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Objective: This study investigated the efficacy, safety, tolerability, and pharmacokinetics of a novel cholesterol absorption inhibitor, FM-VP4, comprising disodium ascorbyl sitostanol phosphate (DASP) and disodium ascorbyl campestanol phosphate (DACP)., Methods: In phase 1, 30 men received a single dose of 100, 200, 400, 800, 1,600, or 2,000 mg FM-VP4 or placebo. In phase 2, 100 men were treated with 100, 200, 400, or 800 mg/day of FM-VP4 or placebo for 4 weeks., Results: The drug was well tolerated at each single or multiple dose level. After 4 weeks of treatment, low-density lipoprotein cholesterol (LDL-C) levels changed by 2.7% in the placebo group and by 2.9%, -4.2%, and -4.6% in the 100, 200, and 800 mg/day groups, respectively, which was not statistically significant. However, 400 mg/day of FM-VP4 significantly decreased LDL-C by 6.5% (p=0.02). Phase 1 showed that DACP and DASP were absorbed into plasma with a median t(max) of 12 h for both components, and clearance was slow with a mean t(1/2lambda) of 57 h. During 4 weeks of treatment, steady state was reached by approximately 8 days., Conclusion: This study demonstrated that up to 800 mg/day of FM-VP4 is safe and well tolerated for at least 4 weeks. Furthermore, the higher doses significantly reduced LDL-C by 7% compared with baseline or by 10% compared with placebo, with the maximum effect reached at 400 mg/day.

Objective: To determine lipoprotein particle concentrations and size in children with familial hypercholesterolemia (FH) and investigate the effect of pravastatin therapy on these measures., Study Design: Lipoprotein particle concentrations and sizes were examined by nuclear magnetic resonance (NMR) spectroscopy in 144 children with FH and 45 unaffected siblings. The effect of pravastatin therapy (20 to 40 mg) on lipoprotein particle concentration and size were compared with placebo after 1 year of treatment, using analysis of covariance., Results: Compared with the unaffected siblings, the children with FH had significantly higher concentrations of very-low-density lipoprotein (VLDL) particles (115.6 nmol/L vs 51.2 nmol/L; P < .001) and low-density lipoprotein (LDL) particles (1726.8 nmol/L vs 955.3 nmol/L; P < .001), and lower concentrations of high-density lipoprotein (HDL) particles (23.2 micromol/L vs 26.9 micromol/L; P < .001). Compared with placebo, pravastatin therapy decreased the concentration of VLDL particles by 35.9 nmol/L (P < .001), of total LDL particles by 342.7 nmol/L (P < .001), of large LDL particles by 189.5 nmol/L (P < .001), and of small LDL particles by 156.2 nmol/L (P = .152), but increased the concentration of total HDL particles by 2.2 micromol/L (P < .001), of large HDL particles by 1.0 micromol/L (P = .006), and of medium HDL particles by 1.1 micromol/L (P = .003). VLDL particle size increased by 1.0 nm (P = .032)., Conclusions: Compared with their healthy siblings, children with FH have an atherogenic lipoprotein profile based on their lipoprotein distribution and lipoprotein particle diameter. Pravastatin therapy can improve, but not fully restore, these lipoprotein abnormalities toward normal levels in these children.

Background: Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown., Methods: We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries., Results: The primary outcome, the mean (+/-SE) change in the carotid-artery intima-media thickness, was 0.0058+/-0.0037 mm in the simvastatin-only group and 0.0111+/-0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P=0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (+/-SD) LDL cholesterol level was 192.7+/-60.3 mg per deciliter (4.98+/-1.56 mmol per liter) in the simvastatin group and 141.3+/-52.6 mg per deciliter (3.65+/-1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups., Conclusions: In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097 [ClinicalTrials.gov].)., (Copyright 2008 Massachusetts Medical Society.)

Introduction: Myeloperoxidase (MPO), an antimicrobial enzyme of the innate immune system, has been proposed to exert a wide array of pro-atherogenic effects throughout all stages of the atherosclerotic process. In view of the potent anti-inflammatory effects of statins in vitro, we evaluated the impact of statin therapy on plasma MPO levels in patients with heterozygous familial hypercholesterolemia (FH), treated with either intensive or conventional lipid-lowering therapy. Furthermore, we evaluated the relation between MPO levels and atherosclerosis progression, as determined by intima media thickness (IMT)., Methods: We measured plasma MPO levels, lipoprotein profiles, high sensitivity-C-reactive protein (hs-CRP) as well as IMT of carotid artery segments in 122 FH patients at baseline and after 2-year treatment with atorvastatin 80 mg or simvastatin 40 mg QD., Results: Baseline median MPO values were 147pM (interquartile range (IQR) 122-217) and 144pM (IQR 118-216) and these increased significantly to 221pM (IQR 144-290) and 255pM (IQR 152-324) during 2-year follow-up in both the atorvastatin 80 mg and simvastatin 40 mg group, respectively. There was no correlation between MPO levels and IMT progression, change in lipoproteins or hs-CRP., Conclusion: In FH patients, statins do not prevent an increase in MPO levels during follow-up. Moreover, MPO levels are not associated with atherosclerosis progression in these patients.

Background: Atherosclerosis is a common multifactorial disease resulting from an interaction between susceptibility genes and environmental factors. The causative genes that contribute to atherosclerosis are elusive. Based on recent findings with a Wistar rat model, we speculated that the gamma-secretase pathway may be associated with atherosclerosis., Methodology/principal Findings: We have tested for association of premature coronary atherosclerosis with a non-synonymous single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu; rs1047552), a SNP previously linked to Alzheimer's disease. Analysis of a Dutch Caucasian cohort (780 cases; 1414 controls) showed a higher prevalence of the risk allele in the patients (odds ratio (OR) = 1.35), albeit not statistically different from the control population. Intriguingly, after gender stratification, the difference was significant in males (OR = 1.63; p = 0.033), but not in females (OR = 0.50; p = 0.20). Since Phe217Leu-mutated APH1B showed reduced gamma-secretase activity in mouse embryonic fibroblasts, the genetic variation is likely functional., Conclusion/significance: We conclude that, in a male-specific manner, disturbed gamma-secretase signalling may play a role in the susceptibility for premature coronary atherosclerosis.

Low-density lipoprotein-cholesterol (LDL-C) lowering is the mainstay of the current treatment guidelines in the management of cardiovascular risk. HMG-CoA reductase inhibitors (statins) are currently the most effective LDL-C-lowering drugs. However, a substantial number of patients do not reach treatment targets with statins. Therefore, an unmet medical need exists for lipid-lowering drugs with novel mechanisms of action to reach the recommended cholesterol target levels, either by monotherapy or combination therapy. Upregulation of the LDL receptor with squalene synthase inhibitors has shown promising results in animal studies but the clinical development of the lead compound lapaquistat (TAK-475) has recently been discontinued. Ezetimibe combined with statins allowed significantly more patients to reach their LDL-C targets. Other inhibitors of intestinal cholesterol absorption such as disodium ascorbyl phytostanol phosphate (FM-VP4) and bile acid transport inhibitors have shown positive results in early development trials, whereas the prospect of acyl coenzyme A: cholesterol acyltransferase inhibition in cardiovascular prevention is dire. Selective inhibition of messenger RNA (mRNA) by antisense oligonucleotides is a new approach to modify cholesterol levels. The inhibition of apolipoprotein B mRNA is in advanced development and mipomersen sodium (ISIS 301012) has shown striking results in phase II studies both as monotherapy as well as in combination with statins.

