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LIMB Ischaemia and leukaemia
Bennet
echolucent/unstable with GSM<32). The aim of our study was to determine whether there is any association between the stromelysin 5A/6A polymorphism (SEL) and plaque echodensity in subjects from a town with a high (Dewsbury) and low (Maidstone) prevelance of coronary heart disease. A total of 233 men (179 from Dewsbury, 154 from Maidstone) and 282 women (120 from Dewsbury, 162 Maidstone) had their carotids scanned. Blood samples were genotyped for the 5A/6A stromelysin (SEL) polymorphism using an allele specific amplification assay. The genotype frequencies were in Hardy-Weinberg equilibrium. A homogeneity test carried out on the SEL genotype frequency distribution of Dewsbury men with GSM>32 and GSM<32, indicated that Dewsbury SEL 5A/5A men are more likely to have echogenic plaques (GSM>32, P-0.002). When the allele frequencies of GSM>32 and GSM<32 subjects were compared, significant differences were obtained, the 6A allele was more prevalent in the GSM<32 subpopulation of Dewsbury men (58% vs 42%, P-0.002). No significant differences were found in the women. The above data indicate that the 6A allele is associated with unstable plaques in Dewsbury men and may explain the increased risk of symptomatic cardiovascular disease in 6A carriers. ~ 3 - ~ IS L I F E T I M E TOBACCO SMOKING ASSOCIATED W I T H ATHEROSCLEROSIS AND ARTERIAL STIFFNESS IN 36-YEAR OLD MEN AND WOMEN? THE AMSTERDAM GROWTH AND HEALTH LONGITUDINAL STUDY E.H.C.M. Bekkering 1, C.M. Bernaards 1, J.W.R. Twisk 1, C.D.A. Stehouwer1'2, W. Van Mechelen 1'3, H.C.G. Kemper 1.
JInstitute for Research in Extramural Medicine, 2Department of Internal Medicine, 3Department of Social Medicine, VU University Medical Center, Amsterdam, The Netherlands In the present study we investigated the relationship between lifetime tobacco smoking between the ages of 13 and 36 years, and atherosclerosis and stiffness of large arteries at age 36 among 194 female and 170 male participants of the Amsterdam Growth and Health Longitudinal Study (AGAHLS). To assess lifetime tobacco smoking, we calculated the number of pack-years (py). Measuring intima-media thickness (IMT) of the common carotid artery assessed atherosclerosis. Distensibility (DC) and compliance coefficients (CC) of the carotid, brachial and femoral artery were measured to assess arterial stiffness. IMT, DC and CC were measured by ultrasonography. Taking into account current smoking behaviour and the median number of py smoked, we compared never smokers (py-0) with current smokers with py~>6. Linear regression analyses were stratified for gender. The results show that current male smokers with py~>6 had a significant larger IMT of the carotid artery ([3-0.050, 95%CI-[0.01; 0.10]) compared with never smokers. This association was not found among current smoking women with py~>6. Additional adjustment for lifestyle did not change any of the associations. No associations were found between lifetime tobacco smoking, and DC and CC, for both men and women. It is concluded that a small atherogenic effect of lifetime tobacco smoking was found for current male smokers with py~>6, but not for women. Between lifetime tobacco smoking and arterial stiffness, no associations were found for both men and women. ~
HOMOCYSTEINEMIA AND CORONARIAN RISK
C. Belizna 1, M.A. Pistorius2, B. Planchon2. J CHU Fundeni, Bucharest,
Romania," 2CHU Hotel Dieu, Nantes, France Hyperhomocysteinemia is considered a strong, independant risk factor for ischaemic stroke, myocardial infarction, and coronarian mortality. Recently, a study performed on 106 patients with ischaemic stroke showed that hyperhomocysteinemia is detected only in the convalescent period. (DJ Meiklejohn; Stroke, 2001:32 57). We studied the correlation.between the coronarian event and homocysteinemia. Methods: We measured at 24 hours after the event and three months later the homocysteinemia, folates, B12 vitamin and serum creatinin levels in 20 coronarian patients (presenting myocardial infarction or severe angina) compared with 18 control sujects. Results: Homocysteinemia was at the same level in patients and controls at 24 hours (8,2 mmol/1 versus,8 mmol/1; p-0,08). Homocysteinemia was significantly elevated in patients at three months delay (8,2[4,8 to 19,2] to 11,1 mmol/1, p<0,001) compared with the levels detected at 24 hours; and they were significantly higher than those of the controls (p-0,04, Mann-Whitney test). This variation was unrelated with folates, B12 and creatinin levels. Conclusion: These results are preliminary and they infirm the consideration that hyperhomocysteinemia is a risk factor in the coronarian events, suggesting that this feature is an epiphenomenon, a consequence of the thrombotic state.
