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Screening for early-stage asymptomatic cancers (eg, cancers of breast and colon) to prevent late-stage malignancies has been widely accepted. However, although atherosclerotic cardiovascular disease (eg, heart attack and stroke) accounts for more death and disability than all cancers combined, there are no national screening guidelines for asymptomatic (subclinical) atherosclerosis, and there is no government- or healthcare-sponsored reimbursement for atherosclerosis screening. Part I and Part II of this consensus statement elaborated on new discoveries in the field of atherosclerosis that led to the concept of the "vulnerable patient." These landmark discoveries, along with new diagnostic and therapeutic options, have set the stage for the next step: translation of this knowledge into a new practice of preventive cardiology. The identification and treatment of the vulnerable patient are the focuses of this consensus statement. In this report, the Screening for Heart Attack Prevention and Education (SHAPE) Task Force presents a new practice guideline for cardiovascular screening in the asymptomatic at-risk population. In summary, the SHAPE Guideline calls for noninvasive screening of all asymptomatic men 45-75 years of age and asymptomatic women 55-75 years of age (except those defined as very low risk) to detect and treat those with subclinical atherosclerosis. A variety of screening tests are available, and the cost-effectiveness of their use in a comprehensive strategy must be validated. Some of these screening tests, such as measurement of coronary artery calcification by computed tomography scanning and carotid artery intima-media thickness and plaque by ultrasonography, have been available longer than others and are capable of providing direct evidence for the presence and extent of atherosclerosis. Both of these imaging methods provide prognostic information of proven value regarding the future risk of heart attack and stroke. Careful and responsible implementation of these tests as part of a comprehensive risk assessment and reduction approach is warranted and outlined by this report. Other tests for the detection of atherosclerosis and abnormal arterial structure and function, such as magnetic resonance imaging of the great arteries, studies of small and large artery stiffness, and assessment of systemic endothelial dysfunction, are emerging and must be further validated. The screening results (severity of subclinical arterial disease) combined with risk factor assessment are used for risk stratification to identify the vulnerable patient and initiate appropriate therapy. The higher the risk, the more vulnerable an individual is to a near-term adverse event. Because10% of the population who test positive for atherosclerosis will experience a near-term event, additional risk stratification based on reliable markers of disease activity is needed and is expected to further focus the search for the vulnerable patient in the future. All individuals with asymptomatic atherosclerosis should be counseled and treated to prevent progression to overt clinical disease. The aggressiveness of the treatment should be proportional to the level of risk. Individuals with no evidence of subclinical disease may be reassured of the low risk of a future near-term event, yet encouraged to adhere to a healthy lifestyle and maintain appropriate risk factor levels. Early heart attack care education is urged for all individuals with a positive test for atherosclerosis. The SHAPE Task Force reinforces existing guidelines for the screening and treatment of risk factors in younger populations. Cardiovascular healthcare professionals and policymakers are urged to adopt the SHAPE proposal and its attendant cost-effectiveness as a new strategy to contain the epidemic of atherosclerotic cardiovascular disease and the rising cost of therapies associated with this epidemic.

Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease.To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI.Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449).Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P.001). Serious myopathy and rhabdomyolysis were rare in both groups.In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.Trial Registration ClinicalTrials.gov Identifier: NCT00159835.

Summary Background The effects of cholesterol-lowering treatment with statins on mortality and risk of cancer beyond the usual 5–6-year trial periods are unknown. We extended post-trial follow-up of participants in the Scandinavian Simvastatin Survival Study (4S) to investigate cause-specific mortality and incidence of cancer 5 years after closure of the trial. Methods 4S was a randomised double-blind trial of simvastatin or placebo in patients with coronary heart disease, serum total cholesterol 5·5–8·0 mmol/L, and serum triglycerides 2·5 mmol/L or lower. The double-blind period lasted for a median of 5·4 years (range for survivors 4·9–6·3) and ended in 1994. After the trial, most patients in both groups received open-label lipid-lowering treatment. National registers were used to assess mortality and causes of death and cancer incidence in the original treatment groups for a median total follow-up time of 10·4 years (range for survivors 9·9–11·3). Analysis was by intention to treat. Findings 414 patients originally allocated simvastatin and 468 assigned placebo died during the 10·4-year follow-up (relative risk 0·85 [95% CI 0·74–0·97], p=0·02), a difference largely attributable to lower coronary mortality in the simvastatin group (238 vs 300 deaths; 0·76 [0·64–0.90], p=0·0018). 85 cancer deaths arose in the simvastatin group versus 100 in the placebo group (0·81 [0·60–1·08], p=0·14), and 227 incident cancers were reported in the simvastin group versus 248 in the placebo group (0·88 [0·73–1·05], p=0·15). Incidence of any specific type of cancer did not rise in the simvastatin group. Interpretation Simvastatin treatment for 5 years in a placebo-controlled trial, followed by open-label statin therapy, was associated with survival benefit over 10 years of follow-up compared with open-label statin therapy for the past 5 years only. No difference was noted in mortality from and incidence of cancer between the original simvastatin group and placebo group.

