ABSTRACTS: H.E.A.R.T UK 20th Annual Medical & Scientific Meeting

ABSTRACTS: H.E.A.R.T UK 20th Annual Medical & Scientific Meeting

Atherosclerosis 188 (2006) S1–S9 Abstracts H.E.A.R.T UK 20th Annual Medical and Scientific Meeting “Big Trouble in Little Britain: Obesity and Cardi...

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Atherosclerosis 188 (2006) S1–S9

Abstracts

H.E.A.R.T UK 20th Annual Medical and Scientific Meeting “Big Trouble in Little Britain: Obesity and Cardiovascular Disease” and “Atkins—Rest in Peace”, University of Kent, Canterbury, UK, Wednesday 28–Friday 30 June 2006

0021-9150/$ – see front matter © 2006 Published by Elsevier Ireland Ltd. doi:10.1016/j.atherosclerosis.2006.06.001

Abstracts / Atherosclerosis 188 (2006) S1–S9

ACCUMULATING SHORT BOUTS OF BRISK WALKING REDUCES POSTPRANDIAL PLASMA TRIACYLGLYCEROL CONCENTRATIONS IN YOUNG MEN M. Miyashita, D.J. Stensel Physical Activity and Health Research Group, School of Sport and Exercise Sciences, Loughborough University, UK Background: Physical activity guidelines for health advise accumulating at least 30 min of moderate-intensity physical activity on most, preferably all, days of the week. Brisk walking reduces postprandial plasma triacylglycerol concentrations, however, no studies are available regarding effects of short (<10 min) bouts of brisk walking on postprandial plasma triacylglycerol concentrations. Methods: Fifteen male subjects, aged 21–28 years, completed three, 2-day trials at least 1 week apart in a randomised, repeated measures design. On day 1, subjects rested (no exercise) or walked briskly in either 10, 3-min bouts (30 min rest between bouts), or one continuous 30-min bout (energy expenditure = 1100 kJ). On day 2, subjects rested and consumed test meals (0.69 g fat, 0.95 g carbohydrate, 0.31 g protein, and 46 kJ/kg body mass) for breakfast and lunch. Venous blood samples were collected in the fasted state and for 7 h postprandially on day 2. Results: Postprandial plasma triacylglycerol concentrations were lower throughout day 2 on the accumulated trial and the continuous trial compared with the control trial (twofactor ANOVA, main effect of trial p = 0.005) with little difference between the accumulated and continuous trials. Conclusion: Accumulating 30 min of brisk walking in short bouts is equally effective in reducing postprandial plasma triacylglycerol concentrations as one continuous 30 min bout. REDUCED OXIDATION OF DIETARY FAT AFTER A SHORT TERM HIGH-CARBOHYDRATE DIET Rachel Roberts1 , Alex Bickerton1 , Barbara A. Fielding1 , Ellen Blaak2 , Anton J.M. Wagenmakers2 , Marjory Gilbert1 , Fredrik Karpe1 , Keith N. Frayn1 1 University

of Oxford, United Kingdom; Maastricht, The Netherlands

2 University

of

High carbohydrate (HC) diets increase fasting and postprandial plasma triglyceride (TG) concentrations. This may result from TG overproduction or inadequate TG clearance. We investigated mechanisms involved in HC-induced hypertriglyceridaemia using stable isotope labelling of exogenous fatty acids. Eight healthy subjects consumed a high or standard carbohydrate isocaloric diet for 3 days in a randomised crossover dietary intervention study. After an overnight fast, subjects ingested a meal including [U-13 C] palmitate. Blood and breath samples were taken prior to the meal and for 6 h. Blood samples were drawn from the femoral artery and from veins

