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Consumer demand for milk and meat from grass‐fed cattle is growing, driven mostly by perceived health benefits and concerns about animal welfare. In a U. S.‐wide study of 1,163 milk samples collected over 3 years, we quantified the fatty acid profile in milk from cows fed a nearly 100% forage‐based diet (grassmilk) and compared it to profiles from a similar nationwide study of milk from cows under conventional and organic management. We also explored how much the observed differences might help reverse the large changes in fatty acid intakes that have occurred in the United States over the last century. Key features of the fatty acid profile of milk fat include its omega‐6/omega‐3 ratio (lower is desirable), and amounts of total omega‐3, conjugated linoleic acid, and long‐chain omega‐3 polyunsaturated fatty acids. For each, we find that grassmilk is markedly different than both organic and conventional milk. The omega‐6/omega‐3 ratios were, respectively, 0.95, 2.28, and 5.77 in grassmilk, organic, and conventional milk; total omega‐3 levels were 0.049, 0.032, and 0.020 g/100 g milk; total conjugated linoleic acid levels were 0.043, 0.023, and 0.019 g/100 g milk; and eicosapentaenoic acid levels were 0.0036, 0.0033, and 0.0025 g/100 g milk. Because of often high per‐capita dairy consumption relative to most other sources of omega‐3 fatty acids and conjugated linoleic acid, these differences in grassmilk can help restore a historical balance of fatty acids and potentially reduce the risk of cardiovascular and other metabolic diseases. Although oily fish have superior concentrations of long‐chain omega‐3 fatty acids, most fish have low levels of α‐linolenic acid (the major omega‐3), and an omega‐6/omega‐3 ratio near 7. Moreover, fish is not consumed regularly, or at all, by ~70% of the U. S. population.

Statins may reduce cardiovascular (CV) morbidity in patients with mild-to-moderate elevations in liver enzyme levels. This post-hoc analysis of the IDEAL study compared intensive versus moderate statin therapy for the prevention of CV events in coronary heart disease patients with normal and elevated baseline levels of serum alanine aminotransferase (ALT). Cox regression analysis was used to investigate the effect of atorvastatin 80 mg/day versus simvastatin 20-40 mg/day on the risk of IDEAL study end points in patients with normal baseline ALT (defined as ALT < ULN [upper limit of normal]) versus elevated baseline ALT (ALT ≥ ULN). Of 8863 IDEAL patients with non-missing baseline ALT values, 7782 (87.8%) had an ALT < ULN and 1081 (12.2%) had an ALT ≥ ULN. In patients with elevated baseline ALT, major CV event rates were 11.5% for simvastatin and 6.5% for atorvastatin, indicating a significant risk reduction with intensive statin therapy (hazard ratio, 0.556; 95% confidence interval, 0.367-0.842; p = 0.0056). Significant heterogeneity of treatment effect was observed for major CV events, cerebrovascular events, and major coronary events, with a trend towards treatment difference for the other outcomes, indicating a greater benefit with atorvastatin in the elevated ALT group. The CV benefit of intensive lipid lowering with atorvastatin compared with a more moderate regimen with simvastatin was generally greater in patients with mildly-to-moderately elevated baseline ALT than patients with normal baseline ALT. Moderate elevations in liver enzyme levels should not present a barrier to prescribing statins, even at higher doses, in high-risk patients

The conference on “Healthy Agriculture, Healthy Nutrition, Healthy People” of the World Council on Genetics, Nutrition and Fitness for Health was held at Olympia, Greece, on October 5-8, 2010. The focus of the conference was on the evolutionary aspects of diet throughout the life cycle in terms of genetic predisposition, health, disease prevention and sedentary life styles; the dietary changes brought about my modern agriculture, agribusiness, food production systems, changes in climate and the need for urban agriculture and architecture, all of which are influenced by governments, national and international policies. Therefore, the role of governments and international organizations was extensively discussed during the last session of the conference by the participants from 20 countries representing six continents, Sağlık için Genetik, Beslenme ve Zindelikte Dünya Konseyi’nin Sağlıklı Tarım, Sağlıklı Beslenme ve Sağlıklı İnsan için Eylem Planı Açılış Konferansı 5-8 Ekim 2010 tarihinde Yunanistan’ın Olimpia şehrinde yapıldı. Konferansın odak noktası genetik yatkınlık, sağlık, hastalığın önlenmesi ve hareketsiz yaşam tarzına yaşam boyunca evrimsel bakış açısıydı. Bu evrimsel bakış, modern tarım, tarım ticareti, gıda üretim sistemleri, iklim değişiklikleri ve kentsel tarım yapılanmaları için hükümetlerce uygulanan ulusal ve uluslararası politikaların hepsini kapsamaktadır. Bundan dolayı, hükümetlerin ve uluslararası kurumların rolü, altı kıtadan 20 ülkeyi temsil eden katılımcılarla konferansın son oturumuna kadar kapsamlı olarak tartışılmıştır

