Hyperlipidemias: Netherlands

Bendermacher BL, Willigendael EM, Teijink JA, Prins MH. · Division of Vascular Surgery, Department of Surgery, Atrium Medical Centre, Heerlen, The Netherlands. · J Thromb Haemost. · Pubmed #16102028 No free full text.

Abstract: Whether symptomatic or not, peripheral arterial disease (PAD), atherosclerosis in the arteries of the lower extremities, is a common disorder in the general population. The prevalence increases with age and under the influence of vascular risk factors. The most classic symptomatic expression of PAD is intermittent claudication. However, the majority of patients with PAD is asymptomatic or has leg symptoms other than classic intermittent claudication. Both symptomatic and asymptomatic subjects with PAD have increased mortality rates, mainly due to cardiovascular and cerebrovascular expressions of atherosclerotic disease. This review focuses on the current available medical therapies for PAD, including risk-factor modification and antiplatelet therapies, as well as strategies for symptomatic relief in both patients with intermittent claudication and patients with critical limb ischemia. In general, risk factor modification and antiplatelet therapy is essential in all patients with PAD to prevent systemic atherosclerotic complications. Furthermore, for symptomatic relief exercise therapy is the main intervention while pharmacological treatment should be only complementary. In patients with critical limb ischemia, when revascularization therapy is not possible, an attempt should be made to avoid amputation with conservative treatment using analgesics, vasodilators and/or anticoagulants. In case of an acute onset of critical limb ischemia, thrombolysis is indicated.

Plat J, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Am J Cardiol. · Pubmed #15992511 No free full text.

Abstract: Incorporation of plant stanol esters into margarine is among the first examples of a functional food with proven low-density lipoprotein (LDL) cholesterol-lowering effectiveness. Recently, there have been many studies on the effects of plant stanols/sterols on cholesterol metabolism. It has been found that the serum LDL cholesterol-lowering effect of plant stanols/sterols originates from reduced intestinal cholesterol absorption, a process in which changes in micellar composition are thought to play a major role. However, recent findings suggest that there is an additional process in which plant stanols/sterols actively influence cellular cholesterol metabolism within intestinal enterocytes. Furthermore, in response to the reduced supply of exogenous cholesterol, receptor-mediated lipoprotein cholesterol uptake is probably enhanced, as shown by increased LDL receptor expression. At recommended intakes of about 2 to 2.5 g/day, products enriched with plant stanol/sterol esters lower plasma LDL cholesterol levels by 10% to 14% without any reported side effects. Thus, plant stanols/sterols can be considered to be effective and safe cholesterol-lowering functional food ingredients.

van Leuven SI, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. · Expert Opin Pharmacother. · Pubmed #15957972 No free full text.

Abstract: The introduction of statins has drastically changed the treatment and prevention of atherosclerotic vascular disease. By lowering lipid levels and reducing the risk of coronary heart disease, these drugs are among the most effective at reducing morbidity and mortality available to clinical practice. In fact, these compounds have demonstrated the reversible nature of the process of atherosclerosis and can be considered the most useful drugs we currently have in our armamentarium in the prevention of atherosclerosis and its clinical sequelae. Atorvastatin provides pronounced lipid lowering in a broad range of individuals with hypercholesterolaemia and, as such, is an appropriate first-line therapy for patients at low to high risk of coronary heart disease. Reductions in total and low-density lipoprotein cholesterol achieved with atorvastatin have been shown to translate into reductions in risk of cardiovascular morbidity and mortality in both primary and secondary prevention settings. Significant clinical benefits have specifically been observed among patients with Type 2 diabetes and in those with acute coronary syndromes. In common with other members of the statin class, atorvastatin is well tolerated, and adverse events are generally mild and transient in nature. Despite the significant clinical benefits provided by atorvastatin, its full potential in the management of atherosclerotic disease has yet to be wholly explored; however, studies currently ongoing will answer many of the outstanding questions.