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draining subcutaneous adipose tissue and forearm, the latter representing muscle, to monitor tissue-specific metabolic substrate partitioning. Systemic TG concentrations were increased in both the fasting (p = 0.005) and postprandial periods (p = 0.022) after the HC diet. Muscle TG clearance was lower after the HC diet (p = 0.015). Significantly less 13 CO2 was exhaled after the HC diet (p = 0.04) and significantly less production of 13 CO2 was seen across forearm muscle (p = 0.04). Systemic 3hydroxybutyrate was significantly lower after the high carbohydrate diet (p = 0.034). We propose that the HC diet may alter partitioning of FA between re-esterification and oxidation in the muscle and liver. This work was funded by the Food Standards Agency, UK. DIETARY FAT IS A MAJOR CONTRIBUTOR TO VLDL PRODUCTION IN THE FED STATE IN HUMANS Leanne Hodson, Toralph Ruge, Ross Milne, Barbara A. Fielding, Keith N. Frayn, Fredrik Karpe Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, United Kingdom Dietary and endogenous fatty acids mix in the postprandial state. Chylomicron remnants and non-esterified fatty acids (NEFA) are taken up by the liver and used for the synthesis of VLDL triglycerides (TG). VLDL metabolism is normally studied in a fasting state and few studies have investigated VLDL postprandially. The objective of the present study was to study VLDL TG metabolism over a 24-h period including sequential meals to better understand underlying causes of hypertriglyceridaemia. Seven healthy males were fed three sequential, eucaloric and macronutrient-identical meals (breakfast, lunch and dinner at 0, 5 and 10 h, respectively) labeled with different [U13 C] fatty acids (linoleic, oleic and palmitic acid) to investigate the incorporation of exogenous fatty acids into VLDLTG. An intravenous infusion of [2 H2 ]palmitic acid was given to investigate endogenous NEFA incorporation into VLDLTG. Blood samples were taken at 0, 5, 10, 15, 18 and 24 h. ApoB-100 VLDL was isolated using immunoaffinity techniques. Incorporation of the [2 H2 ]palmitatic acid into VLDL-TG reached steady state by 5 h suggesting that the rate of plasma NEFA incorporation into VLDL TG is fairly constant over the fed period. Each meal generated a chylomicron peak, the label of which rapidly (2–3 h) appeared in VLDL-TG. The average contribution of meal-derived VLDL TG, based on isotope tracer/tracee ratio, was 47 ± 7% in the fed state and only 20 ± 6% in the fasted state (p < 0.05). Exogenous fatty acids appeared rapidly in the VLDL and this effect was enhanced in the fed period. After meals, around 50% of VLDL TG was derived from the dietary fatty

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Abstracts / Atherosclerosis 188 (2006) S1–S9

acids, whereas after an overnight fast, approximately 80% of VLDL TG was derived from endogenous NEFA, i.e. adipose tissue stores. Dietary fat and endogenous fatty metabolism are major determinants of VLDL TG production. DETERMINING THE EFFECT OF GLUCOSE ON LARGE VERY LOW DENSITY LIPOPROTEIN (VLDL1 ) KINETICS USING A NOVEL METHOD I. AlShayji1 , J.M.R. Gill1 , J. Cooney2 , M.J. Caslake2 1 Institute

of Biomedical and Life Sciences, Glasgow University, Glasgow G12 8QQ, UK; 2 Department of Vascular Biochemistry, Glasgow University, Glasgow G12 8QQ, UK Insulin is a key regulator in triglyceride-rich lipoproteins metabolism. We investigated the effect of glucose on VLDL1 kinetics using a novel ‘Intralipid’ (IL) method. Eight subjects, aged 36.5 ± 13.0 years, BMI 26.9 ± 4.5 kg m−2 and fasting TG 1.7 ± 1.3 mmol l−1 and glucose 5.6 ± 1.1 mmol l−1 (mean ± S.D.), each underwent two IL infusion trials in random order. Subjects were given a bolus IL dose of 0.1 g kg−1 body mass, followed by 75-min IL infusion of 0.1 g kg−1 h−1 . One hour before infusion, subjects were given oral glucose 30 g (in 120 ml) followed by 10 g (in 40 ml) at 15-min intervals (Glucose) or equivalent volume of water (Control). Multiple blood samples were taken during and post-infusion for separation of IL (Sf 400) and VLDL1 (Sf 60–400). Production rates of VLDL1 -apoB and -TG were calculated from the linear rises during infusion. IL-TG clearance rate was determined from the post-infusion exponential decay. The mean concentrations of glucose, insulin and NEFA during and post-infusion in control versus glucose were (5.3 ± 0.9 mmol l−1 versus 8.8 ± 4.3 mmol l−1 , p = 0.024) (9.4 ± 6.7 mU l−1 versus 103.2 ± 93.6 mU l−1 , p = 0.025) and (0.81 ± 0.21 mmol l−1 versus 0.33 ± 0.14 mmol l−1 , p < 0.001), respectively. Glucose reduced VLDL1 -apoB production (28.3 ± 12.4 mg h−1 versus 23.0 ± 14.1 mg h−1 , p = 0.026) and VLDL1 -TG production (1210 ± 738 mg h−1 versus 1033 ± 836 mg h−1 , p = 0.087), but did not alter IL-TG clearance (62 ± 40 pools day−1 versus 87 ± 125 pools day−1 , p = 0.864). In conclusion, the reduction in VLDL1 production when glucose was ingested was detected using a novel ‘IL’ method. SITOSTEROL AND CHOLESTEROL IN CHYLOMICRONS OF TYPE 2 DIABETIC AND NON-DIABETIC SUBJECTS: THE RELATIONSHIP TO ATP BINDING CASSETTE PROTEINS G5 AND G8 AND NIEMANN PICK C1-LIKE 1 MRNA Gerald Tomkin, Sean Lally, Daphne Owens Department of Diabetes and Endocrinology, Trinity College Dublin, Ireland Sitosterolaemia is associated with increased atherosclerosis. Patients with type 2 diabetes have decreased ATP binding cassette proteins (ABC) G5 and G8 and increased