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 30 October-1 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 (NCDs) 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.El Informe Bellagio sobre la actividad agropecuaria y la nutrición para la salud de las personas es el resultado de la reunión celebrada del 30 de octubre al 1 de noviembre del 2012 en el Centro Bellagio de la Fundación Rockefeller, ubicado a orillas del lago de Como (Italia). La reunión se basó en datos científicos, pero estuvo orientada a cuestiones de política. Se trataron ampliamente los temas de la función y la cantidad de las grasas saludables y las grasas poco saludables en los alimentos, con atención especial a su contenido relativo de ácidos grasos omega-3 y omega-6, y de azúcar, en particular fructosa, que pueden ser la causa de la epidemia de enfermedades no transmisibles en el mundo. El informe concluye que el consumo de azúcares, sobre todo en la forma de fructosa de alto contenido energético contenida en las bebidas gaseosas, supone una amenaza grave e insidiosa para la salud, especialmente en la niñez, y que la mayoría de los regímenes alimentarios, aunque con diferencias regionales, contienen cantidades insuficientes de ácidos grasos omega-3 y cantidades demasiado elevadas de ácidos grasos omega-6. Dado que las interacciones entre los genes y los nutrientes durante el crecimiento y el desarrollo, así como en la prevención de las enfermedades, son fundamentales para la salud, deben establecerse en todo el mundo centros regionales de genética, nutrición y buena condición física para promover la salud. Los jefes de Estado y de gobierno deben elevar la nutrición, con carácter de urgencia, al nivel de prioridad nacional, lograr que el acceso a un régimen alimentario saludable se considere un derecho humano, y hacer que la responsabilidad principal en materia de nutrición recaiga en los ministerios de salud, en lugar de en los ministerios de agricultura y ganadería, a fin de que las necesidades de salud orienten las prioridades agropecuarias, y no a la inversa. Debe asignarse a la seguridad nutricional la misma prioridad que a la seguridad alimentaria.

Objectives This post-hoc analysis of the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial was designed to assess the comparative treatment efficacy of high-dose at ...

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: Results from the IDEAL trial. J Intern Med 2010; 267:567-575. Objectiv ...

Background Very few, if any, studies have assessed the ability of apolipoproteins to predict new-onset of congestive heart failure (HF) in statin-treated patients with coronary heart disease (CHD). Aims To employ the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL) study database to assess the association of on-treatment lipoprotein components with prediction of HF events and to compare their predictive value with that of established risk factors such as hypertension and diabetes. Methods We used Cox regression models to study the relationships between on-treatment levels of apolipoproteins A1 and B to subsequent HF. Chi square information value from the log likelihood was used to compare the predictive value of lipoprotein components with established risk factors of HF. Findings In the IDEAL study, on-treatment apolipoproteins proved to be associated with the occurrence of new-onset HF. Variables related to low-density lipoprotein cholesterol (LDL-C) carried less predictive information than those related to high-density lipoprotein cholesterol (HDL-C), and apoA-1 was the single variable most strongly associated with HF. LDL-C was less predictive than both non-HDL-C (total cholesterol minus HDL-C) and apoB. The ratio of apoB to apoA-1 was most strongly related to HF after adjustment for potential confounders, among which diabetes had a stronger correlation with HF than did hypertension. ApoB/apoA-1 carried approximately 2.2 times more of the statistical information value than that of diabetes. Calculation of the net reclassification improvement index revealed that about 3.7% of the patients had to be reclassified into more correct categories of risk once apoB/apoA-1 was added to the adjustment factors. The reduction in risk by intensive lipid-lowering treatment as compared to usual-dose simvastatin was well predicted by the difference in apoB/apoA-1 on-treatment levels. Interpretation The on-treatment ratio of apoB/apoA-1 was the strongest predictor of HF in CHD patients of both IDEAL treatment arms combined, mostly driven by the strong association with apoA-1, whereas LDL-C and non-HDL-C were less able to predict HF outcome. The predictive information value contained within apoB/apoA-1 was about 2.2 times more than that of diabetes. Between-treatment group differences in HF were to a significant extent explained by on-treatment differences in apoB/apoA-1, mostly through the changes in apoB. We argue therefore, on-treatment lipoprotein components contribute to the overall future risk of HF in statin-treated patients with CHD.

The effect of long-term β-adrenergic blockade on plasma lipids and lipoproteins was studied in 68 consecutive patients enrolled in a double-blind controlled trial of alprenolol in myocardial infarction. Thirty-three patients were treated with 200 mg alprenolol twice daily for one year, and 35 patients received placebo. Neither plasma cholesterol, plasma triglycerides nor plasma lipoproteins were significantly influenced by alprenolol.

In a Danish family highly susceptible to ischemic heart disease, hyperlipidemia did not simply cosegregate with a previously undescribed 10 bp deletion in the LDL receptor gene causing heterozygous familial hypercholesterolemia (FH). This mutation, designated as FH DK‐4, deletes 10 nucleotides from ex on 4 coding for the third cysteine‐rich repeat of the ligand‐binding domain. The resulting translational frameshift and stop codon corresponding to amino acid position 181 in the LDL receptor cDNA is predicted to result in a truncated LDL receptor protein. Several family members had hyperlipidemia and early onset of ischemic heart disease not due to the 10 bp deletion, and several family members had unexpectedly high serum lipoprotein(a) contributing to high concentrations of serum LDL cholesterol. The study illustrates important limitations and possibilities of molecular genetic diagnosis.