Fabry disease, or alpha-galactosidase A (alpha-Gal A) deficiency, is a lysosomal storage disorder in which accumulation of globotriaosylceramide (Gb(3)) is thought to be responsible for the development of renal, cardiac and cerebral complications. The availability of enzyme replacement therapy has led to an increased awareness and the screening of patients suffering from complications that may be associated with Fabry disease. An association between alpha-Gal A deficiency and atherosclerosis has been suggested, although there is controversy. We therefore studied the prevalence of Fabry disease in a Dutch cohort of prematurely atherosclerotic males. Measurement of alpha-Gal A activity was performed in plasma of 440 Dutch male patients with premature atherosclerosis. Patients were included if they were under the age of 50 years and had proven coronary and/or peripheral artery disease. Analysis revealed a mean alpha-Gal A activity of 7.75 +/- 3.48 nmol/h per ml (range 0.55-34.36). In 425 patients (96.5%) alpha-Gal A activity was within the reference range (3.2-14.3 nmol/h per ml, based on historical controls); 13 patients (3%) had values above and 2 patients (0.5%) below the reference range. Additional analysis of alpha-Gal A activity in leukocytes and fresh plasma in these two patients revealed normal values (53 and 47 nmol/h per mg (reference range: 32-60 nmol/h per mg) and 31.1 and 14.2 nmol/h per ml, respectively). Thus Fabry disease was not detected, leading to an overall prevalence of 0% (95 CI 0-0.68). In conclusion, screening for Fabry disease in prematurely atherosclerotic patients seems not to be very useful, although a slightly increased prevalence is not excluded.

Objective: Functional and morphological changes of the arterial wall already present in young children with heterozygous familial hypercholesterolemia (HeFH) suggest that treatment should be initiated early in life to prevent premature atherosclerotic cardiovascular disease. The purpose of this study was to assess the efficacy and particularly safety of statin therapy in children with HeFH., Methods and Results: We performed a meta-analysis of randomized, double-blind, placebo-controlled trials evaluating statin therapy in children aged 8 to 18 years with HeFH. Six studies (n=798 children) with 12 to 104 weeks of treatment were included. Total cholesterol, LDL cholesterol, and apolipoprotein B were significantly reduced, whereas HDL cholesterol and apolipoprotein A1 were significantly increased by statin therapy. No statistically significant differences were found between statin- and placebo-treated children with respect to the occurrence of adverse events (RR 0.99; 95% CI: 0.79 to 1.25), sexual development (RR of advancing > or = 1 stage in Tanner classification 0.96; 95% CI: 0.79 to 1.17), muscle toxicity (RR of CK > or = 10 times the upper limit of normal [ULN] 1.38; 95% CI: 0.18 to 10.82), or liver toxicity (RR of > or = 3 times the ULN for ASAT 0.98; 95% CI: 0.23 to 4.26 and for ALAT 2.03; 95% CI: 0.24 to 16.95). We found a minimal difference in growth in favor of the statin group (0.33 cm; 95% CI: 0.03 cm to 0.63 cm)., Conclusion: In addition to the fact that statin treatment is efficacious, our results support the notion that statin treatment in children with HeFH is safe. Thus, even though further studies are required to assess lifelong safety, statin treatment should be considered for all children aged 8 to 18 with HeFH.

Background/objective: To compare early invasive treatment with continued pharmacological treatment in patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia., Methods: Patients with type 2 diabetes mellitus and mild anginal symptoms underwent myocardial perfusion scintigraphy (MPS). Patients with myocardial ischaemia were randomly assigned to early invasive or continued pharmacological treatment. All patients were followed for the occurrence of MACE (death, nonfatal myocardial infarction or hospitalisation for unstable angina pectoris)., Results: A total of 156 patients were randomised when the sponsor (ZonMW) prematurely terminated the study because of a slow recruitment rate. With a mean follow-up of 2.1±0.6 years, 9 of 79 patients assigned to early invasive treatment developed MACE compared with 10 of 77 patients randomised to continued pharmacological treatment, annual event rate 5.4 vs. 6.3%, hazard ratio 0.89, 95% CI 0.36 to 2.20, p=0.34. Due to the limited number of included patients and the low event rate, the study did not have sufficient power for the study objective., Conclusion: Patients with diabetes mellitus type 2, mild anginal symptoms and documented myocardial ischaemia, under appropriate medical treatment, have a lower than anticipated annual event rate of MACE of ±5 to 6% which questions the beneficial effect of early revascularisation.

Purpose: To determine the prevalence and predictors of reversible myocardial perfusion defects, indicative of myocardial ischaemia, in patients with mild, stable anginal complaints [Canadian Cardiovascular Society classification (CCS) I-II/IV] and diabetes mellitus type 2 (T2DM)., Methods: A total of 329 patients with T2DM and stable, mild anginal symptoms (CCS I-II/IV) underwent myocardial perfusion scintigraphy. Perfusion images were assessed using a five-point (semi)-quantitative scoring system according to a 17-segment myocardial model., Results: One-hundred and fifty-six (47%) patients showed reversible myocardial perfusion defects defined as a summed difference score of >or=3. Male gender [odds ratio (OR) 2.28, 95% CI 1.4-3.71, p=0.001], previous myocardial infarction (MI) without revascularisation (OR 3.04, 95% CI 1.28-7.24, p=0.01), and the use of two or more classes of anti-anginal medication (OR 2.36, 95% CI 1.48-3.76, p<0.001) were independent predictors for the presence of reversible defects. By contrast, lipid-lowering therapy reduced the possibility of reversible perfusion defects (OR 0.56, 95% CI 0.33-0.95, p=0.03)., Conclusion: Approximately half of the patients with mild, stable angina pectoris and T2DM showed evidence of myocardial ischaemia. Male gender, previous MI and the use of anti-anginal medication were positive predictors and lipid-lowering therapy was a negative predictor for the results of the scintigraphic stress test.

Aims: We assembled a cohort of patients with familial hypercholesterolaemia (FH) for both basic and clinical research. We used a set of established diagnostic criteria to define FH. Some put forward that a definite diagnosis of FH is made when a mutation in the LDL-receptor (LDLR) gene is identified. We therefore set out to determine in these patients whether patients with a DNA diagnosis would differ significantly from those diagnosed clinically., Methods and Results: We randomly selected 4000 hypercholesterolaemic patients from the Dutch Lipid Clinic network database. Phenotypical data were acquired by reviewing medical records. After review of medical records, 2400 patients could be defined as having FH. An LDLR mutation was identified in 52.3% of these patients. Patients with and without an LDLR mutation demonstrated different clinical and laboratory characteristics. Low-density lipoprotein cholesterol was higher in patients with an LDLR mutation, whereas triglycerides were higher in patients without an LDLR mutation. The phenotypic differences between the groups remained even after stratification for the presence or absence of tendon xanthomas., Conclusion: Despite the use of stringent clinical criteria to define FH patients, two cohorts could be identified within our study population, namely those patients with and those without an LDLR mutation. Our findings suggest that among those without an LDLR mutation, patients with other causes of dyslipidaemia may be present. These observations underline the relevance of genetic testing in FH for clinical practice, for screening purposes, and for research involving these patients.

