hopital Saint-Antoine, Biostatistiques & Sante Publique, Paris, France; 8 UMR 1062 INSERM/1260 INRA, Aix-Marseille University, Faculty of Medicine, Marseille, France; 9 Centre de Pr evention Cardio-vasculaire, CHU Pontchaillou, Rennes, France; 10 Multiplicom N.V, Galileilaan, Niel, Belgium Aim: Cascade screening of Familial Hypercholesterolemia (FH) using genetic testing has been recommended but polygenic origin could reduce the efficiency of such approach. A polyGenic Score (GS) has been described helping to identify polygenic form of FH. We have developed a genetic test combining detection of monogenic form as well as polygenic contribution in FH. Methods: 716 patients with a diagnosis of “possible FH” (Dutch Lipid Clinic Network) were analyzed in routine genetic testing using massive parallel sequencing (ADH MASTR v2, Multiplicom NV) in order to (i) detect mutation in coding regions of LDLR, PCSK9, APOE, and a specific region of APOB and to (ii) genotype the 12 SNPs used for the GS calculation. Results: 353 patients (49,3%) were found to be mutated. The use of GS in non-mutated FH patients increased to more than 90% the probability of a polygenic diagnosis in 88 among 101 (87%) subjects presenting a mild phenotype (maximum Total Cholesterol, maxTC < 320mg/dl). In addition, the GS was correlated to maxTC in patients exhibiting defective mutation. Finally, we fitted a logistic regression to explain the percentage of patients with CAC score above 10 according to GS adjusted for age and found an Odds Ratio of 1.9 and 5 for GS above 1 and 1.25 respectively. Conclusions: We have developed an efficient genetic test allowing the detection of monogenic and polygenic forms of FH. In addition, calculation of the GS in mutated patients may be used to identify subjects at higher cardiovascular risk. HDL metabolism SAG177. IMPACT OF ENDOTHELIAL LIPASE MODIFIED HDL ON ENOS PHOSPHORYLATION, INTRACELLULAR LOCALIZATION AND ACTIVITY Snjezana Radulovic1, Benjamin Gottschalk1, Irene Schilcher1, Kurt Schmidt2, Sasa Frank1. 1 Institute of Molecular Biology and Biochemistry, Medical University Graz, Graz, Austria; 2 Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria Aim: Endothelial lipase (EL) hydrolyses high density lipoprotein (HDL) phospholipids thereby changing HDL composition, size and functionality. EL plasma levels are elevated in patients with various pathologies including coronary artery disease. HDL exerts direct beneficial effects on the vascular endothelium by stimulation of nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS) activation.
We aimed to examine whether EL, by acting on the whole serum, alters the effect of subsequently isolated HDL, on endothelial eNOS phosphorylation, localisation and activity. Methods: Human serum was incubated with HepG2 cells transduced with EL- or LacZ-Adenovirus (Ad). LacZ HDL (control) and EL HDL were isolated by ultracentrifugation. Ea.hy926 cells were treated with 100mg/ml of LacZ or EL HDL for 5h or 16h and analysed by Western Blot, to obtain eNOS and PeNOS protein expressions. eNOS activity was examined by measuring intracellular conversion of L-[3H]arginine into L-[3H]citrulline. eNOS-GFP translocation to the perinuclear region and colocalisation to mitochondria in ECV 304 cells was measured by confocal spinning disk and structured illumination microscopy (SIM), respectively. Results: Our data show that EL modification increases the capacity of HDL to induce eNOS phosphorylation in Eahy 926 cells following 5h and 16h treatments, as well as eNOS activity after 16h-treatment. Furthermore, following 16h pretreatment with EL HDL, eNOS translocation to the perinuclear region and colocalisation to mitochondria are inhibited compared to LacZ HDL.
SAG178. SECRETORY PHOSPHOLIPASE A2 MODIFIED HIGH-DENSITY LIPOPROTEIN POTENTLY SUPPRESSES PLATELET ACTIVATION Gunther Marsche, Michael Holzer, Sanja Curcic. Medical University of Graz, Austria, Graz, Austria Aim: Levels of secretory phospholipases A2 (sPLA2) highly increase under acute and chronic inflammatory conditions. sPLA2 is mainly associated with high-density lipoproteins (HDL) and generates bioactive lysophospholipids implicated in acute and chronic inflammatory processes. Unexpectedly, pharmacological inhibition of sPLA2 in patients with acute coronary syndrome was associated with an increased risk of myocardial infarction and stroke. Given that platelets are key players in thrombosis and inflammation, we hypothesized that sPLA2-induced hydrolysis of HDL-associated phospholipids (sPLA2-HDL) generates modified HDL particles that affect platelet function. Methods: HDL was isolated by density gradient ultracentrifugation and modified by human recombinant type V sPLA2. Platelet GPIIb/IIIa activation, P-selectin expression, superoxide production were assessed by flow cytometry. Analysis of phosphorylation profiles of kinases were assessed using a human Phospho-Kinase Array kit. Platelet aggregation was assessed using the four-channel platelet aggregometer APACT4004.HDL associatedl ysophosphatidylcholines were assessed by mass spectrometry. Results: We observed that sPLA2-HDL potently and rapidly inhibited platelet aggregation induced by several agonists, P-selectin expression, GPIIb/IIIa activation and superoxide production, whereas native HDL showed little effects. sPLA2-HDL suppressed the agonist-induced rise of intracellular Ca++ levels and phosphorylation of Akt and ERK1/2, which trigger key steps in promoting platelet activation. Importantly, sPLA2 in the absence of HDL showed no effects, whereas enrichment of HDL with lysophosphatidylcholines containing saturated fatty acids (the main sPLA2 products) mimicked sPLA2-HDL activities. Conclusions: Our findings suggest that sPLA2 generates lysophosphatidylcholine-enriched HDL particles that might potently modulate platelet function during inflammatory conditions.
SAG179. HIGH-DENSITY LIPOPROTEIN CHOLESTEROL AS A DETERMINANT OF CHANGE IN CORONARY PLAQUE LIPID BURDEN ASSESSED BY NEAR INFRARED SPECTROSCOPY Satoshi Honda1, Samuel Sidharta1, 2, 3, Daisuke Shishikura1, Kohei Takata1, Jordan Andrews1, Susan Kim1, Julie Butters1, Peter Psaltis1, Matthew Worthley1,2, 3, Stephen Nicholls1, 2, 3. 1 South Australian Health and Medical Research Institute, Adelaide, Australia; 2 Royal Adelaide Hospital, Adelaide, Australia; 3 University of Adelaide, Adelaide, Australia