The genes encoding the LDL receptor and apoB were screened for mutations associated with familial hypercholesterolemia (FH) in 408 patients referred to the Lipid Clinic in 1995–2003. The study aimed at testing the ability of three different sets of clinical criteria to predict the results of molecular genetic analysis, and secondly test whether population-based age- and sex-specific percentiles of LDL-cholesterol offer useful supplemental information in the selection of patients for molecular genetic analysis. The patients were retrospectively categorised according to Simon Broome Register Group criteria, Make Early Diagnosis to Prevent Early Death criteria (MEDPED) and the Dutch Lipid Clinic Network criteria, and the distribution of patients was compared to the results of the molecular genetic analysis. The study illustrates a classical dilemma. Mutation detection rates (and specificities) are high only if sensitivity is very low and vice versa: to find most mutation carriers, even patients with only possible FH must be examined by molecular genetic testing leading to mutation detection rates as low as 30–40%.

Aims Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. Methods and results A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2–3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. Conclusions Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.

Patients with homozygous familial hypercholesterolaemia (FH) caused by receptor-negative, low-density lipoprotein (LDL) receptor gene mutations have higher concentrations of LDL-cholesterol in plasma and earlier onset of cardiovascular disease (CVD) than patients homozygous for receptor-defective, LDL receptor mutations. In contrast, it is uncertain whether the severity of atherosclerotic disease differs in heterozygous FH caused by receptor-negative and receptor-defective mutations. The present authors investigated the influence of LDL receptor mutation type on the clinical phenotype in 31 patients with heterozygous FH caused by the receptor-negative, Trp23-stop mutation and in 31 patients heterozygous for the receptor defective Trp66-Gly mutation. Untreated levels of plasma LDL-cholesterol and calculated cholesterol-years score did not differ significantly between the two groups of patients. Detection of vascular disease was based on two approaches: (1) measurement of coronary calcification by spiral computed tomography (CT) scanning; and (2) ultrasonic measurement of carotid intima-media thickness (IMT). Age was significantly correlated to the presence of coronary calcification, but controlling for relevant cofactors, there was no evidence that the receptor-negative mutation caused more calcification than the receptor-defective mutation. Furthermore, carotid IMT was significantly influenced by plasma concentrations of Lp(a) and triglycerides, as well as by age, sex and smoking status, but again, there was no statistically significant effect of LDL receptor gene mutational type. The similarity in vascular phenotypes was probably caused by a similar life-long burden of LDL-cholesterol in the two groups of patients.

An electronic search shows that there is a small but respectable amount of research on psychiatric and neurologic nosology. There is a also a small body of literature on endocrinologic nosology, but cardiologists almost never write about the nosology of heart disease. It does not keep them awake at night. Our understanding of the 20th-century epidemic of coronary artery disease (CAD), which dominates cardiology, has nevertheless been frustrated by problems of nosology. One of the purposes of this article is to discuss how our understanding of the epidemic has depended on classification of disease events and on the methods used to detect them. The other purpose is to show how current reclassifications of CAD and the major metabolic condition conducive to CAD, type 2 diabetes, each affect the practice of cardiology and medicine.

Background —Carriers of the ε4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes. Methods and Results —Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 ε4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in ε4 carriers and to 0.66 (95% confidence interval, 0.35 to 1.24) in other patients ( P =0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with ε4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment. Conclusions —Myocardial infarction survivors with the ε4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.

