82ND EAS CONGRESS,
EAS 2014 MADRID, SPAIN
Plenary Speakers | Workshop Speakers
May 31-June 03, 2014
The 82nd Congress of the European Atherosclerosis Society marks the 50th Anniversary of the Society, an occasion we will celebrate throughout the meeting, which will take place in Madrid, Spain.
The scientific programme features experts at the forefront of research in both clinical and basic science in the field of atherosclerosis. Take part and present your research – abstract submission deadline is January 08, 2014.
Focus on Science: Presenting EAS Madrid 2014 Plenary Speakers
Fredrik Bäckhed is Professor at the University of Gothenburg, Director of the Wallenberg Laboratory for Cardiovascular Research, and co-director for the Center for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, Gothenburg, Sweden. His research has been focused on investigating the role of the gut microbiota in metabolic disease, using a combination of clinical-oriented research and gnotobiotic mouse models. Professor Bäckhed has been the recipient of numerous awards including in 2013, the Prince Daniel Grant for promising young researchers and the DuPont Young Professor Award.
The gut microbiota is increasingly considered an environmental factor contributing to obesity, diabetes and cardiovascular disease. Studies have shown that genetically engineered germ-free mice are resistant to developing diet-induced obesity, glucose intolerance and insulin resistance. However, colonisation of these mice with a normal microbiota increased the amount of body fat by about 50% and reduced insulin sensitivity. Further, shotgun metagenomic analysis of the gut microbiome in obese mice identified an enrichment of genes associated with carbohydrate and lipid metabolism, thereby implicating these 'obesogenic' microbiota in transmission of metabolic disease. Both in animal and human studies, obesity has been linked to a different composition of the gut microbiota.
Recent studies have also identified microbial DNA originating from the mouth and the gut in human atherosclerotic plaques, suggesting that bacteria directly promote the development of atherosclerosis. Further, the gut microbiota were shown to play a role in modulating immune function, by regulating the production of cytokines and chemokines which influence the T cell repertoire of the gut, and other immune mediators.
Taken together, these findings support the hypothesis that the gut microbiota may be a potential therapeutic target in the management of metabolic disease. However there are a number of caveats to current findings: limited subject numbers and heterogeneity in subject characteristics, including diet; interindividual variation in the composition of the gut microbiota; and methodological issues. Thus, the challenge for the future is to delineate the interactions between specific bacteria in the human gut and the host on a molecular level, so as to define their impact on susceptibility to metabolic disease and atherosclerosis in vivo.
Bäckhed F. The gut microbiota — masters of host development and physiology. Nature Reviews Microbiology 2013; doi:10.1038/nrmicro2974
Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature 2012; 489, 242–9.
Reinhardt C, Bergentall M, Greiner T U, Schaffner F, Österlund-Lundén G, Petersen L C, Ruf W,
Bäckhed F. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 2012;483, 627–31.
Ira Tabas is the Richard J. Stock Professor and Vice-Chair of Research in the Department of Medicine and Professor of Pathology & Cell Biology (in Physiology and Cellular Biophysics), Columbia University, New York, USA. Professor Tabas' research focuses on the molecular-cellular mechanisms of atherosclerosis, with an emphasis on macrophage cell biology, endoplasmic reticulum-induced cell death (apoptosis), mechanisms involved in the generation of clinically dangerous atherosclerotic plaques, translational work in mouse models of atherosclerosis, and mechanistic-based correlative studies on human disease tissue. His recent activities have expanded into mechanisms of atherosclerosis in diabetes and obesity, including new studies on liver and adipose tissue.
Atherosclerosis is a chronic inflammatory disease involving activation of innate and adaptive immunity. Recent identification of dendritic cells (DCs) in atherosclerotic plaques, both in humans and animal models, is of critical interest, given the myriad functions of DCs, which include lipid uptake, antigen presentation, efferocytosis, and inflammation resolution. DCs also possess potent antigen-presenting capacity and the ability to activate T cells. However, as different T cell subsets can either promote or suppress atherogenesis, the net effect of DC-mediated T cell activation in the setting of atherosclerosis is a critical question.