Wouters K, Shiri-Sverdlov R, van Gorp PJ, van Bilsen M, Hofker MH. · Department of Molecular Genetics, Universiteit Maastricht, The Netherlands. · Clin Chem Lab Med. · Pubmed #15899668 No free full text.

Abstract: Hyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the APOE3Leiden ( APOE3L ) and the APOE2 knock-in ( APOE 2k) mouse models. These models have outstanding potential, as they are highly responsive to dietary factors and pharmacological interventions.

Painter RC, Roseboom TJ, Bleker OP. · Department of Clinical Epidemiology and Biostatistics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Reprod Toxicol. · Pubmed #15893910 No free full text.

Abstract: Low birth weight is associated with cardiovascular disease in adulthood. Poor maternal nutrition during gestation contributes to low birth weight. In this paper, we review the findings from a cohort of 2414 people, aged 50 years, born as term singletons around the time of the 1944-1945 Dutch famine, of which 912 people participated in an interview and 741 subjects were also available for hospital examination. We found more coronary heart disease, raised lipids, altered clotting and more obesity after exposure to famine in early gestation compared to those not exposed to the famine. Exposure in mid gestation was associated with obstructive airways disease and microalbuminuria. We found decreased glucose tolerance in people exposed to famine in late gestation. These findings show that maternal undernutrition during gestation has important effects on health in later life, but that the timing of the nutritional insult determines which organ system is affected. Future research should shed more light upon the underlying pathophysiology of the far-reaching effects of prenatal exposure to famine.

Olijhoek JK, Martens FM, Banga JD, Visseren FL. · Universitair Medisch Centrum Utrecht, afd. Vasculaire Geneeskunde, Heidelberglaan 100, 3584 CX Utrecht. · Ned Tijdschr Geneeskd. · Pubmed #15868989 No free full text.

Abstract: The metabolic syndrome is a cluster of several vascular risk factors (impaired glucose metabolism, dyslipidaemia, hypertension and central adiposity). The prevalence of the metabolic syndrome is high, varying between 10 and 40% depending on age and sex. This prevalence will increase in the years to come due to the increased prevalence of overweight/obesity. To identify the metabolic syndrome, there is a readily applicable definition for daily clinical practice, i.e. the presence of three or more of the following characteristics: hyperglycaemia, hypertension, low plasma HDL cholesterol level, high plasma triglyceride level and central adiposity. The underlying pathophysiology is not fully clarified, but insulin resistance plays an important role in this syndrome. The metabolic syndrome is associated with increased cardiovascular morbidity and mortality and an increased risk for the development of diabetes mellitus type 2. In subjects with one or two components of the metabolic syndrome and in patients with manifest vascular disease, it seems advisable to be alert to the presence of the other components in order to either diagnose or exclude the metabolic syndrome. Although clinical evidence is lacking, from a pathophysiological point of view it seems reasonable to focus the treatment on reducing insulin resistance, which can be achieved by weight reduction and an increase in physical activity. Treatment of the individual risk factors may also be considered, depending on the degree of vascular risk.

Rodenburg J, Vissers MN, Trip MD, Wiegman A, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15861313 No free full text.

Abstract: 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.

van Oostrom AJ, van Wijk J, Cabezas MC. · Departments of Internal Medicine and Endocrinology, University Medical Centre Utrecht, The Netherlands. · Drugs. · Pubmed #15765889 No free full text.

