OBJECTIVES:Type 2 diabetes mellitus (DM) enhances the development of atherosclerosis and reduces the activity of the oxidative myeloperoxidase (MPO) enzyme. MPO gene has a functional promoter polymorphism -463G/A which leads to high- (GG) and low-expression (AG, AA) genotypes. DESIGN AND METHODS:We studied the association of MPO polymorphism with carotid artery intima-media thickness (IMT) in 198 randomly selected Finnish men of Caucasian origin, 161 non-diabetics and 37 with type 2 DM. Their carotid IMT was measured by high-resolution ultrasonography, and the overall mean IMT value was calculated. MPO genotypes were determined by the PCR-RFLP method. RESULTS:We found significant MPO genotype-by-study-group (control/DM) interactions with the overall mean IMT and internal carotid IMT (p=0.05 and p=0.04, respectively). Among non-diabetic subjects, the overall carotid IMT was 7.3% higher in subjects with the low-activity genotype when compared to the high-activity (G/G) group. The results remained significant after adjustment for total cholesterol and smoking (p=0.015). No similar genotypic association was found for the subjects with type 2 DM. CONCLUSIONS:This data suggests that in subjects with normal glucose metabolism, MPO gene variation may modify the carotid artery IMT.

Leukocytosis is known to predict future cardiovascular events even in subjects without coronary heart disease (CHD), but its association with early atherosclerotic changes has remained less certain. The aim of the present study was to investigate how the blood leukocyte count compares with several other risk factors for CHD in determining carotid artery intima-media thickness (IMT) and subclinical carotid atherosclerosis in a population sample. Both carotid arteries were investigated with high-resolution B-mode ultrasound in a community-based sample of 219 randomly selected men aged 50–59 years to calculate the mean maximum IMT (MMax IMT) of 12 standard sites. Risk factor assessment included several traditional biochemical risk factors, blood pressure, maximal oxygen consumption and work load on ergometry, life-style habits and hematologic parameters. As genetic determinants, apolipoprotein E and A-IV polymorphisms were studied. According to multivariate regression analysis, age (P < 0.0001), blood leukocyte count (P < 0.0001) and systolic blood pressure (P < 0.042) were the only significant predictors of MMax IMT. MMax IMT increased linearly from the lowest tertile of blood leukocyte count (1.14 ± 0.20 mm) to the second (1.18 ± 0.25 mm) and to the highest tertile (1.25 ± 0.27 mm, P = 0.019). This difference remained significant after adjustment with age, systolic blood pressure and smoking (P = 0.032). Leukocytes seem to have an independent role in the early arterial damage and they may reflect subclinical disease. This implies that leukocyte count is undervalued in the diagnostics and prognostics of carotid atherosclerosis.

Objective—Increased carotid artery intima-media thickness (IMT) and increased coronary artery calcium (CAC) are noninvasive surrogate indices of prevalent coronary artery disease (CAD). We compared CAC to IMT for noninvasive detection of prevalent CAD in participants whose coronary status was identified by coronary angiography. Methods and Results—Male and female CAD patients (≥50% stenosis in one or more coronary artery, n=79) and controls (no lumen irregularities, n=93) were identified using coronary angiography. Mean maximum carotid IMT was quantified using B-mode ultrasound and total CAC was measured using ECG-gated helical computed tomography (HCT). Carotid IMT was ≈20% higher in CAD cases compared with controls (P<0.001), whereas mean CAC was 1000% higher in CAD cases than controls (P<0.0001). In multivariable models adjusted for age and sex, IMT greater than the median (1.13 mm) was associated with 2-fold increase in likelihood of prevalent CAD compared with scores below that cut point (P=0.015). CAC scores that exceeded the median score of 92 were associated with 28-fold increase in likelihood of prevalent CAD (P<0.0001). Although associations of increased IMT with prevalent CAD were similar in males and females, CAC scores above the median in females were associated with 39-fold increase in odds of prevalent CAD, whereas males with elevated CAC had 19-fold risk of CAD. Conclusion—HCT-measured CAC compares favorably with carotid IMT measured by B-mode ultrasound as a noninvasive index of prevalent CAD.