Niemann Pick C1-like1 (NPC1L1) both causing increased chylomicron cholesterol. Aim: to examine the relationship between chylomicron sitosterol and intestinal ABCG5 and G8 and NPC1L1 gene expression, 6 h after a sitosterol-enriched, high fat meal. Six type 2 diabetic patients (HbA1 6.6% ± 1.1) and six control subjects were examined. mRNA was measured by RT-PCR and sitosterol by GLC. Fasting serum cholesterol for diabetic and control subjects were 5.0 + 0.9 and 4.7 ± 1.1 mmol/l. Sitosterol was significantly increased in diabetic patients (1.0 ± 0.4 nmol/ml plasma versus 0.7 ± 0.3 nmol/ml plasma, p < 0.02). Postprandial chylomicron cholesterol was 85 ± 24 ␮mol/ml plasma in the diabetic patients versus 73 ± 46 ␮mol/ml for control subjects and chylomicron triglyceride was 175 ± 63 ␮mol/ml plasma versus 150 ± 98 ␮mol/ml plasma. ABCG5 mRNA at 0.67 ± 0.71 versus 0.21 ± 0.09 and ABCG8 at 0.24 ± 0.47 AU versus 0.13 ± 0.11 AU were lower in diabetic patients and NPC1L1 mRNA was significantly higher in the diabetic patients (1.93 ± 0.47 AU versus 0.97 ± 0.34 AU p < 0.002). There was a positive correlation between sitosterol and NPC1L1 mRNA (r = 0.54, p < 0.05). The study suggests that decreased ABCG5 and G8 and increased NPC1L1 in diabetes results in an increase in chylomicron sitosterol due to defective sitosterol handling. Whether these findings are related to the increased atherosclerosis in diabetes needs further investigation. EXERCISE ENHANCES FAT OXIDATION AND VASCULAR FUNCTION INDEPENDENTLY OF ENERGY DEFICIT F.L. Burton1 , D. Malkova1 , M.J. Caslake2 , J.M.R. Gill1 1 Institute

of Diet, Exercise & Lifestyle (IDEAL), University of Glasgow, Glasgow G12 8QQ, UK; 2 Department of Vascular Biochemistry, University of Glasgow, Glasgow G12 8QQ, UK Moderate intensity exercise increases fasting and postprandial fat oxidation [1] and improves vascular function [2] for at least 24-h post-exercise. However, it is unclear whether these changes are the consequence of exercise per se or the associated energy deficit. This study aimed to investigate the effects of prior exercise, with and without energy deficit, on fasting and postprandial substrate utilisation and vascular function. Eleven men (41.6 ± 2.3 years, BMI 31.3 ± 1.0 kg m−2 ) [mean ± S.E.M.] completed three 2-day trials in random order. On Day 1: subjects rested (C), walked at 50% VO2 max to expend 6.5 kcal kg−1 body mass (duration 91.8 ± 4.2 min) (ED), or completed the same walk with the energy expended replaced (END). For 2 days prior to and on Day 1, subjects avoided physical activity (except for the study walks) and alcohol and the experimenter provided all food. On Day 2, subjects arrived after a 12-h fast and consumed a test breakfast and lunch (each with 97 g CHO, 33 g fat, 28 g protein, 3.3 MJ). Expired air and pulse wave velocity (PWV) were measured over an 8.5-h observation period.

Abstracts / Atherosclerosis 188 (2006) S1–S9

Postprandial energy expenditure did not differ between trials (NS). Over the 8.5-h observation period, fat oxidation was C; 38.1 ± 2.1 g, END; 42.0 ± 2.3 g, ED; 44.8 ± 2.7 g (p < 0.01 for END and ED versus C). Fasting PWV measurements were C; 10.2 ± 1.3 m s−1 , END; 9.4 ± 1.0 m s−1 , ED; 9.3 ± 1.3 m s−1 (p < 0.02 for END and ED versus C). In conclusion, prior moderate intensity exercise increases fat oxidation and decreases PWV independently of energy deficit. This project was funded by TENOVUS Scotland. References [1] Hansen K, et al. Sports Med 2005;35:363–73. [2] Gill JMR, et al. J Am Coll Cardiol 2004;44:2375–82. METABOLIC SYNDROME RISK FACTOR RESPONSES DURING A RESIDENTIAL WEIGHT LOSS CAMP FOR OVERWEIGHT AND OBESE CHILDREN J.P. Hobkirk1 , R.F.G.J. King1 , D. Radley1 , P.K. Mackreth1 , C.B. Cooke1 , J.H. Barth2 , P.J. Gately1 1 Leeds Metropolitan University, Leeds, UK; 2 Leeds General