To test the effects of fluvastatin on low-density lipoprotein (LDL) receptor activity in patients with heterozygous familial hypercholesterolemia, the authors measured LDL receptor activity in stimulated T-lymphocytes prepared from 34 patients before and after treatment with 40 mg fluvastatin daily for 12 weeks. Maximally induced pretreatment LDL receptor activities did not correlate with pretreatment plasma cholesterol levels or with changes in plasma cholesterol levels during treatment, and there were no significant changes in LDL receptor activity during treatment. Barring methodological problems, two explanations are possible. Insofar that LDL receptor activity in lymphocytes reflects LDL receptor activity in the liver, the results suggest that the primary response to treatment with fluvastatin in heterozygous familial hypercholesterolemia (FH) patients is not enhanced LDL receptor activity. Alternatively, fluvastatin increases LDL receptor activity in hepatocytes but has little effect on receptor-dependent lipoprotein catabolism in extrahepatic tissues in vivo.

Heterozygous familial hypercholesterolemia (FH) is one of the most common potentially fatal single-gene diseases leading to premature coronary artery disease, but the majority of heterozygous FH patients have not been diagnosed. FH is due to mutations in the gene coding for the low-density lipoprotein (LDL) receptor, and molecular genetic diagnosis may facilitate identification of more FH subjects. The Danish spectrum of 29 different mutations, five of which account for almost half of heterozygous FH, is intermediate between that of countries such as South Africa, where three mutations cause 95% of heterozygous FH in the Afrikaners, and Germany or England, where there are many more mutations. In clinical practice, a strategy for the genetic diagnosis of heterozygous FH, tailored to the mutational spectrum of patients likely to be seen at the particular hospital/region of the country, will be more efficient than screening of the whole LDL receptor gene by techniques such as single-strand conformation polymorphism (SSCP) analysis in every heterozygous FH candidate. In Aarhus, Denmark, we have chosen to examine all heterozygous FH candidates for the five most common LDL receptor gene mutations (W23X, W66G, W556S, 313+1G→A, 1846−1G→A) and the apoB-3500 mutation by rapid restriction fragment analysis. Negative samples are examined for other mutations by SSCP analysis followed by DNA sequencing of the exon indicated by SSCP to contain a mutation. If no point mutation or small insertion/deletion is detected, Southern blot or Long PCR analysis is performed to look for the presence of large gene rearrangements. In conclusion, our data suggest that an efficient molecular diagnostic strategy depends on the composition of common and rare mutations in a population.

Agreement between the European societies of atherosclerosis, cardiology, and hypertension on how to prevent coronary heart disease in clinical practice resulted in recommendations published in 1994. They were recently revised as a result of new evidence, particularly from clinical trials, of lowering of serum cholesterol.1Underlying the concept of joint European recommendations has been the explicitly stated premise that they should be adapted to national conditions and resources. With remarkable alacrity this has now been accomplished in the UK with the publication of recommendations from the British Cardiac Society, the British Hyperlipidaemia Association, and the British Hypertension Society (endorsed by the British Diabetic Association).2 As indicated in the title, the joint British recommendations on prevention of coronary heart disease in clinical practice closely mirror the European guidelines. One example is the simple recommendation that total cholesterol

EDITOR—Last year Jackson reported on five men who developed impotence with profound lethargy and inertia after starting treatment with or increasing the dose of simvastatin. This resolved after treatment was discontinued.1 The author also cited reports of impotence with this drug from Australia. View this table: Number of men in the Scandinavian simvastatin survival study spontaneously reporting temporary or permanent impotence or sexual dysfunction (placebo 1803, simvastatin 1814) …

