- Email: [email protected]
Renin-angiotensin system polymorphisms and risk of cardiovascular disease in familial hypercholesterolaemia
Tuesday June 27, 2000: Poster Abstracts P: W16 New Aspects of Pharmacological Treatment
130
apo E phenotype (coded with two dummy variables) entered the model after plasma triglycerides, plasma urea nitrogen, oral contraceptive use and alcohol intake, in this order, and it explained 4% (p < 0.01) of the variance of vit. A levels in women. Conclusion: Allele ~2 increases vit. A levels in women independently of its influence on lipid levels.
I TuP25.Wl5
Renin-angiotensin system polymorphiims and risk of cardiovascular disease in familial hypercholesterolaemia
A. Wierzbicki, M. Lambert-Hammill, Hospital, London, UK
P. Lumb, M. Crook.
St.Thomas’
Objective: The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolaemia (FH). Methods: Polymorphism frequencies for angiotensin-I converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T and angiotensin-II type I receptor (AG2R) Al 166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolaemia of whom 26.7% and 41.6% respectively had established CHD. Results: None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolaemia. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (OR = 3.03), smoking (OR = 2.91), diastolic blood pressure (OR = 3.70). plasma glucose (OR = 3.51) and the AG2R Al 166C polymorphism (OR = 3.10 (CI 1.20-7.52) as risk factors for CHD in patients with FH. Conclusion: The angiotensin II receptor Al 166C polymorphism may interact with severe hypercholesterolaemia. and other risk factors to increase risk of CHD in FH patients.
I
TuP26.Wl5
Additional effect of Cblamydia pneumoniae infection to genetic factors in the development of coronary artery disease
R. Hirano, Y. Momiyama, K. Miyazaki, N. Isomura, N. Katayama, T. Hisada, S. Sawada, A. Yonemura, K. Higashi, T. Shibuya, H. Nakamura, F. Ohsuzu. National Defense Medical College, Saitama, Japan Objective: To test the hypothesis that Chlamydia pneumoniae (CP) infection may have some additional effects to genetic factors (the angiotensin converting enzyme (ACE) gene D/l polymorphism and the platelet glycoprotein (GP) Iba gene 14?hr/Met polymorphism) in the development of coronary artery disease (CAD). Methods: We analyzed serum IgG antibody to CP in 125 consecutive patients (pts) who had cardiac catheterization. The cut off index of IgG titer was measured by ELISA, the index > 1.10 being considered positive. The ACE and GPIbo polymorphisms were analyzed using polymerase chain reaction after DNA extraction from peripheral blood. Results: Of the 125 pts, 92 had significant CAD (>50% stenosis). The prevalence of CP IgG seropositivity was 46% in pts with CAD and 24% in those without CAD (p = NS). The percentages of ACE D-allele and GPIbo Met-allele carriers were 64% and 23% in pts with CAD versus 55% and 18% in those without CAD, respectively (p = NS). Notably, the percentage of CP IgG-seropositive pts who had ACE D-allele was significantly higher in pts with CAD (26%) than in those without CAD (6%) (p < 0.05). However, the percentage of CP IgG-seropositive pts who had GPIbo Met-allele was 9% in pts with CAD versus 3% in those without CAD (p = NS). Conclusion: CP infection may have some additional effects to genetic factors, especially ACE D/I polymorphism, in the development of CAD.
P:W16
I
TuPl W16
NEW
ASPECTS OF PHARMACOLOGICAL TREATMENT
The therapeutic effect of ptobucol and pravastatin on common carotid intima-media thickness progression in asymptomatic hypercholestetolemic Japanese patients
Yasunori Sawavama, Jun Hayashi, Naoyasu Maeda, Chie Shimizu, Yoko Tanaka, Seizaburo Kashiwagi. Department of General Medicine, Kyushu University Hospital, Japan Objective: This study was to test the effect of lipid reduction on the carotid
intima-media thickness (IMT) in hypercholesterolemic patients in Fukuoka, Japan. Methods: A total of 157 asymptomatic hypercholesterolemic patients (mean age 69.4 years) were assigned to probucol (500 mg/day, n = 75), pravastatin (10 mg/day, n = 61) or matched control (diet alone, n = 21). The 2-year change in lipids and in IMT in the common carotid artery and incidence of major cardiovascular events were surveyed. Ultrasound-detected carotid atherosclerosis (CA) as defined by a mean maximum IMT (MMaxIMT) 2 1.3 mm. Results: The serum LDL cholestrol level was significantly reduced by 31% in probucol group and by 43% in the pravastatin group and by 26% in the diet alone group (P i 0.0001, P < 0.0001, P < 0.01, respectively). Probucol and pravastatin groups with CA resulted in a significant reduction of the MMaxIMT (p < 0.01, p < 0.05, respectively) and a signihcant MMaxIMT in the diet alone group after 2 years (p < 0.001). There was a significant relationship between the reduction of MmaxIMT and serum LDL cholesterol in the probucol group (p < 0.05). Moreover, major cardiovascular events were significant fewer in the probucol group than in the other groups (p < 0.05). Conclusion: These observations suggest that lipid reduction prevents from the progression of MMaxIMT in the common carotid artery, and that probucol is more effective in reducing the risk of major cardiovascular events in hypercholesterolemic patients than pravastatin.