Infirmary, Leeds, UK Metabolic syndrome prevalence has risen in children from 4.2% to 6.4% in 8 years. Dietary modification and physical activity favourably modify metabolic syndrome risk factors, therefore we examined the impact of a residential weight loss camp on these risk factors. Fifty-one overweight and obese children (19 boys and 32 girls), mean age 14.4 ± 2.0 years, BMI 33.7 ± 7.2 kg m−2 were assessed. Anthropometric and fasting blood variables were measured before and after the camp (mean stay 31 ± 13 days). Campers undertook physical activity (5 h per day), dietary modification (1300–3300 kcal day−1 ) and lifestyle education classes six per week). Significant reductions (p < 0.0001) were observed in all metabolic syndrome risk factors except systolic blood pressure; waist girth decreased from 96.1 ± 13.5 cm pre to 91.7 ± 12.6 cm post, triglycerides 1.06 ± 0.41 mmol L−1 pre to 0.83 ± 0.32 mmol L−1 post, HDL-C 1.20 ± 0.25 mmol L−1 pre to 1.11 ± 0.24 mmol L−1 post, T-C/HDLC ratio 3.50 ± 0.76 pre to 2.99 ± 0.65 post, glucose 4.83 ± 0.35 mmol L−1 pre to 4.52 ± 0.28 mmol L−1 post. Systolic blood pressure reduced from 117 ± 10 mmHg−1 pre to 115 ± 10 mmHg−1 post and diastolic blood pressure 69 ± 7 mmHg−1 pre to 65 ± 8 mmHg−1 post. Favourable changes occurred in a number of risk factors demonstrating the potential of this form of intervention for acute improvements. Research is required to investigate the durability of these changes and the relationship with weight change.

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DOES INCLUSION OF APOB MEASUREMENTS CLUSTER WITH, OR AUGMENT THE PHENOTYPE OF THE METABOLIC SYNDROME? A.L. Dennis, E.J. Cheeseman, F. Karpe Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University, Churchill Hospital, Oxford, UK Introduction: The metabolic syndrome (MeS) is a clustering of common metabolic abnormalities associated with insulin resistance (IR) and the development of cardiovascular disease (CVD). Apolipoprotein B (Apo B) appears to be a better risk predictor of CVD than routine lipid profiles. Aims: To estimate the prevalence of MeS within a healthy population. To investigate if ApoB is a useful independent measure for the identification of individuals with MeS. To investigate if a raised apoB augments the phenotype of MeS. Design: Data from 568 subjects (aged 30–50 years) recruited to the Oxford Biobank were analysed using the EGIR, ATPIII and IDF definitions. The criteria for impaired fasting glucose were modified to >5.6 mmol/l. Insulin sensitivity was estimated by fasting insulin and glucose concentrations (HOMA-S). The cut-off for elevated ApoB concentrations was set to 75th percentile of the concentration measured in the population. Results: The identification rate of MeS in women/men according to the EGIR, ATPIII and IDF criteria were 5.9/12.9, 6.9/18.3 and 8/19%, respectively. The likelihood of detecting elevated ApoB in women with MeS was increased three-fold. The corresponding figure for men was two-fold. However, HOMA-S was almost identical comparing MeS women with normal or raised Apo B (p = 0.86). Conclusion: Apo B clusters with the conventional factors used to identify the MeS, in particular in women, but does not seem to augment the phenotype. FAVOURABLE EFFECTS ON PAI-1 OF THE INSULIN-SENSITISERS, METFORMIN AND PIOGLITAZONE, INDEPENDENT OF GLYCAEMIC CONTROL J.M. Lawrence1,2 , J. Reid2,3 , G.J. Taylor2 , C.A. Stirling3 , J.P.D. Reckless2,3 Health Care NHS Trust, Salisbury, UK; 2 School for Health, University of Bath, Bath, UK; 3 Diabetes and Lipid Research, Royal United Hospital, Bath, UK

1 Salisbury

Introduction: Obesity, metabolic syndrome and type 2 diabetes are linked to elevated levels of PAI-1 and fibrinogen, which are associated with increased ischaemic heart disease. Both metformin and thiazolidinediones decrease PAI-1 but there are few comparative studies. Method: Sixty overweight subjects (BMI > 27 kg/m2 ) with type 2 diabetes, previously on diet (7.0% > HbA1c > 10%) or low dose oral hypoglycaemic agents (HbA1c < 7.5%) were randomised to pioglitazone, metformin or gliclazide following withdrawal of oral hypoglycaemics and 3 months dietary

