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Small deep infarction and resistance to activated protein C
71st EAS Meeting Abstracts accepted for presentation in the abstract book 0.39). The ratio of total cholesterol to HDL-C increased significantly from 4.5+1.1 to 5.0+1.4 (p = 0.01). In a subset of 13 volunteers that showed the most pronounced increase in LDL-C, we investigated lipoprotein profiles in more detail, focusing on lipoprotein particle composition in the VLDL-. IDL- and LDL-fractions (seperated by sequential density ultracentrifugation). The ratios of cholesterol to apolipoprotein B in the lipoprotein fractions/particles VLDL, IDL and LDL were 2.1 -t-0.33 vs. 2.14±0.35 (p = 0.94). 1.844-0.23 vs. 1.85±0.18 (p = 0.98) and 1.795=0.I3 vs. 1.79-t-0.22 (p = 0.97), respectively, and remained virtually unchanged during treatment. In conclusion, an increase in HDL-C, as seen in previous studies, cannot be confirmed in this prospective study in healthy volunteers. Furthermore we conclude that the atherogenicity of lipoprotein particles, as indicated by their relative content ofapoB and cholesterol is unchanged although HDL-C and total cholesterol are slightly shifted towards a more unfavourable ratio. To obtain answers on the influence of CBZ on the mechanisms regulating apoB metabolism tracer kinetic studies are required. HIGH CONCENTRATIONS OF LIPOPROTEIN (A) ARE ASSOCIATED W I T H URINARY PROTEIN E X C R E T I O N IN PATIENTS W I T H DIABETES AND VASCULAR DISEASE
A. Zambanini 1. M.R. Smith 1. A. Cox 1, J. Foxton 1, A.S. Wierzbicki 2, M.D. Feher 1 . 1Department t#'Clinical PharmacoloKv, Chelsea: Westminster Hospital London: 2Department of Chemical Pathology Guy's & St. Thomas" Hospital Trust, St. Thomas Hospital. London. UK Mechanisms linking the association of proteinuria and cardiovascular disease (CVD) in diabetes, are at present unclear. Lipoprotein (a) lip Ca)] is a recognised atherogenic and thrombogenic factor which at a concentration of 300 mg/L or more, is associated with clinical CVD. Few studies have assessed the relationship between Lp(a) and proteinuria in diabetic patients with and without CVD. We performed a cross-sectional study of 287 stable diabetic patients, measuring serum Lp(a) concentration and assessing for proteinuria by both protein dipstick test and a single urine albumin to creatinine ratio. Clinical CVD was defined as the presence of ischaemic heart disease, cerebrovascular disease or peripheral vascular disease. The group comprised 175 men, 112 women, age range 22 to 96 years, duration of diabetes 1 to 61 years, and insulin treatment recorded in 26%. For the total group, there was no increased frequency of Lp(a) > 300 mg/L with increasing proteinuria (28% with no microalbuminuria, 26% with microalbuminuria and 30% with proteinuria). However in the group with CVD the prevalence of Lp(a) _> 300 mg/L was 10% with no microalbuminuria, 37% with microalbuminuria* and 53% with proteinuria* (*p < 0.05). Increased urinary protein excretion and Lp(a) > 300 mg/L are associated with CVD. This may be another mechanism explaining the excess of cardiovascular events in these patients. PRIMARY PREVENTION OF CORONARY DISEASE IN DIABETES; LIMITATIONS OF THE M E T H O D S USED TO ESTIMATE CHD RISK
A. Zambanini 1, M.R. Smith 1, M.D. Feher 1'2. IBeta Cell Diabetes Centre. Chelsea; Westminster Hospital, London; 2 Section of Clinical Pharmacology Imperial College School of Medicine. UK Several tables/charts and computer based programs have been devised for the assessment of risk in the primary prevention of coronary heart disease (CHD). Five different methods (New Zealand table, Sheffield table, Joint European Societies Guidelines Chart, Framingham Risk Calculator and Coronary Events Risk Calculator) were assessed on their applicability to patients with diabetes. Data for the algorithms were derived from two epidemiological studies, IFramingham Heart Study and the Munster Heart Study) and include only small numbers of diabetic patients in = 237 and 377 respectively). Similarities in risk components included age, gender, smoking, hypertension, and total cholesterol. Diabetes was included but was not classified according to type I or type 2 diabetes. The presence ofproteinuria, a major cardiovascular risk factor in diabetes, was included in only one method (NZ table). Assumptions regarding HDL, which are inappropriate for type 2 diabetes, were made in two methods (Sheffield and Joint European Society). Despite the strong triglyceride-CHD link in diabetes and importance of CHD family history, only one method (CERCA) included these as risk factors. LVH was included in only two methods (Framingham & Sheffield). Each method differed in the calculated (ranging from annual through to 5, 8, and 10 year)