The metabolic syndrome, which is a set of lipid and nonlipid risk factors of metabolic origin linked with insulin resistance, is believed to be associated with an elevated risk for cardiovascular disease, but few have studied this association in prospective long-term cardiovascular outcomes trials. Placebo data from the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) were used post hoc to estimate the long-term relative risk of major coronary events (MCEs) associated with the metabolic syndrome, after excluding diabetes mellitus. In 4S and AFCAPS/TexCAPS, respectively, placebo-treated patients with the metabolic syndrome were 1.5 (95% confidence interval 1.2 to 1.8) and 1.4 (95% confidence interval 1.04 to 1.9) times more likely to have MCEs than those without it. Of the components of the metabolic syndrome, low high-density lipoprotein levels were associated with elevated risk of MCEs in both studies, whereas high triglycerides in 4S and elevated blood pressure and obesity in AFCAPS/TexCAPS were associated with significantly increased relative risk. Patients with the metabolic syndrome showed increased risk of MCEs irrespective of their Framingham-calculated 10-year risk score category (>20% vs =20%). These data demonstrate that the metabolic syndrome is associated with increased risk of MCEs in both hypercholesterolemic patients with coronary heart disease in 4S and in those with low high-density lipoprotein cholesterol but without coronary heart disease in AFCAPS/TexCAPS. It appears that the metabolic syndrome is associated with risk that is not entirely accounted for by traditional risk scoring paradigms.

Background—Although atherosclerosis often leads to lumen narrowing and symptomatic cardiovascular disease, it is now recognized that arteries have the potential to compensate by enlarging in response to atherosclerosis. We tested the hypotheses that carotid arterial interadventitial (IA) and lumen diameters were related to wall thickness and that carotid arterial diameters of individuals with coronary artery disease (CAD) differed from those of CAD-free controls. Methods and Results—We measured lumen diameter, IA diameter, and intima-media thickness (IMT) using B-mode ultrasound in the common and internal carotid arteries of 141 CAD case patients and 139 disease-free control subjects. Common carotid IA diameter was greater in CAD cases than controls after adjustment for age, height, and sex (P <0.01). Common carotid lumen diameter was marginally larger in individuals with greater IMT (P =0.06) but was not associated with case status. Conversely, mean internal carotid IA and lumen diameters were smaller in CAD cases than controls in both univariable and multivariable models (both P <0.001), and lumina were smaller in individuals with greater IMT. Despite these cross-sectional differences in carotid artery dimensions, we were unable to detect any statistically significant interactive effects of CAD case status on the association of IMT with arterial dimensions. Conclusions—Internal carotid artery lumen and IA diameters are both smaller in CAD cases than controls. The association of increased IMT with arterial dimensions varies in a manner that is segment-specific for the common and internal carotid arteries.