Objectives: This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary ar ...

Background: Patients at high risk of cardiovascular disease frequently fail to reach recommended low-density lipoprotein cholesterol (LDL-C) goals, partly because statin doses are not titrated to optimal effect. The ECLIPSE study was designed to compare the efficacy and safety of force-titrated treatment with rosuvastatin (10–40 mg) with that of atorvastatin (10–80 mg) in high-risk patients with hypercholesterolemia. Methods: In this 24-week, open-label, randomized, multinational, parallel-group study, 1,036 patients were randomized to rosuvastatin (n = 522) or atorvastatin (n = 514). Results: At all time points, a significantly greater percentage of patients on rosuvastatin treatment achieved the NCEP ATP III LDL-C goal of Conclusion: Rosuvastatin titrated across its recommended dose range provides a more favorable effect on lipoprotein variables than atorvastatin, enabling more high-risk patients to achieve recommended LDL-C goals.

Background Estimates of incidence are crucial to the planning of public health measures, but most studies of incidence of, for example, acute myocardial infarction (MI) are troubled by methodological problems such as; (i) selection biases of the patients being included for study, (ii) lack of identification and control of the cohort under observation, (iii) inconsistencies in the use of diagnostic criteria, and (iv) missing data. We aimed to measure directly the incidence of the entire spectrum of the acute coronary syndrome (ACS), consisting of unstable angina pectoris, MI and sudden cardiac death (SCD), by use of the new criteria for MI as proposed in 2000. Design Cohort study. Methods From a cohort of 138 290 residents of the municipality of Aarhus, Denmark, aged 30-69 years, with a demographic structure known at the individual population member level, we prospectively identified all consecutive ACS patients from 1 April 2000 to 31 March 2002. The population was identified from Danish Population Registers. Results A total of 189 victims of SCD and 457 ACS patients who survived until admission to hospital were present. Consequently, crude incidence rate of ACS was 234 per 100000 person-years. Unstable angina pectoris constituted for 16.9%, MI for 53.8% and SCD for 29.3% of ACS patients. Conclusions Crude incidence rates of ACS were 137 and 331 per 100 000 person years for women and men, respectively. The incidence rate of ACS, as measured directly, was insignificantly 6% higher than expected from Danish administrative databases. Eur J Cardiovasc Prev Rehabil 14:608-614 © 2007 The European Society of Cardiology

Examination of low-density lipoprotein (LDL) receptor gene, its promoter, and most of exon-intron boundaries from 74 probands with familial hypercholesterolemia (FH) of St. Petersburg revealed 34 mutations and 8 widely spread polymorphisms at this locus. Only four mutations were considered neutral, while the other 30 are likely to cause familial hypercholesterolemia (FH). Mutations in the LDL receptor gene, causing the disease, were identified in 41 (55%) out of 74 families with FH. Mutation R3500Q in apolipoprotein B (APOB) gene was not detected in all probands. Therefore in the families lacking mutations hypercholesterolemia was caused by mutations in the introns of the LDL receptor gene or by other genetic factors. Nineteen mutations causing disease progression were described in St. Petersburg for the first time, while 18 of them are specific for Russia. Among Ashkenazi Jews, predominant mutation G197del was detected in 30% (7 out of 22) of patients with FH. In the Slavic population of St. Petersburg, no predominant mutations were detected. Only five mutations were identified in two Slavic families, while 24 were found in unique families. These data are indicative of the lack of a strong founder effect for FH in the St. Petersburg population.

Contains fulltext : 50695.pdf (Publisher’s version ) (Closed access) There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B

A locus on chromosome 1p34.1-p32 has been linked to autosomal dominant Familial Hypercholesterolemia (FH) and is termed the third FH locus. We tested whether this third FH locus is linked to the FH phenotype in 20 Danish families, with 158 members, without pathogenic mutations in the genes, encoding the low-density lipoprotein (LDL) receptor or apolipoprotein B (apoB). We could exclude the third FH locus as a cause of FH by genetic linkage analysis in the families taken together. Since haplotype analysis of each family nevertheless suggested that the FH phenotype co-segregated in a manner consistent with linkage to the third FH locus in three small pedigrees, we performed sequencing analysis without being able to demonstrate mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, the main candidate gene in the third FH locus. By the same combination of genetic linkage and molecular analysis we could also exclude mutations in the gene for the LDL receptor adaptor protein and in the gene for cholesterol-7-alpha-hydroxylase as causes of FH in our sample. Although not indicating linkage to any known loci, our data still indicate that another dominant gene may be involved in causing a FH phenotype.

