Quality of life, anxiety and concerns of children with familial hypercholesterolemia and their parents

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Katusic

~'2-~ VITAMIN C REDUCES AORTIC LESION FORMATION AND IMPROVES ENDOTHELIUM-DEPENDENT RELAXATIONS IN ATHEROSCLEROTIC MICE L.V. d' Uscio, L. Smith~Z.S. Katusic. Mayo Clinic, Rochester, ~

USA

Our objective was to determine the effects ofantioxidant Vit C on endothelial NOS function in apolipoprotein E (apoE)-deficient mice. Mice were treated for 26 28 weeks with Western-type fat-diet with or without Vit C (1% per kg chow). Isometric force of aortic rings was recorded and compared to control C57BL/6J mice. Vascular superoxide anion was measured by lucigenin-enhanced chemiluminescence. Basal plasma levels of Vit C were significantly reduced in apoE-deflcient mice (P<0.05 vs. C57BL/6J mice). Chronic Vit C treatment decreased aortic atherosclerotic lesion area by 51% in apoE-deficient mice (P<0.05 vs. apoE group; n-5). In addition, both elevated nitrotyrosine abundance and superoxide anion levels were reduced after Vit C treatment (264±28 cpm/microg; P<0.05 vs. apoE group: 539±64 cpm/microg; n-9). Vit C improved NO-mediated endothelium-dependent relaxations to acetylcholine (83±2%; P<0.05 vs. apoE group: 58±4%) and endothelium-independent relaxations to NO-donor diethylammonium (Z)1-(N,N-diethylamino)diazen-l-ium-l,2-diolate (pD2:7.8±0.1 vs. 7.5±0.1 for apoE group; P<0.05). In conclusion, our results suggest that Vit C may increase biological activity of NO in part by stimulating endothelial NOS enzymatic activity, and by reduction of superoxide anion production in atherosclerotic mice. ~

RIBOZYME-MEDIATED GENE TARGETING OF TRANSCRIPTIONAL COACTIVATORS, CREB BINDING PROTEIN (CBP) AND p300 REVEALED T H E I R INDISPENSABLE ROLES IN ADIPOCYTE DIFFERENTIATION THROUGH THE REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA

T. Kawada 1,2, N. Takahashi 1'2, T. Yamamoto 1, T. Goto 1, A. Taimatsu 1, N. Aoki 3, H. Kawasaki4, K. Taira 5, K.K. Yokoyama 6, Y. Kamei 7, T. Fushiki 1. ]Division of Food Science and Biotechnology, Kyoto

University," 2project for Obesity and Lipid Metabolism Regulation, BRAIN, Tokyo; 3Department of Applied Molecular Bioscience, Nagoya University," 4Department of Chemical and Biotechnology, The University of Tokyo," SGene Discovery Research, AIST, Tsukuba; 6Tsukuba Life Science Center, RIKEN, Tsukuba; 7pREST, Japan Science and Technology Corporation, Tokyo, Japan The cAMP response element-binding protein-binding protein (CBP) and p300 are common coactivators for several transcriptional factors. It has been reported that both CBP and p300 are significant for the activation of peroxisome proliferator-activated receptor-gamma (PPARy), which is a crucial nuclear receptor in adipogenesis. However, it remains unclear whether CBP and/or p300 are physiologically essential to the activation of PPARg in adipocytes and adipocyte differentiation. In this study, we investigated the physiological significance of CBP/p300 in NIH3T3 cells transiently expressing PPARg and CBP, and in 3T3-L1 preadipocytes stably expressing CBP- or p300-specific ribozymes. In PPARg-transfected NIH3T3 cells, induction of expression of PPARg target genes such as adipocyte fatty acid-binding protein (aP2) and lipoprotein lipase (LPL) by adding thiazolidinedione was enhanced depending on the amount of a CBP expression plasmid transfected. Expression of aP2 and LPL genes, as well as glycerol-3-phosphate dehydrogenase activity and triacylglyceride accumulation following adipogenic induction, was largely suppressed in 3T3-L1 adipocytes expressing either the CBP- or p300-specific active ribozymes but not in inactive ribozyme-expressing ceils. These data suggest that both CBP and p300 are indispensable for the full activation of PPARg and adipocyte differentiation, and that they do not mutually complement in the process. ~'~

NEUTROPHIL SUPEROXIDE ANION GENERATION DURING ATORVASTATIN AND FLIVASTATIN TREATMENT USED IN CORONARY HEART DISEASE PRIMARY PREVENTION