What should be the role of genetic testing in cardiovascular medicine? If we adopt genetic testing on a broad scale, moreover, should we also base diagnosis of disease on molecular genetic rather than clinical criteria whenever molecular genetic analysis is possible? These two questions arise from reading the report in this issue of the EHJ by van Aalst-Cohen et al . on familial hypercholesterolaemia (FH).1 The Dutch group of researchers is experienced in studying FH, which in many countries was the first cardiovascular disease for which genetic testing was implemented as part of a screening program. By screening relatives of an index patient for the particular mutation in the index patient known or thought to be responsible for the clinical picture of FH, the Dutch group has identified a large number of FH patients (2818 index cases and 7079 relatives with a mutation in either the LDL receptor gene or the apoB gene).2 They have also shown that participation in such a screening program (cascade genetic testing) importantly raises the number of patients on cholesterol-lowering treatment,3 and researchers in the UK have shown that cascade genetic testing is more cost-effective than screening of the general population.4 There is little doubt, therefore, that genetic testing is valuable when a mutation can be demonstrated in the index patient. The tricky issue is nosological, i.e. the use of molecular genetic analysis for the purpose of defining disease. For the report published in the current issue … *Corresponding author. Tel: +45 86 97 90 67; Telefax: +45 89 49 76 49. E-mail address : dorte.damgaard{at}dadlnet.dk

In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation ,aGt o Ctransition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH. © 1997 Elsevier Science Ireland Ltd.

Abstract A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B-100 (FDB). In 205 FDB patients from Germany (n=73), the Netherlands (n=87), and Denmark (n=45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene ( Sfa NI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women ( Sfa NI: P =.04 and .03 for TC and LDL-C, respectively; Nco I: P =.003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S+A+N+ allele had 13% to 20% higher TC than non-S+A+N+ subjects ( P =.02 [TC, men]; P =.01 [LDL-C, men]; P =.005 [TC, women]; and P =.004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e 3 e 2 , e 3 e 3 , and e 3 e 4 ) with cholesterol concentrations was seen in S+A+N+ but not in non-S+A+N+ subjects and in P−P− but not in P+P+ or P+P− subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.

References 1 Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004;328:1519. 2 Belanger C, Speizer FE, Hennekens CH, Rosner B, Willett W, Bain C. The nurses’ health study: current findings. Am J Nurs 1980;80:1333. 3 Keys A, Aravanis C, Blackburn HW et al. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand Suppl 1966;460:1–392. 4 Mariotti S, Capocaccia R, Farchi G, Menotti A, Verdecchia A, Keys A. Differences in the incidence rate of coronary heart disease between north and south European cohorts of the Seven Countries Study as partially explained by risk factors. Eur Heart J 1982;3:481–87. 5 Rose G. Incubation period of coronary heart disease. Br Med J (Clin Res Ed) 1982;284:1600–1. (Reprinted Int J Epidemiol 2005;34:242–44.) 6 Ross SD, Allen IE, Connelly JE et al. Clinical outcomes in statin treatment trials: a meta-analysis. Arch Intern Med 1999;159: 1793–1802. 7 Vartiainen E, Puska P, Pekkanen J, Tuomilehto J, Jousilahti P. Changes in risk factors explain changes in mortality from ischaemic heart disease in Finland. BMJ 1994;309:23–27. 8 Rose G. Sick individuals and sick populations. Int J Epidemiol 2001;30:427–32. 9 Tuomilehto J, Kuulasmaa K. WHO MONICA Project: assessing CHD mortality and morbidity. Int J Epidemiol 1989;18:S38–S45. 10 The INTERSALT Co-operative Research Group. Sodium, potassium, body mass, alcohol and blood pressure: the INTERSALT Study. J Hypertens Suppl 1988;6:S584–S586. 11 Ounpuu S, Negassa, A,Yusuf S. INTER-HEART: a global study of risk factors for acute myocardial infarction. Am Heart J 2001;141:711–21. 246 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

