Nutrición y epigenética en aterosclerosis /Nutrition and epigenetics in atherosclerosis

It is clear that nutrition in utero and at critical periods in childhood affects the risk of metabolic disorders and atherosclerosis later in life. Epigenetics provides conceptual and methodological instruments to explain these observations from a molecular point of view. The promise of epigenetics is to indicate novel strategies for prevention and therapy of atherosclerosis and associated risk factors.

Changes in diet are likely to reduce cardiovascular disease (CVD), but after decades of active research and heated discussion the question still remains: what is the optimal diet to achieve this goal? Is a low fat, as traditionally recommended by multiple medical societies? Or a high monounsaturated fat as predicated by the Mediterranean diet? Perhaps a high polyunsaturated fat based on the cholesterol lowering effects? The right answer may be all of the above but not for everybody. A well-known phenomenon in nutrition research and practice is the dramatic variability in interindividual response to any type of dietary intervention. There are many other factors influencing response, and they include, among many others, age, sex, physical activity, alcohol, and smoking as well as genetic factors that will help to identify vulnerable populations/individuals that will be benefit from a variety of more personalized and mechanistic based dietary recommendations. This potential could and needs to be developed within the context of nutritional genomics that in conjunction with systems biology may provide the tools to achieve the holy grail of dietary prevention and therapy of CVD. This approach will break with the traditional public health approach of “one size fits all.”

The diet-heart hypothesis, proposed at the beginning of the last century, was essentially based on the relationship between dietary saturated fat, serum cholesterol and coronary heart diseases. In the last few years it has become more and more evident that this kind of hypothesis is too reductive for many reasons. First of all atherogenesis is a complex process due to different risk factors, not only serum cholesterol levels. Secondly, dietary components may act on all these risk factors, thus influencing cardiovascular risk through different biological pathways. This means that, in the identification of the optimal diet for cardiovascular disease prevention, the influence of dietary components on all the possible cardiovascular risk factors, LDL cholesterol, but also blood pressure, other plasma lipids, thrombotic tendency, diabetes, insulin sensitivity, postprandial blood glucose and lipids, low-grade systemic inflammation, oxidative stress should be considered

Se analiza la evolución de los hábitos alimentarios de la población española desde 1991 hasta la actualidad a partir de los datos recogidos en los tres estudios transversales de la cohorte DRECE (Dieta y Riesgo de Enfermedades cardiovasculares en España) en los periodos: 1991-92; 1996-97 y 2005-06. El consumo de los diferentes grupos de alimentos, el análisis de macro y micronutrientes se mostrarán de manera descriptiva y en asociación con diferentes marcadores de riesgo cardiovascular y mortalidad.

El programa DRECE consiste en un estudio longitudinal que se inició en 1992 y que está permitiendo realizar el seguimiento de cuna cohorte de 4878 incividuos en toda España. En esta ponencia, analizaremos los principales Factores de riesgo basales y la evolución del perfil lipídico de la población en estos 15 años de seguimiento.

4560 DRECE subjects have been followed during 12 years. Vital status and cause of death revealed 100 exitus. Surprisingly cancer is the most frequent cause (42%) in this cohort. Cardiovascular mortality accounts for 18 %. Diabetes mellitus appears as main risk factor for the earliest cardiovascular death.

Michael Aviram. Lipid Research Laboratory, Rambam Medical Center, Haifa, Israel

As macrophage foam cell formation, the hallmark of early atherogenesis, is increased under oxidative stress and since polyphenols – rich nutrients, as well as HDL possess anti-oxidative properties, we analyzed the effect of dietary antioxidants and that of HDL- associated paraoxonase1 (PON1) on macrophage foam cell formation and on atherosclerosis development. The interrelationship between pomegranate hydrolyzable tannin (punicalagin) free radicals scavenging, and PON1 lipo-lactonase activity on oxidized phospholipids, was shown to significantly attenuate atherosclerosis development.

Andrew D. Watson. Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA

Oxidation of phospholipids in low-density lipoproteins (LDL) stimulates an inflammatory response in vascular wall cells and contributes to the development of atherosclerosis. One mechanism by which high-density lipoproteins (HDL) and HDL mimetic peptides protect against atherogenesis is by interfering in the production and action of oxidized phospholipids and facilitating their removal from the vessel wall and circulation.

Robin P. Choudhury. Department of Cardiovascular Medicine, University of Oxford and Wellcome Trust Clinical Fellow and Consultant Cardiologist, UK

From early fatty streak lesions to advanced plaques, macrophage-derived foam cells are integral to the development and progression of atherosclerosis. Recent elucidation of molecular and cellular processes involving macrophages has suggested numerous therapeutic targets. We will consider actual and potential macrophage-directed pharmacologic interventions; the development of drugs targeting these pathways and the emergence of sensitive imaging techniques that have been able to identify changes in plaque size and composition in response to treatment.