J. Kowalski, J. Kedziora, J. Blaszczyk, L. Pawlicki, J. Grycewicz, E. Rapacka. Military Medical University, Lodz, Poland Neutrophil superoxide anion generation was measured during atorvastatin and fluvastatin treatment in patients with risk of coronary heart disease. The patients were randomly allotted into three groups. The atorvastatin group

comprised 16 patients who were administered the drug orally 10 mg a day at bedtime. The fluvastatin group consisted of 18 patients on an oral dose of 40 mg once daily at bedtime. The control group comprised 12 healthy subjects with no drug administration. Our study has been approved by the Local Ethics Committee. Blood samples were collected from cubital vein before and after 6-weeks treatment with those drugs and once in the control group. Superoxide anion generation in the whole blood without and with opsonised zymosan (OZ) stimulation was determined according to Bellavite et al. methods using superoxide dismutase from bovine erythrocytes. In atorvastatin group statistically significant (p<0.05) decrease in superoxide anion generation by nonstimulated as well as OZ stimulated neutrophils was observed after 6-weeks treatment period. In fluvastatin group no changes in neutrophil superoxide anion generation were observed after 6-weeks treatment period. Our study has shown additional non-lipid mechanism of atorvastatin used in coronary heart disease primary prevention. ~3"~ THE ADIPOCYTE AS AN ENDOCRINE AND A NO PRODUCING ORGAN U. Keller q, B. Mtiller q, P. Linscheid 2. 1Division of Endocrinology,

2Department of Research, University Hospital, Basel, Switzerland Insulin resistance and its associated metabolic syndrome is provoked by obesity. Adipose tissue appears to act as an endocrine organ by releasing numerous signalling molecules including cytokines such as TNFa, IL-6 and resistin. Insulin-sensitizing effects of thiazolidinediones have been described both in vivo and in vitro. However, the underlying molecular mechanisms of action of these compounds and the cause and effect of enhanced cytokine production in adipose tissue of obese subjects are unknown. Inflammationmediated high level synthesis of nitric oxide has been suggested to act as a mediator of insulin resistance in muscle and adipose tissue. Nitric oxide production interferes both with insulin-mediated glucose uptake and with the antilipolytic effect of insulin. Obesity-mediated in vivo insulin resistance is prevented in genetic NOS 2 - / - knock-out mice unable to express iNOS. Thiazolidinediones are a new class of insulin-sensitising drugs used for the treatment of type 2 diabetes. As PPARg-agonists they prevent or reverse cytokine-induced insulin resistance in vitro and in vivo. Thiazolidinediones were found to inhibit the expression of inducible nitric oxide synthase in macrophages and in 3T3-L1 adipocytes. The present data confirm the rate-limiting role of tetrahydrobiopterin in nitric oxide synthesis in 3-T3-adipocytes. PPARg activation with rosiglitazone not only inhibited cytokine induced nitric oxide generation, but also the expression of guanosine triphosphate cyclohydrolase, the first enzyme and controlling step in the de novo pathway of tetrahydrobiopterin synthesis. Accordingly, the synthesis of tetrahydrobiopterin was reduced by about 50%. Furthermore, rosiglitazone diminished cytokine-mediated transcriptional downregulation of the endothelial isoform of nitric oxide synthase. These data identify new targets of PPARg-activation in cytokine-modulated synthesis of nitric oxide in adipocytes. They suggest that enhanced production of inflammatory cytokines participate in obesity-related insulin resistance and that nitric oxide acts as an autocrine mediator. ~-~

QUALITY OF LIFE, ANXIETY AND CONCERNS OF CHILDREN W I T H FAMILIAL HYPERCHOLESTEROLEMIA AND T H E I R PARENTS

S. De Jongh q, M.C. Kerckhoffs q, M.A. Grootenhuis2, B.E Last 2, H.D. Bakker 3. JDepartment of Vascular Medicine, 2paediatric Psychosocial

Department, Emma Children's Hospital, Academic Medical Center," 3Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands Rationale: To assess the influence of statin therapy on quality of life, anxiety and concerns of children with familial hypercholesterolemia (FH) and their parents. Patients and Methods: 69 FH children on statin therapy and 87 parents (51 families) participated in this study. Quality of life of the children, and anxiety levels of both the children and their parents, were investigated using self-report questionnaires. Additionally, a questionnaire was designed to evaluate FH specific concerns of these children and their parents on six different topics: 1. knowledge about FH, 2. experience of the disease, 3. family communication, 4. screening, 5. diet and 6. experience of medication therapy. Results: FH children and their parents report no problems with regard to quality of life and anxiety. In contrast, the FH survey did show specific FH related concerns. One-third of the children thinks FH can be cured, 43.5%