Background —The Scandinavian Simvastatin Survival Study (4S) randomized 4444 patients with coronary heart disease (CHD) and serum cholesterol 5.5 to 8.0 mmol/L (213 to 310 mg/dL) with triglycerides ≤2.5 mmol/L (220 mg/dL) to simvastatin 20 to 40 mg or placebo once daily. Over the median follow-up period of 5.4 years, one or more major coronary events (MCEs) occurred in 622 (28%) of the 2223 patients in the placebo group and 431 (19%) of the 2221 patients in the simvastatin group (34% risk reduction, P Methods and Results —The Cox proportional hazards model was used to assess the relationship between lipid values (baseline, year 1, and percent change from baseline at year 1) and MCEs. The reduction in MCEs within the simvastatin group was highly correlated with on-treatment levels and changes from baseline in total and LDL cholesterol, apolipoprotein B, and less so with HDL cholesterol, but there was no clear relationship with triglycerides. We estimate that each additional 1% reduction in LDL cholesterol reduces MCE risk by 1.7% (95% CI, 1.0% to 2.4%; P Conclusions —These analyses suggest that the beneficial effect of simvastatin in individual patients in 4S was determined mainly by the magnitude of the change in LDL cholesterol, and they are consistent with current guidelines that emphasize aggressive reduction of this lipid in CHD patients.

The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) study is an investigator-initiated trial designed to determine whether additional clinical benefit might be gained through a strategy that decreases levels of low-density lipoprotein cholesterol levels better than those currently achieved with established statin therapy in patients who have coronary heart disease. IDEAL is a multicenter prospective, randomized, open-label, blinded, end point classification study. Patients who had myocardial infarction were randomized to prescription treatment with 80 mg/day of atorvastatin or 20 mg/day of simvastatin (the dose was increased to 40 mg/day at week 24 in those patients whose plasma total cholesterol remained >5.0 mmol/L, or 190 mg/dl, or whose low-density lipoprotein cholesterol remained >3.0 mmol/L, or 115 mg/dl). The primary clinical outcome variable is the time to initial occurrence of a major coronary event, which is defined as nonfatal acute myocardial infarction, coronary death, or resuscitated cardiac arrest. The study is designed to have a power of 90% to detect a relative decrease of 20% in the atorvastatin-group compared with the simvastatin-group in the number of major events caused by coronary heart disease over approximately 5.5 years. The 8,888 randomized patients had the following characteristics: mean age 61.7 +/- 9.5 years, 19.1% women (mean age 64.0 +/- 9.5 years), baseline total cholesterol 5.1 +/- 1.0 mmol/L (197 mg/dl), low-density lipoprotein cholesterol 3.2 +/- 0.9 mmol/L (124 mg/dl), and high-density lipoprotein cholesterol 1.2 +/- 0.3 mmol/L (46 mg/dl). Drug treatment before randomization consisted of statins in 77% of patients, aspirin in 78.9%, beta blockers in 75.1%, and angiotensin-converting enzyme inhibitors in 30%

Guidelines aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of guidelines have been issued in recent years by different organisations--European Society of Cardiology (ESC), American Heart Association (AHA), American College of Cardiology (ACC), and other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing guidelines. In spite of the fact that standards for issuing good quality guidelines are well defined, recent surveys of guidelines published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilisation of health resources. In addition, the legal implications of medical guidelines have been discussed and examined, resulting in position documents, which have been published by a specific task force. The ESC Committee for practice guidelines (CPG) supervises and coordinates the preparation of new guidelines and expert consensus documents produced by task forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these guidelines or statements.

Major clinical end-point trials of cholesterol lowering with statins have shown consistent benefits in prevention of cardiovascular disease. Lessons from these trials include the findings that cardiovascular risk reduction is: (1) dependent on baseline cardiovascular risk; (2) dependent on magnitude of low-density lipoprotein cholesterol (LDL-C) reduction achieved with treatment; and (3) independent of initial LDL-C level. Ongoing studies will help to identify new markers of higher risk/higher treatment benefit and to define the merits of more aggressive LDL-C lowering.

Guidelines aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making. A great number of guidelines have been issued in recent years by different organizations-European Society of Cardiology (ESC), American Heart Association (AHA), American College of Cardiology (ACC), and other related societies. By means of links to web sites of National Societies several hundred guidelines are available. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing guidelines. In spite of the fact that standards for issuing good quality guidelines are well defined, recent surveys of guidelines published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilization of health resources. In addition, the legal implications of medical guidelines have been discussed and examined, resulting in position documents, which have been published by a specific Task Force. The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The Committee is also responsible for the endorsement of these guidelines or statements. The rationale for an active approach to the prevention of cardiovascular diseases (CVD) is …

There is considerable evidence suggesting that the current low-density lipoprotein cholesterol (LDL-C) goals to prevent coronary heart disease could be lower. This evidence includes calculations of physiological LDL-cholesterol levels and data from observational and interventional epidemiologic studies, including the Heart Protection Study. However, Heart Protection Study data can also be taken to support a strategy based on percentage reductions in LDL-C rather than a strategy of attaining absolute values of LDL-C. More effective LDL-C lowering agents, as well as combination drug therapy, will reduce LDL-C more efficiently, but it remains to be documented that such therapy is accompanied by greater reduction in risk for coronary heart disease. Moreover, even very intensive therapy will not reduce LDL-C to physiological concentrations in many patients. These considerations justify increasing emphasis on reduction in overall, multifactorial risk in individual patients at the expense of a focus on individual risk factors.