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Abstracts / Atherosclerosis 188 (2006) S1–S9

run-in. In the next 3 months drug therapy was uptitrated to achieve fasting glucose of <7.0 mmol/l, then maintained for a further 3 months. Blood samples were taken at randomisation and 6 months. Levels of PAI-1 and fibrinogen were measured in plasma. Results: HbA1c improved equally in the three groups. After 6 months levels of PAI-1 were decreased significantly in patients on metformin (109.1:91.1 ng/ml, p = 0.016) and pioglitazone (123.9:95.9 ng/ml, p < 0.001) but not with gliclazide (131.5:140.9 ng/ml, p = 0.21). There were no significant changes in fibrinogen [metformin (3.33:3.31 g/l, p = 0.89), pioglitazone (3.29:3.22 g/l, p = 0.71), gliclazide (3.35:3.50 g/l, p = 0.27)]. Conclusion: Compared with gliclazide, metformin and pioglitazone significantly reduced PAI-1 independent of glycaemic control. Reduction in PAI-1 may help explain the effects of metformin on macrovascular disease in UKPDS and of pioglitazone in PROACTIVE. PIOGLITAZONE FAVOURABLY AFFECTS THE ADIPOKINE PROFILE OF OVERWEIGHT PATIENTS WITH TYPE 2 DIABETES INDEPENDENT OF GLYCAEMIC CONTROL J. Reid1,2 , J.M. Lawrence1,3 , G.J. Taylor1 , C.A. Stirling2 , J.P.D. Reckless1,2 for Heath, University of Bath, Bath, UK; 2 Diabetes and Lipid Research, Royal United Hospital, Bath, UK; 3 Salisbury Health Care NHS Trust, Salisbury, UK 1 School

Introduction: Obesity, metabolic syndrome and type 2 diabetes are linked to insulin resistance and abnormal adipokine profiles, with the leptin:adiponectin ratio being a possible biomarker for atherosclerosis. Thiazolidinediones may improve adipokine levels in these patients, but is this independent of glucose lowering? We compared the effects of pioglitazone and metformin (two insulin-sensitisers) with gliclazide on adiponectin, leptin and resistin in overweight type 2 patients. Method: Sixty type 2 diabetes patients (BMI > 27 kg/m2 ), on diet (HbA1c < 10.0%) or low dose oral hypoglycaemics (HbA1c < 7.5%) were randomised to pioglitazone, metformin or gliclazide after 3 months dietary run-in. Therapy was uptitrated over 3 months aiming for fasting glucose <7.0 mmol/l, then maintained for 3 months. Blood was taken at randomisation and 6 months to measure serum adiponectin, leptin and resistin. Results: Pioglitazone decreased resistin (11.3:10.5 ng/ml; p = 0.05) and increased adiponectin (5.6:13.8 ␮g/ml; p < 0.001) with no significant change on gliclazide or metformin. Leptin increased on gliclazide (18.8:23.9 ng/ml; p = 0.01), with no significant change on pioglitazone or metformin. Correspondingly the leptin:adiponectin ratio increased on gliclazide (3.4:4.4; p < 0.02), decreased on pioglitazone (3.1:2.0; p = 0.10), a significant difference

between the two groups (p = 0.04) [ANOVA] but remained unchanged on metformin (3.3:3.4; p = 0.80). Conclusion: Effects of pioglitazone on the adipokine profile are favourable compared with metformin and gliclazide. DEVELOPMENT OF SENSITIVE AND SPECIFIC AGE- AND GENDER-SPECIFIC LDL-CHOLSTEROL CUT-OFFS FOR DIAGNOSIS OF RELATIVES WITH FH IN CASCADE TESTING S.E. Humphries1,2 , B. Starr1 , S.G. Hadfield1 , J. Defesche3 , P. Landsberg4 , L. Ose5 , T.P. Leren5 , D. Damgaard6 , H.A.W. Neil7 1 London IDEAS GKP, United Kingdom; 2 Centre for Cardio-

vascular Genetics, UCL, London; 3 AMC, Amsterdam, The Netherlands; 4 StOEH, Amsterdam, The Netherlands; 5 Lipid Clinic & Medical Genetics, Rikshospitalet-Radiumhospitalet HF, Oslo, Norway; 6 Medicine & Cardiology, Aarhus, Denmark; 7 Public Health & Primary Health Care, University of Oxford, United Kingdom Background and objectives: The plasma total and LDL-C levels that are used as diagnostic criteria for Familial Hypercholesterolaemia (FH) probands are too stringent for use in relatives, given their higher prior probability of being FH (50% versus 1/500). Our objective was to develop more appropriate lipid-level criteria and to test their accuracy and utility in case identification against published cut-offs from USA (MedPed). Subjects and methods: Using genetically tested first degree relatives of known Netherlands FH probands (mutation carriers/non-carriers n = 825/2469), age- (10 year bands) and gender-specific LDL-C diagnostic cutoffs for first degree relatives were constructed using Bayesian statistics. These were used to test similar data from Denmark (n = 169/161) and Norway (n = 374/742). Results: The cutoffs correctly identified 81% (95%CI = 78–83%) in the Netherlands data, performing better amongst relatives <45 years compared to older ages (p < 0.001). Compared with the Netherlands, ageand gender-adjusted mean LDL-C levels were significantly higher in the Denmark and Norway subjects, for both mutation carriers and non-carriers. After adjusting for the difference in the means, the cut-offs showed a similar performance in identifying mutation status: Denmark 81% (78–86%), Norway 84% (82–86%). These cut-offs performed significantly better than the published MedPed cut-offs (p < 0.001). Conclusions: Country-specific cut-offs may lead to greater accuracy for identifying FH patients. The cut-offs developed here have a balanced specificity and sensitivity, which is appropriate for cascade testing.