El informe del Bellagio sobre agricultura saludable, nutrición saludable, población saludable es el resultado de la reunión mantenida en el Centro Bellagio de la Fundación Rockefeller en el Lago de Como en Italia, entre el 29 de octubre y el 2 de noviembre de 2012. La reunión basada en la ciencia, fue orientada hacia la política. Se discutió extensamente el papel y la cantidad de grasas saludables y perjudiciales, con atención al contenido relativo de los ácidos grasos omega-3 y omega-6, el azúcar, y particularmente la fructosa en los alimentos que pueden conllevar la epidemia de enfermedades no transmisibles (EnT) a través del mundo. El informe concluye que el consumo del azúcar, especialmente en forma de fructosa de alta energía utiizada en bebidas refrescantes, posee una amenaza muy importante de la salud, especialmente en niños, y la mayoría de las dietas, aunque con diferencias regionales, son deficientes en ácidos grasos omega-3 y demasiado altas en ácidos grasos omega-6. Las interacciones gen-nutriente en el crecimiento y desarrollo y en la prevención de la enfermedad son fundamentales para la salud, por lo que deberían establecerse a través de todo el mundo Centros regionales de Genética, Nutrición y Condición Física para la Salud. Los jefes de estado y gobierno deben priorizar dentro de sus nacionales de forma urgente la Nutrición, cuyo acceso a una dieta saludable debería considerarse un derecho humano y dirigir la responsabilidad para que la Nutrición tenga un lugar en los Ministerios de Salud, más que la agricultura de modo que los requerimientos de salud conduzcan a prioridades agrícolas, y no viceversa. La seguridad nutricional debería ser considerada como prioridad como lo es la seguridad alimentaria. The Bellagio report on healthy agriculture, healthy nutrition, healthy people is the result of the meeting held at the Rockefeller Foundation Bellagio Center in Lake Como, Italy, 29 october-2 november 2012. The meeting was science-based but policy-oriented. The role and amount of healthy and unhealthy fats, with attention to the relative content of omega-3 and omega-6 fatty acids, sugar, and particularly fructose in foods that may underlie the epidemics of non-communicable diseases (NCD's) worldwide were extensively discussed. The report concludes that sugar consumption, especially in the form of high energy fructose in soft drinks, poses a major and insidious health threat, especially in children, and most diets, although with regional differences, are deficient in omega-3 fatty acids and too high in omega-6 fatty acids. Gene-nutrient interactions in growth and development and in disease prevention are fundamental to health, therefore regional Centers on Genetics, Nutrition and Fitness for Health should be established worldwide. Heads of state and government must elevate, as a matter of urgency, Nutrition as a national priority, that access to a healthy diet should be considered a human right and that the lead responsibility for Nutrition should be placed in Ministries of Health rather than agriculture so that the health requirements drive agricultural priorities, not vice versa. Nutritional security should be given the same priority as food security.

Polymorphisms in the genes for the low-density lipoprotein (LDL) receptor ligands, apolipoprotein E (apoE), and apolipoprotein B (apoB) are associated with variation in plasma levels of LDL cholesterol. Lp(a) lipoprotein(a) [Lp(a)] is LDL in which apoB is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined isoforms differing in molecular weight, which are inversely correlated with Lp(a) concentrations in blood. The interaction of apo(a) with triglyceride-rich lipoproteins differs with the size of apo(a), and therefore the effects of apoE gene polymorphism on Lp(a) levels could also depend on apo(a) size. We have investigated the possible effect of genetic variation in the apoE and apoB genes on plasma Lp(a) concentrations in 466 white men with different apo(a) phenotypes. Overall there was no significant association between the common apoE polymorphism and Lp(a), but in the subgroup with apo(a)-S4, concentrations of Lp(a) differed significantly among the apoE genotypes (P = 0.05). Lp(a) was highest in the apoE genotypes epsilon 2 epsilon 3 and epsilon 3 epsilon 3 and lowest in genotype epsilon 3 epsilon 4, and the apoE polymorphism was estimated to account for about 2.4% of the variation in Lp(a). In contrast, in the subgroup with apo(a)-S2 Lp(a) was significantly lower (P = 0.04) in apoE genotype epsilon 2 epsilon 3 than in genotype epsilon 3 epsilon 3. Lp(a) concentrations did not differ among the XbaI (P = 0.65) or SP 24/27 (P = 0.26) polymorphisms of the apoB gene. The expected effects of both apoE and apoB polymorphism on LDL levels were significant in the whole population sample and in subjects with large-sized apo(a) isoforms (P0.01), whereas no effect was seen in those with low molecular weight apo(a) isoforms. We conclude that the influence of apoE genotypes on Lp(a) concentrations depends on the size of the apo(a) molecule in Lp(a), possibly because both apo(a)-S4 and apoE4 have high affinity for triglyceride-rich lipoproteins and may be taken up and degraded rapidly by remnant receptors.