Objective: To examine the effect of plant stanols on lipids and endothelial function in pre-pubertal children with familial hypercholesterolemia (FH)., Study Design: Children with FH (n=42), aged 7-12 years, were enrolled in a double-blind crossover trial, in which they consumed 500 mL of a low-fat yogurt enriched with 2.0 g of plant stanols and 500 mL of a low-fat placebo yogurt for 4 weeks, separated by a 6-week washout period. Lipid profiles and endothelial function were assessed after both consumption periods. Endothelial function was measured as flow-mediated dilation (FMD) of the brachial artery., Results: This daily intake of 2.0 g of stanols significantly decreased the levels of total cholesterol (TC) by 7.5% and low-density lipoprotein cholesterol (LDL-C) by 9.2% as compared with placebo. High-density lipoprotein cholesterol and triglyceride levels remained unaltered. The reduction of LDL-C levels did not improve FMD, which was 10.5%+/-5.1% after plant stanol consumption and 10.6%+/-5.0% after placebo consumption, respectively (P=.852)., Conclusion: This study demonstrates that plant stanols reduce LDL-C levels in children with FH without improving endothelial function.

Of all patients presenting with coronary, artery disease, 20-30% already have a diagnosis of diabetes mellitus type 2. Of the remaining patients, another 15-20% are found at presentation to have diabetes mellitus and 30% have glucose intolerance. Both conditions are major risk factors for the recurrence of coronary artery disease and mortality. The treatment of patients with diabetes mellitus type 2 always includes improvement in lifestyle, adequate blood-glucose control, cholesterol-lowering therapy and blood-pressure control. Furthermore, if one or more other traditional cardiovascular risk factors are present, or if the patient is over 40 years of age, acetylsalicylic acid must be added. Finally, with a prior history of coronary-artery disease, patients must be given an angiotensin converting enzyme (ACE) inhibitor. During percutaneous coronary interventions, patients with diabetes mellitus type 2 are preferably treated with a drug-eluting stent in combination with clopidogrel, and in case of an acute coronary syndrome, glycoprotein (GP) IIb/IIIa receptor antagonists are added to the standard treatment.

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment. Forty mildly hypercholesterolemic subjects were randomized to the following treatments for 4 weeks each: 10 mg/day ezetimibe combined with 25 g/day control spread; 10 mg/day ezetimibe combined with 25 g/day spread containing 2.0 g of plant sterols; 25 g/day spread containing 2.0 g of plant sterols; and placebo treatment consisting of 25 g/day control spread. Combination treatment of plant sterols and ezetimibe reduced low density lipoprotein cholesterol (LDL-C) by 1.06 mmol/l (25.2%; P < 0.001) compared with 0.23 mmol/l (4.7%; P = 0.006) with plant sterols and 0.94 mmol/l (22.2%; P < 0.001) with ezetimibe monotherapy. LDL-C reduction conferred by the combination treatment did not differ significantly from ezetimibe monotherapy (-0.12 mmol/l or -3.5%; P = 0.13). Additionally, the plasma lathosterol-to-cholesterol ratio increased with all treatments. Sitosterol and campesterol ratios increased after plant sterol treatment and decreased upon ezetimibe and combination therapy. Our results indicate that the combination of plant sterols and ezetimibe has no therapeutic benefit over ezetimibe monotherapy in subjects with mild hypercholesterolemia.

The inhibition of cholesteryl ester transfer protein (CETP) has recently been shown to effectively increase high-density lipoprotein (HDL) cholesterol. This study examined the use of the CETP inhibitor JTT-705 combined with pravastatin. In a randomized, double-blind, placebo-controlled trial, 155 patients with type II dyslipidemia using pravastatin 40 mg were treated with placebo or JTT-705 300 or 600 mg. Four weeks of treatment with JTT-705 600 mg led to a 30% decrease in CETP activity (p <0.001), a 28% increase in HDL cholesterol (p <0.001), and a 5% decrease in low-density lipoprotein cholesterol (p <0.03). Combination therapy using JTT-705 and pravastatin effectively increases HDL cholesterol levels and is safe and well tolerated up to 4 weeks of administration.

Background: Pseudoxanthoma elasticum (PXE) is an inherited disorder of elastic tissue. We recently found that heterozygosity for the frequent (0.8% prevalence in Dutch population) R1141X mutation in the PXE gene coding for the ABCC6 transporter, is associated with a fourfold risk of premature coronary artery disease. Yet, it is not clear whether or not heterozygosity for this mutation results in a mild PXE phenotype. The objective of our study was to determine if skin and/or eye abnormalities related to a PXE phenotype could be found in patients with premature coronary artery disease, with and without the R1141X mutation., Methods: R1141X mutation carriers with premature coronary artery disease (cases) and patients with premature coronary artery disease with no-or not known-mutation (controls) were studied. Cases and controls were examined for PXE-like skin changes and retinal angioid streaks, peau d'orange or pigment epithelium changes., Results: 7 cases and 31 controls were analysed. In both the mutation-positive and the control group, skin inspection and eye fundus examination did not reveal any dermatological or ocular signs of PXE., Conclusions: Carriers for the ABCC6 R1141X mutation, which is frequent and confers a high risk of premature coronary artery disease, do not commonly have skin or eye abnormalities consistent with a mild PXE phenotype.

In the 2-year Atorvastatin versus Simvastatin on Atherosclerosis Progression extension study, patients with familial hypercholesterolemia who continued to take atorvastatin 80 mg for an additional 2 years had complete arrest of the progression of mean carotid intima-media thickness (0.89 mm at the start vs 0.90 mm at the end of the study, p = 0.58). In contrast, patients previously taking simvastatin 40 mg had significant regression of intima-media thickness (0.95 mm at the start vs 0.92 mm at the end of the study, p = 0.01). Therefore, both placebo- and statin-treated patients with familial hypercholesterolemia are best treated with high-dose atorvastatin, a therapeutic regimen that induces atherosclerosis regression and is safe and well tolerated over a 4-year period.

Objective: To determine the contribution of classical risk factors to the development of cardiovascular disease (CVD) in patients with heterozygous familial hypercholesterolaemia (FH)., Design: A retrospective, multi-centre, cohort study. Extensive data were collected by scrutinizing medical records and the use of questionnaires. Multivariate Cox regression was used to study the relationship between potential risk factors and the occurrence of CVD., Setting and Subjects: We included 2400 FH patients from 27 Dutch lipid clinics. The diagnosis of FH was based upon the presence of a low-density lipoprotein receptor mutation or upon strict clinical criteria., Main Outcome Measures: Cardiovascular mortality and CVD., Results: During 112.943 person-years, 782 (32.6%) patients had had at least one cardiovascular event. Male gender (RR 2.82, 95% CI 2.37-3.36), smoking (RR 1.67, 95% CI 1.40-1.99), hypertension (RR 1.36, 95% CI 1.06-1.75), diabetes mellitus (RR 2.19, 95% CI 1.36-3.54), low HDL-C (RR 1.37, 95% CI 1.15-1.63) and elevated lipoprotein(a) levels (RR 1.50, 95% CI 1.20-1.79) proved to be independent CVD risk factors. These six risk factors explained 18.7% of the variation in the occurrence of CVD., Conclusions: Male gender, smoking, hypertension, diabetes mellitus, HDL cholesterol and lipoprotein(a) levels proved to be important risk factors for CVD in FH patients. In addition to the routine institution of statin therapy, controlling these factors needs special attention in the management of this disorder.