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.

Statusartikel

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.

Studies of the cholesterol lowering effect of statin therapy as a function of low-density lipoprotein (LDL)-receptor mutation type have not produced a clear picture, possibly because they included patients with several different kinds of LDL-receptor mutations. We studied the response to treatment with fluvastatin in 28 patients with heterozygous familial hypercholesterolemia as a result of a receptor-negative mutation (Trp23-stop) and in 30 patients with a receptor-binding defective mutation (Trp66-Gly) to test the hypothesis that response to treatment depends on the type of mutation. Patients were randomized to 12 weeks of treatment with fluvastatin 40 mg daily and 12 weeks of placebo treatment, preceded by a placebo run-in period of 8 weeks in a double-blind, cross-over design. Untreated plasma concentrations of lipids and lipoproteins were similar in the two groups of patients. Plasma cholesterol and LDL cholesterol response to therapy tended to be less marked in receptor-binding defective patients, but the differences were not statistically significant. A tabulation of the results of the present and earlier studies suggests that differences in treatment response as an apparent function of LDL-receptor gene mutational type occur mainly in populations with recent genetic admixture (

Epidemiological studies published since 1996 have established that hypertriglyceridemia can predict risk of cardiovascular disease in a manner statistically independent of HDL cholesterol. Nevertheless, the relationship of concentrations of plasma triglycerides to risk of cardiovascular disease remains less than straightforward, partly because triglycerides are carried in lipoproteins of different atherogenicity, partly because hypertriglyceridemia is associated with non-lipid atherogenic and thrombogenic processes. For example, the association of highest risk of cardiovascular disease to moderate rather than to severe hypertriglyceridemia can be understood in terms of the distribution of triglycerides between different classes of plasma lipoproteins. It is counter-intuitive to most clinicians, however, and hence it can result in the misdirection of clinical efforts including drug therapy. Fibrates lower plasma triglycerides, and raise HDL, efficiently and with few immediate side-effects. Central to their mode of action is activation of certain nuclear receptors in cells. There is no necessary connection, however, between that fascinating biochemistry and clinical benefit as defined by reductions in rates of death by coronary artery disease. A review of trials of cholesterol-lowering by diet and drugs, published between 1966 and 1996, included 12 trials of therapy with fibrates or placebo in more than 21000 patients. Overall, these trials indicated no benefit in terms of reduction in risk of coronary deaths. The period since 1996 has seen the publication of four additional trials of treatment of 6144 patients with fibrates or placebo. Two of them were major trials. The VA-HIT was very encouraging, because treatment with gemfibrozil produced a signficant reduction in the combined incidence of fatal and non-fatal coronary events. There was no significant reduction in coronary deaths, however. The results of BIP were frankly disappointing, because they demonstrated no significant effect of treatment with bezafibrate on either the primary end-point of the trial or on rates of coronary death. Clinical indications for the use of fibrates can obviously not be based on biochemical insights, however intriguing in their own right, but they have also not been satisfactorily defined by the randomized clinical trials published to date. Hope remains, however, that some clarification will result from ongoing trials of fibrate treatment of patients with type II diabetes.

The Scandinavian Simvastatin Survival Study (4S) and other randomized clinical trials have demonstrated that cholesterol-lowering treatment with statins improves prognosis in patients with coronary atherosclerosis compared with placebo. The effect of therapy with statins beyond the typical 5 to 6 years' duration of the trials, in particular regarding the risk of cancer, has not been investigated. This study examines the long-term effects of simvastatin for up to 8 years on cause-specific mortality in patients with coronary heart disease (CHD). We performed an observational, government registry-based study of mortality in the groups originally randomized to simvastatin or placebo in the 4S over an additional 2-year follow-up period, so that the median total follow-up period was 7.4 years (range 6.9 to 8.3 in surviving patients). Randomization took place at outpatient clinics at 94 clinical centers in Denmark, Finland, Iceland, Norway, and Sweden from 1988 to 1989. Of 4,444 patients with CHD, 2,223 and 2,221 were randomized to treatment with placebo or simvastatin therapy, respectively. Patients received treatment with simvastatin, starting at 20 mg/day, with titration to 40 mg/day at 12 or 24 weeks if total cholesterol was >5.2 mmol/L (200 mg/dl), or placebo. After the double-blind period, most patients in both treatment groups received simvastatin as open-label prescription. Of the 1,967 patients originally treated with placebo and surviving the double-blind period, 97 (4.9%) died during the following 2 years. In the group randomized to simvastatin the corresponding number was 74 of the 2, 039 survivors (3.6%). Adding these deaths to those occurring during the original trial, the total was 353 (15.9%) and 256 (11.5%) deaths in the groups originally randomized to placebo and simvastatin, respectively. The relative risk was 0.70 (95% confidence interval 0. 60 to 0.82, p = 0.00002). The total number of cancer deaths was 68 (3.1%) in the placebo group and 52 (2.3%) in the simvastatin group (relative risk 0.73, 95% confidence interval 0.51 to 0.05, p = 0. 087), and the numbers of noncardiovascular and other deaths were similar in both groups. We therefore conclude that treatment with simvastatin for up to 8 years in patients with CHD is safe and yields continued survival benefit.