195
CHD risk. The importance of ethnic origin for CHD risk and diabetes is well recognised; none of the methods included this as a risk factor. Diabetes is associated with marked increased CHD risk and recent RCTs (e.g. 4S, CARE, LIPID, UKPDS, HOT studies) confirm clear treatment benefits for specific risk factors. Thus the methods of assessing CHD risk due to their inconsistencies may have only a limited role in future practice as the emerging evidence is that patients with diabetes should be treated as for secondary prevention. D O N ' T F O R G E T DIET W.G. Simpson 1 , K. Hesketh 2, J. Brooml 1. tDepartment s of Clinical Biochemist~; 2Dietetics, Aberdeen Rovallnfirmary, Aberdeen, UK We examined the added effect of strict dietary control in obese patients already established on lipid-lowering drugs. Nine obese patients (BMI range 30-41) at high risk of coronary vascular disease, who had already been commenced on (and responded to) lipid lowering agents (statin, fibrate or combined therapy) were offered intensive dietary control. By the first return visit (usually 1 month), the average weight lost was 7.3% (range 6.9 to 9.3%). This was associated with a marked drop in cholesterol (mean 19.3%, range 42.2 to 8.0%), a rise in HDL (mean 5.4%, range -5.8 to +33.3%), and a drop in triglyceride (mean 32%, range -7.6 to +20%), along with improvements in blood pressure. Much is made of the overwhelming evidence for hypolipidaemic drugs; it is very easy to forget that in the major intervention studies, dietary advice was reinforced, and so the beneficial effect may have been of the combination of diet and drug. Our study at least shows that diet can still have a major role to play. S M A L L DEEP INFARCTION AND RESISTANCE TO ACTIVATED PROTEIN C N.A. Guseva I , V.G. lonova2, M.Ju. Maximova2, L.I. Patrushev3, S.M. Strukova 1 . l Department of Human and Animal Physiology,
Lomonosou Moscow State UniuersiO, 119899; 21nstute of Neurology of Russian Academy of Medical Science, Moscow: 3Shemyakin-Ouchinnikov Institute of Bioorganic Chemistr); RAS. Mosco)t; Russia Background: Small deep infarctions are an interesting phenomenon, which observed in patients with long standing arterial hypertension and artherosclerosis. They are diagnosed by computer tomography (CT) in quantity from 1-2 to even 10. At the same time there are no sufficient results about state of blood coagulation and protein C system from such patients. Resistance to activated protein C (APC-R) was recently discovered as a most common risk factor for venous and arterial thrombosis. It is usually caused by replacement of Arg506 to Gin in coagulation factor V molecule, named Factor V Leiden. Objectives: To investigate coincidence of small deep infarctions and presence of Factor V Leiden mutation. Materials and Methods: Patients aged younger than 60 with small deep infarctions were studied. The stroke was confirmed by clinical assessment and by a CT/MRI scane. Factor V Leiden mutation was diagnosed by polimerase chain reaction (PCR), accompanied by restriction with Mnll and by allele-specific PCR. Results: 2 of 9 patients were heterozygous for Factor V Leiden mutation. Conclusions: It is possible that Factor V Leiden mutation may be associated with mechanisms which predispose to small deep infarctions developing. This genetic defect might be in a latent form and be revealed in association with arterial hypertension and atherosclerosis. The results suggest that detecting of Factor V Leiden mutation may give an additional information about small deep infarction etiology and prevention. USE O F THE DI9S394 T E T R A N U C L E O T I D E REPEAT IN T H E DIAGNOSIS OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A