A plethora of different mutations in the gene for the low density receptor (LDLR) are responsible for the autosomal dominant inherited disorder familial hypercholesterolemia (FH). However, only a few splice site mutations have been identified in this gene. We here report a defect presumably affecting the splicing of precursor mRNA, resulting from a novel mutation, a G to A transition at the terminal nucleotide of intron 12, of the LDLR gene detected in three unrelated families with heterozygous FH. This mutation markedly reduced the steady-state transcript level of the mutant LDLR allele as compared to the corresponding normal LDLR allele in heterozygous FH patients as measured by a fluorescence based, allele-specific quantitation technique. In the FH families, the acceptor splice site mutation cosegregates with hypercholesterolemia, and it is associated with onset of ischemic heart disease in the fifth and sixth decade of life.

Mutations in the gene for the low density lipoprotein (LDL) receptor cause the autosomal dominant disease familial hypercholesterolemia (FH), the prevalence of which is about 0.2% in most populations. By PCR-SSCP analysis and direct sequencing, we identified the receptor-negative Trp 23 -Stop LDL receptor mutation (FH Cincinnati-5) in 10 of 63 FH probands and the receptor-defective Trp 66 -Gly LDL receptor mutation (FH French Canadian-4) in another 10 of the 63 FH probands. These two mutations thus account for 30% of diagnosed FH families in Denmark. Comparison of the mean lipid concentrations (unadjusted and adjusted for age), including serum total cholesterol and LDL-cholesterol, showed no significant differences between the two groups of FH heterozygote probands (cholesterol: 10.7 mmol/l vs. 10.7 mmol/l) and between the probands and 16 and 22 non-proband family members with the Trp 23 -stop (cholesterol: 10.1 mmol/l) and Trp 66 -Gly (cholesterol: 10.7 mmol/l) mutations, respectively.

Long-term treatment of survivors of an acute myocardial infarction with angiotensin-converting enzyme inhibitors has a beneficial impact on their long-term outcome. We tested the hypothesis that captopril could reductively cleave the lipoprotein(a) molecule and in addition act as a scavenger of oxygen free radicals. In a double-blind trial, 20 patients were randomized to receive either captopril 50 mg daily or corresponding placebo. patients were followed for a period of 30 days. Blood samples were drawn prior to randomization and after 30 days of treatment. Plasma concentrations of lipoprotein(a) and malondialdehyde were evaluated. Captopril treatment produced a significant reduction in plasma content of lipoprotein(a) (0.05) and at day 30 the plasma content of lipoprotein(a) was also significantly lower than that in the placebo group (p0.05). furthermore, on day 30 plasma concentrations of malondialdehyde, an indicator of oxidative damage, were significantly lower in the captopril group when compared to baseline values and corresponding placebo group values (p0.05). The observed effect of captopril treatment on lipoprotein(a) and malondialdehyde might be ascribed to the sulfhydryl group in the captopril molecule.

New opportunities are emerging for preventing the consequences of serious diseases because of the discovery of causal mutations in specific gene loci. MED PED is an international collaboration to Make Early Diagnoses and Prevent Early Deaths in MEDical PEDigres.

Eskimos of the east coast of Greenland very rarely had contacts with Caucasians until late in the 19th century. Their genes are therefore likely to be similar to those in the original Eskimo gene pool. We have compared serum concentrations of Lp(a) and apo(a) phenotypes in 78 East Greenland Eskimos (EGE) with those in Eskimos from Western Greenland (WGE) (n=100) and Caucasian Danes (n=466). Lp(a) levels were higher in EGE (median: 11.9 mg/dl [95% CI: 9.1–16.4]) than in Danes (p

