- Email: [email protected]
M.485 Relation between collateral formation and flow-mediated vasodilation in patients with coronary artery disease
112
Miscellaneous
Caparevic
Conclusion: It is vitally important to identify diabetic type 2 patients with accelerated atherosclerotic vascular disease, because aggressive therapy with &'ugs, such as statins, could lower the oxidized LDL levels.
~.~82]
OXIDIZED LDL AND CONVENTIONAL LIPID RISK FACTORS IN YOUNG SUBJECTS W I T H O U T CLINICAL CARDIOVASCULAR DISEASE
Z. Caparevic, N. Kostic, B. Pencic, M. Deldeva, S. Ilic, V. Milosevic, B. Brkic. CHC Dr D. Misovic, University of Medicine, Department of
Endocrinology, Department of Cardiology, Belgrade, Serbia and Montenegro Background and Aims: Oxidized LDL (ox LDL) has been attributed a key role in the accelerated atherosclerotic vascular disease. The aim of this study was to estimate relations between ox LDL and conventional lipid risk factors for coronary heart disease CHD in young subjects without clinical cardiovascular disease. Materials and Methods: Investigation was pel£ormed in 27 hypercholesterolemic young subjects (46.6-4-2.7 year) without clinical signs of CHD during the follow-up period (group A) and in 26 normocholesterolemic healthy subjects (group B). Triglycerides, total-C and HDL-C were measured by enzymatic methods. LDL-C was calculated using the Friedewald formula. Ox-LDL was determined by ELISA (Mercodia AB, Uppsala, Sweden) Results: We found that ox LDL was significantly higher in group A than in group B (158.09-4-48.33 vs 77.60-4-32.84 IU/1; p<0.01). Conventional lipid profile (total Ch, LDL-Ch, HDL-Ch and Tg) as well as LDL/HDL ratio and Tg/HDL ratio, were significantly higher in group A (p=0.01). We analyzed COlvelations between ox LDL and other lipids. We found that in group A ox LDL significantly positive COlvelated with total-Ch (r=0.747; p=0.005), LDL-Ch (1=0.868; p=0.005), Tg (r=0.853; p=0.007), HDL-Ch (1--0.840; p=0.009), LDL/HDL (r=0.636; p=0.05) and Tg/HDL (r=0.685; p=0.05). In group B we found significant COlvelations between ox LDL with Tg (r=0.828; p=0.005), LDL/HDL (1"=0.734; p=0.02) and Tg/HDL (r=0.708; p=0.01). Conclusions: These findings identify high plasma ox LDL as a possible indicator of increased risk for CHD among healthy young hypercholesterolemic subjects.
•
NOVEL CYP3A4 GENE MUTATIONS: CONTRIBUTION TO THE PHARMACOGENETIC PROFILE OF H Y P E R C H O L E S T E R O L E M I C INDIVIDUALS TREATED WITH ATORVASTIN
S. Cavalli, I. Moretti, L. Matsumoto, L. Salazar, M. Hil-oyuki, N. Forti, J. Diament, M. Chiara, A. Faludi, R. Dominguez. Faculty of Pharmceutical
Sciences USP, Heart Institute (InCor) USP, Dante Pazzanese Cardiologic Institute, S o Paulo, Brazil Statins are HMG-CoA reductase inhibitors that have revolutionized the ~eatrnent and prevention of coronm'y hem't diseases. The response to statins is influenced by a number of factors, including envh'oment and genetic determinants, such as vm'iants of proteins involved in lipid metabolism and drug bioavailability. CYP3A4 is the most abundant isoenzyme of cytochrome P450 family in adult human liver and plays a pivotal role in the metabolism of many &'ugs, including some statins. The large variability of CYP3A4 expression among individuals may have a strong impact on the efficacy of &'ug ~eatrnent. In order to investigate the role of CYP3A4 variants in response to atorvastatin, CYP3A4 gene was screened for mutations in 32 white individuals with Familial and 88 (63 whites and 25 blacks) non-Familial Hypercholesterolemia fi'om Brazil ~eated with atorvastatin (10mg/d/4w). The coding region of the CYP3A4 gene was analyzed by PCR-SSCP analysis and DNA sequencing. We found one novel silent (c.l134A>G) mutation and five novel missense (L373V, E374A, D380A, $398I, A403H) mutations in exon 11. Frequencies of mutations in exon 11 vm'ied fi'om 0.040 to 0.060 and fi'om 0.008 to 0.016 in blacks and whites, respectively. After atorvastatin therapy (10mg/d/4w), cma'iers of exon 11 mutations have higher reduction (53%) of LDL-C levels than the non-can'iers (38%) indicating that mutations in exon 11 of the CYP3A4 gene maybe associated with higher response to atorvastatin in Brazilian hypercholesterolemic individuals. Therefore, the identification of the CYP3A4 variants may contribute to the pharrnacogenetic profile of patients ~eated with lowering-lipid &'ugs. Granted by: FAPESP and Pfizer
~
S.