Abstracts / Atherosclerosis 188 (2006) S1–S9

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GENETIC TEST RESULTS IN FH NEED CAREFUL INTERPRETATION

WHY AUDIT? A REPORT ON THE FIRST PHASE OF THE DH FH CASCADE TESTING PROJECT

Mabella Farrer1 , Devi Nair3 , Alison Taylor4 , Sian Tabrah4 , Ros Whittall2 , Gail Norbury4 , Steve Humphries1,2

S.G. Hadfield1 , S.E. Humphries1 , B.J. Starr1 , D. Bhatnagar2 , R. Cramb3 , S. Egan4 , G. Ferns5 , A. Jones6 , C.B. Marenah7 , J. Marples8 , P. Prinsloo7 , M.F. Stewart9 , L. Sandle10 , T. Wang5,11

1 London IDEAS Genetics Knowledge Park, United Kingdom; 2 Centre

for Cardiovascular Genetics, RF&UCL Medical School, London, United Kingdom; 3 Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom; 4 NE Thames Regional Molecular Genetics Laboratory, Great Ormond Street, London, United Kingdom Background: More than 800 different sequence changes in LDLR have been reported in patients with FH. However, not all reported changes are FH-causing, so any genetic test results need to be interpreted with care. Methods: Patients defined by Simon Broome criteria as definite and possible FH were recruited for DNA testing and cascade family tracing. Sequence changes were evaluated as recommended by Cotton 1998. Results: Of 29 different LDLR DNA results, 6 (20%) were previously unreported, but fulfilled the criteria for pathogenicity. One previously reported mutation (p.V827I) (Hobbs et al., 1992; Zakharova et al., 2005) was found in a patient in a homozygous form. The patient had possible FH (untreated total cholesterol 7.6 mmol/l no personal history of CHD but a brother with CABG at 58 years). Cascade testing showed that only half of the proband’s children had elevated cholesterol, the brother had neither elevated cholesterol nor inherited the mutation, and that neither of the proband’s parents had a history of early heart disease. Molecular testing demonstrated that the proband was not carrying an LDLR deletion. V827 is highly conserved across species, and I827 was absent from 100 healthy UK subjects. Conclusion: Although fulfilling many of the criteria to be FH-causing, the p.V827I missense change does not co-segregate with elevated cholesterol levels, and appears unlikely to be pathogenic. Ideally, all reported LDLR sequence changes should be tested by in vitro functional assays before reporting.

1 London

IDEAS Genetics Knowledge Park, United Kingdom; 2 The Pennine Acute Hospitals, United Kingdom; 3 University Hospital Birmingham, United Kingdom; 4 Royal Bournemouth Hospital, United Kingdom; 5 Royal Surrey County Hospital, United Kingdom; 6 Birmingham Heartlands, United Kingdom; 7 Nottingham City Hospital, United Kingdom; 8 Wrightington, Wigan & Leigh NHS Trust, United Kingdom; 9 Salford Royal Hospitals NHS Trust, United Kingdom; 10 Trafford Healthcare NHS Trust, United Kingdom; 11 Frimley Park Hospital, United Kingdom Background: The DH FH Cascade Testing Audit Project is assessing the feasibility of cascade testing for Familial Hypercholesterolaemia (FH) within the NHS. The first phase of the project, an audit of current practice, was undertaken to: (i) ensure that FH patients identified as a result of the project were offered appropriate advice and treatment (ii) to make a valid appraisal of the impact of additional resources on family tracing. Methodology: Medical records of known FH patients (over 18 years of age and diagnosed before 31 December, 2003) were accessed to obtain information on diagnosis, treatment and family tracing. Results: Analyses, to date, have shown that patients are diagnosed correctly, 93% meeting Simon Broome criteria, and are offered appropriate advice and treatment, 90% are on a statin. The audit indicates greater variability in family tracing between the sites, for example: • A family pedigree is in the notes (mean 26%, range <1–61%). • Advice was given to contact and recommend testing of 1st degree relatives (mean 16%, range <1–61%). • The proportion of relatives contacted and tested (mean 30%, range 5–44%). Conclusion: FH patients are well cared for in lipid clinics; improvements in the effectiveness of family tracing may be made by providing the resources to manage FH as a genetic condition.