Jensen JM, Gerdes LU, Jensen HK, Christiansen TM, Brorholt-Petersen JU, Faergeman O (Aarhus Amtssygehus University Hospital, Aarhus, Denmark). Association of coronary heart disease with age-adjusted aortocoronary calcification in patients with familial hypercholesterolaemia. J Intern Med 2000; 247: 479–484. Objectives. Existing algorithms of risk of coronary heart disease (CHD) do not pertain to patients with familial hypercholesterolaemia (FH), whose arteries have been exposed to hypercholesterolaemia since birth. We studied a cohort of FH patients to compare four diagnostic models of CHD: traditional risk factors of CHD (age, sex, cholesterol, hypertension, smoking and body mass index), cholesterol year score, and aortic as well as coronary calcium measured by spiral computed tomography (CT). Subjects. We invited 88 individuals with molecularly defined FH of whom 80 (91%) decided to participate. Results. Analysis of receiver operating characteristic curves showed that the age-adjusted coronary calcium score was more strongly associated with clinical manifestations of CHD than were traditional risk factors (P

We report a functional characterization of the W23X and W66G low density lipoprotein (LDL) receptor gene mutations. The authors used two-color fluorescence flow cytometry to measure LDL receptor activity in stimulated T-lymphocytes, prepared from patients heterozygous for the W23X or W66G mutation, and compared the results with measurements of LDL receptor activity in stimulated T-lymphocytes prepared from unrelated healthy control subjects. It was found that the W23X mutation significantly reduced LDL receptor expression and LDL binding and internalization, and that the W66G mutation significantly reduced LDL receptor expression and LDL binding. LDL internalization in patients heterozygous for the W66G mutation was not significantly reduced. The data support the concepts that the W23X mutation prevents production of LDL receptors (class I) and that the W66G mutation produces LDL receptors unable to recycle normally in cells (class V).

In the present study, we have characterized a unique splice donor G to A substitution in the moderately conserved + 5 position in intron 10 of the low-density lipoprotein (LDL) receptor gene. In two Danish families, carriers of the 1592 + 5G --> A mutation display a clinical phenotype ranging from healthy normocholesterolemic persons to classical heterozygous familial hypercholesterolemia (FH) patients. Reverse transcription-polymerase chain reaction (RT-PCR) of RNA from Epstein Barr virus (EBV)-transformed lymphoblasts obtained from members of both families demonstrated abnormal splicing generating two aberrant mRNAs due to either alternative splicing and skipping of exon 10 or activation of a cryptic splice site in intron 10 inserting 66 intronic base pairs. These abnormally spliced mRNAs were predicted to encode two abnormal receptor proteins containing an in-frame deletion of 75 amino acids and an insertion of 22 novel amino acids, respectively. Results obtained by immunofluorescence staining, flow cytometry, and confocal microscopy of transfected Chang and COS-7 cells expressing normal and mutant LDL receptors were compatible with nearly complete retention of the mutant proteins in the endoplasmic reticulum. Quantitative measurements of LDL receptor mRNAs from EBV-transformed lymphoblasts, however, did not reveal any significant differences in variant mRNA contents between mutation carriers in the families that could be related to degree of hypercholesterolemia.

BACKGROUND Studies indicate that human peripheral blood mononuclear cells mirror low-density lipoprotein (LDL) receptor activity of other cells in the body. To measure LDL receptor activity in patients with heterozygous familial hypercholesterolemia (FH), we prepared peripheral blood mononuclear cells from individuals with molecularly verified LDL receptor defective (Trp66-Gly mutation, n = 18) or receptor negative (Trp23-stop mutation, n = 17) heterozygous FH and from healthy individuals (n = 24). METHODS The cells were stimulated to express maximum LDL receptor by preincubation in lipoprotein-free medium. They were then incubated at 4 degrees or 37 degrees C with fluorescently conjugated LDL (DiI-LDL). T-lymphocytes and monocytes were identified by fluorescently conjugated monoclonal antibodies. DiI-LDL bound (at 4 degrees C) or internalized (at 37 degrees C) by the cells was measured using flow cytometry. Knowing the LDL receptor gene mutation of the FH patients allowed us to compare the diagnostic capability of our functional assay with the DNA diagnosis. RESULTS The diagnostic accuracy did not allow our assay to be used for diagnosis of individual cases of heterozygous FH. CONCLUSIONS We suggest that our two-color fluorescence flow cytometry assay can be used to characterize functionally gene mutations causing LDL receptor dysfunction in patients with heterozygous FH.