The recommended therapy of hypercholesterolemia in children consists of dietary modification and bile acid-binding resins. Unfortunately, the lipid-lowering efficacy of bile acid-binding resins is modest, and moreover, long-term compliance is poor because of side effects. In contrast, hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are widely used in adults and are considered to be the first choice in the treatment of hypercholesterolemia in that age category. In the last few years, several randomized trials have been conducted to evaluate the efficacy, safety, and tolerability of statin therapy in both children and adolescents. In this article, we review statin therapy in hypercholesterolemic children in terms of efficacy, safety, pharmacokinetics, and psychosocial functioning. Statins are not only effective in reducing low-density lipoprotein cholesterol levels in children with familial hypercholesterolemia but also improve endothelial function and reduce the progressive thickening of the intima media complex of the carotid arteries. Statins seem safe at the longer term in children in terms of plasma levels of liver enzymes and liver function, creatine kinase levels, and muscle function, as well as growth and sexual development. Long-term follow-up studies are needed to assess whether statin treatment started early in children with familial hypercholesterolemia can prevent future cardiovascular events.

Background: Toll-like receptor-4 (TLR4) is a major receptor for inflammatory stimuli potentially involved in the pathogenesis of atherosclerosis, such as lipopolysaccharide (LPS) and heat-shock proteins. The Asp299Gly polymorphism of the TLR4 gene has been associated with a reduced intima-media thickness (IMT) of the common carotid artery in healthy individuals. We have investigated whether the presence of the Asp299Gly polymorphism in patients with familial hypercholesterolaemia (FH) has a similar protective effect, and whether it influences the effects of HMG-CoA reductase treatment., Materials and Methods: A cohort of 293 FH patients and 200 healthy volunteers were genotyped for the presence of the Asp299Gly allele using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Intima-media thickness measurements, inflammatory parameters and the effect of HMG-CoA reductase inhibitors were compared between the patients with and without Asp299Gly allele., Results: The Asp299Gly allele was present in 10.6% of the FH patients and 11.0% of the healthy individuals. Whereas the FH patients carrying the Asp299Gly allele displayed a reduced absolute IMT value compared with the FH patients carrying the wild-type allelle, the difference did not reach statistical significance. In addition, the effect of treatment with HMG-CoA reductase inhibitors was not influenced by the presence of Asp299Gly allele., Conclusion: The presence of the Asp299Gly allele of the TLR4 gene does not seem to exert a major influence on the progression of atherosclerosis in patients with FH.

Objective: To investigate whether high-dose simvastatin therapy could reduce carotid and femoral artery intima-media thickness (IMT) in patients with familial hypercholesterolemia (FH) to prevent cardiovascular disease., Background: Imaging of arterial walls with B-mode ultrasonography is increasingly used as a noninvasive surrogate marker of cardiovascular disease. Intervention trials using this modality have shown that by reducing risk factors, progression of atherosclerosis was inhibited., Methods: After a washout period of 6 weeks, all patients with FH started monotherapy with simvastatin, 80 mg/d, for 2 years. The primary end point was the change (in millimeters) of the mean combined far-wall IMT of predefined carotid and femoral arterial segments at 2 years., Results: We included a total of 153 patients with FH. Mean +/- SD combined baseline IMT was 1.07 +/- 0.23 mm. After treatment with simvastatin for 2 years, this IMT decreased by a mean of 0.081 mm (95% confidence interval, -0.109 to -0.053; P<.001), with its largest reduction in the femoral artery (-0.283 mm; P<.001). An actual decrease of combined IMT was seen in 69.8% of all patients., Conclusions: High-dose simvastatin therapy reduces arterial wall IMT in more than two thirds of the patients, with its largest effect on the femoral artery. Furthermore, patients with FH who were treated with both statin and antihypertensive medication experienced a significantly greater benefit in terms of IMT reduction.

Objective: Recently, polymorphisms in thrombospondin (THBS) genes coding for THBS-1 (N700S), THBS-2 (T>G substitution in 3'-untranslated region), and THBS-4 (A387P) genes were proposed to modulate the risk of premature coronary artery disease (CAD) or myocardial infarction (MI). It was our objective to verify this hypothesis in an independent cohort., Methods and Results: We performed a case-control study among patients (n=503) referred to our institution for symptomatic CAD that occurred before the age of 50 years and a group of age- and sex-matched population-based controls free of CAD (n=1071). The THBS-1 variant allele was not associated with an altered risk of premature CAD or MI. Homozygosity for the THBS-2 variant allele and the THBS-4 variant (387P) allele was significantly associated with a reduced risk of premature MI compared with wild-type individuals (OR=0.44, 0.24 to 0.84 and OR=0.43, 0.22 to 0.85, respectively). The latter observation is in contrast with a previous report, although confidence intervals overlap., Conclusions: We conclude that a relationship between the THBS-1 N700S polymorphism and premature CAD is unlikely. For the THBS-4 A387P polymorphism, additional studies are required to elucidate its role in premature CAD. Finally, we conclude that the THBS-2 polymorphism is associated with a reduced risk of premature MI.

Background: High sensitivity C-reactive protein (hs-CRP) has emerged as the best studied and most promising marker of inflammation in atherosclerotic vascular disease., Materials and Methods: The ASAP (effects of Atorvastatin vs. Simvastatin on Atherosclerosis Progression) study was a 2-year randomised, double-blind trial with 325 familial hypercholesterolemia patients, treated with torvastatin 80 mg or imvastatin 40 mg. Intima media thickness (IMT) of carotid artery segments and hs-CRP levels were determined at baseline, 1 and 2 years., Results: Baseline median hs-CRP values were 2.1 mg/l (interquartile range (IQR) 0.9-5.2) and 2.0 mg/l (IQR 0.8-3.0) and after 2 years these levels decreased to 1.1 mg/l (IQR 0.6-2.4) and 1.5 mg/l (IQR 0.6-3.0) in the atorvastatin 80 mg and simvastatin 40 mg group, respectively. These changes were significant within as well as between the two groups. No correlations were observed between change in hs-CRP after 2 years and change in lipids. A significant correlation was found in univariate analysis between the decrease of hs-CRP and the reduction of IMT., Conclusions: Our results show that atorvastatin 80 mg reduces hs-CRP levels to a greater extent than simvastatin 40 mg. Furthermore, we show that the extent of hs-CRP reduction is associated with the progression rate of the atherosclerotic process as measured by IMT.