73rd EAS Congress

Kiortsis of the children suffer from the fact they have FH, but taking medication makes them feel safer (62.3%). Almost 38% of the parents experience FH as a burden to their family and 79.3% suffer because their child has FH. Conclusion: Our findings show that statin therapy does not influence the psychosocial functioning of FH children and their parents. To improve the knowledge of FH and family communication, the families would benefit from additional information focussing on the various aspects of living with FH. This would provide a helpful instrument in making these families aware of the disease and improving family communication and might lead to a better compliance. ~

EFFECT OF COMBINED HYPOTENSIVE AND HYPOLIPIDEMIC THERAPY ON CHD METABOLIC RISK FACTORS IN NIDDM PATIENTS

L. Khadipash, M. Mamedov, O. Kosmatova, N. Perova. National Research

Center for Preventive Medicine, Moscow, Russia Aim: To investigate an effect of combined hypotensive and hypolipidemic therapy on insulin resistance and global coronary risk in NIDDM patients. Methods: Twenty four patients with metabolic syndrome aged 40 60 years had been taken 10 mg enalapril and 10 mg simvastatin per day for 8 weeks. The following criteria were used: SBP 140 179 mm Hg and/or DBP 90 109 mm Hg; total cholesterol (CH) ~>250 mg/dl and/or triglycerides (TG) ~>200 mg/dl; BMI ~>25 kg/sq.m, waist to hip circumference ratio (WHR) ~> 0.90 for men and ~> 0.80 for women; postprandial glucose ~> 140 mg/dl, fasting immunoreactive insulin ~>22.0 mkU/ml and fasting and postprandial glucose to insulin ratio <6.0. The following parameters were measured before and after combined therapy: fasting and postprandial glucose and immunoreactive insulin. Global coronary risk calculated by model based on an 8-year follow-up of the PROCAM. Results: The level of postprandial blood glucose reduced on 10.4%, fasting immunoreactive insulin decreased on 45.7% (from 19.6±1.7 to 10.6±2.1 mkU/ml, p<0.001), postprandial insulin on 50.6% (from 33.3±3.2 to 16.4±3.1 mkU/ml, p<0.001). The fasting glucose to insulin ratio increased on 152.2%, the postprandial glucose to insulin ratio on 117.7%. Basal global coronary risk in NIDDM patients with metabolic syndrome was 35.7%, after 8 weeks of combined therapy it decreased by 17.3% (p<0.001). Conclusion: The combined therapy with enalapril and simvastatin in doses 10 mg/day during 8 weeks significantly improved insulin resistance and led to 2-fold decrease of global coronary risk in NIDDM patients with full cluster of metabolic syndrome. ~1]

TOLL-LIKE RECEPTOR 4 POLYMORPHISMS AND ATHEROGENESIS IN HUMANS

S. Kiechl 1, E. Lorenz 2, M. Reindl 2, C.J. Wiedermann3, J. Willeit 1, D. Schwartz4. JDepartment of Neurology, University Clinic Innsbruck,

Austria; 2Wake Forest University Medical School, NC, USA," 3Department of Internal Medicine, University Clinic Innsbruck, Austria," 4Department of Medicine and Genetics, Duke University Medical Center and Veterans Affairs Medical Center, Durham, NC, USA Background: Subjects capable of producing a prominent inflammatory response to bacterial pathogens and other stress factors have advantages in the innate immune defense but may be at an increased longterm risk of atherosclerosis. To evaluate this hypothesis, we determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4), that confer substantial differences in the inflammation elicited by bacterial lipopolysaccharide, are related to the development of atherosclerosis. Methods: As part of the 5-year follow-up, the Bruneck Study cohort (n-810) was screened for the TLR4 polymorphisms Asp299Gly and Thr399Ile. Extent and progression of atherosclerosis was assessed by highresolution duplex ultrasound. Results: As compared to the wild-type, subjects with the Asp299Gly TLR4 allele (n-55) exhibited lower levels of pro-inflammatory cytokines, acute-phase reactants and soluble adhesion molecules. Although these subjects were found to be more susceptible to severe bacterial infections, they faced a lower risk of incident carotid atherosclerosis (OR 0.54 (0.32 to 0.98) P-0.048) and had a lower common carotid artery intima-media thickness. Conclusions: The Asp299Gly TLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to Gram negative pathogens are associated with a decreased atherosclerosis risk. The TLR4 pathway appears to contribute significantly to the low-grade systemic inflammation evident in healthy individuals. These findings are consistent