RELATION BETWEEN COLLATERAL FORMATION AND FLOW-MEDIATED VASODILATION IN PATIENTS W I T H CORONARY ARTERY DISEASE elik, S. Kaplan, R. Y lmaz, M. Baykan. KT
Faculty of Medicine,
Trabzon, Turkey ~
M O L E C U L A R GENETICS OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN M O R O C C O
C. Boileau, L. Masana, A. Adlouni, M. E1Messad. INSERM U383. H pital Necker-Enfants Malades, Paris, France; URL. Facultad de Medicina, Universidad Rovira I Virgili, Reus, Spain; Laboratoire de Recherche sur les Lipoprot ines, Laboratoire de Biochimie, Facult des Sciences A n Chock, Casablanca, Morocco Familial hypercholesterolemia (FH) is a genetic disorder mainly caused by defects in the LDLR gene, although it can also be due to alterations in the gene encoding the apoB o1"in other unidentified genes. Objective: To define mutations causing FH phenotype in a sample of 12 Moroccan probands. When members of these families were available, we pel£orrned a clinical and biochemical detection of FH in relatives and a co-segregation study of the disease and the identified mutation. Methods: 46 FH individuals fi'om 12 unrelated families have been studied. The LDLR gene has been screened by PCR-SSCP analysis, DNA sequencing and southern blot analysis. The apoB gene has been screened for the presence of the R3500Q and R3531C mutations by PCR and restriction enzyme digestion analysis. Results: In otu" sample, none of the patients can'ied either of R3500Q and R3531C mutations in the apoB gene. However, 6 probands and theft" lelatives FH showed mutations in the LDLR gene (2 major rean'angements: FH Morocco-1 and FH Morocco-2 and 4 misense mutations: C113R, G266C, P664L, C690S). Conclusion: we describe the molecular changes likely to cause FH in a group of 46 Moroccan patients with a clinical diagnosis for FH. Thelefore, molecular identification of mutant alleles was possible in 50% of all cases. For the remaining cases, the molecular basis of FH lemains unknown. It can be explained by the SSCP technique limits to detect all single basepail" changment, o1" by the intervention of other genes causing a FH-like phenotype.
Background- Flow-mediated vasodilation (FMD) of the brachial artery, a non-invasive parameter of endothelial function, is COl~elated with cardiovascular risk factors. The relationship between FMD and collateral formation in patients with coronary artery disease (CAD)has not been investigated. This study was performed to test the hypothesis that an impail'ment of FMD in the brachial artery is related to the plesence of poor collaterals. Methods and Results- In 91 patients with at least one coronary artery stenosis of 90% o1" greater, collaterals wele assessed angiographically by the Rentrop grading (grade 0-3), establishing two groups: 42 patients with poor collaterals vessels (Rentrop grade 0 o1"1) and 49 patients with good collaterals vessels (Rentrop grade 2 o1"3). Using high-resolution ul~asound, both the FMD and sublingual nitroglycerin-induced vasodilation in the brachial artery were measured in all patients. FMD was not significantly different between the patients with poor collaterals and those with good collaterals (4.55-4-0.69 vs 4.52-4-0.64, p= 0.83). Condusions- Lack of association between an impah'ment of FMD in the brachial artery and the presence of poor collaterals was observed, suggesting that collateral formation is a complex phenomenon consisting of several distinct processes.
~
CYSTEINE PROTEASE-CATHEPSINS AND VASCULAR REMODELING AFTER BALLOON-INJURY
X. Cheng, M. Kuzuya, T. Sasaki, S. Kanda, T. Shibata, K. Nakamura, M. Ushiyama, Q. Di, G. Shi, A. Iguchi. Nagoya University, Graduate
School of Medicine, Nagoya, Japan; University of California, San Francisco, USA Objectives: In the present study, we evaluated the expressions of cathepsins Sand K and theft" inhibitor cystatin C mRNA and proteins during vasculm" remodeling in a rat balloon injury model. We also addressed the elastolytic activity in balloon-injured carotid arteries. Methods: Male Wister 37 rats (3 to 4 months old; Japan SLC, Shizuoka, Japan) were anesthetized and received balloon catheter injtu'y. Balloon-
74th EAS Congress, 17-20 April 2004, Seville, Spain
Miscellaneous
Caparevic
Conclusion: It is vitally important to identify diabetic type 2 patients with accelerated atherosclerotic vascular disease, because aggressive therapy with &'ugs, such as statins, could lower the oxidized LDL levels.