Abstract: Atherosclerosis is the major cause of death in the world. Fasting and postprandial hyperlipidaemia are important risk factors for coronary heart disease (CHD). Recent developments have undoubtedly indicated that inflammation is pathophysiologically closely linked to atherogenesis and its clinical consequences. Inflammatory markers such as C-reactive protein (CRP), leucocyte count and complement component 3 (C3) have been linked to CHD and to hyperlipidaemia and several other CHD risk factors. Increases in these markers may result from activation of endothelial cells (CRP, leucocytes, C3), disturbances in adipose tissue fatty acid metabolism (CRP, C3), or from direct effects of CHD risk factors (leucocytes). It has been shown that lipoproteins, triglycerides, fatty acids and glucose can activate endothelial cells, most probably as a result of the production of reactive oxygen species. Similar mechanisms may also lead to leucocyte activation. Increases in triglycerides, fatty acids and glucose are common disturbances in the metabolic syndrome and are most prominent in the postprandial phase. People are in a postprandial state most of the day, and this phase is proatherogenic. Inhibition of the activation of leucocytes, endothelial cells, or both, is an interesting target for intervention, as activation is obligatory for adherence of leucocytes to the endothelium, thereby initiating atherogenesis. Potential interventions include the use of unsaturated long-chain fatty acids, polyphenols, antioxidants, angiotensin converting enzyme inhibitors and high-dose aspirin, which have direct anti-inflammatory and antiatherogenic effects. Furthermore, peroxisome proliferator activating receptor gamma (PPARgamma) agonists and statins have similar properties, which are in part independent of their lipid-lowering effects.

Sol BG, van der Bijl JJ, Banga JD, Visseren FL. · Department of Vascular Medicine, University Medical Center Utrecht, The Netherlands. · J Vasc Nurs. · Pubmed #15741961 No free full text.

Abstract: In current clinical practice, adequate cardiovascular risk reduction is difficult to achieve. Treatment is primarily focused on clinical vascular disease and not on long-term risk reduction. Pertinent to success in vascular risk reduction are proper medication use, weight control, healthy food choices, smoking cessation, and physical exercise. Atherosclerotic vascular disease and its risk constitute a chronic condition, which poses specific requirements on affected patients and caregivers who should be aware of the chronicity. In patients with vascular disease, there is lack of awareness of their chronic condition because of the invisibility of most risk factors. In other patient groups with chronic illness, self-management programs were successful in achieving behavioral change. This strategy can also be useful for patients with vascular disease to adapt and adhere to an improved lifestyle. Self-management refers to the individual's ability to manage both physical and psychosocial consequences including lifestyle changes inherent to living with a chronic condition. Interventions that promote self-management are based on enhancing self-efficacy. In self-management, attention can be given to what is important and motivational to the individual patient. In this article the challenge of nursing care promoting self-management for patients with vascular risk and how this care can be applied will be explained. Nurses can play a central role in vascular risk management with a self-management approach for patients with chronic vascular disease. In vascular prevention clinics, nursing care can be delivered that includes medical treatment of vascular risks (hypertension, hypercholesterolemia, hyperglycemia, and hyperhomocystinemia) and counseling on promoting self-management (changes in diet, body weight, smoking habits, and level of exercise). Nursing interventions based on self-management promotion can provide a new and promising approach to actually achieve vascular risk reduction.

Hovens MM, Tamsma JT, Beishuizen ED, Huisman MV. · Department of General Internal Medicine, Leiden University Medical Centre, PO Box 9600, Leiden, C01-R, 2300 RC, the Netherlands. · Drugs. · Pubmed #15733008 No free full text.

Abstract: Morbidity and mortality in patients with type 2 diabetes mellitus is largely dominated by the occurrence of cardiovascular disease (CVD). Treatment of known risk factors of CVD has proven to be beneficial in terms of reduction in risk of major CVD events in the general population. Recent trials have provided information on the treatment of hyperglycaemia, hypertension, dyslipidaemia and platelet aggregation in the patient with type 2 diabetes.Strict glycaemic control is not associated with a significant reduction in CVD risk, although new hypoglycaemic agents may offer additional benefits. In contrast, it has been demonstrated that treatment of hypertension and dyslipidaemia significantly reduce cardiovascular risk. Meticulous control of blood pressure to a level < or =130/80 mm Hg, preferably using renin-angiotensin system-modulating agents, is of proven value. Use of HMG-CoA reductase inhibitors (statins) as low-density lipoprotein (LDL)-cholesterol-lowering therapy, initiated at a level of > or =2.60 mmol/L is firmly established. Recent trials lend support to lowering the target level for LDL-cholesterol-lowering therapy to < or =1.81 mmol/L. Mainly based on risk analogy, international guidelines advocate the use of aspirin (acetylsalicylic acid) in the primary prevention of CVD in patients with type 2 diabetes. However, there is no support from large trials that the estimated 25% risk reduction in primary prevention in a high-risk population is the same in the subgroup with diabetes.An intensified approach in order to identify and treat cardiovascular risk factors in patients with type 2 diabetes, stratified to individual patients, is necessary to reduce the excess cardiovascular burden of these patients.