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with the hypothesis under evaluation and indicate that innate immunity may play a role in atherogenesis. [ ~ ' ~ APOLIPOPROTEIN B-100/APOLIPOPROTEIN A-I RATIO IS THE MOST USEFUL INDICATOR F O R CORONARY ARTERY DISEASE IN KOREANS H.-K. Kim, K.-W. Park, E.-K. Choi, D.-H. Kim, S. Oh, I.-H. Chae, H.-S. Kim, C.-H. Kim, D.-W. Sohn, B.-H. Oh, M.-M. Lee, Y.-B. Park, Y..-S. Choi. Heart Research Institute, Department of Internal Medicine,

Cardiovascular Research Laboratory, Seoul National University Hospital, Seoul, Korea Objectives: The relation between the apolipoprotein(apo) B-100/apo A-I ratio and coronary artery disease has not been well investigated. The aim of this study was to investigate the association between apolipoprotein B-100 or the apo B-100/apo A-I ratio and coronary artery disease(CAD). Methods: The study population consisted of 194 patients who underwent coronary angiography and had received no lipid-lowering medication. Stenosis of over 50% in 1 or more coronary arteries was classified as CAD

(+). Results: HDL-C and apo A-I were significantly higher in females than in males (p-0.011 and 0.036). In the total population apo A-I, HDL-C and the apo B-100/apo A-I ratio were significantly related to CAD (p-0.002, 0.004, and 0.008 respectively). In the male group (n-111), the apo B-100/ apo A-I ratio, apo B-100, the apo B/apo A-I ratio, LDL-C, non-HDL-C and total cholesterol were independently related to CAD (p-0.001, 0.002, 0.006, 0.041, 0.041 and 0.044 separately). In the female group (n-83), only the apo B-100/apo A-I ratio was related to CAD (p-0.043). The apo B-100/apo A-I ratio was the only parameter that was significantly related to CAD in all three groups. Conclusion: The apo B-100/apo A-I ratio was the most useful indicator for discriminating between CAD(+) and CAD(-). ~ff3] ARTERIAL STIFFNESS IN PATIENTS W I T H DIABETIC NEPHROPATHY. COMPARISON AMONG DIFFERENT ARTERIAL SEGMENTS E. Kimoto, T. Shoji, K. Shinohara, M. Komatsu, A. Tanaka, S. Fujiwara, H. Koyama, M. Emoto, Y. Nishizawa. Osaka City University Graduate

School of Medicine, Osaka, Japan Arterial stiffening is known to occur in several disease conditions including diabetes mellitus and end-stage renal disease, and it has significant impacts on cardiac functions, peripheral circulation and cardiovascular mortality. The aims of this study were to examine the change in arterial stiffness in various stages of diabetic nephropathy, and to compare the effects of diabetic nephropathy among different segments of arteries. The subjects were 261 patients with type 2 diabetes and 127 healthy control subjects comparable in age and gender. The diabetic patients were divided into four categories of nephropathy (normo-, micro-, and clinical albuminuria, and renal failure). Arterial stiffness was evaluated by measuring pulse wave velocity (PWV) in the heart-carotid (hc), heart-femoral (hf), heart-brachial (hb), and femoral-ankle (fa) segments using an automatic waveform analyzer (BP-203RPE, Colin, Japan). As the stage of nephropathy was advanced, PWV was significantly increased in the hi', hc, hb segments, but not in the fa segment. PWV in the patients with renal failure was increased by 65%, 30%, 19% and 6% in the hf, hc, hb, and fa segment when compared with the healthy control values. Multiple regression analyses in the diabetic patients showed that renal function was a significant factor affecting PWV in the hf and hc segments independent of age, gender, blood pressure and smoking. These results indicate that nephropathy worsens arterial stiffness in type 2 diabetes patients, and that the influence was greater in central than peripheral arteries. ~ 3 - ~ EFFECTS OF CUPRESSUS SEMPERVIRENS CONE EXCTRACT ON LIPID PROFILE IN WISTAR RATS S. Karkabounas 1, D. Kiortsis 1, J. Zelovitis 1, P. Skafida 1, C. Demetzos4, M. Malamas 2, M. Elisaf3, A. Evangelou 1. 1Laboratory of Physiology,

2Laboratory of Pharmacology, 3Department of Internal Medicine, University of Ioannina; 4Department of Pharmacognosy, School of Pharmacy, University of Athens, Greece Background: It has been suggested that a hydroalcoholic extract of the cones of cupressus sempervirens might have a lipid lowering effect. The

73rd EAS Congress