Background: In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C), statins also raise high-density lipoprotein cholesterol (HDL-C).Hypothesis: Recent studies have shown that treatment with simvastatin results in larger increases in HDL-C than those seen with atorvastatin. The results of three clinical studies are analyzed, comparing the effects of simvastatin and atorvastatin on HDL-C and apolipoprotein A-I (apo A-I) in the total cohort and in several subgroups of hypercholesterolemic patients. The three studies were all multicenter, randomized clinical trials that included simvastatin (20-80 mg) and atorvastatin (10-80 mg) treatment arms. The subgroup analyses performed were gender; age (< 65 and greater than or equal to 65 years); baseline HDL-C (male: < 40 or greater than or equal to 40 mg/dl; female: < 45 or > 45 mg/dl), baseline LDL-C (< 160 or greater than or equal to 160 mg/dl), and baseline triglycerides (< 200 or greater than or equal to 200 mg/dl).Results: Both drugs produced similar increases in HDL-C levels at low doses; however, at higher drug doses (40 and 80 mg), HDL-C showed a significantly greater increase with simvastatin than with atorvastatin (p < 0.05 to < 0.001). Therefore, while HDL-C remained consistently elevated across all doses of simvastatin, there appeared to be a pattern of decreasing HDL-C with an increasing dose of atorvastatin. A similar negative dose response pattern was also observed with apo A-I in atorvastatin-treated patients, suggesting a reduction in the number of circulating HDL particles at higher doses. Both drugs reduced LDL-C and triglycerides in a dose-dependent fashion, with atorvastatin showing slightly greater effects. The differential effects of atorvastatin and simvastatin on HDL-C and apo A-I were observed for both the whole study cohorts and all subgroups examined; thus, no consistent treatment-by-subgroup interactions were observed.Conclusion: The data presented show that, across different hypercholesterolemic patient subgroups, simvastatin increases HDL-C and apo A-I more than atorvastatin at higher doses, with evidence of a negative dose response effect on HDL-C and apo A-I with atorvastatin, but not simvastatin.

Background— A multicenter, randomized, double-blind, placebo-controlled study was conducted to evaluate LDL cholesterol–lowering efficacy, overall safety, and tolerability and the influence on growth and pubertal development of simvastatin in a large cohort of boys and girls with heterozygous familial hypercholesterolemia (heFH). Methods and Results— A total of 173 heFH children (98 boys and 75 girls) were included in this study. After a 4-week diet/placebo run-in period, children with heFH were randomized to either simvastatin or placebo in a ratio of 3:2. Simvastatin was started at 10 mg/d and titrated at 8-week intervals to 20 and then 40 mg/d. During a 24-week extension period, the patients continued to receive simvastatin (40 mg) or placebo according to their assignment. After 48 weeks of simvastatin therapy, there were significant reductions of LDL cholesterol (−41%), total cholesterol (−31%), apolipoprotein B (−34%), VLDL cholesterol (−21%), and triglyceride (−9%) levels. HDL cholesterol and apolipoprotein A-I levels were increased by 3.3% and 10.4%, respectively (not significant). No safety issues became evident. Except for small decreases in dehydroepiandrosterone sulfate compared with placebo, there were no significant changes from baseline in adrenal, gonadal, and pituitary hormones in either treatment group. Conclusions— Simvastatin significantly reduced LDL cholesterol, total cholesterol, triglyceride, VLDL cholesterol, and apolipoprotein B levels and was well tolerated in children with heFH. There was no evidence of any adverse effect of simvastatin on growth and pubertal development. Therefore, simvastatin at doses up to 40 mg is a well-tolerated and effective therapy for heFH children.

Background-Intimal medial thickness of the extracranial carotid arteries (IMT) is related to coronary artery disease (CAD) and CAD risk factors. Few studies have explored the association of risk factors with progression of IMT, and none have evaluated their associations with IMT progression specifically in patients with and without CAD.Methods and Results-We used coronary angiography to identify 280 patients equally divided between men and women and those with either greater than or equal to50% coronary artery stenosis or no CAD. Risk factors were measured at baseline and IMT was measured at baseline and yearly for 3 years in 241 of these individuals. Baseline risk factors and CAD status were related to IMT progression. IMT of patients with CAD progressed 3 times faster than that of patients with no CAD (mean+/-SEM, 33.7+/-7.4 versus 8.9+/-7.1 mum/year; P=0.02), and CAD status and high-density lipoprotein (HDL) cholesterol were independently associated with IMT progression. Male sex, increased waist to hip ratio, cigarette smoking, increased triglycerides, and decreased HDL cholesterol were associated with increased progression in CAD patients.Conclusions-Patients with CAD have more rapid progression of IMT than CAD-free controls, and risk factors are related to progression in them.

Objective: To describe the rationale, design and baseline data of a study conducted to determine the efficacy, safety and tolerability of simvastatin in children and adolescents with heterozygous familial hypercholesterolaemia (heFH).