Recent findings provide evidence that endogenous MyD88-mediated DC activation and maturation is atheroprotective via activation of regulatory T cells (Tregs), which suppresses monocyte recruitment via decreasing the levels of monocyte chemokine MCP-1, probably in a TGF-β–dependent manner. Further, Treg-induced TGF-β may further enhance the antiinflammatory and antiatherosclerotic response through direct actions of TGF-β on DCs themselves. Such insights suggest potential for DC-mediated antiatherosclerosis vaccines, perhaps in combination with agents that activate endogenous cell biological processes involved in the stability and function of Tregs and/or in the feedback suppression of inflammatory T effector cells.
Tabas I, Glass CK. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 2013; 339:166-72.
Subramanian M, Thorp E, Hansson GK,
Tabas I. Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest 2013;123:179-88.
Ozcan L, Wong CCL, Li G, Xu T, Pajvani U, Park SKR, Wronska A, Chen B-X, Marks AR, Fukamizu A, Johannes Backs, Singer HA, Yates JRIII, Accili D,
Tabas I. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metabolism 2012;15:1–13.
Johan Kuiper is Professor of Therapeutic Immunomodulation at Leiden University, The Netherlands. His recent research focuses on investigation of immunomodulation of inflammatory responses that lead to the development of atherosclerotic plaques. Regulation of pro-inflammatory cytokines by various strategies such as tolerance induction, [DNA] vaccination and modulation of the activity of natural killer T cells are the main areas of research. Dendritic cell therapy is also being exploited as a new therapy for atherosclerosis. Professor Kuiper is an Established Investigator of the Netherlands Heart Foundation.
Treatment of atherosclerosis is based on lipid lowering therapies that slow the progression of this inflammatory disease, but is unable to fully inhibit lesion development or progression. Vaccination has been shown to be very effective in managing immune disease, thereby providing a rationale for investigating its use in atherosclerosis. However, a key issue is selection of the appropriate antigen to target.
To date, vaccination strategies for atherosclerosis have focused on targeting of lipid-antigens, inflammation-derived antigens, and most recently cell-based approaches. Lipid-based approaches investigated include cholesteryl ester transfer protein (CETP) B cell epitopes, most recently using human intestinal trefoil factor (TFF3), which offers the possibility of oral administration; vaccination against oxidised low-density lipoprotein (LDL); apolipoprotein (apo)B100 p210 peptide; and 2D03-IgG antibody therapy. Inflammation-based strategies include those targeting heat shock proteins, which act as sentinels in cellular stress responses; cytokines/growth factors, specifically interleukin-2 and interkeukin 15; and metabolic factors, such as ghrelin, a peptide hormone involved in feeding behaviour, energy metabolism, and glucose/insulin metabolism. Recently, attention has focused on the use of dendritic cells (DC), due to their capacity to regulate immune mechanisms in atherogenesis. Data suggest that tolerogenic DC therapy may be a feasible approach to prevent systemic inflammation. However, while current studies have been aimed at preventing development of atherosclerosis, a more relevant strategy from the clinical perspective may be to target lesion progression or even regression.
de Jager SCA,
Kuiper J. Vaccination strategies in atherosclerosis. Thromb Haemost 2011;106:796-803.
Foks AC, Ran IA, Wasserman L, Frodermann V, Ter Borg MN, de Jager SC, van Santbrink PJ, Yagita H, Akiba H, Bot I,
Kuiper J, van Puijvelde GH. T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis. Arterioscler Thromb Vasc Biol 2013;33:2558-65.
Foks AC, van Puijvelde GH, Bot I, ter Borg MN, Habets KL, Johnson JL, Yagita H, van Berkel TJ,
Kuiper J. Interruption of the OX40-OX40 ligand pathway in LDL receptor-deficient mice causes regression of atherosclerosis. J Immunol 2013;191:4573-80.
Carlos Fernández-Hernando is Professor at the Department of Medicine (Division of Cardiology) and Cell Biology of the Langone Medical Center, University of New York. His work focuses on determining the role of microRNAs, a novel class of small non-coding RNAs that mediate post-transcriptional gene silencing, in the metabolism of cholesterol and other related cardiovascular diseases. Recent findings include characterisation of miR-33 as a regulator of high-density lipoprotein (HDL) biogenesis, cellular cholesterol efflux and glucose metabolism; and miR-144 as a regulator of cholesterol metabolism via suppression of expression of the ATP binding cassette transporter (ABCA1).