Nierman MC, Rip J, Twisk J, Meulenberg JJ, Kastelein JJ, Stroes ES, Kuivenhoven JA. · Department of Vascular Medicine (G1-113), Academic Medical Centre, University of Amsterdam, The Netherlands. · Neth J Med. · Pubmed #15719847 links to  free full text

Abstract: Lipoprotein lipase (LPL) deficiency is a rare, hereditary disorder of lipoprotein metabolism characterised by severely increased triglyceride levels, and associated with an increased risk for pancreatitis. Since no adequate treatment modality is available for this disorder, we set out to develop an LPL gene therapy protocol. This paper focuses on the clinical presentation of LPL deficiency, summarises the preclinical investigations in animal models and describes the rationale to evaluate gene therapy for this monogenetic disorder of lipid metabolism in humans.

Tushuizen ME, Diamant M, Heine RJ. · Department of Endocrinology/Diabetes Centre, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands. · Postgrad Med J. · Pubmed #15640422 links to  free full text

Abstract: The worldwide prevalence of type 2 diabetes mellitus has reached epidemic proportions. The so-called traditional risk factors cannot fully explain the excessive cardiovascular disease risk of type 2 diabetic patients. Numerous studies indicate that postprandial metabolic derangements, most notably hyperglycaemia and hypertriglyceridaemia, which are exaggerated and prolonged in type 2 diabetes, are important cardiovascular disease risk factors since they induce oxidative stress and endothelial dysfunctions. This review discusses the current evidence showing that postprandial dysmetabolism may indeed constitute an important cardiovascular disease risk factor as well as the mechanisms underlying this association. Finally, some possible therapeutic options and recommendations for future research are discussed.

Smelt AH, de Beer F. · Department of General Internal Medicine, Leiden University Medical Center, Leiden 2300 RC, The Netherlands. · Semin Vasc Med. · Pubmed #15630634 No free full text.

Abstract: In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is familial dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.

de Graaf J, van der Vleuten G, Stalenhoef AF. · Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen, 6500 HB Nijmegen, The Netherlands. · Semin Vasc Med. · Pubmed #15630632 No free full text.

Abstract: Familial combined hyperlipidemia (FCH) is the most common inherited hyperlipidemia in humans, affecting 1 to 3% of the adult population and up to 20% of patients with premature myocardial infarction. FCH is traditionally diagnosed by total plasma cholesterol and/or triglyceride levels above the 90th percentile adjusted for age and gender; however, the diagnosis of FCH based on these diagnostic criteria is inconsistent in 26% of the subjects over a five-year period, emphasizing the need for re-evaluation of the diagnostic criteria for FCH. Recently, a nomogram was developed based on absolute apolipoprotein B levels in combination with triglyceride and total cholesterol levels adjusted for both age and gender to simply and accurately diagnose FCH. When percentiles of triglyceride and total cholesterol adjusted for age and gender are not available in a population, the definition of FCH can be established based on hypertriglyceridemia (> 1.5 mmol/l) and hyperapoB (> 1200 mg/l). Standardized and simple diagnostic criteria are necessary to further delineate the pathogenesis of FCH. Several metabolic pathways have been suggested to be important in causing the FCH phenotype including hepatic VLDL overproduction either with or without impaired clearance of triglyceride-rich lipoproteins from plasma. The presence of insulin resistance and obesity in FCH patients further contribute to the expression of the lipidphenotype. A disturbed adipose tissue metabolism that results in an increased plasma free fatty acid pool may be the culprit in the pathogenesis of FCH.

van der Steeg WA, Kuivenhoven JA, Klerkx AH, Boekholdt SM, Hovingh GK, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #15529021 No free full text.

