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Analysis and study of sudden cardiac deaths due to atherosclerosis, in the county of Trikala, Greece
Gander
[•-i']
T LYMPHOCYTE FUNCTIONS MEDIATED BY oxLDL IN RELATION TO ATHEROSCLEROSIS
T. Fulop, N. Douxiech, A. Larbi, A. Khalil. Institut Universitaire de
G~riatrie de Sherbrooke, D~partement de M~decine, Facult~ de M~decine, Universit~ de Sherbrooke, Quebec, Canada Atherosclerosis is the histological substrate of cardiovascular diseases for which age is the strongest independent risk factor. This starts at the intrauterine life and develop fully later in life with clinical manifestations. The etiology of atherosclerosis is not fully known, but it is well accepted that LDL, mainly in its oxidized form play an important role by initiating the inflammatory process being the basis of atherosclerosis. T lymphocytes are designed to perform effector functions after activation by a specific antigen via the T cell receptor. The aim of the present study was to determine the role of lymphocytes derived from individuals of various ages towards stimulation by LDL/oxLDL. Methods: LDL, monocytes and lymphocytes were obtained from healthy young and elderly subjects. The LDL were oxidized by radiolysis of water. The proliferation of T cells was measured by [3H]-thymidine incorporation, whereas the apoptosis was determined by the expression of Annexin V by FACScan. Molecules participating in the signal transduction were measured by Western blot. GSH and GSSG were determined by HPLC. Results: There is a differential activation of T cells by the degree of oxidation and the origin of LDLs. The oxLDLs of young and elderly subjects induced the apoptosis of T cells, however to a different extent. OxLDL of elderly induced more apoptosis in T cells than that of young subjects. Nevertheless, the T cells of elderly were always more susceptible to oxLDL than that of young subjects. OxLDL of elderly subjects in the presence of monocytes inhibited the proliferation of lymphocytes either from young or elderly subjects. OxLDL of young subjects induced proliferation either in T cells of young or elderly subjects, however the latter was significantly less. The signal transduction is altered either by oxLDL or in T cells of elderly. Conclusion: These results indicate that a lack of reactivity of the T cells with aging as well as an altered composition of LDL with aging are responsible for the progression and the increased clinical manifestations of atherosclerosis with aging. ~
MODULATION OF NO PRODUCTION BY oxLDL OF VARIOUS O R I G I N IN HUVEC
A. Larbi 1, A. Khalil 1, T. Fulop 1, M. David-Dufilho 2, A. Brunet 2, M.-A. Devynck2. Jlnstitut Universitaire de G~riatrie de Sherbrooke,
Universit~ de Sherbrooke, Sherbrooke, Quebec, Canada," 2Laboratoire de Recherche CardioVasculaire, CNRS, Facult~ de M~decine, Necker, Paris, France Introduction: It is well known that one the first event is the endothelial
dysfunction manifesting by an altered NO production. Lipoproteins, mainly LDL in its oxidized form, were able to modulate the NO production. Moreover, with aging the incidence of cardiovascular diseases is increasing. The aim of the present study was to investigate the effect of LDL from subjects of various ages and in various oxidative status on NO production and eNOS activation in HUVECs. Materials a n d Methods: We obtained LDL and HDL from healthy male subjects of three age-groups (1825, 3539, ~>60 yrs) and oxidized by gamma irradiation of water. To study their oxidative status the conjugated dienes formation was measured. The HUVECs were at there second passage. The LDL were used in 50 microg/ml for various time periods. The NO was measured by HPLC and the eNOS activation by phosphorylation on Western blot. Results: Our results showed that the more the LDL originate from aged subjects and more they are oxidized, more they are able to decrease significatively the NO production, because they inhibit the eNOS activation. Conclusion: This impairment of NO production by LDL with aging could contribute to the increased incidence of atherosclerosis and consequently cardiovascular diseases with aging. ~ 1 - ~ ANALYSIS AND STUDY OF SUDDEN CARDIAC DEATHS DUE TO ATHEROSCLEROSIS, IN THE COUNTY OF TRIKALA, GREECE T. Galeas 1, I. HaLzizisis2, H. Zisis 1, S. Mylonas 1, A. Papadopoulos 1.
] General Hospital of Trikala," 2Rural Medical Office, Greece The purpose of this work is to analyse and study the cases of sudden cardiac deaths that occured in the county of Trikala during the period of 19902000.