ITuP2.Wl6
Colesevelam HCI (Welchol’“), a new, potent, well tolerated, non systemic, lipid lowering agent
M. Davidson, D. Hunninghake, T. Olson, J. Donovan, S. Burke. Chicago Ctr. for Clinical Research, Chicago; Heart Disease Prevention Ctr. Minneapolis; GelTex Pharmaceuticals, Waltham, USA Objective: To develop a safe, non-absorbed, LDL cholesterol reducing drug that provides convenient monotherapy and can be an effective component of combination therapy. Methods: Seven placebo-controlled trials incorporating 1,350 diet stable patients explored the safety and efficacy of colesevelam alone and in combination with HMG-CoA reductase inhibitors (HMGRI). Patients with Fredrickson type IIa hyperlipoproteinemia constituted the primary population. Combination therapy studies were conducted with concurrent administration of lovastatin, simvastatin and atorvastatin. Results: Treatment with colesevelam demonstrated dose dependent statistically significant reductions in LDL cholesterol and was effective whether the dose was administered once or twice per day (Figure). Side effects, including gastrointestinal, were comparable between treatment and placebo groups. Colesevelam demonstrated at least additive efficacy in reducing LDL-C when combined with an HMGRI, compared with individual agents in the same trial.
Conclusion: Colesevelam hydrochloride is a safe, convenient and effective therapy for reducing LDL-C alone or in combination with an HMGRI. Compared to historical data with other bile acid sequestrants, colesevelam hydrochloride was 46 times more potent.
ITuP3.Wl6
F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in the casein-fed rabbits
D. Junouero, F. Bruniquel, X. N’Guyen, J.-M. Autin, J.-F. Patoiseau, A.-D. Degryse, EC. Colpaert, A. Delhon. Centre de Recherche Pierre Fabre, 17 ave. Jean Moulin, 81106 Castres Cedex, France F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New-Zealand rabbits fed a cholesterol-free casein-rich diet. Endogenous hypercholesterolemia (EH) pre-established for 8 weeks was used to compare treatments with F 12511 and atorvastatin for a further S-week period, and
XIith Jnternational Symposium on Athemsclerosis,
Stockholm, Sweden, June 25-29,
2000
130
apo E phenotype (coded with two dummy variables) entered the model after plasma triglycerides, plasma urea nitrogen, oral contraceptive use and alcohol intake, in this order, and it explained 4% (p < 0.01) of the variance of vit. A levels in women. Conclusion: Allele ~2 increases vit. A levels in women independently of its influence on lipid levels.
I TuP25.Wl5
Renin-angiotensin system polymorphiims and risk of cardiovascular disease in familial hypercholesterolaemia
A. Wierzbicki, M. Lambert-Hammill, Hospital, London, UK
P. Lumb, M. Crook.
St.Thomas’
Objective: The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolaemia (FH). Methods: Polymorphism frequencies for angiotensin-I converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T and angiotensin-II type I receptor (AG2R) Al 166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolaemia of whom 26.7% and 41.6% respectively had established CHD. Results: None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolaemia. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (OR = 3.03), smoking (OR = 2.91), diastolic blood pressure (OR = 3.70). plasma glucose (OR = 3.51) and the AG2R Al 166C polymorphism (OR = 3.10 (CI 1.20-7.52) as risk factors for CHD in patients with FH. Conclusion: The angiotensin II receptor Al 166C polymorphism may interact with severe hypercholesterolaemia. and other risk factors to increase risk of CHD in FH patients.
I
TuP26.Wl5
Additional effect of Cblamydia pneumoniae infection to genetic factors in the development of coronary artery disease
R. Hirano, Y. Momiyama, K. Miyazaki, N. Isomura, N. Katayama, T. Hisada, S. Sawada, A. Yonemura, K. Higashi, T. Shibuya, H. Nakamura, F. Ohsuzu. National Defense Medical College, Saitama, Japan Objective: To test the hypothesis that Chlamydia pneumoniae (CP) infection may have some additional effects to genetic factors (the angiotensin converting enzyme (ACE) gene D/l polymorphism and the platelet glycoprotein (GP) Iba gene 14?hr/Met polymorphism) in the development of coronary artery disease (CAD). Methods: We analyzed serum IgG antibody to CP in 125 consecutive patients (pts) who had cardiac catheterization. The cut off index of IgG titer was measured by ELISA, the index > 1.10 being considered positive. The ACE and GPIbo polymorphisms were analyzed using polymerase chain reaction after DNA extraction from peripheral blood. Results: Of the 125 pts, 92 had significant CAD (>50% stenosis). The prevalence of CP IgG seropositivity was 46% in pts with CAD and 24% in those without CAD (p = NS). The percentages of ACE D-allele and GPIbo Met-allele carriers were 64% and 23% in pts with CAD versus 55% and 18% in those without CAD, respectively (p = NS). Notably, the percentage of CP IgG-seropositive pts who had ACE D-allele was significantly higher in pts with CAD (26%) than in those without CAD (6%) (p < 0.05). However, the percentage of CP IgG-seropositive pts who had GPIbo Met-allele was 9% in pts with CAD versus 3% in those without CAD (p = NS). Conclusion: CP infection may have some additional effects to genetic factors, especially ACE D/I polymorphism, in the development of CAD.