Familial hypercholesterolemia (FH) is an autosomal inherited disorder caused by different mutations in the low density lipoprotein (LDL) receptor gene. It has been demonstrated that there is an increased risk of coronary heart disease (CHD) in heterozygous FH subjects, although this excess CHD is not only explained by the LDL-cholesterol concentration or the class of the LDL-receptor mutation. To investigate if a common polymorphism at the platelet glycoprotein (GP) IIIa gene locus could be related to CHD phenotypic variation in heterozygous FH, we have carried out a case-control study. We have studied 40 cases and 40 controls matched for age, sex and genetic defect in the LDL-receptor gene. Allele frequency of Pl A2 polymorphism for cases and controls was 20 and 22.5%, respectively, and the difference was not significant. In conclusion, our data do not support any association between the GP IIIa polymorphism and the increased prevalence of acute coronary syndromes in the heterozygous FH subjects.

This summary is taken from the Second Joint Task Force of European and other Societies Recommendations on Prevention of Coronary Heart Disease in Clinical Practice. The second Task Force was convened by the European Society of Cardiology (ESC), the European Atherosclerosis Society (EAS) and the European Society of Hypertension (ESH), the societies responsible for the original 1994 Task Force recommendations on coronary prevention (Chairman Professor K Pyorala) and consisted of a writing group, other invited members and specialists, together with representatives of other European societies and organisations as listed in the appendix. The full Task Force first met in November 1997 to review the original recommendations and agree on the principles for revision. The Writing Group then prepared a new draft of the recommendations and the specialist contributions of Professor Daan Kromhout (diet), Professor Kristina Orth-Gomer (socioeconomic, psychosocial factors and behavioural change), Professor Francois Cambi...

Aim To assess differences in treatment of ischaemic heart disease in the Scandinavian countries. Methods and Results The Scandinavian Simvastatin Survival Study (4S) lasted 5·4 years and showed that death rates in 4444 patients with coronary heart disease were 30% lower in those treated with simvastatin to lower serum cholesterol than in those given placebo. Apart from this main result, the 4S provided detailed information on rates of death and other manifestations of coronary heart disease, as well as on use of non-lipid forms of therapy. There were substantial differences in 4S placebo group rates of mortality, coronary deaths and major coronary events between countries. Surgical and medical therapy varied importantly between countries. Conclusions Major inter-country differences in rates of death and myocardial infarction in patients with coronary heart disease were likely to be due to a composite of differences in baseline characteristics including smoking. They occurred in a setting of very uneven exploitation of the potential for improving survival of patients with ischaemic heart disease.

We used a fluorescence flow cytometry assay with a monoclonal low density lipoprotein (LDL) receptor-specific antibody to detect LDL receptor expression on blood T lymphocytes and monocytes. We prepared peripheral blood mononuclear cells from patients with genetically verified LDL receptor-defective (Trp66-Gly mutation, n = 17) or receptor-negative (Trp23-stop mutation, n = 17) heterozygous familial hypercholesterolemia (FH) and from healthy individuals (n = 24). The cells were stimulated to express the maximum amount of LDL receptor by preincubation in lipoprotein-deficient medium. A dual-labeling technique allowed flow cytometric analysis of LDL receptor expression on cells identified by fluorescently conjugated surface marker antibodies. Knowing the LDL receptor gene mutation of the FH patients allowed us to compare the diagnostic capability of this functional assay with the DNA diagnosis and to validate the assay with molecular genetics instead of clinical indices of heterozygous FH. T lymphocytes expressed more LDL receptors and gave better diagnostic results than monocytes, and cells from patients with either the Trp66-Gly or the Trp23-stop mutation had variable but significantly reduced LDL receptor expression. The data indicate that this fluorescence flow cytometry assay is unsuitable for diagnosis of individual cases of heterozygous FH but that it may be useful for functionally characterizing mutations in the LDL receptor gene.

(1998). Prevention of Coronary Heart Disease in Clinical Practice. Summary of Recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Blood Pressure: Vol. 7, No. 5-6, pp. 262-269.

Coronary heart disease (CHD) emerged in North America and Europe as a leading cause of disease and death in the mid 20th century, and is now rapidly increasing in developing nations. By the mid 1980s, American and European academic institutions had issued several sets of guidelines indicating ways to prevent CHD. Continually revised and broadly disseminated since then, CHD guidelines have become increasingly based on evidence derived from several fields of medical science including prospective clinical trials. All CHD guidelines emphasise a healthy lifestyle and the judicious use of drugs, and the focus now is on the cost of, and barriers to, the implementation of internationally adopted CHD guidelines, and on methods by which to make them acceptable and useful at national and local levels. Such methods include the development of national guidelines and the organisation of shared care programmes and healthcare teams.