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PATIENTS’ UNDERSTANDINGS HYPERCHOLESTEROLAEMIA

Abstracts / Atherosclerosis 188 (2006) S1–S9

OF

FAMILIAL

Kate Weiner Institute for the Study of Genetics, Biorisks & Society, University of Nottingham, Law & Social Sciences Building, University Park, Nottingham, NG7 2RD, United Kingdom Familial hypercholesterolaemia (FH) is one of the most common hereditary conditions in the UK. There is, however, very little published work concerning patients’ experiences of this condition, and existing studies have tended to focus on experiences and views at the point of diagnosis. This paper presents findings of a qualitative study concerned with patients’ everyday experiences and understandings of FH. The study focussed on how patients understand FH, including the hereditary aspects of the condition and what the condition means to patients’ everyday lives and life plans. It draws on 31 interviews with FH patients undertaken at a lipid clinic in the north of England. All the participants had an established diagnosis of definite FH, with the length of time since diagnosis ranging from 1 to 20 years. The data suggest that this group of seasoned clinic attendees, almost without exception, see FH as highly controllable and heart disease as avoidable. This can be linked to their ideas about the causes of heart disease, which were multifaceted. FH was not linked with a strong disease identity for these participants, for example only the minority talked of being aware of a family history of heart disease or hypercholesterolemia prior to their own diagnosis. Being diagnosed with FH, and being aware that one is ‘at risk’ of heart disease were seen as largely unproblematic. However, there was some talk of worry or resistance to this knowledge, particularly relating to younger people. These findings will be related to current policy and practice concerning FH. BENEFITS OF SALMON EATING ON TRADITIONAL AND NOVEL VASCULAR RISK FACTORS IN YOUNG, HEALTHY SUBJECTS J.J. Lara1 , M. Economou1 , A.M. Wallace2 , A. Rumley3 , G. Lowe3 , C. Slater1 , M. Caslake3 , N. Sattar3 , M.E.J. Lean1 1 Division

of Developmental Medicine, University of Glasgow, Glasgow, UK; 2 Department of Clinical Biochemistry, Glasgow Royal Infirmary, Glasgow, UK; 3 Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK Background: Epidemiological evidence supports an association between consumption of oil-rich fish and a lower risk for cardiovascular diseases. The present clinical study tested the hypothesis that oil-rich fish consumption improves traditional and novel vascular risk factors. Methods: Forty-eight (16 men) healthy adults aged 20–55 years, with a BMI 20–29, consumed 125 g/day of salmon for a 4-week period followed by a 4-week period with no-fish. Subjects were instructed to maintain dietary and physical activity

patterns during the period of study. Blood pressure, anthropometric, body composition and dietary information with fasting blood samples to determine traditional and novel CHD risk markers and plasma fatty acids were obtained before and after each period. Results: Compared to no-fish, eating salmon significantly decreased systolic and diastolic blood pressure as well as mean arterial blood pressure by 4%, triglycerides by 15%, and LDL-cholesterol by 7%, and significantly increased HDL cholesterol by 5% (p < 0.05). The changes in blood pressure and lipids alone with salmon intake predict around a 25% reduction in CHD risk based on the PROCAM risk calculator. Plasma adiponectin demonstrated a tread towards improvement (8.39 ␮mol/L with salmon and 7.52 with nofish; p = 0.086) but no significant changes were found either in plasma leptin, glucose or insulin after salmon consumption. Conclusion: Daily consumption of salmon improved traditional risk predictors for CHD in non-obese subjects. LOW GLYCAEMIC LOAD, HIGH-PROTEIN DIETS HAVE A MORE BENEFICIAL IMPACT ON LIPID PROFILES THAN TRADITIONAL DIETS IN SUBJECTS WITH METABOLIC SYNDROME R. Mukhtar1,2 , J. Reid1,2 , H. Fishlock3 , R. Laws1 , A.M. Robinson1 , J. Reckless1,2 1 Royal United Hospital, Bath UK; 2 University of Bath, Bath,

UK; 3 Great Western Hospital, Swindon, UK Background: Obesity has risen globally with a corresponding increase in type 2 diabetes and CVD, prompting interest in prevention. Weight loss through diet and lifestyle changes has an effect on lipids and CV risk. Many diets claim to benefit people with metabolic syndrome (MS), but comparative studies are rare. We compared lipid effects of two energyrestricted diets, low fat/high carbohydrate (conventional) and low glycaemic load (GL) with Atkins’ diet in 108 MS subjects. Method: Subjects fulfilling MS ATPIII criteria were randomised for dietary intervention for 1 year, and monitored regularly. Total (TC), high- (HDL-C) and low-densitylipoprotein cholesterol (LDL-C), and triglycerides (Tg) (mmol/l) were measured at baseline, 3, 6 and 12 months. Results: Mean baseline TC, HDL-C, LDL-C and Tg were 5.69, 1.35, 3.41 and 2.01 mmol/l respectively. Tg, fell significantly for conventional, GL and Atkins’ diets, at 3 (−0.37, −0.42, −0.53) and 6 months (−0.41, −0.54, −0.42) (all p < 0.05), inter-group differences being insignificant. Atkins’ increased HDL-C at 3 (p = 0.00) (−0.01, +0.02, +0.22) and 6 months (p < 0.03) (+0.06, +0.08, +0.23). LDL-C fell with GL (p < 0.04) at 3 months, but rose with Atkins’ (p < 0.46) (+0.12, −0.23, +0.87). LDL-C changes at 6 months were insignificant (−0.01, −0.11, +0.22) as were TC:HDL-C ratio changes (−0.28, −0.31, 0.45).