111
M a t e r i a l - M e t h o d : Material of the study were 268 successive cases of sudden cardiac deaths, age>18, that occured out of hospital. Necrotomy took place in the General Hospital of Trikala. These cases were classified according to the year of death, sex, age, place of residence and cause of death as written in the death certificates that were based on the medical examiner reports. There was no reference of age in 12 cases and residence in 14 cases. The population of the county of Trikala is 139.500 and population of the city is 51.670.Sudden cardiac death is defined as the natural unexpected, cardiac aetiology death occuring within an hour from the onset of acute symptoms. X 2 method and t-test were used for the statistical analysis. Results: Sudden cardiac deaths: a) year 1990:24, 1991:31, 1992:36, 1993:11, 1994:26, 1995:25, 1996:21, 1997:16, 1998:26, 1999:26, 2000:26 b) sex: 214 males (80%), mean age 60.5, 54 females (20%), mean age 67. c) Age: 1524:1 (1 male, 0 female), 2504:9 (8 males, 1 female), 35M4:18 (17 males, 1 female), 45 54:47 (43 males, 4 females), 55~64:58 (46 males, 12 females), >65:123 (92 males, 32 females), d) Place of living: city of Trikala: 73, rest county: 157, other areas: 24. e) Cause: Acute myocardial infarction: 242 (90.2%), Acute cardiac failure: 19 (7%), Heart failure: 3 (1.2%), Acute cardiogenic pulmonary edema: 1 (0.4%), unexplained: 3 (1.2%). Conclusion: 1) Sudden cardiac deaths are mainly observed in men and are increased according to age in both sexes. 2) They mostly occur in rural areas. 3) The major cause of sudden cardiac death is blood vessel atherosclerosis.
~ i - ~ PHARMACOLOGICAL INTERFERENCE W I T H INTESTINAL BILE ACID TRANSPORT REDUCES PLASMA CHOLESTEROL IN LDL RECEPTOR/APOE DEFICIENCY C. Galman 1, A.-M. Ostlund-Lindqvist2, A. Bjorquist2, L. Svensson2, B. Angelin 1, M. Rudling 1. 1Metabolism Unit, Center for Metabolism
and Endocrinology, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institute at Huddinge University Hospital, Stockholm," 2Molecular Biology, Cell Biology and Biochemistry, Astra Zeneca R&D, Molndal, Sweden Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often suboptimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the hepatic enzyme CYP7A1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of a drug belonging to a new class of lipid-lowering agents which inhibit SLC10A2, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. CYP7A1 activity and mRNA were induced severalfold, and hepatic HMGCoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed toatherosclerosis risk factors. Thus, we do not deny the importance of classical risk factors but assign a new role to them as endothelial stressors in the early phases of the disease. More recently, we have demonstrated a highly significant correlation between infectious load (especially infections of the respiratory tract) and the odds ratio for atherosclerosis. We have also provided proof that of the common denominator for various infectious organisms incriminated to be pathogenetically relevant in atherogenesis, such as Chlamydia, H.pylori, and others, is the high degree of immunologic crossreactivity against their homologues of HSP 60. ~1--5] PLTP EXPRESSION IN THE CENTRAL NERVOUS SYSTEM OF R A B B I T S R. Gander 1, P. Eller 1, S. Kaser 1, I. Theurl 1, D. Walter, T. Sauper 1, A. Ritsch 1, J.R. Patsch 1, B. Foeger 1. 1Department of Medicine,
2Department of Biochemical Pharmacology, University of Innsbruck, Austria Within the past few years, lipoprotein metabolism within the central nervous system (CNS) has attracted increasing attention. Apolipoproteins, lipoprotein-receptors and lipoprotein-modifying enzymes are synthesized by neuronal cells within the brain. The lipid transport system in cerebrospinal fluid (CSF) is indispensible for processes as different as synapse formation,
73rd EAS Congress
[•-i']
T LYMPHOCYTE FUNCTIONS MEDIATED BY oxLDL IN RELATION TO ATHEROSCLEROSIS
T. Fulop, N. Douxiech, A. Larbi, A. Khalil. Institut Universitaire de