MicroRNAs (miRNAs) are short (22 nucleotides) noncoding RNA molecules that have emerged as critical regulators of gene expression at the posttranscriptional level. MiRNAs typically control the expression of their target genes by imperfect base pairing to the 3' untranslated regions of messenger RNAs (mRNAs), thereby inducing repression of the target mRNA. Initially described in cancer, recent findings have also demonstrated a key role in cardiovascular disease and atherosclerosis. MiRNAs control endothelial cell, vascular smooth muscle cell and macrophage functions, and thereby regulate the progression of atherosclerosis.
Interest has focused on the therapeutic potential of miRNAs in the light of recent findings from animal models. Overexpression of miR-144 reduced ABCA1 expression and attenuated apolipoprotein A1 in macrophages. miR-144 was also shown to play a key role in homeostatic regulation of cholesterol metabolism, inhibiting the expression of ABCA1 in the liver, thereby attenuating both cholesterol efflux to apolipoprotein A1 and HDL biogenesis. Conversely, silencing of miR-144
in vivo increased hepatic ABCA1 and plasma HDL levels in mice. Thus, miR-144 regulated both macrophage cholesterol efflux and HDL biogenesis in the liver. Data from animal models also showed that therapeutic silencing of miR-33 significantly reduces the progression of atherosclerosis and improves HDL functionality independently of plasma HDL cholesterol concentration. Preliminary data suggest that miR-33a/b coordinates genes regulating fatty acid metabolism and insulin signalling, suggesting potential as novel therapeutic targets for a range of metabolic diseases. Taken together, these findings suggest future possibilities for miRNAs as biomarkers and therapeutic targets in atherosclerosis and cardiovascular disease.
Rotllan N, Ramírez CM, Aryal B, Esau CC,
Fernández-Hernando C. Therapeutic silencing of microRNA-33 inhibits the progression of atherosclerosis in Ldlr-/- mice--brief report. Arterioscler Thromb Vasc Biol 2013;33:1973-7.
Ramírez CM, Rotllan N, Vlassov AV, Dávalos A, Li M, Goedeke L, Aranda JF, Cirera-Salinas D, Araldi E, Salerno A, Wanschel A, Zavadil J, Castrillo A, Kim J, Suárez Y,
Fernández-Hernando C. Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ Res 2013;112:1592-601.
Norata GD, Sala F, Catapano AL,
Fernández-Hernando C. MicroRNAs and lipoproteins: a connection beyond atherosclerosis? Atherosclerosis 2013;227:209-15.
Marja-Riitta Taskinen is Emerita Professor of Internal Medicine, University of Helsinki, Finland. Professor Taskinen has contributed significantly to the understanding of lipoprotein abnormalities, genetics and pathophysiology in type 2 diabetes, insulin resistance and the metabolic syndrome. Recent research has also focused on family studies of both the familial combined hyperlipidaemia and low high-density lipoprotein (HDL) traits. Professor Taskinen has received numerous international honours and awards, including the Claude Bernard Award (European Association for the Study of Diabetes [EASD] 2002), the Edwin Bierman Award (American Diabetes Association, 2004) and the Finnish Foundation for Cardiovascular Research Award (2011). She is actively involved in activities of the EAS, EASD, International Atherosclerosis Society, International Diabetes Federation, and the International Task Force for Prevention of Coronary Heart Disease.
Atherogenic dyslipidaemia, characterised by high levels of plasma triglycerides and remnants, low levels of HDL cholesterol and a preponderance of small dense low-density lipoprotein (LDL)-particles, is a common feature of type 2 diabetes mellitus. Overproduction of large very low-density lipoprotein (VLDL) particles is a fundamental defect driving lipoprotein changes associated with this dyslipidaemia. Increased flux of free fatty acids to the liver promotes triglyceride production, and in turn stimulates the secretion of apolipoprotein B (apoB) and very low-density lipoprotein (VLDL) cholesterol. The increase in hepatic VLDL cholesterol production correlates with the degree of liver fat accumulation. Increased liver fat has been shown to increase triglycerides by a combination of increased secretion and severely impaired clearance of triglyceride-rich VLDL1 particles, and increased plasma levels of apolipoprotein C-III due to impaired clearance. These atherogenic lipid abnormalities precede the diagnosis of type 2 diabetes by several years.