Enzo Nisoli. Center for Study and Research on Obesity, Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy

Metabolic syndrome is a particularly challenging clinical condition to treat because of its complex molecular basis. Impaired cell metabolism has been suggested as a putative pathophysiological process. Recently, we have reported that mitochondrial biogenesis and function are increased by nitric oxide in various cell types and tissues. Moreover, we found that endothelial nitric oxide synthase null mutant mice are affected by visceral fat accumulation, high blood pressure, and insulin resistance with concomitant reduction of mitochondrial content in several tissues, including adipose tissue and skeletal muscle. This implies that a detective nitric oxide production might be linked to cell metabolism dysfunction. Here we summarize our view on this issue and propose a novel pathophysiological hypothesis for metabolic syndrome with putative therapeutic implications.

Carlos Macaya. Instituto Cardiovascular, Hospital Clínico San Carlos, Madrid, Spain

Nuevos avances en cardiología intervencionista / New advances in interventional cardiology

La implantación percutánea de prótesis valvulares y la reparación, también percutánea de la válvula mitral son técnicas en fase de investigación preclínica y ya clínica en algunos casos. En la enfermedad arterial coronaria, la introducción de los stents liberadores de fármacos (SLF) antiproliferativos en la cardiología intervencionista ha relegado el problema de la reestenosis postangioplastia a un segundo plano. Por otro lado, su uso casi generalizado de los SLFs ha tenido impacto clínico en forma de aumentar cada vez más el número de pacientes con enfermedad de tronco coronario izquierdo y de 3 vasos que se revascularización con intervenciones percutáneas. No obstante se está observando un problema que afecta a la seguridad de estos SLFs, la magnitud y prevención de la trombosis tardía de estos SLFs está por definir y aunque el problema es infrecuente, las consecuencias clínicas son muy graves, con una tasa de mortalidad al año superior al 50%. El desarrollo de nuevos stents con fármacos y el desarrollo de nuevas técnicas de imagen pueden optimizar los resultados, tanto de eficacia como de seguridad de los SLFs.

Iris Rajman. EU Exploratory Program Phase Medicine, Eli Lilly & Co., Erl Wood ELCL, UK

Desarrollo farmacológico: Utilización de marcadores biológicos en la evaluación de eficacia / Drug Development: Use of Biomarkers in Evaluation of Efficacy

There are many challenges for clinical development of new cardiovascular medicines. Greater use of efficacy biomarkers may provide support in both early and late clinical development. Biomarkers of efficacy may be used as level 1, 2 or 3 biomarkers. Some of the challenges and options for biomarker use in clinical development of new drugs to treat ‘atherosclerosis ‘ will be discussed.

Conferencia Clausura / Closure Address
Moderador /Chairperson: José A. Gutiérrez Fuentes

Ira Tabas. Department of Medicine, Columbia University, New York, USA

Impacto de la resistencia insulínica sobre los condicionantes de muerte de los macrófagos en la aterosclerosis avanzada / The Impact of Insulin Resistance on Macrophage Death Pathways in Advanced Atherosclerosis

Macrophage death in advanced atherosclerosis causes plaque necrosis, which promotes plaque rupture and acute atherothrombotic vascular events. Of interest, plaque necrosis and atherothrombotic disease are markedly increased in diabetes and metabolic syndrome. We discovered a novel "multi-hit" macrophage apoptosis pathway that appears to be highly relevant to advanced atherosclerosis. The elements of the pathway include: (a) activation of the unfolded protein response (UPR) by cholesterol overloading of the endoplasmic reticulum or by other UPR activators known to exist in atheromata; and (b) combinatorial signaling involving two macrophage pattern recognition/atherogenic lipoprotein receptors—the type A scavenger receptor (SRA) and toll-like receptor 4 (TLR4). The downstream apoptosis effectors include CHOP (GADD153) for the UPR and JNK and STAT1 for SRA/TLR4 signaling. Remarkably, components of this pathway are enhanced in macrophages with defective insulin signaling, including UPR activation and SRA expression. As a result, insulin-resistant macrophages show increased susceptibility to apoptosis when exposed to UPR activators and SRA/TLR4 ligands. Moreover, the advanced lesions of atherosclerosis-prone mice reconstituted with insulin-resistant macrophages show increased macrophage apoptosis and plaque necrosis. Based on these findings, we propose that one mechanism of increased plaque necrosis and atherothrombotic vascular disease in insulin resistant syndromes is up-regulation of a multi-hit signal transduction pathway involved in advanced lesional macrophage death.