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LIMB ISCHAEMIA AND LEUKAEMIA
C. Belizna 1, M.A. Pistorius2, B. Planchon 2. j CHU Fundeni, Bucharest,
Romania," 2CHU Hotel Dieu, Nantes, France Limb embolism may reveal a haematological malignancy. We present the case of a 51 years old patient, admitted for left foot ischaemia and disseminated intravascular coagulation. His past medical history showed diabetus, hypertension, and hypercholesterolemia. One month earlier he presented left buttock pain, treated by antiinflamatory drugs. Despite that, the symptoms were aggravating, with presence of a cold painful left foot. A doppler ultrasound revealed femoraly, tibial and peroneal arteries occlusion, confirmed by arteriography. A thromboembolectomy was performed and the patient was dismissed. He was admitted one month latter for recurrent pain. Blood tests showed 8400/mm3 leukocytes with 43% promyelocytes, a,3 g/1 hemoglobin and schistocytes, 90000/mm3 platelets, high titers of fibrin degradation products, and elevated clotting times. He was transfered in the Haematology department. Bone marrow examination and cytogenetic tests concluded at acute myeloid leukaemia (AML) type 3 FAB. Intensive chemotherapy was started, but the patient presented anuria, requiring dialysis. Left foot gangrena necessitate leg amputation. Few days latter he had confusion and cerebral TDM revealed frontal haematoma with ventricular inondation. The patient died one day latter. Acute myeloid leukaemia is a rapidly progressive malignancy. Death could occur in less than two months if untreated. The usual presentation is leucostasis with pulmonary and cerebral infarcts, or dyspnoea, related to massive mediastinal lymphadenopathy. The atypical presentation of limb ischaemia has to be remembered and simple blood tests such as peripheral blood film, together with careful clinical examination performed. ~ 4 - ~ THE LDL RECEPTOR GENE IN FH: IS THE FOUNDER OF THE FAMILY READY TO STEP INTO THE ERA OF CLINICAL PRACTICE? R Benlian. Hopital Saint Antoine, Paris, France Over a decade of genotype-phenotype relationship studies in familial hypercholesterolemia (FH) have confirmed the diagnostic value of clinical hallmarks of the disease. Despite environmental or epigenetic influences, the LDLR gene effect on plasma LDL cholesterol, and aggressiveness of atherosclerosis appears prominent across populations. Furthermore, inadequacy of conventional versus aggressive LDLC-lowering therapy was recently demonstrated in heterozygous FH. Although molecular diagnosis provides a biological basis for disease evaluation and management, genetic testing has remained limited. Indeed in homozygous FH, in the context of prenatal diagnosis and in the perspective of corrective therapy, DNA analysis although costly imposes itself due to high precision and safety. This holds as well for the detection of mutation carriers among relatives. However, knowledge of genetic causes for FH has brought up a higher level of complexity in case evaluation. About 700 disease-causing mutations are described, with a distribution varying from a few alleles in inbred populations to hundreds in highly admixed populations. Furthermore, a significant proportion of clinically diagnosed FH heterozygotes, were found negative mutation carriers by early screening strategies. The recently released LDLR genomic sequence gave an opportunity to identify intronic mutations altering splicing in about half of these individuals. In parallel more adequate clinical selection, and high throughput genotyping improve cost-effectiveness of DNA diagnosis. DNA testing may now be implemented as part of disease assessment in controlled studies aiming at optimizing management of these high-risk individuals. ~ 4 - ~ INTERLEUKIN-6 LEVELS AND GENOTYPES IN RELATION TO MYOCARDIAL INFARCTION; RESULTS FROM THE SHEEP STUDY A.M. Bennet 1, J. Prince 2, L. Lyrenes3, B. Wiman4, J. Frostegard5'6, U. De Faire 1'7. JDivision of Cardiovascular Epidemiology, Institute of
Environmental Medicine," 2Division of Clinical Genomics, Center for Genomics and Bioinformatics," 3Division of Biochemical Toxicology, Institute of Environmental Medicine," 4Division of Coagulation Research, 5Division of Rheumatology, 6Centre for Molecular Medicicine, 7Department of Cardiology, Karolinska Hospital, Stockholm, Sweden Interleukin-6 (IL-6) is a key proinftammatory cytokine which may contribute to the risk for myocardial infarction (MI). 1162 first time MI cases and 1510 controls enrolled in the Stockholm heart epidemiology program (SHEEP)
73rd EAS Congress