Moreover, despite a seemingly "healthy" lipid profile in type 1 diabetes, there is evidence of lipoprotein abnormalities which are not revealed by conventional lipid parameters. Studies show that VLDL are frequently enriched in esterified cholesterol, and HDL particles are often enriched in triglycerides, which may lead to loss of potentially atheroprotective HDL particle functionality. Elucidating the mechanisms underlying lipoprotein abnormalities in both types of diabetes will potentially provide insights to improved clinical management.
Taskinen MR, Olofsson SO, Levin M. Ectopic lipid storage and insulin resistance: a harmful relationship. J Intern Med 2013;274:25-40.
Adiels M, Matikainen N, Westerbacka J, Söderlund S, Larsson T, Olofsson SO, Borén J,
Taskinen MR. Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity. Atherosclerosis 2012;222:222-8.
Taskinen MR, Adiels M, Westerbacka J, Söderlund S, Kahri J, Lundbom N, Lundbom J, Hakkarainen A, Olofsson SO, Orho-Melander M, Borén J. Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects. Arterioscler Thromb Vasc Biol 2011;31:2144-50.
Philip Newsome is Professor of Experimental Hepatology and Clinical Director of the Birmingham University Stem Cell Centre, UK. The focus of his work is understanding cellular contributions to repair following liver injury. A major interest is in studying the trafficking, engraftment and functional contribution that bone marrow stem cells and hES-derived hepatocytes make to liver injury/regeneration. Professor Newsome is the clinical lead for the metabolic liver service at the Liver Unit in Birmingham. This includes cohorts of patients with Non-alcoholic fatty liver disease (NAFLD), tyrosinaemia, glycogen storage disease, porphyria and cystic fibrosis, who are likely candidates for cell therapy in the future. Thus, his research interest in NAFLD covers both basic science and clinical components.
Non-alcoholic fatty liver disease (NAFLD) is a condition defined by excessive fat accumulation in the form of triglycerides in the liver, with a disease spectrum ranging from simple steatosis (fatty liver), through non-alcoholic steatohepatitis (NASH) to fat with fibrosis and ultimately cirrhosis. Simple steatosis is largely benign and non-progressive, whereas NASH, characterised by hepatocyte injury, inflammation and fibrosis can lead to cirrhosis, liver failure and hepatocellular carcinoma. NAFLD is strongly associated with obesity, insulin resistance, hypertension and dyslipidaemia and is now regarded as the hepatic manifestation of the metabolic syndrome and the most common cause of liver disease in Western countries. The pathogenesis of NAFLD is thought to be due to the effects of hyperinsulinaemia associated with insulin resistance leading to an increased uptake and synthesis of free fatty acids resulting in simple fatty liver, together with multiple pathogenetic factors including oxidative damage, dysregulated hepatocyte apoptosis, activation of the profibrogenic transforming growth factor (TGF)-beta pathway, dysregulation of multiple adipokines and hepatic stellate cell activation. These pathways probably play the most prominent role in the pathogenesis of NASH.
The optimal management of patients with NAFLD/NASH remains a clinical challenge. Lifestyle changes are currently the cornerstone of treatment. Despite a number of trials of pharmacological agents, so far no highly effective treatment is available. Bariatric surgery may be beneficial for obese patients with NASH, but should be considered early before progression to cirrhotic disease. Ongoing studies are evaluating a number of novel agents for treatment of NAFLD/NASH including human glucagon-like peptide-1 analogues, and a dual peroxisome proliferator–activated receptor (PPAR)α/δ agonist.
Armstrong MJ, Barton D, Gaunt P, Hull D, Guo K, Stocken D, Gough SC, Tomlinson JW, Brown RM, Hübscher SG,
Newsome PN; LEAN trial team. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial. BMJ Open 2013;3(11):e003995.
Newsome PN, Allison ME, Andrews PA, Auzinger G, Day CP, Ferguson JW, Henriksen PA, Hubscher SG, Manley H, McKiernan PJ, Millson C, Mirza D, Neuberger JM, Oben J, Pollard S, Simpson KJ, Thorburn D, Tomlinson JW, Wyatt JS; British Transplant Society. Guidelines for liver transplantation for patients with non-alcoholic steatohepatitis. Gut 2012;61:484-500.
Newsome PN. New horizons for stem cell therapy in liver disease. J Hepatol;56:496-9.