Background: Fibric acid derivatives and HMG-CoA reductase inhibitors are effective in combination for treating patients with familial dysbetalipoproteinaemia and severe combined dyslipidaemia, but combination therapy affects compliance and increases the risk of side effects., Aim: To evaluate the efficacy and safety of monotherapy with atorvastatin, an HMG-CoA reductase inhibitor with superior efficacy in lowering low density lipoprotein cholesterol and triglyceride concentrations, in patients with dysbetalipoproteinaemia and severe combined dyslipidaemia., Methods: Atorvastatin was tested as single drug treatment in 36 patients with familial dysbetalipoproteinaemia and 23 patients with severe combined dyslipidaemia., Results: After 40 weeks of 40 mg atorvastatin treatment decreases in total cholesterol, triglycerides, and apolipoprotein B of 40%, 43%, and 41%, respectively, were observed in the combined dyslipidaemia group, and of 46%, 40%, and 43% in the dysbetalipoproteinaemic patients. Target concentrations of total cholesterol (< 5 mmol/l) were reached by 63% of the patients, and target concentrations of triglycerides (< 3.0 mmol/l) by 66%. Treatment with atorvastatin was well tolerated and no serious side effects were reported., Conclusions: Atorvastatin is very effective as monotherapy in the treatment of familial dysbetalipoproteinaemia and severe combined dyslipidaemia.

Background: Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Recently, we and others have identified mutations in the gene coding for the ABCC6 transporter in PXE patients with ocular and skin involvement. In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Given the association between CVD and PXE, we hypothesized that heterozygosity of this ABCC6 mutation could also confer an increased risk for CVD., Methods and Results: To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age- and sex-matched population-based controls who were free of coronary disease. Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; P<0.001). Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, P= 0.001)., Conclusion: The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD.

Background: Use of cholesterol-lowering regimens has been shown to reduce the risk of coronary heart disease (CHD), both in primary and secondary prevention. However, there have been few studies of the relative benefits and risks of the various cholesterol-lowering agents in patient groups with specific risk factors for CHD., Objective: The primary goal of this study was to compare the proportions of adult patients with primary hypercholesterolemia and a moderate to high risk for CHD achieving National Cholesterol Education Program low-density lipoprotein cholesterol (LDL-C) goals with titrate-to-goal regimens of simvastatin and fluvastatin., Methods: This was a multicenter, prospective, randomized, double-blind, parallel-group study enrolling adult patients with type IIa or IIb primary hypercholesterolemia, LDL-C levels <6.0 mmol/L (<232.0 mg/dL), and triglyceride levels <4.5 mmol/L (<398.6 mg/dL), and either CHD or other atherosclerotic disease (the CHD, or high-risk, group), or multiple risk factors for CHD (the MRF, or moderate-risk, group). After a 6-week washout period, patients were randomized to 18 weeks of treatment at an initial dosage of simvastatin 10 mg once daily or fluvastatin 20 mg once daily. At 6- and 12-week titration visits, the dosage in patients who had not acheived the LDL-C goal could be increased to simvastatin 20 mg once daily and then 40 mg once daily, or to fluvastatin 40 mg once daily and then 40 mg twice daily. Lipid profiles were obtained at each titration visit and at the end of treatment. In addition to the comparison between treatments, secondary comparisons were made between the CHD and MRF subgroups within each treatment group. Statistical significance was assessed using analysis of variance., Results: A total of 478 patients were enrolled, 237 in the simvastatin group and 241 in the fluvastatin group. There were no significant between-group differences in patients' characteristics at baseline. At the end of the study, 60.8% (135/222) of patients in the simvastatin group had reached target LDL-C goals, compared with 35.1% (76/216) in the fluvastatin group (P < 0.001). In the simvastatin CHD and MRF subgroups, 49% and 73%, respectively, reached the LDL-C target, compared with 19% and 50% in the corresponding fluvastatin subgroups (P < 0.001). The proportion of patients requiring titration was higher in the fluvastatin group than in the simvastatin group (87.1% and 64.1%, respectively; P = 0.001). The incidence of adverse events was similar between groups., Conclusion: In this study, more patients with primary hypercholesterolemia and CHD or multiple risk factors for CHD reached LDL-C goals with simvastatin treatment and required less titration than those who received fluvastatin treatment.

Objectives: To compare the effects of concentrated n-3 fatty acids (Omacor™) and gemfibrozil in patients with severe hypertriglyceridaemia. The primary objective was to measure the change in serum triglyceride (TG), and the secondary objectives were to study the changes in total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), apolipoproteins and free fatty acids., Patients and Study Design: 89 patients with severe hypertriglyceridaemia (defined as plasma TG >4.5 mmol/L) were randomised to receive in a double-blind fashion either Omacor™, a capsule containing the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at a dosage of 4 g/day, or gemfibrozil 1200 mg/day for 12 weeks., Results: The baseline characteristics of the two randomised groups were similar. Compared with baseline, n-3 fatty acids and gemfibrozil reduced mean TG levels by 28.9 and 51.2%, respectively (p = 0.007). TC was decreased 10.2% with n-3 fatty acids, and 13.0% with gemfibrozil (p = 0.51), and VLDL-C was reduced 11.8 and 19.4% (p = 0.49) with n-3 fatty acids and gemfibrozil, respectively. HDL-C was increased by both compounds; n-3 fatty acids elevated HDL-C by only 1.2%, whereas it was elevated 27.9% by gemfibrozil (p = 0.012)., Conclusions: Our study indicated that both n-3 fatty acids and gemfibrozil markedly decreased TG levels in patients with severe hypertriglyceridaemia. Gemfibrozil, however, decreased TG levels and increased HDL-C significantly more than n-3 fatty acids.

A man aged 35 and a woman aged 30 visited a lipid clinic because of a raised total cholesterol level, which was also present in a number of first-degree relatives. Apart from the lipid abnormalities they had no risk factors for coronary disease. Both proved to have familial hypercholesterolaemia. The man had vague angina pectoris symptoms and a high dose of cholesterol synthesis inhibitors was prescribed. Coronary angiography showed severe stenoses; a coronary balloon angioplasty was successfully performed. The woman, however, died at age 33 suddenly from myocardial infarction. Familial hypercholesterolaemia may cause unexpected cardiovascular complications and sudden death of young persons. Timely diagnosis of the condition on the basis of adequate anamnesis and thorough physical examination, more rapid administration of cholesterol-lowering agents and alertness for anginous complaints may prevent myocardial infarctions and save lives in these patients.

Background: Cranial irradiation for children with brain tumors frequently leads to neuroendocrine deficiencies. In this controlled study, the authors investigated risk factors for cardiovascular disease (CVD) for long term survivors of childhood brain cancer. They also tested whether the presence of these risk factors was related to endocrine status., Methods: In 26 survivors of childhood brain cancer (mean age, 25.8 years; mean posttreatment interval, 16 years) and 29 healthy controls (mean age, 27.7 years), the blood pressure, smoking habits, body mass index (BMI), and waist/hip (W/H) ratio were determined. Lipids and lipoproteins were measured and endocrine function was assessed. Carotid intima-media thickness (IMT) measurements were performed by high resolution ultrasonography., Results: In the survivors of childhood brain cancer, systolic blood pressure and W/H ratio were elevated compared with controls. The cholesterol/high density lipoprotein ratio (4.7 +/- 1.7 vs. 3.4 +/- 0.8 mmol/L, P = 0.0005), low density lipoprotein cholesterol level (3.3 +/- 0.9 vs. 2.8 +/- 0.6 mmol/L, P = 0.027), and apolipoprotein B level (P = 0.001) were higher in survivors of childhood brain cancer, whereas HDL cholesterol was lower (P = 0.005). The IMT was increased in the survivor group, but only in the carotid bulb (0.63 mm +/- 1.6 vs. 0.53 mm +/- 1.1, P = 0.02), not in the internal or common carotid artery. In the absolute growth hormone deficient (GHD) population (n = 9), LDL cholesterol and apolipoprotein B levels were elevated and the W/H ratio was particularly increased compared with the other survivors of childhood brain cancer., Conclusions: For long term survivors of brain cancer, the risk for CVD is strongly increased due to dyslipidemia, central obesity, and elevated systolic blood pressure, particularly for those with GHD. The first effects of this increased risk for CVD were observed in the carotic bulb, as assessed by IMT measurements. Efforts should be directed at CVD prevention by risk factor control.