A. Horinek, R. Ceska, M. Vrablik. IIFa Internal Department. I st Medical FaculO, The Charles Unioersi~., Prague, Czech Republic Background: Familial hypercholesterolemia is a common genetic disorder caused by LDL-receptor gene mutation. As the direct mutation screening remains complex, recently a more efficient approach to co-segregation studies has been developed. The approach is based on highly informative tetranucleotide repeat, flanking the LDLR gene region, designated D 19S394. This marker is situated only 150 kilobases telomeric to the LDLR gene and therefore serves as an extremely useful marker. Here we are presenting our first experiences with this new method of co-segregation analysis in FH
71st EAS Congress and Satellite Symposia
A. Zambanini 1. M.R. Smith 1. A. Cox 1, J. Foxton 1, A.S. Wierzbicki 2, M.D. Feher 1 . 1Department t#'Clinical PharmacoloKv, Chelsea: Westminster Hospital London: 2Department of Chemical Pathology Guy's & St. Thomas" Hospital Trust, St. Thomas Hospital. London. UK Mechanisms linking the association of proteinuria and cardiovascular disease (CVD) in diabetes, are at present unclear. Lipoprotein (a) lip Ca)] is a recognised atherogenic and thrombogenic factor which at a concentration of 300 mg/L or more, is associated with clinical CVD. Few studies have assessed the relationship between Lp(a) and proteinuria in diabetic patients with and without CVD. We performed a cross-sectional study of 287 stable diabetic patients, measuring serum Lp(a) concentration and assessing for proteinuria by both protein dipstick test and a single urine albumin to creatinine ratio. Clinical CVD was defined as the presence of ischaemic heart disease, cerebrovascular disease or peripheral vascular disease. The group comprised 175 men, 112 women, age range 22 to 96 years, duration of diabetes 1 to 61 years, and insulin treatment recorded in 26%. For the total group, there was no increased frequency of Lp(a) > 300 mg/L with increasing proteinuria (28% with no microalbuminuria, 26% with microalbuminuria and 30% with proteinuria). However in the group with CVD the prevalence of Lp(a) _> 300 mg/L was 10% with no microalbuminuria, 37% with microalbuminuria* and 53% with proteinuria* (*p < 0.05). Increased urinary protein excretion and Lp(a) > 300 mg/L are associated with CVD. This may be another mechanism explaining the excess of cardiovascular events in these patients. PRIMARY PREVENTION OF CORONARY DISEASE IN DIABETES; LIMITATIONS OF THE M E T H O D S USED TO ESTIMATE CHD RISK
A. Zambanini 1, M.R. Smith 1, M.D. Feher 1'2. IBeta Cell Diabetes Centre. Chelsea; Westminster Hospital, London; 2 Section of Clinical Pharmacology Imperial College School of Medicine. UK Several tables/charts and computer based programs have been devised for the assessment of risk in the primary prevention of coronary heart disease (CHD). Five different methods (New Zealand table, Sheffield table, Joint European Societies Guidelines Chart, Framingham Risk Calculator and Coronary Events Risk Calculator) were assessed on their applicability to patients with diabetes. Data for the algorithms were derived from two epidemiological studies, IFramingham Heart Study and the Munster Heart Study) and include only small numbers of diabetic patients in = 237 and 377 respectively). Similarities in risk components included age, gender, smoking, hypertension, and total cholesterol. Diabetes was included but was not classified according to type I or type 2 diabetes. The presence ofproteinuria, a major cardiovascular risk factor in diabetes, was included in only one method (NZ table). Assumptions regarding HDL, which are inappropriate for type 2 diabetes, were made in two methods (Sheffield and Joint European Society). Despite the strong triglyceride-CHD link in diabetes and importance of CHD family history, only one method (CERCA) included these as risk factors. LVH was included in only two methods (Framingham & Sheffield). Each method differed in the calculated (ranging from annual through to 5, 8, and 10 year)
195