G~riatrie de Sherbrooke, D~partement de M~decine, Facult~ de M~decine, Universit~ de Sherbrooke, Quebec, Canada Atherosclerosis is the histological substrate of cardiovascular diseases for which age is the strongest independent risk factor. This starts at the intrauterine life and develop fully later in life with clinical manifestations. The etiology of atherosclerosis is not fully known, but it is well accepted that LDL, mainly in its oxidized form play an important role by initiating the inflammatory process being the basis of atherosclerosis. T lymphocytes are designed to perform effector functions after activation by a specific antigen via the T cell receptor. The aim of the present study was to determine the role of lymphocytes derived from individuals of various ages towards stimulation by LDL/oxLDL. Methods: LDL, monocytes and lymphocytes were obtained from healthy young and elderly subjects. The LDL were oxidized by radiolysis of water. The proliferation of T cells was measured by [3H]-thymidine incorporation, whereas the apoptosis was determined by the expression of Annexin V by FACScan. Molecules participating in the signal transduction were measured by Western blot. GSH and GSSG were determined by HPLC. Results: There is a differential activation of T cells by the degree of oxidation and the origin of LDLs. The oxLDLs of young and elderly subjects induced the apoptosis of T cells, however to a different extent. OxLDL of elderly induced more apoptosis in T cells than that of young subjects. Nevertheless, the T cells of elderly were always more susceptible to oxLDL than that of young subjects. OxLDL of elderly subjects in the presence of monocytes inhibited the proliferation of lymphocytes either from young or elderly subjects. OxLDL of young subjects induced proliferation either in T cells of young or elderly subjects, however the latter was significantly less. The signal transduction is altered either by oxLDL or in T cells of elderly. Conclusion: These results indicate that a lack of reactivity of the T cells with aging as well as an altered composition of LDL with aging are responsible for the progression and the increased clinical manifestations of atherosclerosis with aging. ~
MODULATION OF NO PRODUCTION BY oxLDL OF VARIOUS O R I G I N IN HUVEC
A. Larbi 1, A. Khalil 1, T. Fulop 1, M. David-Dufilho 2, A. Brunet 2, M.-A. Devynck2. Jlnstitut Universitaire de G~riatrie de Sherbrooke,
Universit~ de Sherbrooke, Sherbrooke, Quebec, Canada," 2Laboratoire de Recherche CardioVasculaire, CNRS, Facult~ de M~decine, Necker, Paris, France Introduction: It is well known that one the first event is the endothelial
dysfunction manifesting by an altered NO production. Lipoproteins, mainly LDL in its oxidized form, were able to modulate the NO production. Moreover, with aging the incidence of cardiovascular diseases is increasing. The aim of the present study was to investigate the effect of LDL from subjects of various ages and in various oxidative status on NO production and eNOS activation in HUVECs. Materials a n d Methods: We obtained LDL and HDL from healthy male subjects of three age-groups (1825, 3539, ~>60 yrs) and oxidized by gamma irradiation of water. To study their oxidative status the conjugated dienes formation was measured. The HUVECs were at there second passage. The LDL were used in 50 microg/ml for various time periods. The NO was measured by HPLC and the eNOS activation by phosphorylation on Western blot. Results: Our results showed that the more the LDL originate from aged subjects and more they are oxidized, more they are able to decrease significatively the NO production, because they inhibit the eNOS activation. Conclusion: This impairment of NO production by LDL with aging could contribute to the increased incidence of atherosclerosis and consequently cardiovascular diseases with aging. ~ 1 - ~ ANALYSIS AND STUDY OF SUDDEN CARDIAC DEATHS DUE TO ATHEROSCLEROSIS, IN THE COUNTY OF TRIKALA, GREECE T. Galeas 1, I. HaLzizisis2, H. Zisis 1, S. Mylonas 1, A. Papadopoulos 1.
] General Hospital of Trikala," 2Rural Medical Office, Greece The purpose of this work is to analyse and study the cases of sudden cardiac deaths that occured in the county of Trikala during the period of 19902000.