Abstract: PURPOSE OF REVIEW: This review summarizes novel human data on cholesteryl ester-transfer protein (CETP) and atherosclerosis and the possible use of CETP inhibitors in the treatment of dyslipidemia. In addition, it will underline that therapeutic targeting of the high-density lipoprotein (HDL) metabolism entails more than simply observing changes in cholesterol levels of this lipoprotein. RECENT FINDINGS: Two pharmacological small-molecule inhibitors of CETP, JTT-705 and torcetrapib, have recently been shown to effectively raise HDL cholesterol in humans without serious side effects when either used as a monotherapy or combined with statins that lower low-density lipoprotein cholesterol. Importantly, prospective data from the Epic-Norfolk study furthermore indicate that elevated CETP concentration in conjunction with elevated triglyceride levels are associated with increased odds for cardiovascular events. Data from the Diabetic Atherosclerosis Intervention Study furthermore show that elevated CETP concentration is associated with increased progression of coronary atherosclerosis in patients with type 2 diabetes who use fenofibrate. SUMMARY: Long-term studies will have to show whether CETP inhibition decreases the risk of atherosclerotic disease in dyslipidemic patients. Increased CETP activity might be detrimental under hypertriglyceridemic conditions which is of importance when considering that a large proportion of patients at increased risk from coronary artery disease exhibit elevated triglyceride levels. Studies into the effects of CETP inhibition in hypertriglyceridemic patients therefore seem warranted. Awaiting the first data on the effect of CETP inhibition on surrogate endpoints for atherosclerosis, this review furthermore outlines that the complexity of HDL metabolism will necessitate a wide variety of studies on many aspects of this intriguing lipoprotein.

de Grooth GJ, Klerkx AH, Stroes ES, Stalenhoef AF, Kastelein JJ, Kuivenhoven JA. · Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands. · J Lipid Res. · Pubmed #15342674 links to  free full text

Abstract: Although the atheroprotective role of HDL cholesterol (HDL-c) is well documented, effective therapeutics to selectively increase plasma HDL-c levels are not yet available. Recent progress in unraveling human HDL metabolism has fuelled the development of strategies to decrease the incidence and progression of coronary artery disease (CAD) by raising HDL-c. In this quest for novel drugs, cholesteryl ester transfer protein (CETP) represents a pivotal target. The role of this plasma protein in HDL metabolism is highlighted by the discovery that genetic CETP deficiency is the main cause of high HDL-c levels in Asian populations. The use of CETP inhibitors to effectively increase HDL-c concentration in humans was recently published and data with regard to the effect on human atherosclerosis are expected shortly. This review discusses the potential of CETP inhibitors to protect against atherosclerosis in the context of the current knowledge of CETP function in both rodents and humans.

de Graaf L, Brouwers AH, Diemont WL. · Netherlands Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH 's-Hertogenbosch, The Netherlands. · Br J Clin Pharmacol. · Pubmed #15327593 links to  free full text

Abstract: AIMS AND METHODS: To describe patients with decreased libido during use of a HMG-CoA-reductase-inhibitor, and to discuss causality and pharmacological hypotheses for this association by analysis of the adverse drug reactions (ADR) database of the Netherlands Pharmacovigilance Centre Lareb. RESULTS: Eight patients were identified as having decreased libido during use of statins. In two of these cases testosterone levels were determined and appeared to be decreased. CONCLUSION: Decreased libido is a probable adverse drug reaction of HMG-CoA-reductase-inhibitors and is reversible. The ADR may be caused by low serum testosterone levels, mainly due to intracellular cholesterol depletion.

Vermes A, Vermes I. · Department of Clinical Pharmacy, University Medical Center Rotterdam, Rotterdam, The Netherlands. · Am J Cardiovasc Drugs. · Pubmed #15285699 No free full text.