Despedida / Farewell

Ponente: Andreu Palou
Departamento de Biología Fundamental y Ciencias de la Salud, Universidad de las Islas Baleares, Spain

Evaluación Científica de riesgos en materia de Seguridad Alimentaria en la Unión Europea / Scientific Risk Evaluation For Food Security In The European Union

La evaluación de riesgos en materia de seguridad alimentaria comprende al menos las siguientes etapas: a) identificación del problema y análisis del contexto en el que se desenvuelve; b) caracterización del riesgo y justificación de cualquier juicio de valor o estrategia aplicada en la evaluación del riesgo; c) elucidación de los mecanismos; d) análisis de posibles opciones aplicables en la gestión del riesgo.
Sin embargo, la evaluación del riesgo no proporciona toda la información en la que deben basarse las decisiones políticas o de gestión del riesgo. En todo caso, es importante que todas las partes interesadas o afectadas por la posible decisión de gestión, hayan tenido la oportunidad de hacer sus aportaciones al propio proceso de gestión del riesgo: organizaciones de consumidores, industrias alimentarias, instituciones de investigación y formación, así como entidades legisladoras / reguladoras. Las características o principios para un buen asesoramiento científico incluyen, como elementos principales: la independencia (de toda clase de poderes e influencias) y la transparencia (con amplia publicidad de las decisiones, incluidos los detalles y procedimientos), además de la excelencia científica. Junto a ello es preciso que el estudio o evaluación científica se efectúe en un contexto real, práctico, que sea efectivo, y que pueda ser comprendido (transparente) por personas no especializadas. Probablemente la Unión Europea y los EEUU mantienen el suministro de alimentos más seguro del planeta, y la credibilidad conseguida por los actuales paneles científicos europeos (Autoridad Europea en Seguridad Alimentaria, European Food Safety Authority (EFSA) o instituciones como la FDA americana (Food and Drug Administration. Administración de Drogas y Alimentos de los Estados Unidos), no es ajena a la aplicación de los citados principios La creación de la EFSA en 2002 (http://www.efsa.eu.int/), ha supuesto la unificación en Europa de las funciones de dictamen, arbitraje y asesoramiento científico que provisionalmente se asignaron al Comité científico de la Alimentación Humana (SCF, Scientific Committee on Food, 1997-2002) y a otros comités en 1997, y la consolidación de un proceso de mejora cualitativa en Europa, con una reestructuración iniciada a partir de 1996, que no fue ajena a las crisis alimentarias. La revisión de las diferentes actividades que llevan a cabo los diversos Paneles Científicos de la EFSA (aditivos, saborizantes y materiales en contacto, en alimentación humana; aditivos y productos o substancias usados en alimentación animal; productos dietéticos, nutrición y alergias; organismos modificados genéticamente; productos para la protección vegetal; peligros biológicos; contaminantes en la cadena alimentaria; salud y bienestar animal, residuos y salud vegetal) permite un acercamiento a como se canalizan y tratan los problemas en el día a día de la evaluación científica de riesgos asociados a la alimentación en la Unión Europea.

Tratamiento farmacológico en prevención primaria / Drug treatment in primary Prevention

Cardiovascular diseases represent the 1st cause of morbidity and mortality in Western countries. There are several major risk factors involved in the development of these diseases. Enormous efforts have been done to achieve several drugs able to reduce these factors, and to demonstrate their efficacy and safety profile, not only in achieving the control of every particular risk factor, but also reducing the incidenc e of cardiovascular events. However, as all drugs have an economic cost and a potential incidence of adverse effects, not all the general population can receive these drugs to prevent the disease. Several clinical guidelines and recommendations have been developed as a tool to be applied in daily clinical practice in primary prevention of the disease, approaching the clinical evidence to the doctor. These aspects will be discussed in a colloquial and interactive style.

Tratamiento farmacológico en prevención secundaria / Farmacological treatment in secondary prevention

Cardiovascular secondary prevention plays a major role in cardiovascular morbidity and mortality since the average age of the general population is increasing constantly and the prevalence and risk of cardiovascular disease goes parallel. Lifestyle modification; including smoking cessation, normalization of cholesterol plasma levels, glucose and triglycerides, changes in eating habits and physical exercise in order to obtain a BMI < 25, is an essential part of the general approach for secondary prevention in order to maximize the effectivity of drug therapy. Nowadays; statins are at the central stage of the pharmacological treatment, since a large number of trials have indicated a significant reduction of coronary events (more than 30%). ACE inhibitors may apparently reduce the plaque formation and rupture, avoiding the coronary vascular disaster. Also beta-blockers and aspirin (clopidogrel when aspirin is contraindicated) can be applied for therapeutic measures. Guidelines and practical algorithms may be an excellent help to stratify cardiovascular risk and to establish a good approach for secondary prevention.

•  Ponencias de 20 minutos / 20-minute talks
•  30 minutos de discusión al finalizar la mesa / 10-minute discussion after each session
•  Seminarios: En grupos reducidos, orientados a la discusión y actualización de aspectos prácticos relacionados con la prevención, el diagnóstico y el tratamiento

Fundación Lilly

ENGLISH <> SPANISH : TRADUCCIÓN SIMULTANEA <> SIMULTANEOUS TRANSLATION PROVIDED