echolucent/unstable with GSM<32). The aim of our study was to determine whether there is any association between the stromelysin 5A/6A polymorphism (SEL) and plaque echodensity in subjects from a town with a high (Dewsbury) and low (Maidstone) prevelance of coronary heart disease. A total of 233 men (179 from Dewsbury, 154 from Maidstone) and 282 women (120 from Dewsbury, 162 Maidstone) had their carotids scanned. Blood samples were genotyped for the 5A/6A stromelysin (SEL) polymorphism using an allele specific amplification assay. The genotype frequencies were in Hardy-Weinberg equilibrium. A homogeneity test carried out on the SEL genotype frequency distribution of Dewsbury men with GSM>32 and GSM<32, indicated that Dewsbury SEL 5A/5A men are more likely to have echogenic plaques (GSM>32, P-0.002). When the allele frequencies of GSM>32 and GSM<32 subjects were compared, significant differences were obtained, the 6A allele was more prevalent in the GSM<32 subpopulation of Dewsbury men (58% vs 42%, P-0.002). No significant differences were found in the women. The above data indicate that the 6A allele is associated with unstable plaques in Dewsbury men and may explain the increased risk of symptomatic cardiovascular disease in 6A carriers. ~ 3 - ~ IS L I F E T I M E TOBACCO SMOKING ASSOCIATED W I T H ATHEROSCLEROSIS AND ARTERIAL STIFFNESS IN 36-YEAR OLD MEN AND WOMEN? THE AMSTERDAM GROWTH AND HEALTH LONGITUDINAL STUDY E.H.C.M. Bekkering 1, C.M. Bernaards 1, J.W.R. Twisk 1, C.D.A. Stehouwer1'2, W. Van Mechelen 1'3, H.C.G. Kemper 1.
JInstitute for Research in Extramural Medicine, 2Department of Internal Medicine, 3Department of Social Medicine, VU University Medical Center, Amsterdam, The Netherlands In the present study we investigated the relationship between lifetime tobacco smoking between the ages of 13 and 36 years, and atherosclerosis and stiffness of large arteries at age 36 among 194 female and 170 male participants of the Amsterdam Growth and Health Longitudinal Study (AGAHLS). To assess lifetime tobacco smoking, we calculated the number of pack-years (py). Measuring intima-media thickness (IMT) of the common carotid artery assessed atherosclerosis. Distensibility (DC) and compliance coefficients (CC) of the carotid, brachial and femoral artery were measured to assess arterial stiffness. IMT, DC and CC were measured by ultrasonography. Taking into account current smoking behaviour and the median number of py smoked, we compared never smokers (py-0) with current smokers with py~>6. Linear regression analyses were stratified for gender. The results show that current male smokers with py~>6 had a significant larger IMT of the carotid artery ([3-0.050, 95%CI-[0.01; 0.10]) compared with never smokers. This association was not found among current smoking women with py~>6. Additional adjustment for lifestyle did not change any of the associations. No associations were found between lifetime tobacco smoking, and DC and CC, for both men and women. It is concluded that a small atherogenic effect of lifetime tobacco smoking was found for current male smokers with py~>6, but not for women. Between lifetime tobacco smoking and arterial stiffness, no associations were found for both men and women. ~
HOMOCYSTEINEMIA AND CORONARIAN RISK
C. Belizna 1, M.A. Pistorius2, B. Planchon2. J CHU Fundeni, Bucharest,
Romania," 2CHU Hotel Dieu, Nantes, France Hyperhomocysteinemia is considered a strong, independant risk factor for ischaemic stroke, myocardial infarction, and coronarian mortality. Recently, a study performed on 106 patients with ischaemic stroke showed that hyperhomocysteinemia is detected only in the convalescent period. (DJ Meiklejohn; Stroke, 2001:32 57). We studied the correlation.between the coronarian event and homocysteinemia. Methods: We measured at 24 hours after the event and three months later the homocysteinemia, folates, B12 vitamin and serum creatinin levels in 20 coronarian patients (presenting myocardial infarction or severe angina) compared with 18 control sujects. Results: Homocysteinemia was at the same level in patients and controls at 24 hours (8,2 mmol/1 versus,8 mmol/1; p-0,08). Homocysteinemia was significantly elevated in patients at three months delay (8,2[4,8 to 19,2] to 11,1 mmol/1, p<0,001) compared with the levels detected at 24 hours; and they were significantly higher than those of the controls (p-0,04, Mann-Whitney test). This variation was unrelated with folates, B12 and creatinin levels. Conclusion: These results are preliminary and they infirm the consideration that hyperhomocysteinemia is a risk factor in the coronarian events, suggesting that this feature is an epiphenomenon, a consequence of the thrombotic state.