Abstract: Adverse drug reactions are common; they are responsible for a number of debilitating side effects and are a significant cause of death following drug therapy. It is now clear that a significant proportion of these adverse drug reactions, as well as therapeutic failures, are caused by genetic polymorphism, genetically based interindividual differences in drug absorption, disposition, metabolism, or excretion. HMG-CoA reductase inhibitors are generally very well tolerated and easy to administer with good patient acceptance. There are only two uncommon but potentially serious adverse effects related to HMG-CoA reductase inhibitor therapy: hepatotoxicity and myopathy. The occurrence of lethal rhabdomyolysis in patients treated with cerivastatin has prompted concern on the part of physicians and patients regarding the tolerability of HMG-CoA reductase inhibitors. Apart from pravastatin and rosuvastatin, HMG-CoA reductase inhibitors are metabolized by the phase I cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The best-characterized pharmacogenetic polymorphisms are those within this enzyme family. One of these enzymes, CYP2D6, plays an important role in the metabolism of simvastatin. It has been shown that the cholesterol-lowering effect as well as the efficacy and tolerability of simvastatin is influenced by CYP2D6 genetic polymorphism. Because the different HMG-CoA reductase inhibitors differ, with respect to the degree of metabolism by the different CYP enzymes, genotyping may help to select the appropriate HMG-CoA reductase inhibitor and the optimal dosage during the start of the treatment and will allow for more efficient individual therapy. A detailed knowledge of the genetic basis of individual drug response is potentially of major clinical and economic importance.

Rodenburg J, Vissers MN, Wiegman A, Trip MD, Bakker HD, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands. · Curr Opin Lipidol. · Pubmed #15243213 No free full text.

Abstract: PURPOSE OF THIS REVIEW: This review provides an update on recent advances in the diagnosis and management of children with familial hypercholesterolemia. RECENT FINDINGS: A large cross-sectional cohort study of paediatric familial hypercholesterolemia demonstrated that affected children had a 5-fold more rapid increase of carotid arterial wall intima-media thickness during childhood years than their affected siblings. This faster progression led to a significant deviation in terms of intima-media thickness from the age of 12 years and onwards. Low-density lipoprotein cholesterol was a strong and independent predictor of carotid artery intima-media thickness in these children, which confirms the pivotal role of low-density lipoprotein cholesterol for the development of atherosclerosis. In this condition lipid lowering by statin therapy is accompanied by carotid intima-media thickness regression in familial-hypercholesterolemic children, which suggests that initiation of low-density lipoprotein cholesterol-reducing medication in childhood already can inhibit or possibly reduce the faster progression of atherosclerosis. Furthermore, these trials demonstrated that statins are safe and do not impair growth or sexual development in these children. Conversely, products containing plant sterols reduced low-density lipoprotein cholesterol levels by 14%, but did not improve endothelial dysfunction as assessed by flow-mediated dilatation. SUMMARY: Children with familial hypercholesterolemia clearly benefit from lipid-lowering strategies. Statins are safe agents and have been proven to reduce elevated low-density lipoprotein cholesterol levels significantly. In addition, statins improve surrogate markers for atherosclerosis. Therefore these agents should become the pivotal therapy in children with familial hypercholesterolemia.

Defesche JC, Lansberg PJ, Umans-Eckenhausen MA, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15199434 No free full text.

Abstract: Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western society and predisposes for premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated. Maximum health benefit can be obtained in FH if treatment is started as early as possible, as the World Health Organization has recently recommended. In 1994 we initiated an active case-finding program for individuals with FH, based on family investigation and DNA-testing. In an initial pilot study we established that active family screening supported by DNA diagnostics resulted in the identification of substantial numbers of FH heterozygotes and determined that diagnosis by DNA analysis was superior to conventional cholesterol measurement. Since its initiation, the program has led to the identification of more than 6000 individuals with FH, of whom the greatest part was not adequately treated at the time of identification. Our findings indicate not only that this case-finding approach is effective in identifying FH patients who otherwise would not have been identified but also that the vast majority of these patients seek treatment and are successfully started on cholesterol-lowering therapy to reduce their risk of premature cardiovascular disease. Here we describe an effective model to identify and bring under treatment large numbers of individuals affected by FH.

van Aalst-Cohen ES, Jansen AC, de Jongh S, de Sauvage Nolting PR, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Semin Vasc Med. · Pubmed #15199431 No free full text.