Mutations in the LDL receptor are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations of the LDL receptor gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL receptor gene mutations in a population represents a prerequisite for the implementation of nation-wide genetic testing for FH. In this study, the frequency and geographical distribution of 13 known mutations were evaluated in a cohort of 1223 FH patients. We identified 358 mutation carriers, representing 29% of the FH cohort. Four mutations (N543H-2393de19, 1359--1G-->A, 313 + 1 G-->A and W23X) occurred with a relatively high frequency, accounting for 22.4% of the entire study cohort. Two of these common FH mutations (N543H-2393de19 and 1359 - 1G-->A) showed a preferential geographic distribution. Second, to further expand the array of LDL receptor gene mutations, we conducted mutation analysis by denaturing gradient gel electrophoresis (DGGE) in 141 children with definite FH. A mutation was identified in 111 patients, involving 16 new single base substitutions and four small deletions and insertions, which brings the number of different FH-causing mutations in our country up to 61. Our data indicate that an estimate of the prevalence of specific mutations, as well as the compilation of a database of all FH-causing mutations in a given country, can facilitate selection of the most appropriate molecular diagnostic approach.

Objective: Hypercholesterolaemia is strongly associated with increased vessel wall thickness as measured by ultrasound. The question is whether aggressive cholesterol lowering with high-dose atorvastatin can alter intima media thickening to a greater extent than conventional therapy in patients with familial hypercholesterolaemia (FH). The baseline characteristics of a double-blind, randomised trial are described to determine whether two active treatments (high-dose atorvastatin 80mg versus conventional dose simvastatin 40mg), administered over a period of 2 years, may retard the process of intima media thickening in the carotid and femoral arteries of patients with FH., Design and Patients: 325 patients with FH were randomised. Patients entered an 8-week placebo period in which all lipid-lowering medication was discontinued. Thereafter, baseline measurements of lipoprotein parameters and intima media thickness (IMT) of carotid and femoral artery were performed., Results: Baseline low density lipoprotein (LDL) cholesterol (±SD) levels were 8.11 ± 1.92 mmol/L (312 ± 73 mg/dl) in men and 8.22 ± 1.91 mmol/L (316 ± 73 mg/dl) in women, respectively. Mean posterior wall IMT in the left common carotid artery (CCA) was significantly greater in men (0.94 ± 0.29mm) compared with women (0.85 ± 0.20) [p < 0.05]. A similar difference was found for the internal carotid artery (ICA). In the carotid bifurcation, IMT was 1.20 ± 0.50mm in men and 1.1 ± 0.54mm in women. The IMT of the common femoral artery (CFA) was 2.03 ± 0.88mm in men with cardiovascular disease (CVD) and 1.63 ± 0.70mm in men without CVD (p < 0.05). Strikingly, plaques were present in all men and 95% of the women with CVD. The cholesterol-year score and HDL cholesterol levels partially explained the variation in IMT in the carotid bifurcation, whereas gender and smoking contributed to the variation in IMT in the CFA in this group of patients., Conclusion: The patients participating in the Atorvastatin and Simvastatin on Atherosclerosis Progression (ASAP) trial constitute the largest well-documented FH population exhibiting marked increases in IMT of both carotid and femoral arteries and a very high prevalence of plaques, indicating extreme CVD risk. Since lipid-lowering therapy provides the highest benefit in precisely such patients, the ASAP trial will help assess whether aggressive LDL cholesterol intervention leads to retardation of subclinical atherosclerosis progression, as estimated with ultrasonographically assessed IMT.

The D9N substitution is a common mutation in the lipoprotein lipase (LPL) gene. This mutation has been associated with reduced levels of HDL cholesterol and elevated triglycerides (TG) in a wide variety of patients. We investigated the influence of this D9N mutation on lipid and lipoprotein levels and risk for cardiovascular disease (CVD) in patients with familial hypercholesterolemia (FH). A total of 2091 FH heterozygotes, all of Dutch extraction, were screened for the D9N mutation using standard polymerase chain reaction techniques, followed by specific enzyme digestion. A total of 94 FH subjects carried the D9N mutation at a carrier frequency of 4.5%. Carriers of other common LPL mutations, such as the N291S and the S447X were excluded. Clinical data on 80 FH individuals carrying the D9N were available and were compared with a FH control group matched for age, sex, and body mass index (n=203). Analysis revealed significantly higher TG (P=0.01) and lower HDL-cholesterol levels (P=0.002). Dyslipidemia was more pronounced in D9N carriers with higher body mass index. Moreover, FH patients carrying this common LPL mutation were at higher risk for CVD, (odds ratio=2.8; 95% CI, 1.43 to 5.32; P=0.002). The common D9N LPL mutation leads to increased TG and decreased HDL plasma levels in patients with FH. These effects are most apparent in those FH heterozygotes with an increased body mass index. Furthermore, this mutation, present in 4.5% of Dutch FH heterozygotes, leads to increased risk for CVD.

It is unknown whether the variation in severity of cardiovascular disease (CVD), seen in patients with familial hypercholesterolemia (FH), is reflected in the intima-media thickness (IMT) of carotid and femoral arteries. We measured IMT in both these arteries in 248 consecutive patients with FH, attending our Lipid Clinic. One hundred and six patients were classified as having CVD, while the remaining FH subjects had no clinical evidence of CVD. IMT measurements of 20 prespecified carotid and femoral arterial wall segments of the FH groups with and without CVD were compared. All IMTs in both groups were severely thickened with respect to normal controls. Furthermore, the highest IMTs and the largest absolute differences were observed in the common femoral artery (1.23 +/- 0.46 mm vs 1.10 +/- 0.51 mm; P = 0.006). In subjects with CVD, the distributions of IMT within tertiles for both arterial segments were opposite to those found in FH patients without CVD, (P < 0.05, for both segments). The mean IMT of, in particular, the common femoral artery is thicker in FH individuals with CVD compared with those without. Some FH patients have abnormal IMT of the femoral artery, whereas in others the carotid artery is more affected. Therefore, in FH patients, combined assessment of the carotid and femoral arterial walls provides a more accurate estimation of total atherosclerotic burden in FH.