Ira Goldberg is Professor of Medicine, Chief of the Division of Preventive Medicine and Nutrition, Institute of Human Nutrition, Presbyterian Hospital, Columbia University, New York. One of the key interests of his laboratory is understanding the effects of lipid uptake on cardiac function using mouse models that either overexpress or do not express lipoprotein lipase (LPL) in the heart. Recent work has helped to delineate the role of LPL in the pathophysiology of cardiac lipotoxicity.
Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (i.e. diabetic cardiomyopathy) is also increasingly recognised as a clinical entity. In patients with type 2 diabetes, ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and cardiomyocyte apoptosis, a process referred to as lipotoxicity.
The basis of cardiac lipotoxicity is the excessive accumulation of fatty acids or their intermediates in cardiomyocytes. Studies have implicated fatty acids, fatty acyl coenzyme A, and ceramide in cardiomyocyte lipotoxicity. Fatty acids are the source of energy for cardiac muscle and are required for the synthesis of several structural lipids, including phospholipids and sphingolipids. Fatty acids are taken up by heart via hydrolysis of triglycerides within lipoproteins by the action of lipoprotein lipase or by transport of albumin-bound free fatty acids (FFAs). In the setting of cardiometabolic disease, elevated circulating levels of FFA levels promote greater fatty acid uptake by the heart. When lipid uptake exceeds oxidation, more acyl CoA is shunted to the synthesis of ceramide.
There is growing evidence from studies using genetically modified mouse models that ceramide plays an important role in the pathogenesis of lipotoxic heart disease. Ceramide accumulation in the heart was correlated with the extent of cardiac dysfunction. However, the exact pathophysiology in humans is not yet fully understood. There are also conflicting data for the effects of triglyceride accumulation, being detectable both in patients with and without systolic and diastolic cardiac dysfunction. These uncertainties highlight the need for further study to ascertain the primary cause of cardiac lipotoxicity in patients with type 2 diabetes or metabolic syndrome.
Goldberg IJ, Trent CM, Schulze PC. Lipid metabolism and toxicity in the heart. Cell Metab 2012;15:805-12.
Goldberg IJ. Sphingolipids, lipotoxic cardiomyopathy, and cardiac failure. Heart Fail Clin 2012;8:633-41.
Naveed Sattar is Professor of Metabolic Medicine, University of Glasgow. His research interests focus on the causes, screening and prevention of heart disease, diabetes and obesity. He has expertise in biomarkers and epidemiology and increasingly in clinical trials and has published over 200 original papers, many of relevance to diabetes pathways, treatments and outcomes. He also contributes to the Emerging Risk Factor Collaboration led by colleagues in Cambridge and is part of the Scottish Diabetes Research Network (SDRN) epidemiology group. He has been awarded national and international prizes for his research, including the 2011 Minkowski prize awarded by the European Association for Study of Diabetes.
Epidemiologic studies have been critical in defining classical risk factors, including high blood pressure, dyslipidaemia, smoking, diabetes and lifestyle factors (physical inactivity and diet), which operate at both population and individual levels. The identification of these factors has resulted in the development of effective population-wide and high-risk approaches to prevention of cardiovascular disease (CVD).
Other biomarkers, including those of inflammation, have attracted attention as potential novel risk factors for CVD, diabetes or diabetes-related complications, but require further study to confirm whether the associations are causal. Identification of such factors could help in further understanding the pathophysiology of CVD, provide additional targets for intervention, or improve patient risk stratification beyond that with current approaches, especially in those at high risk of CVD. However, it is not enough to show a novel causal or noncausal biomarker is 'independently associated' with CVD, but it must also add incrementally to CVD prediction beyond classical risk factors.
Combining data from studies of genetics, imaging, metabolomics and proteomics may help to provide insights into causal pathways and a patient's response to treatment. Ultimately, major prospective intervention studies will serve as the litmus test for these parameters.
Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia 2013;56:686-95.
Wannamethee SG, Shaper AG, Whincup PH, Lennon L,
Sattar N. Adiposity, adipokines, and risk of incident stroke in older men. Stroke 2013;44:3-8.