Background In some previous studies, Hin dIII and Pvu II restriction fragment length polymorphisms (RFLPs) in the lipoprotein lipase ( LPL) gene were associated with coronary heart disease and plasma concentrations of HDL cholesterol and triglycerides. However, the populations studied were relatively small and heterogeneous in regard to age, sex, and ethnic background. Methods and Results Associations of a Hin dIII (intron 8) and a Pvu II (intron 6) RFLP in the LPL gene with plasma concentrations of cholesterol, HDL cholesterol, non-HDL cholesterol, and triglycerides were studied in 457 randomly selected 40-year-old Danish men. The Hin dIII and the Pvu II sites were in strong linkage disequilibrium. The frequencies of the H + and P + alleles (+ denotes presence of cutting site) were 0.717 and 0.464, respectively. In multivariate analysis, there was a clear gene dosage effect of the H + allele on HDL. The lowest HDL cholesterol concentration was in the H + H + group, the highest concentration was in the H − H − group, and the H + H − group had intermediate HDL concentrations ( P =.03). There was a similar, but not statistically significant gene dosage effect on triglyceride concentrations, with the highest value seen in the H + H + group. There were no other associations between LPL RFLPs and lipoprotein components. In males reporting family history of premature ischemic heart disease, the H + H + genotype was overrepresented (odds ratio, 2.75; 95% confidence interval, 1.37 to 5.53). Conclusions The results suggest that genetic variation in or near the LPL gene plays a role in interindividual differences in HDL cholesterol concentration and in risk of atherosclerosis and ischemic heart disease in men.

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL) particle in which apolipoprotein B-100 (apoB) is attached to a glycoprotein called apolipoprotein(a) [apo(a)]. Apo(a) has several genetically determined phenotypes differing in molecular weight, to which Lp(a) concentrations in plasma are inversely correlated. High plasma levels of Lp(a) are associated with atherosclerotic diseases. It is therefore of interest to study whether factors other than the apo(a) gene locus are involved in the regulation of Lp(a) concentrations. We measured plasma concentrations of Lp(a) and other lipoproteins and determined apo(a) phenotypes in 31 patients with hyperthyroidism, before and after the patients had become euthyroid by treatment. The mean concentration of LDL cholesterol rose from 2.67 to 3.88 mmol/l (P

Thirty patients with familial defective apolipoprotein B-100 were treated in a two-period (8 weeks each) cross-over study with pravastatin and gemfibrozil. Cholesterol, LDL cholesterol, and apo B were reduced by 20–25% (P < 10−4) by pravastatin and by 4–6% by gemfibrozil (pravastatin vs. gemfibrozil:P < 10−4). Response to pravastatin was variable and not correlated to gender, age, or apo E genotype. Gemfibrozil lowered triglycerides by 25% (P < 10−4) and raised HDL cholesterol by 11%. The effects of pravastatin on these two interrelated variables were significantly smaller. Both drugs increased Lp(a) significantly by about 10%. The LDL cholesterol lowering effect of pravastatin in patients with FDB is similar to that observed in patients with familial hypercholesterolemia.

A total of 5000 consecutively samples newborn screening cards were anonymously selected for screening for the apolipoprotein B-3500 (apo B-3500) mutation, which causes familial defective apolipoprotein B-100 (FDB). The mutation was found in 5 of 5000 Danish children, of whom 2 were twins. This indicates a lower prevalence of this mutation in Danes than that reported in the UK, Germany, USA, Austria, Canada and especially Switzerland. Haplotype studies suggest that Caucasian subjects with the apo B-3500 mutation have a common founder. The apparently lower prevalence in Denmark than in Switzerland and Central Europe may indicate that the mutation was brought from these areas to Denmark after the initial settling of Denmark. In 101 unrelated Danish subjects with familial hypercholesterolemia, diagnosed on clinical and biochemical criteria including tendon xanthomata, 2 were heterozygous for the apo B-3500 mutation (2%).

The association of polymorphic alleles of the apolipoprotein B gene (Insertion/Deletion-, Xbal-, MspI-, EcoRI-, and 3′-VNTR polymorphisms) with variation in lipid concentrations (total cholesterol (T-C), HDL cholesterol (HDL-C), and log-triglycerides (TG)) in plasma was studied in 259 men and 59 women with moderate hypercholesterolemia (T-C 5.5–8.0 mmol/l and TG < 2.5 mmol/l) and ischemic heart disease, especially in relation to the effect of sex and age. The XbaI and the Ins/Del polymorphic alleles were associated with variation in T-C, but only in patients below the 75th percentile for age. The XbaI and Ins/Del polymorphic alleles were synergistically associated with variation in T-C: the X+ and the Del alleles were associated with higher cholesterol concentrations. Younger male patients had the highest frequency of haplo-types including both the X+ and the Del alleles, but the most striking difference was a significantly higher frequency of haplotypes including both the X — and the Ins alleles in female and in older male patients. The heterogeneity of association of polymorphic alleles in the apolipoprotein B gene to complex traits like hypercholesterolemia and ischemic heart disease in this study could explain why in most studies the X+ allele has been associated with higher cholesterol levels, whereas the X — allele has been associated with symptomatic atherosclerosis. The results of our study emphasize the importance of age and sex in measured genotype association studies.