A sequence variation in the 3'-untranslated region of the prothrombin (PT) gene (20210 G-->A) was recently claimed to be associated with elevated plasma prothrombin levels and an increased risk for venous and arterial thrombosis. We examined the prevalence of the 20210 A allele in the prothrombin gene in 400 healthy controls and in 263 patients with proven premature atherosclerotic disease. In addition, we measured prothrombin, prothrombin fragment 1 + 2, thrombin-antithrombin (TAT) complex and D-dimer levels in plasma from carrier and non-carrier patients. The frequency of the variant allele was 1% in the control subjects and 2.7% in the patient group, yielding a relative risk (RR) for the 20210 A allele of 2.7 (95% CI 0.8-9.4). All heterozygotes in the patient group were found to have had a myocardial infarction (MI), yielding a RR for MI of 4.2 (95% CI 1.2-14.6). Plasma prothrombin levels in carriers (126+/-10) were higher than in non-carriers (103+/-1, P=0.02). The levels of TAT complexes (16+/-9 v 6+/-1 microg/ml, P=0.02) as well as of prothrombin fragment 1 + 2 (1.5+/-0.3 v 1.0+/-0.1 nmol/l, P=0.02) were also elevated in carriers of the mutation. Our findings suggest that the 20210 G-->A mutation in the prothrombin gene is a genetic risk factor for MI. In addition, our data provide evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease.

The idiopathic hypereosinophilic syndrome (HES) is a leukoproliferative disorder characterized by sustained eosinophilia (> 1.5 x 10(9)/l) and (multi-)organ dysfunction caused by infiltration of eosinophils. Especially the heart is frequently affected. In this report, we describe 2 patients with HES and Löffler's endomyocarditis. Prednisone is the drug of choice for treatment. Both our patients responded very well to prednisone and came into remission. If prednisone fails, there are other therapeutic options like myelosuppressive drugs (hydroxyurea and vincristine) or interferon-alpha. We review the literature with regard to clinical presentation, diagnosis and treatment.

An increased total plasma homocysteine level is an established risk factor for atherosclerotic vascular disease. The plasma level of homocysteine is influenced by both environmental and genetic factors. An important genetic determinant of plasma homocysteine is a common amino acid dimorphism (Ala222Val) in the methylenetetrahydrofolate reductase (MTHFR) gene. Individuals homozygous for the Val allele have significantly higher homocysteine levels than those with an Ala/Val or Ala/Ala genotype. Moreover, the Val/Val genotype has been claimed to be a strong genetic risk factor for atherosclerosis. The aim of the present study is: (1) to determine the risk associated with the MTHFR dimorphism by comparing the genotype distribution in patients with premature atherosclerosis with that in a group of healthy controls; and (2) to investigate the relationship between the MTHFR genotype and parameters of homocysteine metabolism. The patient group consisted of 257 consecutive referred individuals with angiographically proven premature ( <50 years of age) arterial disease (coronary, and/or peripheral vascular disease). A total of 272 healthy hospital workers without a history of vascular disease were selected as a control group. The MTHFR-genotype was determined by PCR and gel-electrophoresis. A methionine-loading test was performed on 245 patients, and, in addition to homocysteine, levels of folate and vitamin B12 were measured. We found a strong correlation between MTHFR genotype and plasma homocysteine levels both before and after methionine loading. In addition, the MTHFR genotype seems important for the inverse relationship between homocysteine and folate and vitamin B12 levels. Lastly, the MTHFR genotype distribution was not different between patient and control groups. MTHFR genotype is a strong determinant of plasma homocysteine levels. Moreover, the plasma level of folate, which by itself influences homocysteine levels, is also dependent on the MTHFR genotype. In Val/Val genotypes, low levels of both folate and B12 lead to a relatively large increase in homocysteine levels. Nevertheless, the MTHFR genotype does not increase the risk for premature coronary artery disease.

It has been proposed that iron accumulation may contribute to atherogenesis by increasing free radical formation and oxidative stress. Epidemiological studies in which the association of iron status with atherosclerosis was assessed raised conflicting results. To test whether genetic haemochromatosis is associated with increased atherosclerosis, we determined the prevalence of two mutations in the HFE gene related to haemochromatosis (845G-->A; Cys282Tyr. and 187 C-->G, His63Asp) in 265 consecutive patients with premature (<50 years of age) angiographically-proven atherosclerotic disease (coronary and/or peripheral), and in 272 healthy controls. PCR amplification followed by RsaI (Cys282Tyr analysis) and BclI (His63Asp analysis) restriction digestion was employed to define the genotypes. The mutant Cys282Tyr allele had a frequency of 0.07 among controls and 0.04 among patients (carrier frequency of 14.0% and 8.3%, respectively). The frequency of the His63Asp mutant allele was 0.14 (28.6% of carriers) in controls and 0.11 (22.2% of carriers) in patients. Five of 265 patients (1.1%) and 9/272 controls (3.3%) were compound heterozygotes. In conclusion, a lower prevalence of the Cys 282Tyr mutation and a similar frequency of the His63Asp mutation was observed in patients with atherosclerotic disease in comparison with normal controls. These findings do not support an association between haemochromatosis and atherogenesis.

Two patients with amiodarone-induced thyrotoxicosis were treated successfully with potassium perchlorate and carbimazole while treatment with amiodarone was continued. These antithyroid drugs were stopped after the patients had became clinically and biochemically euthyroid. During follow up, when treatment with amiodarone continued, thyrotoxicosis did not recur. Amiodarone-induced thyrotoxicosis seems to be a transient condition that can be treated successfully with a short course of antithyroid drugs without stopping amiodarone treatment.

Purpose: To determine the incidence and predictability and to elucidate the pathogenesis of amiodarone-induced thyrotoxicosis (AIT) and hypothyroidism (AIH)., Patients and Methods: A prospective study was performed in 58 consecutive euthyroid patients living in an area with moderately sufficient iodine intake, who had never been treated for thyroid disease and who started amiodarone therapy for the first time., Main Outcome Measures: Development of thyrotoxicosis or hypothyroidism., Results: The follow-up period was 6 to 54 months (mean, 21 months). The incidence of AIT was 12.1%. A steady occurrence of new cases was observed. The development of AIT was unpredictable and of unexplained sudden onset. The incidence of AIH was 6.9%. All AIH cases occurred early in the course of amiodarone therapy. The development of AIH was related to pre-existent thyroid disease: the relative risk for women with microsomal and/or thyroglobulin autoantibodies prior to treatment was 13.5 (95% confidence interval 3.2 to 57.4). The development of AIT or AIH was not related to the extent of iodine overload or to the occurrence of de novo thyroid autoantibodies. When a decreased thyrotropin (TSH) response to thyrotropin-releasing hormone occurred (in the absence of AIT), continuation of amiodarone medication was associated with a normalization of the TSH response in eight of 11 cases (73%); in contrast, an increased TSH response (in the absence of AIH) returned to normal in one of four cases (25%)., Conclusion: In euthyroid subjects living in an area with a moderately sufficient intake of iodine, there is a higher incidence of AIT than of AIH. AIH is an early event, occurring especially in women with thyroid autoantibodies prior to treatment. Cases of AIT continue to occur during amiodarone therapy; its development is unpredictable and of unexplained sudden onset. The value of regular thyroid function testing is therefore limited during amiodarone administration.