Miller AM, Purves D, McConnachie A, Asquith DL, Batty GD, Burns H, Cavanagh J, Ford I, McLean JS, Packard CJ, Shiels PG, Turner H, Velupillai YN, Deans KA, Welsh P, McInnes IB,
Sattar N. Soluble ST2 associates with diabetes but not established cardiovascular risk factors: a new inflammatory pathway of relevance to diabetes? PLoS One 2012;7:e47830.
Jane Armitage, UK: Residual cardiovascular risk: management beyond statins
Jane Armitage is Professor of Clinical Trials and Epidemiology and Honorary Consultant in Public Health Medicine at the University of Oxford. She joined the Clinical Trial Service Unit (CTSU) in 1990 from a background in clinical medicine, with particular experience in respiratory medicine, geriatrics and diabetes. She has coordinated a series of large-scale clinical trials of therapeutic modulation of atherogenic dyslipidaemia in people with or at risk of vascular disease including the MRC/BHF Heart Protection Study, SEARCH and HPS2-THRIVE, as well as the ASCEND trial of aspirin and fish oils in diabetes. Her main research interests are in lipoproteins and cardiovascular epidemiology.
Statins represent the cornerstone for lowering low-density lipoprotein cholesterol (LDL-C) to prevent cardiovascular disease (CVD). However, it is clear that even with potent statin therapy, a high risk of CVD events persists, especially in individuals with cardiometabolic disease.
Other lipids and lipoproteins have been implicated as contributors to this risk. There is emerging evidence to support a role for elevated triglyceride-rich lipoproteins and remnants (with or without low high-density lipoprotein cholesterol [HDL-C]), especially in individuals with insulin-resistant conditions. The role of HDL-C itself is contentious. Although low HDL-C plasma concentration is established as a risk factor for coronary heart disease, thereby providing a firm basis for integration of HDL-C levels into the SCORE charts for global CV risk assessment, recent trials of HDL-raising agents have been disappointing. Genetic analyses also suggest that HDL-C plasma concentration is not the most appropriate marker for CV risk, which might be explained by the heterogeneity of the HDL particle population, in terms of size, molecular composition, structure, intravascular metabolism and biological function. Alternative HDL parameters, including HDL particle number or measures of HDL function, may represent better markers of residual CVD risk. Additionally, elevated lipoprotein(a) [Lp(a)], a recognised CV risk factor, has been implicated as a determinant of residual risk, although so far there are limited treatment options for specifically targeting Lp(a).
Finally, the development of inhibitors of proprotein convertase subtilisin kexin type 9 (PCSK9) offers the possibility of substantial lowering of LDL-C beyond that achieved with statin therapy.
HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91.
Parish S, Offer A, Clarke R, Hopewell JC, Hill MR, Otvos JD,
Armitage J, Collins R; Heart Protection Study Collaborative Group. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation 2012;125:2469-78.
Armitage J. LDL cholesterol targets--how low to go? Curr Opin Lipidol 2012;23:265-70.
Bertrand Cariou, France: PCSK9 Inhibition
Bertrand Cariou is Professor of Endocrinology, Nantes University Hospital, France. His research interests include diabetes and metabolic diseases, including dyslipidaemia. Proprotein convertase subtilisin kexin type 9 (PCSK9), an endogenous inhibitor of the low-density lipoprotein (LDL) receptor pathway has been a key focus of his research. Professor Cariou is currently involved in numerous phase III studies of monoclonal anti-PCSK9 antibody therapy in patients at high risk of cardiovascular disease (CVD).
Lowering low-density lipoprotein cholesterol (LDL-C) is the primary priority for management of dyslipidaemia. However, even with intensive statin therapy, it is recognised that a substantial proportion of patients at high risk of CVD do not attain LDL-C goal.
Proprotein convertase subtilisin kexin type 9 (PCSK9), a post-translational regulator of LDL receptor activity, plays a pivotal role in controlling circulating LDL-C levels. Identification of loss of function PCSK9 mutations offered a novel possibility to managing LDL-C. Carriers of these loss of function variants not only had significantly lower LDL-C plasma levels, resulting from higher LDL receptor levels and increased LDL-C turnover, but also had lower prevalence of subclinical atherosclerosis and clinical CVD events.