~.~82]
OXIDIZED LDL AND CONVENTIONAL LIPID RISK FACTORS IN YOUNG SUBJECTS W I T H O U T CLINICAL CARDIOVASCULAR DISEASE
Z. Caparevic, N. Kostic, B. Pencic, M. Deldeva, S. Ilic, V. Milosevic, B. Brkic. CHC Dr D. Misovic, University of Medicine, Department of
Endocrinology, Department of Cardiology, Belgrade, Serbia and Montenegro Background and Aims: Oxidized LDL (ox LDL) has been attributed a key role in the accelerated atherosclerotic vascular disease. The aim of this study was to estimate relations between ox LDL and conventional lipid risk factors for coronary heart disease CHD in young subjects without clinical cardiovascular disease. Materials and Methods: Investigation was pel£ormed in 27 hypercholesterolemic young subjects (46.6-4-2.7 year) without clinical signs of CHD during the follow-up period (group A) and in 26 normocholesterolemic healthy subjects (group B). Triglycerides, total-C and HDL-C were measured by enzymatic methods. LDL-C was calculated using the Friedewald formula. Ox-LDL was determined by ELISA (Mercodia AB, Uppsala, Sweden) Results: We found that ox LDL was significantly higher in group A than in group B (158.09-4-48.33 vs 77.60-4-32.84 IU/1; p<0.01). Conventional lipid profile (total Ch, LDL-Ch, HDL-Ch and Tg) as well as LDL/HDL ratio and Tg/HDL ratio, were significantly higher in group A (p=0.01). We analyzed COlvelations between ox LDL and other lipids. We found that in group A ox LDL significantly positive COlvelated with total-Ch (r=0.747; p=0.005), LDL-Ch (1=0.868; p=0.005), Tg (r=0.853; p=0.007), HDL-Ch (1--0.840; p=0.009), LDL/HDL (r=0.636; p=0.05) and Tg/HDL (r=0.685; p=0.05). In group B we found significant COlvelations between ox LDL with Tg (r=0.828; p=0.005), LDL/HDL (1"=0.734; p=0.02) and Tg/HDL (r=0.708; p=0.01). Conclusions: These findings identify high plasma ox LDL as a possible indicator of increased risk for CHD among healthy young hypercholesterolemic subjects.
•
NOVEL CYP3A4 GENE MUTATIONS: CONTRIBUTION TO THE PHARMACOGENETIC PROFILE OF H Y P E R C H O L E S T E R O L E M I C INDIVIDUALS TREATED WITH ATORVASTIN
S. Cavalli, I. Moretti, L. Matsumoto, L. Salazar, M. Hil-oyuki, N. Forti, J. Diament, M. Chiara, A. Faludi, R. Dominguez. Faculty of Pharmceutical
Sciences USP, Heart Institute (InCor) USP, Dante Pazzanese Cardiologic Institute, S o Paulo, Brazil Statins are HMG-CoA reductase inhibitors that have revolutionized the ~eatrnent and prevention of coronm'y hem't diseases. The response to statins is influenced by a number of factors, including envh'oment and genetic determinants, such as vm'iants of proteins involved in lipid metabolism and drug bioavailability. CYP3A4 is the most abundant isoenzyme of cytochrome P450 family in adult human liver and plays a pivotal role in the metabolism of many &'ugs, including some statins. The large variability of CYP3A4 expression among individuals may have a strong impact on the efficacy of &'ug ~eatrnent. In order to investigate the role of CYP3A4 variants in response to atorvastatin, CYP3A4 gene was screened for mutations in 32 white individuals with Familial and 88 (63 whites and 25 blacks) non-Familial Hypercholesterolemia fi'om Brazil ~eated with atorvastatin (10mg/d/4w). The coding region of the CYP3A4 gene was analyzed by PCR-SSCP analysis and DNA sequencing. We found one novel silent (c.l134A>G) mutation and five novel missense (L373V, E374A, D380A, $398I, A403H) mutations in exon 11. Frequencies of mutations in exon 11 vm'ied fi'om 0.040 to 0.060 and fi'om 0.008 to 0.016 in blacks and whites, respectively. After atorvastatin therapy (10mg/d/4w), cma'iers of exon 11 mutations have higher reduction (53%) of LDL-C levels than the non-can'iers (38%) indicating that mutations in exon 11 of the CYP3A4 gene maybe associated with higher response to atorvastatin in Brazilian hypercholesterolemic individuals. Therefore, the identification of the CYP3A4 variants may contribute to the pharrnacogenetic profile of patients ~eated with lowering-lipid &'ugs. Granted by: FAPESP and Pfizer
~
S.