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4
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73
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LIMB ISCHAEMIA AND LEUKAEMIA
C. Belizna 1, M.A. Pistorius2, B. Planchon 2. j CHU Fundeni, Bucharest,
Romania," 2CHU Hotel Dieu, Nantes, France Limb embolism may reveal a haematological malignancy. We present the case of a 51 years old patient, admitted for left foot ischaemia and disseminated intravascular coagulation. His past medical history showed diabetus, hypertension, and hypercholesterolemia. One month earlier he presented left buttock pain, treated by antiinflamatory drugs. Despite that, the symptoms were aggravating, with presence of a cold painful left foot. A doppler ultrasound revealed femoraly, tibial and peroneal arteries occlusion, confirmed by arteriography. A thromboembolectomy was performed and the patient was dismissed. He was admitted one month latter for recurrent pain. Blood tests showed 8400/mm3 leukocytes with 43% promyelocytes, a,3 g/1 hemoglobin and schistocytes, 90000/mm3 platelets, high titers of fibrin degradation products, and elevated clotting times. He was transfered in the Haematology department. Bone marrow examination and cytogenetic tests concluded at acute myeloid leukaemia (AML) type 3 FAB. Intensive chemotherapy was started, but the patient presented anuria, requiring dialysis. Left foot gangrena necessitate leg amputation. Few days latter he had confusion and cerebral TDM revealed frontal haematoma with ventricular inondation. The patient died one day latter. Acute myeloid leukaemia is a rapidly progressive malignancy. Death could occur in less than two months if untreated. The usual presentation is leucostasis with pulmonary and cerebral infarcts, or dyspnoea, related to massive mediastinal lymphadenopathy. The atypical presentation of limb ischaemia has to be remembered and simple blood tests such as peripheral blood film, together with careful clinical examination performed. ~ 4 - ~ THE LDL RECEPTOR GENE IN FH: IS THE FOUNDER OF THE FAMILY READY TO STEP INTO THE ERA OF CLINICAL PRACTICE? R Benlian. Hopital Saint Antoine, Paris, France Over a decade of genotype-phenotype relationship studies in familial hypercholesterolemia (FH) have confirmed the diagnostic value of clinical hallmarks of the disease. Despite environmental or epigenetic influences, the LDLR gene effect on plasma LDL cholesterol, and aggressiveness of atherosclerosis appears prominent across populations. Furthermore, inadequacy of conventional versus aggressive LDLC-lowering therapy was recently demonstrated in heterozygous FH. Although molecular diagnosis provides a biological basis for disease evaluation and management, genetic testing has remained limited. Indeed in homozygous FH, in the context of prenatal diagnosis and in the perspective of corrective therapy, DNA analysis although costly imposes itself due to high precision and safety. This holds as well for the detection of mutation carriers among relatives. However, knowledge of genetic causes for FH has brought up a higher level of complexity in case evaluation. About 700 disease-causing mutations are described, with a distribution varying from a few alleles in inbred populations to hundreds in highly admixed populations. Furthermore, a significant proportion of clinically diagnosed FH heterozygotes, were found negative mutation carriers by early screening strategies. The recently released LDLR genomic sequence gave an opportunity to identify intronic mutations altering splicing in about half of these individuals. In parallel more adequate clinical selection, and high throughput genotyping improve cost-effectiveness of DNA diagnosis. DNA testing may now be implemented as part of disease assessment in controlled studies aiming at optimizing management of these high-risk individuals. ~ 4 - ~ INTERLEUKIN-6 LEVELS AND GENOTYPES IN RELATION TO MYOCARDIAL INFARCTION; RESULTS FROM THE SHEEP STUDY A.M. Bennet 1, J. Prince 2, L. Lyrenes3, B. Wiman4, J. Frostegard5'6, U. De Faire 1'7. JDivision of Cardiovascular Epidemiology, Institute of
Environmental Medicine," 2Division of Clinical Genomics, Center for Genomics and Bioinformatics," 3Division of Biochemical Toxicology, Institute of Environmental Medicine," 4Division of Coagulation Research, 5Division of Rheumatology, 6Centre for Molecular Medicicine, 7Department of Cardiology, Karolinska Hospital, Stockholm, Sweden Interleukin-6 (IL-6) is a key proinftammatory cytokine which may contribute to the risk for myocardial infarction (MI). 1162 first time MI cases and 1510 controls enrolled in the Stockholm heart epidemiology program (SHEEP)
73rd EAS Congress