P:W16
I
TuPl W16
NEW
ASPECTS OF PHARMACOLOGICAL TREATMENT
The therapeutic effect of ptobucol and pravastatin on common carotid intima-media thickness progression in asymptomatic hypercholestetolemic Japanese patients
Yasunori Sawavama, Jun Hayashi, Naoyasu Maeda, Chie Shimizu, Yoko Tanaka, Seizaburo Kashiwagi. Department of General Medicine, Kyushu University Hospital, Japan Objective: This study was to test the effect of lipid reduction on the carotid
intima-media thickness (IMT) in hypercholesterolemic patients in Fukuoka, Japan. Methods: A total of 157 asymptomatic hypercholesterolemic patients (mean age 69.4 years) were assigned to probucol (500 mg/day, n = 75), pravastatin (10 mg/day, n = 61) or matched control (diet alone, n = 21). The 2-year change in lipids and in IMT in the common carotid artery and incidence of major cardiovascular events were surveyed. Ultrasound-detected carotid atherosclerosis (CA) as defined by a mean maximum IMT (MMaxIMT) 2 1.3 mm. Results: The serum LDL cholestrol level was significantly reduced by 31% in probucol group and by 43% in the pravastatin group and by 26% in the diet alone group (P i 0.0001, P < 0.0001, P < 0.01, respectively). Probucol and pravastatin groups with CA resulted in a significant reduction of the MMaxIMT (p < 0.01, p < 0.05, respectively) and a signihcant MMaxIMT in the diet alone group after 2 years (p < 0.001). There was a significant relationship between the reduction of MmaxIMT and serum LDL cholesterol in the probucol group (p < 0.05). Moreover, major cardiovascular events were significant fewer in the probucol group than in the other groups (p < 0.05). Conclusion: These observations suggest that lipid reduction prevents from the progression of MMaxIMT in the common carotid artery, and that probucol is more effective in reducing the risk of major cardiovascular events in hypercholesterolemic patients than pravastatin.
ITuP2.Wl6
Colesevelam HCI (Welchol’“), a new, potent, well tolerated, non systemic, lipid lowering agent
M. Davidson, D. Hunninghake, T. Olson, J. Donovan, S. Burke. Chicago Ctr. for Clinical Research, Chicago; Heart Disease Prevention Ctr. Minneapolis; GelTex Pharmaceuticals, Waltham, USA Objective: To develop a safe, non-absorbed, LDL cholesterol reducing drug that provides convenient monotherapy and can be an effective component of combination therapy. Methods: Seven placebo-controlled trials incorporating 1,350 diet stable patients explored the safety and efficacy of colesevelam alone and in combination with HMG-CoA reductase inhibitors (HMGRI). Patients with Fredrickson type IIa hyperlipoproteinemia constituted the primary population. Combination therapy studies were conducted with concurrent administration of lovastatin, simvastatin and atorvastatin. Results: Treatment with colesevelam demonstrated dose dependent statistically significant reductions in LDL cholesterol and was effective whether the dose was administered once or twice per day (Figure). Side effects, including gastrointestinal, were comparable between treatment and placebo groups. Colesevelam demonstrated at least additive efficacy in reducing LDL-C when combined with an HMGRI, compared with individual agents in the same trial.
Conclusion: Colesevelam hydrochloride is a safe, convenient and effective therapy for reducing LDL-C alone or in combination with an HMGRI. Compared to historical data with other bile acid sequestrants, colesevelam hydrochloride was 46 times more potent.
ITuP3.Wl6
F 12511, a novel ACAT inhibitor, and atorvastatin regulate endogenous hypercholesterolemia in a synergistic manner in the casein-fed rabbits
D. Junouero, F. Bruniquel, X. N’Guyen, J.-M. Autin, J.-F. Patoiseau, A.-D. Degryse, EC. Colpaert, A. Delhon. Centre de Recherche Pierre Fabre, 17 ave. Jean Moulin, 81106 Castres Cedex, France F 12511, a novel ACAT inhibitor, lowers plasma cholesterol levels in New-Zealand rabbits fed a cholesterol-free casein-rich diet. Endogenous hypercholesterolemia (EH) pre-established for 8 weeks was used to compare treatments with F 12511 and atorvastatin for a further S-week period, and
XIith Jnternational Symposium on Athemsclerosis,
Stockholm, Sweden, June 25-29,
2000