HMG-CoA reductase inhibitors effectively reduce the concentration of low density lipoproteins (LDL) in plasma. Lipoprotein(a) [Lp(a)] may be as atherogenic as LDL. A few studies, only one of which was placebo controlled, suggest that the HMG CoA reductase inhibitors either do not affect Lp(a) or they increase Lp(a). The response of Lp(a) to HMG-CoA reductase inhibition has not been related to apolipoprotein(a) phenotypes in previous studies. We conducted a double-blind, placebo controlled study of pravastatin in 51 patients with familial hypercholesterolemia (FH) (n = 43) or probable FH (n = 8). All patients had LDL-cholesterol concentration above 4.1 mmol l-1 despite treatment with diet and bile acid sequestration. In patients assigned to pravastatin (n = 34), the mean concentrations of total cholesterol and LDL cholesterol fell significantly (P < 0.01) when compared to placebo. Lp(a) increased (P < 0.01) from a mean (+/- SD) of 33.6 +/- 40.8 mg dl-1 to 41.1 +/- 46.1 mg dl-1 on pravastatin but was unchanged during placebo treatment. The percentage increase in Lp(a) was the same in patients with different apo(a) phenotypes, and hence the absolute increase in Lp(a) was greatest in patients with the low molecular weight apo(a) phenotypes.

Lipoprotein(a) [Lp(a)] is a low density lipoprotein (LDL), in which apolipoprotein B-100 (apo B-100) is attached to apolipoprotein(a) [apo(a)], a glycoprotein of variable size. Lp(a) may be as atherogenic as LDL. In normal populations, Lp(a) concentrations in plasma are largely determined by the apo(a) gene locus on chromosome 6, but regulation of synthesis and catabolism of Lp(a) is poorly understood. In some studies, a PvuII restriction fragment length polymorphism (RFLP) in the LDL receptor gene seems to affect concentrations of LDL in plasma, and other studies have indicated that Lp(a) catabolism could be mediated by the LDL receptor. We therefore expected that the PvuII polymorphism in the LDL receptor gene might be associated with Lp(a) levels in 170 Caucasian men aged 40 years, selected to have a high representation of low molecular weight apo(a) phenotypes. However, plasma concentrations of cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and Lp(a) were all unrelated to the LDL receptor gene PvuII polymorphism both in the group as a whole and when it was subgrouped by apo(a) phenotype. Therefore our data do not support the concept that this particular LDL receptor gene polymorphism is associated with LDL receptor function, and our data therefore neither support nor rule out a role for the LDL receptor in Lp(a) catabolism.

We have studied the possible association of 5 polymorphisms in the apoB gene [a 9-bp insertion/deletion length polymorphism in the signal peptide coding region, XbaI, MspI, and EcoRI restriction fragment length polymorphisms (RFLPs) and a 15-bp variable number of tandem repeats (VNTR) region 3′ to the apoB gene] with plasma concentrations of cholesterol, high density lipoprotein cholesterol, triglycerides and apolipoprotein B-100 in 464 randomly selected Danish men born in 1948. The XbaI RFLP and the insertion/deletion length polymorphism were significantly associated with plasma concentration and inter-individual variation of cholesterol and apolipoprotein B-100 (1.77% and 1.37% of sample variance in cholesterol, and 1.4% and 1.39% of sample variance in apoB). The association was particularly strong in men with a body mass index less than 25 kg/m2 (the mean value of the whole cohort) (3.43% and 2.93% of sample variance in cholesterol, and 3.1% and 2.13% of sample variance in apoB). The XbaI RFLP and the insertion/deletion length polymorphism were in strong linkage disequilibrium, explaining why independent associations of these two polymorphisms with cholesterol and apoB could not be established. There were no other associations between apoB gene polymorphisms and lipoprotein components.