Background The Scandinavian Simvastatin Survival Study (4S) demonstrated pronounced reductions in mortality and major coronary events in a cohort of patients with established coronary heart disease (CHD). The present study provides a detailed, post hoc assessment of the efficacy and safety of simvastatin therapy in the following subgroups of 4S patients: those ≥65 years of age, those Methods and Results The 4S cohort of 4444 CHD patients included 827 women and 1021 patients ≥65 years of age. Total cholesterol at baseline was 5.5 to 8.0 mmol/L with triglycerides ≤2.5 mmol/L. Patients were randomized to therapy with simvastatin 20 to 40 mg daily or placebo for a median follow-up period of 5.4 years. End points consisted of all-cause and CHD mortality, major coronary events (primarily CHD death and nonfatal myocardial infarction), other acute CHD and atherosclerotic events, hospitalizations for CHD and cardiovascular events, and coronary revascularization procedures. Mean changes in serum lipids were similar in the different subgroups. In patients ≥65 years of age in the simvastatin group, relative risks (95% confidence intervals) for clinical events were as follows: all-cause mortality, 0.66 (0.48 to 0.90); CHD mortality, 0.57 (0.39 to 0.83); major coronary events, 0.66 (0.52 to 0.84); any atherosclerosis-related event, 0.67 (0.56 to 0.81); and revascularization procedures, 0.59 (0.41 to 0.84). In women, the corresponding figures were 1.16 (0.68 to 1.99); 0.86 (0.42 to 1.74), 0.66 (0.48 to 0.91), 0.71 (0.56 to 0.91), and 0.51 (0.30 to 0.86), respectively. Conclusions Cholesterol lowering with simvastatin produced similar reductions in relative risk for major coronary events in women compared with men and in elderly (≥65 years of age) compared with younger patients. There were too few female deaths to assess the effects on mortality in women. Because mortality rates increased substantially with age, the absolute risk reduction for both all-cause and CHD mortality in simvastatin-treated subjects was approximately twice as great in the older patients.

Background: Although treatment of myocardial overload effectively reduces death from progression of heart failure, it is not known whether the retardation of progressive coronary artery disease obtained with lipid lowering treatment will prevent the onset and consequences of heart failure in patients without previous symptoms of heart failure. Methods and Results: In the Scandinavian Simvastatin Survival Study, 4444 patients with coronary heart disease without evidence of heart failure were randomized to placebo (n = 2223) or simvastatin 20–40 mg (n = 2221) and followed for more than 5 years. Among the patients who received placebo, 228 (10.3%) were diagnosed with heart failure during follow-up evaluation compared with 184 (8.3%) of patients who received simvastatin (P < .015). Mortality was 31.9% in the placebo group and 25.5% in the simvastatin group among patients who developed heart failure. These compare with 9.2 and 6.6%, respectively, among non-heart failure patients. There were 45 hospitalizations because of acute heart failure in the placebo group and 23 in the simvastatin group (NS). Patients who developed heart failure were more likely to have suffered a recurrent myocardial infarction and have a history of diabetes, peripheral artery disease, and hypertension than patients who did not develop congestive heart failure. Conclusion: Long-term prevention with simvastatin reduces the occurrence of heart failure in a cohort of patients with coronary heart disease without previous evidence of congestive heart failure.

The objective of the present study was to examine the possible associations between low molecular weight (LMW) apolipoprotein(a) (apo(a)) isoforms (F,B,S1,S2) and coronary heart disease (CHD). We conducted a nested case-control (prospective) study of five cohorts of white men: The 1936 cohort (baseline 1976, n 548) and four cohorts from MONICA I born in 1923 (n463), 1933 (n491), 1943 (n504) and 1953 (n 448) studied at baseline in 1983. At follow up in 1991, 52 subjects had developed a first myocardial infarction and 22 had been hospitalized with angina pectoris. Plasma samples obtained at baseline were stored frozen until 1993‐94, when case samples (n 74) were analyzed together with samples from matched (disease free) controls (n190). In a statistical model (conditional logistic regression) including all age groups, cholesterol (or apo B) level (PB0.01), systolic blood pressure (P0.05) and smoking (P 0.02) predicted CHD. In the statistical model Lp(a) interacted significantly with age (OR5.7; 95% CI: 1.4‐23.6; P0.016), and high Lp(a) (over 45 mg:dl) was associated with significantly increased risk in subjects under 60 years (OR3.82; 95% CI: 1.47‐9.96), but not in older men (OR 0.67; 95% CI: 0.235‐1.89). Therefore, we studied the impact of Lp(a):apo(a) and other variables in subjects who had been under 60 years when they became cases. Among the younger subjects the presence of LMW apo(a) isoforms significantly predicted the development of CHD (OR3.83; 95% CI: 1.18‐12.4). The increased risk pertained to high Lp(a) (above versus below 45 mg:dl: OR 3.68; 95% CI: 1.03‐13.10), and to Lp(a) concentrations when entered into the model as a continuous variable (P 0.04). Cholesterol or apo B (PB0.01), smoking (P0.02), systolic blood pressure (P 0.05) and low alcohol consumption (under nine drinks:week) (P0.04) were also significant predictors of CHD. We conclude that LMW apo(a) isoforms are significantly associated with increased risk of CHD in men under 60 years. © 1997 Elsevier Science Ireland Ltd.

OBJECTIVE To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events. RESEARCH DESIGN AND METHODS A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5–8.0 mmol/l, and serum triglycerides ≤ 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6–18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures. RESULTS Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30–1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27–0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43–0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58–0.87; P = 0.001), 0.68 (95% CI, 0.60–0.77; P < 0.0001), and 0.74 (95% CI, 0.68–0.82; P < 0.0001). CONCLUSIONS The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.