CHD risk. The importance of ethnic origin for CHD risk and diabetes is well recognised; none of the methods included this as a risk factor. Diabetes is associated with marked increased CHD risk and recent RCTs (e.g. 4S, CARE, LIPID, UKPDS, HOT studies) confirm clear treatment benefits for specific risk factors. Thus the methods of assessing CHD risk due to their inconsistencies may have only a limited role in future practice as the emerging evidence is that patients with diabetes should be treated as for secondary prevention. D O N ' T F O R G E T DIET W.G. Simpson 1 , K. Hesketh 2, J. Brooml 1. tDepartment s of Clinical Biochemist~; 2Dietetics, Aberdeen Rovallnfirmary, Aberdeen, UK We examined the added effect of strict dietary control in obese patients already established on lipid-lowering drugs. Nine obese patients (BMI range 30-41) at high risk of coronary vascular disease, who had already been commenced on (and responded to) lipid lowering agents (statin, fibrate or combined therapy) were offered intensive dietary control. By the first return visit (usually 1 month), the average weight lost was 7.3% (range 6.9 to 9.3%). This was associated with a marked drop in cholesterol (mean 19.3%, range 42.2 to 8.0%), a rise in HDL (mean 5.4%, range -5.8 to +33.3%), and a drop in triglyceride (mean 32%, range -7.6 to +20%), along with improvements in blood pressure. Much is made of the overwhelming evidence for hypolipidaemic drugs; it is very easy to forget that in the major intervention studies, dietary advice was reinforced, and so the beneficial effect may have been of the combination of diet and drug. Our study at least shows that diet can still have a major role to play. S M A L L DEEP INFARCTION AND RESISTANCE TO ACTIVATED PROTEIN C N.A. Guseva I , V.G. lonova2, M.Ju. Maximova2, L.I. Patrushev3, S.M. Strukova 1 . l Department of Human and Animal Physiology,
Lomonosou Moscow State UniuersiO, 119899; 21nstute of Neurology of Russian Academy of Medical Science, Moscow: 3Shemyakin-Ouchinnikov Institute of Bioorganic Chemistr); RAS. Mosco)t; Russia Background: Small deep infarctions are an interesting phenomenon, which observed in patients with long standing arterial hypertension and artherosclerosis. They are diagnosed by computer tomography (CT) in quantity from 1-2 to even 10. At the same time there are no sufficient results about state of blood coagulation and protein C system from such patients. Resistance to activated protein C (APC-R) was recently discovered as a most common risk factor for venous and arterial thrombosis. It is usually caused by replacement of Arg506 to Gin in coagulation factor V molecule, named Factor V Leiden. Objectives: To investigate coincidence of small deep infarctions and presence of Factor V Leiden mutation. Materials and Methods: Patients aged younger than 60 with small deep infarctions were studied. The stroke was confirmed by clinical assessment and by a CT/MRI scane. Factor V Leiden mutation was diagnosed by polimerase chain reaction (PCR), accompanied by restriction with Mnll and by allele-specific PCR. Results: 2 of 9 patients were heterozygous for Factor V Leiden mutation. Conclusions: It is possible that Factor V Leiden mutation may be associated with mechanisms which predispose to small deep infarctions developing. This genetic defect might be in a latent form and be revealed in association with arterial hypertension and atherosclerosis. The results suggest that detecting of Factor V Leiden mutation may give an additional information about small deep infarction etiology and prevention. USE O F THE DI9S394 T E T R A N U C L E O T I D E REPEAT IN T H E DIAGNOSIS OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A
A. Horinek, R. Ceska, M. Vrablik. IIFa Internal Department. I st Medical FaculO, The Charles Unioersi~., Prague, Czech Republic Background: Familial hypercholesterolemia is a common genetic disorder caused by LDL-receptor gene mutation. As the direct mutation screening remains complex, recently a more efficient approach to co-segregation studies has been developed. The approach is based on highly informative tetranucleotide repeat, flanking the LDLR gene region, designated D 19S394. This marker is situated only 150 kilobases telomeric to the LDLR gene and therefore serves as an extremely useful marker. Here we are presenting our first experiences with this new method of co-segregation analysis in FH
71st EAS Congress and Satellite Symposia