OBJECTIVEAt higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind, dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety. PRIMARY HYPOTHESIS: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels.METHODSA total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks.RESULTSDuring the first 12 weeks of the study, simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin, while producing slightly lower reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses. In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%).CONCLUSIONSAt the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.

Background — Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study. Methods and Results — In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and β-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction ( P =0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup. Conclusions — Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.

BACKGROUND AND AIM Recently, several studies have indicated there may be differences among statins regarding a possible association between therapy and a reduction in risk of fractures. No data from prospective randomised clinical trials designed to assess either biochemical or clinical effects on bone metabolism are yet available. We assayed levels of biochemical markers of bone formation in stored serum samples from a recently completed randomised clinical trial conducted to compare the effects of simvastatin and atorvastatin on the lipid profile of patients with hypercholesterolaemia. METHODS AND RESULTS This 12-week, randomised, multicenter, open-label study was designed to compare the safety and lipid-lowering efficacy of simvastatin 40 mg or 80 mg with that of atorvastatin 20 mg or 40 mg in 846 hypercholesterolaemic patients. Stored serum samples from this study were analysed to compare the effects of simvastatin and atorvastatin on 2 biomarkers of bone turnover, bone-specific alkaline phosphatase (BSAP), a marker of bone formation, and C-teleopeptide of type 1 collagen (CTx), a marker of bone resorption. Treatment with simvastatin 40 and 80 mg/day, but not atorvastatin 20 and 40 mg/day, led to significant (p < 0.05) reductions in BSAP in both men (4.1-5.4% reduction) and women (4.2-7.4% reduction). In addition, there appeared to be a dose-dependent effect with greater reductions in BSAP seen with the 80 mg dose of simvastatin. Treatment with either 20 mg or 40 mg of atorvastatin had no significant effect on BSAP levels on the groups as a whole or in the gender-specific subgroups. CTx showed a small, but not statistically significant, decrease with simvastatin, again with an apparent dose-related trend. Atorvastatin treatment generally resulted in small, non significant increases in CTx. CONCLUSIONS The present serum bone biomarker results show that treatment with simvastatin, but not atorvastatin, decreases BSAP and suggest that simvastatin may have a beneficial effect on bone turnover.

The enzyme paraoxonase (PON) can eliminate lipid peroxides and is believed to protect against low-density lipoprotein oxidation. A common polymorphism in the PON gene (PON1) causes an amino acid substitution of methionine (M) for leucine (L) at position 55 in the protein, which changes the activity of PON and can affect the risk of atherosclerosis. Because smoking is associated with increased lipid peroxidation, we studied the relationship between PON M/L55 polymorphism and the carotid artery intima-media thickness (IMT) in smokers or previous smokers (n = 112) and nonsmokers (n = 87). IMT was measured at 3 standardized segments by B-mode ultrasonography, and the overall mean IMT value of 199 randomly selected men (mean age 54.2 [plusmn] 3.0 years) was calculated. Subjects with IMT [gt ] 1.7 mm in at least 1 standard site were considered to have carotid artery atherosclerotic disease (CAAD). For analysis, L55 homozygotes were compared with the M55 allele carriers. Nonsmoking L55 homozygotes had an 8.9% (95% confidence interval [CI], 1.6 to 16.8) higher overall mean IMT than M55 allele carriers. In smokers, however, the M55 allele carriers tended to have higher overall mean IMT values than L55 homozygotes. There was also a statistically significant interaction between M/L55 genotype and smoking status on CAAD (P = .009) by logistic regression analysis. Among nonsmokers, the L55 homozygotes had an odds ratio of 4.22 (95% CI, 1.06 to 16.8) for CAAD compared with nonsmoking M55 allele carriers. Contrary to nonsmokers, the smoking M55 allele carriers had an odds ratio of 2.22 (95% CI, 0.82 to 6.01) for CAAD when the L55/L55 genotype of smokers was a reference group. These data suggest that in nonsmoking men, a PON L55/L55 genotype may represent a genetic risk factor for CAAD. The reverse effect in smokers implies that the ability of PON to protect against CAAD is influenced by cigarette smoking. The efficiency of this inhibition probably depends on the PON M/L55 genotype.