RELATION BETWEEN COLLATERAL FORMATION AND FLOW-MEDIATED VASODILATION IN PATIENTS W I T H CORONARY ARTERY DISEASE elik, S. Kaplan, R. Y lmaz, M. Baykan. KT
Faculty of Medicine,
Trabzon, Turkey ~
M O L E C U L A R GENETICS OF FAMILIAL H Y P E R C H O L E S T E R O L E M I A IN M O R O C C O
C. Boileau, L. Masana, A. Adlouni, M. E1Messad. INSERM U383. H pital Necker-Enfants Malades, Paris, France; URL. Facultad de Medicina, Universidad Rovira I Virgili, Reus, Spain; Laboratoire de Recherche sur les Lipoprot ines, Laboratoire de Biochimie, Facult des Sciences A n Chock, Casablanca, Morocco Familial hypercholesterolemia (FH) is a genetic disorder mainly caused by defects in the LDLR gene, although it can also be due to alterations in the gene encoding the apoB o1"in other unidentified genes. Objective: To define mutations causing FH phenotype in a sample of 12 Moroccan probands. When members of these families were available, we pel£orrned a clinical and biochemical detection of FH in relatives and a co-segregation study of the disease and the identified mutation. Methods: 46 FH individuals fi'om 12 unrelated families have been studied. The LDLR gene has been screened by PCR-SSCP analysis, DNA sequencing and southern blot analysis. The apoB gene has been screened for the presence of the R3500Q and R3531C mutations by PCR and restriction enzyme digestion analysis. Results: In otu" sample, none of the patients can'ied either of R3500Q and R3531C mutations in the apoB gene. However, 6 probands and theft" lelatives FH showed mutations in the LDLR gene (2 major rean'angements: FH Morocco-1 and FH Morocco-2 and 4 misense mutations: C113R, G266C, P664L, C690S). Conclusion: we describe the molecular changes likely to cause FH in a group of 46 Moroccan patients with a clinical diagnosis for FH. Thelefore, molecular identification of mutant alleles was possible in 50% of all cases. For the remaining cases, the molecular basis of FH lemains unknown. It can be explained by the SSCP technique limits to detect all single basepail" changment, o1" by the intervention of other genes causing a FH-like phenotype.
Background- Flow-mediated vasodilation (FMD) of the brachial artery, a non-invasive parameter of endothelial function, is COl~elated with cardiovascular risk factors. The relationship between FMD and collateral formation in patients with coronary artery disease (CAD)has not been investigated. This study was performed to test the hypothesis that an impail'ment of FMD in the brachial artery is related to the plesence of poor collaterals. Methods and Results- In 91 patients with at least one coronary artery stenosis of 90% o1" greater, collaterals wele assessed angiographically by the Rentrop grading (grade 0-3), establishing two groups: 42 patients with poor collaterals vessels (Rentrop grade 0 o1"1) and 49 patients with good collaterals vessels (Rentrop grade 2 o1"3). Using high-resolution ul~asound, both the FMD and sublingual nitroglycerin-induced vasodilation in the brachial artery were measured in all patients. FMD was not significantly different between the patients with poor collaterals and those with good collaterals (4.55-4-0.69 vs 4.52-4-0.64, p= 0.83). Condusions- Lack of association between an impah'ment of FMD in the brachial artery and the presence of poor collaterals was observed, suggesting that collateral formation is a complex phenomenon consisting of several distinct processes.
~
CYSTEINE PROTEASE-CATHEPSINS AND VASCULAR REMODELING AFTER BALLOON-INJURY
X. Cheng, M. Kuzuya, T. Sasaki, S. Kanda, T. Shibata, K. Nakamura, M. Ushiyama, Q. Di, G. Shi, A. Iguchi. Nagoya University, Graduate
School of Medicine, Nagoya, Japan; University of California, San Francisco, USA Objectives: In the present study, we evaluated the expressions of cathepsins Sand K and theft" inhibitor cystatin C mRNA and proteins during vasculm" remodeling in a rat balloon injury model. We also addressed the elastolytic activity in balloon-injured carotid arteries. Methods: Male Wister 37 rats (3 to 4 months old; Japan SLC, Shizuoka, Japan) were anesthetized and received balloon catheter injtu'y. Balloon-
74th EAS Congress, 17-20 April 2004, Seville, Spain