Abstracts / Atherosclerosis 188 (2006) S1–S9

Conclusion: GL and Atkins’ favourably affect lipids, implying that changes to conventional diets may be warranted for MS subjects. Changes to Atkins’, by reducing saturated fat, may prevent LDL rise. POTENTIAL FOR USE OF LYCOPENE-FREE TOMATO EXTRACTS AS DIETARY ANTIPLATELET AGENTS Niamh O’Kennedy1 , Lynn Crosbie1 , Veronica Song1 , John I. Broom2 , David J. Webb3 , Asim K. Duttaroy4 1 Provexis plc, The Rowett Research Institute, Aberdeen, UK; 2 The

Robert Gordon University, Aberdeen, UK; 3 Centre for Cardiovascular Science, University of Edinburgh, UK; 4 University of Oslo, Norway Normal platelet function is essential for haemostasis. However certain conditions, e.g. atherosclerosis, contribute to chronic platelet activation and can lead to a prothrombotic state. The role of antiplatelet medication in preventing thrombosis-linked adverse events in CVD patients is well established, and an area of current interest is the potential of antiplatelet agents in primary prevention of CVD. We have shown that antiplatelet components from tomato extracts modulate platelet function in vitro by mechanisms including inhibition of platelet surface protein expression and ␣-granule secretion. The ex vivo antiplatelet efficacy of a lycopene-free tomato extract has been tested in 190 healthy human subjects, in five placebo-controlled trials. The different mechanisms of action displayed in vitro lead to effects on different aggregation pathways ex vivo. In the acute setting, a significant antiplatelet effect (8–23% inhibition, compared to control) was observed 3 h after extract consumption, with effects persisting for up to 18 h. Both ADP and collagenmediated platelet aggregation were affected, and release of thromboxane B2 and soluble p-selectin by platelets was reduced. When tomato extract was consumed on a daily basis over 6 weeks, the antiplatelet effects observed were reproducible, but not cumulative. Plasma triglycerides were also reduced (9% reduction compared to controls), during chronic supplementation trials. Our results suggest that lycopene-free tomato extracts are of interest in the context of primary prevention of CVD.

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WALKING TO HEALTH: EFFECTS OF A HOMEBASED PROGRAMME OF BRISK WALKING ON CARDIOVASCULAR RISK FACTORS IN HEALTHY, SEDENTARY ADULTS M.A. Tully1 , M.E. Cupples1 , N. Hart1 , J. McEneny2 , K.J. McGlade1 , W.S. Chan3 , I.S. Young2 1 Department of General Practice, Queens University Belfast,

Northern Ireland, United Kingdom; 2 Centre for Clinical and Population Sciences, Queen’s University Belfast, Northern Ireland, United Kingdom; 3 Department of Family Medicine and General Practice, RCSI, Ireland Introduction: Regular exercise reduces the risk of cardiovascular disease and has a positive impact on obesity. Current recommendations are that every adult should accumulate at least 30 min of moderate intensity exercise on most days of the week. We compared the effects of unsupervised walking programmes at and below this level. Methods: Male (n = 42) and female (n = 64) sedentary employees of the Northern Ireland Civil Service aged 40–65 years were randomly allocated to one of two walking groups (brisk walk for 30 min on 3 (n = 44) or 5 (n = 42) days per week, for 12 weeks) or to a control (n = 20) group. Fitness (10 M short walk test), BMI, blood pressure (BP), Framingham risk score and lipoproteins were measured before and after the programme. Participants wore pedometers and recorded their walking time in a diary. Results: The programme was completed by 88.8% of the 3-day group (39/44), 85.7% (36/42) of the 5-day group and 90% (18/20) of the control group. Significant improvements in BMI, waist, hip, systolic BP, 10-year risk of CHD and fitness were observed in the 3-day group. In the 5-day group, significant improvements were observed in waist, hip, systolic and diastolic BP, 10-year risk of stroke and fitness. Conclusions: This study provides evidence of the benefits to cardiovascular risk and obesity from unsupervised home-based walking programmes at and below the current recommendation in healthy sedentary 40–65 year olds.