High-density lipoprotein (HDL) levels are inversely related to the risk of coronary heart disease (CHD). 1 Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in AdultsSummary of the second report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA. 1993; 269: 3015-3023 Crossref PubMed Scopus (2924) Google Scholar Recently, a double-blind, placebo-controlled study with gemfibrozil in men with CHD in whom the primary lipid abnormality was a low HDL cholesterol level (the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial [VA-HIT]) suggested that even modest increases in HDL cholesterol and reductions in triglycerides could significantly reduce the risk of CHD. 2 Rubins H.B. Robins S.J. Collins D. Fye C.L. Anderson J.W. Elam M.B. Faas F.H. Linares E. Schaefer E.J. Schectman G. Wilt T.J. Wittes J. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study GroupGemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999; 341: 410-418 Crossref PubMed Scopus (3206) Google Scholar In addition to lowering low-density lipoprotein (LDL) cholesterol and triglycerides, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) raise the levels of HDL cholesterol and apolipoprotein (apo) A-I, the major protein constituent of HDL. However, a recent study showed that at higher doses, simvastatin increased HDL cholesterol and apo A-I significantly more than atorvastatin. 3 Crouse III, J.R. Frohlich J. Ose L. Mercuri M. Tobert J.A. Effects of high doses of simvastatin and atovastatin on high-density lipoprotein cholesterol and apolipoprotein A-I. Am J Cardiol. 1999; 83: 1476-1477 Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar To confirm these findings, a 36-week, multicenter, double-blind, dose titration study was performed to evaluate the effects of simvastatin (40 to 80 mg/day) and atorvastatin (20 to 40 mg/day) on HDL cholesterol and apo A-I levels at doses expected to provide similar large reductions in LDL cholesterol. This article reports the results of a predefined interim analysis performed after the first 12 weeks of the study. CorrectionAmerican Journal of CardiologyVol. 86Issue 7Preview Full-Text PDF

BACKGROUND AND AIM:Clinical data suggesting that larger decreases in low density lipoprotein cholesterol (LDL-C) result in greater reductions in coronary heart disease events have led to the establishment of aggressive LDL-C targets for the treatment of hypercholesterolemia. In view of this, the efficacy and safety of a new maximum dose of simvastatin, 80 mg, were evaluated in 9 studies involving 2819 hypercholesterolemic patients. This report focuses on the combined results from the 4 main or Pivotal studies in which a total of 1936 patients received simvastatin 40 or 80 mg for 36 to 48 weeks. METHODS AND RESULTS:The Pivotal studies had similar randomized, multicenter, controlled, double-blind, parallel-group designs. Their combined results demonstrated a significant advantage in the LDL-C-lowering effect for the 80 mg dose. At week 24, the mean percentage reductions (95% confidence intervals) from baseline in LDL-C for the 40 and 80 mg groups were -39.8% (-40.9, -38.7) and -45.7% (-46.5, -45.0) respectively (p < 0.001, between groups), and larger reductions in total cholesterol and triglycerides were also observed in the 80 mg group. Both doses were well tolerated. No new or unexpected adverse events were observed and the overall clinical event profiles were similar in the two groups. Clinically significant hepatic transaminase increases (> 3 times the upper limit of normal/ULN) and myopathy (muscle symptoms plus creatine kinase increase > 10 times ULN) occurred infrequently with both doses. Simvastatin 80 mg had a comparable efficacy and safety profile in women and men as well as in non-elderly and elderly patients. CONCLUSIONS:Simvastatin 80 mg provides additional LDL-C and triglyceride reductions compared to the 40 mg dose and has an excellent safety and tolerability profile.