111
M a t e r i a l - M e t h o d : Material of the study were 268 successive cases of sudden cardiac deaths, age>18, that occured out of hospital. Necrotomy took place in the General Hospital of Trikala. These cases were classified according to the year of death, sex, age, place of residence and cause of death as written in the death certificates that were based on the medical examiner reports. There was no reference of age in 12 cases and residence in 14 cases. The population of the county of Trikala is 139.500 and population of the city is 51.670.Sudden cardiac death is defined as the natural unexpected, cardiac aetiology death occuring within an hour from the onset of acute symptoms. X 2 method and t-test were used for the statistical analysis. Results: Sudden cardiac deaths: a) year 1990:24, 1991:31, 1992:36, 1993:11, 1994:26, 1995:25, 1996:21, 1997:16, 1998:26, 1999:26, 2000:26 b) sex: 214 males (80%), mean age 60.5, 54 females (20%), mean age 67. c) Age: 1524:1 (1 male, 0 female), 2504:9 (8 males, 1 female), 35M4:18 (17 males, 1 female), 45 54:47 (43 males, 4 females), 55~64:58 (46 males, 12 females), >65:123 (92 males, 32 females), d) Place of living: city of Trikala: 73, rest county: 157, other areas: 24. e) Cause: Acute myocardial infarction: 242 (90.2%), Acute cardiac failure: 19 (7%), Heart failure: 3 (1.2%), Acute cardiogenic pulmonary edema: 1 (0.4%), unexplained: 3 (1.2%). Conclusion: 1) Sudden cardiac deaths are mainly observed in men and are increased according to age in both sexes. 2) They mostly occur in rural areas. 3) The major cause of sudden cardiac death is blood vessel atherosclerosis.
~ i - ~ PHARMACOLOGICAL INTERFERENCE W I T H INTESTINAL BILE ACID TRANSPORT REDUCES PLASMA CHOLESTEROL IN LDL RECEPTOR/APOE DEFICIENCY C. Galman 1, A.-M. Ostlund-Lindqvist2, A. Bjorquist2, L. Svensson2, B. Angelin 1, M. Rudling 1. 1Metabolism Unit, Center for Metabolism
and Endocrinology, Department of Medicine and Molecular Nutrition Unit, Center for Nutrition and Toxicology, NOVUM, Karolinska Institute at Huddinge University Hospital, Stockholm," 2Molecular Biology, Cell Biology and Biochemistry, Astra Zeneca R&D, Molndal, Sweden Reduction of plasma cholesterol by statins is fundamental to prevent coronary heart disease. Such therapy is often suboptimal, however, particularly in patients with reduced LDL receptors (familial hypercholesterolemia), and novel or adjuvant therapies are therefore warranted. Cholesterol elimination is profoundly influenced by the rate of its conversion to bile acids (BA), regulated by the hepatic enzyme CYP7A1. Induced fecal loss of BA by resin treatment reduces plasma cholesterol, presumably through induction of hepatic LDL receptors (LDLR). We here describe the effect of a drug belonging to a new class of lipid-lowering agents which inhibit SLC10A2, the intestinal transporter responsible for active uptake of BA. Treatment reduced plasma cholesterol by 40% in mice devoid of both the LDLR and its ligand, apoE, while triglycerides and HDL cholesterol were unchanged. CYP7A1 activity and mRNA were induced severalfold, and hepatic HMGCoA reductase mRNA increased, mirroring an induced synthesis of BA and cholesterol. The addition of a statin potentiated the effect, leading to reductions of plasma total and LDL cholesterol by 64% and 70%, respectively. These effects could not be attributed toatherosclerosis risk factors. Thus, we do not deny the importance of classical risk factors but assign a new role to them as endothelial stressors in the early phases of the disease. More recently, we have demonstrated a highly significant correlation between infectious load (especially infections of the respiratory tract) and the odds ratio for atherosclerosis. We have also provided proof that of the common denominator for various infectious organisms incriminated to be pathogenetically relevant in atherogenesis, such as Chlamydia, H.pylori, and others, is the high degree of immunologic crossreactivity against their homologues of HSP 60. ~1--5] PLTP EXPRESSION IN THE CENTRAL NERVOUS SYSTEM OF R A B B I T S R. Gander 1, P. Eller 1, S. Kaser 1, I. Theurl 1, D. Walter, T. Sauper 1, A. Ritsch 1, J.R. Patsch 1, B. Foeger 1. 1Department of Medicine,
2Department of Biochemical Pharmacology, University of Innsbruck, Austria Within the past few years, lipoprotein metabolism within the central nervous system (CNS) has attracted increasing attention. Apolipoproteins, lipoprotein-receptors and lipoprotein-modifying enzymes are synthesized by neuronal cells within the brain. The lipid transport system in cerebrospinal fluid (CSF) is indispensible for processes as different as synapse formation,
73rd EAS Congress