Objective: To determine whether long-term amiodarone treatment is associated with a rise in plasma cholesterol, and, if so, to analyze its relation with thyroid function., Design: Consecutive entry trial, including cardiac patients who initiated amiodarone medication but excluding those with abnormal thyroid function (defined as peak thyroid-stimulating hormone [TSH] response to thyrotropin-releasing hormone [TRH] less than 2.8 or greater than 22.0 mU/L) either before or during amiodarone treatment., Patients: Twenty-three patients who remained euthyroid were studied., Intervention: Oral administration of amiodarone (mean duration of treatment, 17 months; range, 6 to 30 months)., Measurements: Fasting plasma lipids, thyroid hormones, and peak TSH to TRH values were recorded before and every 6 months during amiodarone treatment., Results: Plasma cholesterol gradually increased from 5.1 +/- 0.2 mmol/L before treatment to 6.9 +/- 0.8 mmol/L after 30 months of amiodarone medication (P less than 0.001); the peak TSH response to TRH did not change. When age- and sex-specific reference values were applied, 30% of the patients had cholesterol values above the 75th percentile before treatment; this number rose to 69% after 2 years of treatment. The rise in plasma cholesterol was associated with an equal increase in apoprotein B. Plasma cholesterol was not related to the daily dose of amiodarone or to plasma concentrations of amiodarone, desethylamiodarone, thyroxine (T4), triiodothyronine (T3), or reverse triiodothyronine (rT3). Linear regression analysis indicated a positive relation between plasma cholesterol and the cumulative dose of amiodarone (r = 0.25, P less than 0.05)., Conclusion: Long-term amiodarone treatment is associated with a dose-dependent increase in plasma cholesterol that is independent of thyroid function.

We tested the hypothesis that an increase in spontaneous aggregability of platelets in vitro predicts mortality and coronary events in patients who have survived a recent myocardial infarction. A cohort of 149 survivors of infarction entered our study three months after the index infarction and was followed for five years. At entry and at intervals of six months, spontaneous platelet aggregation (SPA) was tested and graded as positive (aggregation within 10 minutes), intermediate (aggregation after 10 to 20 minutes), or negative (no aggregation within 20 minutes). During follow-up, 6.4 percent (6 of 94) of the patients in the SPA-negative group died, as compared with 10.3 percent (3 of 29) in the SPA-intermediate group and 34.6 percent (9 of 26) in the SPA-positive group. As compared with the SPA-negative group, the SPA-intermediate group had a relative risk of death of 1.6 (95 percent confidence interval, 0.5 to 5.5) and the SPA-positive group had a risk of 5.4 (95 percent confidence interval, 2.2 to 13.4). At least one cardiac event (cardiac death or recurrent nonfatal myocardial infarction) occurred in 14.9 percent (14 of 94 patients) of the SPA-negative group, 24.1 percent (7 of 29) of the SPA-intermediate group, and 46.2 percent (12 of 26) of the SPA-positive group. A positive test result continued to have prognostic value throughout the five-year study. We conclude that spontaneous platelet aggregation in vitro is a useful biologic marker for the prediction of coronary events and mortality in this low-risk group of survivors of a myocardial infarction. A causal relation is suggested but not proved by our study.

We measured thyrotropin in plasma by an ultrasensitive immunoradiometric assay (TSH-IRMA, "Sucrosep," Boots-Celltech), before and after thyroliberin (TRH) stimulation, in 71 patients with suspected thyroid-function disorders. Thirty-three were taking amiodarone; none was receiving (anti)thyroid drugs. The patients were divided into four groups, according to their TSH response to TRH (as measured previously by conventional TSH-RIA) and the concentrations of thyroxin (T4) and triiodothyronine (T3) in their plasma. Observed ranges of plasma TSH-IRMA (milli-int. units/L) before and after TRH were: euthyroid (n = 20), 0.2-3.0 and 1.7-15.5; subclinically hypothyroid (n = 14), 4.3-18.5 and 20-75; hyperthyroid (n = 17), less than 0.09 and less than 0.09-0.4; and subclinically hyperthyroid (n = 20), less than 0.09-1.1 and less than 0.09-2.6. Evidently TSH-IRMA results for a single sample completely distinguish hyperthyroidism from euthyroidism. However, TSH-IRMA values may also be undetectable in subclinical hyperthyroidism. The TSH response to TRH can be predicted from basal TSH-IRMA results less than 0.09 or greater than or equal to 0.8 milli-int. unit/L, intermediate values can be associated with either a normal TSH response (euthyroidism) or a decreased TSH response (subclinical hyperthyroidism only). We advocate TSH-IRMA as the first diagnostic test of thyroid function for amiodarone-treated patients.

The effect of ristocetin on the binding of [125I]factor VIII to platelets was studied. High and low affinity F.VIII binding sites exist on platelets. The high affinity sites bind 13 times more F.VIII than the low affinity sites. Ristocetin increased the binding of F.VIII to both types of binding sites by increasing the affinity of F.VIII for the platelet and increasing the total number of platelet binding sites. Chymotrypsin-treated platelets were not aggregated by ristocetin and F.VIII: these platelets have less of the major platelet membrane glycoproteins and bind much less [125I]F.VIII than do buffer-treated platelets with and without ristocetin.

Iodine excess is associated with a low thyroidal radioiodine uptake due to dilution of the radioisotope by the increased stable iodide pool. We studied thyroidal uptake of radioisotopes in cardiac patients with iodine excess due to amiodarone treatment. 99mTc-pertechnetate scintigraphy was performed in 13 patients receiving long term amiodarone therapy. Five patients had a clearly visible thyroid gland, and 8 patients had no or a very faint thyroid image. All patients with positive scans had an increased plasma TSH level, whereas all patients with negative scans had a normal or absent TSH response to TRH. Thyroidal uptake and discharge of 123I were studied in 30 other patients. Group I (n = 11) had normal plasma TSH responses to TRH and no iodine excess, group II (n = 7) had normal TSH responses to TRH and excess iodine from metrizoate angiography in the previous month, group III (n = 7) had normal or decreased TSH responses to TRH while receiving long term amiodarone therapy, and group IV (n = 5) had increased TSH responses to TRH while receiving long term amiodarone therapy. The mean radioiodine uptake value in group I [5.4 +/- 0.8% (+/- SE) at 60 min] was higher than those in group II (2.3 +/- 0.7%; P = 0.009) and group III (0.8 +/- 0.3%; P = 0.0005), but not different from that in group IV (5.3 +/- 1.2%; P = NS). Radioiodine discharge after perchlorate (expressed as a percentage of the 60 min uptake) in group I (10.1 +/- 2.2%) was lower than those in group II (24.9 +/- 10.6%; P = 0.05) and group III (28.8 +/- 5.3%; P less than 0.005), whereas discharge in group IV (58.0 +/- 6.1%) was greater than those in group II (P less than 0.05) and group III (P less than 0.01). In conclusion, 1) thyroid visualization by 99mTc-pertechnetate and thyroid radioiodine uptake during iodine excess are decreased in euthyroid and hyperthyroid patients, but preserved in hypothyroid patients. 2) The organification defect induced by iodine excess is greater in iodide-induced hypothyroidism than in eu- or hyperthyroidism. These findings may be explained by the increased TSH secretion in hypothyroidism and/or by decreased thyroidal concentration of an unknown specific iodinated compound (whose concentration and action vary with the total organic iodine content of the thyroid) that mediates the inhibition of iodide transport.