Abstract: Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.

Demacker PN. · Laboratory of General Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands. · Semin Vasc Med. · Pubmed #15199429 No free full text.

Abstract: Laboratory-based coronary heart disease risk assessment classically involves measurement of lipids and lipoproteins. In this review, information is provided on the methods commonly used in laboratories for the diagnosis of hyperlipidemia, including aspects of precision and accuracy. The latter, when fulfilled, allows the use of uniform reference values. Special attention is paid to the risk estimation using apolipoprotein B and lipoprotein(a) measurement. The overall aim of this review is to simplify the laboratory-based risk estimation for coronary heart disease and to provide help in interpreting the results for effective prevention and treatment of this complex disease.

de Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Circulation. · Pubmed #15198964 links to  free full text

Abstract: Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls.

van Dijk KW, Rensen PC, Voshol PJ, Havekes LM. · Department of Human Genetics, Leiden University Medical Center, PO Box 9503, 2000 RA Leiden, The Netherlands. · Curr Opin Lipidol. · Pubmed #15166778 No free full text.

Abstract: PURPOSE OF REVIEW: Apolipoprotein (apo)CIII and apoAV play an important role in triglyceride metabolism as evidenced by the unambiguous and opposing phenotypes of transgenic and knockout mouse models. In this review we discuss studies on the genetics, protein structure, and regulation of apoCIII and apoAV and compare their potential molecular mechanisms of action in triglyceride metabolism. We examine the hypothesis that apoCIII and apoAV synergistically affect triglyceride metabolism. RECENT FINDINGS: It has now been firmly established that variation in plasma triglyceride levels in a wide range of human populations is strongly associated with genetic variation at the chromosomal locus encoding both the APOC3 and APOA5 genes, the APOA1/C3/A4/A5 gene cluster. The close physical linkage of these genes and the frequent concurrence of genetic variants, however, complicate the assignment of specific metabolic defects to specific polymorphisms. Recent insight into the regulation of APOC3 and APOA5 gene expression and structural modeling studies on the apoAV protein have provided novel clues for the potential molecular mechanisms responsible for the effects of apoCIII and apoAV on triglyceride metabolism. SUMMARY: Hypertriglyceridemia is a major independent risk factor in the development of cardiovascular disease. Moreover, triglyceride-derived fatty acids are thought to play a key role in the development and progression of the metabolic syndrome. As modulators of triglyceride metabolism, apoCIII and apoAV are key players and potential therapeutic targets. However, little is known of their molecular mechanism and potential cooperativity. Rational therapeutic application will require the filling of this hiatus in our knowledge.

Dippel DW, van der Worp HB. · Erasmus Medisch Centrum, afd. Neurologie, Postbus 1738, 3000 DR Rotterdam. · Ned Tijdschr Geneeskd. · Pubmed #15141647 No free full text.

Abstract: In patients who have recently had a TIA or stroke, the risk of new serious cardiovascular disease is decreased by the pharmacological reduction of the serum cholesterol level and blood pressure; this has been convincingly demonstrated by randomised clinical trials. There is sufficient evidence that cholesterol-lowering treatment is effective in patients with a TIA or cerebral infarction who have a total cholesterol > or = 3.5 mmol/l. The results from a trial in patients with only a TIA or a minor stroke will have to answer the question whether cholesterol-lowering treatment will be effective in patients > 80 years, and whether higher dosages of simvastatin will be more effective in these patients. Antihypertensive therapy is effective in preventing recurrent stroke and myocardial infarction in patients with a recent stroke or TIA. It is obvious that the treatment should be started with a diuretic and that a second agent should be added if necessary. On epidemiological grounds, vigorous treatment is also justified in patients with a normal or mildly elevated blood pressure; caution and a custom-tailored approach are essential, however, in each individual patient.