As a consequence, PCSK9 has emerged as a key pharmacological target in the management of hypercholesterolaemia. Current approaches in clinical development have focused on mimetic peptides and monoclonal antibodies that exclusively target circulating PCSK9 and therefore its extracellular function. Data from short- to mid-term studies show that these treatments are effective, lowering plasma levels by >50% in statin-treated patients with no indication of any adverse signal. Clearly, the key question is whether these PCKS9 inhibitors can impact CVD outcomes, which is being addressed by ongoing Phase III trials.
Le May C, Berger JM, Lespine A, Pillot B, Prieur X, Letessier E, Hussain MM, Collet X,
Cariou B, Costet P. Transintestinal cholesterol excretion is an active metabolic process modulated by PCSK9 and statin involving ABCB1. Arterioscler Thromb Vasc Biol 2013;33:1484-93.
Cariou B, Langhi C, Le Bras M, Bortolotti M, Lê KA, Theytaz F, Le May C, Guyomarc'h-Delasalle B, Zaïr Y, Kreis R, Boesch C, Krempf M, Tappy L, Costet P. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets. Nutr Metab (Lond). 2013;10:4.
Cariou B, Le May C, Costet P. Clinical aspects of PCSK9. Atherosclerosis 2011;216:258-65.
Anne Tybjaerg-Hansen, Denmark: Genetic risk factors and Mendelian Randomization
Anne Tybjaerg-Hansen is Professor and Chief Physician, Department of Clinical Biochemistry, Section for Molecular Genetics Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. Her research interests focus on the use of gene screening and single nucleotide polymorphism genotyping to identify candidate genes involved in lipid metabolism, as well as lung disease, hypertension, haemochromatosis, venous thromboembolism, cancer and dementia. Professor Tybjaerg-Hansen is a member of the European Atherosclerosis Society Consensus Panel.
Mendelian randomisation is a statistical technique for assessing causal associations between risk factors and disease outcomes by incorporating genetic information. A genetic variant must satisfy three characteristics to be evaluated using this approach. First, the variant is associated with the risk factor of interest. Second, the variant differentiates the population into two arms, as in a randomised trial, which do not differ with respect to confounding variables. Consequently, any difference in outcome is due to the presence of the variant. Third, the genetic variant affects the outcome solely via the risk factor of interest, without the involvement of other biological pathways. Thus, the genetic variant represents a proxy for the risk factor, with random allocation of genes considered a natural randomisation to show causation.
The use of Mendelian randomisation enables differentiation of biomarkers and genes of relevance with respect to therapeutic intervention, from those that are solely markers of disease. In previous studies, Mendelian randomisation has been used to show causality between lipoprotein(a) and cardiovascular disease, including aortic valve stenosis; remnant cholesterol and ischaemic heart disease, as well as nonfasting glucose levels with ischaemic heart disease. In the light of increasing availability of data from genome wide association studies and genome sequencing, it is anticipated that the use of this technique will expand further.
Tybjærg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol. 2013 Oct 10. pii: S0735-1097(13)05582-4.
Jørgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG,
Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826-33.
Christoffersen M, Frikke-Schmidt R, Schnohr P, Jensen GB, Nordestgaard BG,
Tybjaerg-Hansen A. Visible age-related signs and risk of ischemic heart disease in the general population: a prospective cohort study. Circulation 2013 Dec 13. [Epub ahead of print].
Focus on EAS Madrid 2014: Workshops
Risk factors, epidemiology, prevention, and treatment of cardiovascular disease
Emilio Ros, Spain: The Mediterranean diet
Emilio Ros is Director of the Lipid Clinic and Senior Consultant, Endocrinology and Nutrition Service, Hospital Clínic, Barcelona. Among other affiliations, Professor Ros is a member, founder and past Vice-president of the Spanish Atherosclerosis Society (SEA), and a member of the European Atherosclerosis Society (EAS) and International Atherosclerosis Society (IAS). His research interests focus on nutrition, plant sterols, erythrocyte membrane fatty acids, genetic dyslipidaemias, cardiovascular risk assessment and vascular imaging techniques. Professor Ros is the lead of the PREDIMED study, a long-term nutritional intervention study, which is evaluating the effect of the Mediterranean diet in the primary prevention of cardiovascular diseases in persons at high risk of cardiovascular disease.
Lifestyle intervention is the first fundamental step in cardiovascular disease prevention. In this context, there is extensive support for the health benefits of a "Mediterranean diet", characterised by intake of fruit and vegetables, fish, whole grain cereals, legumes, unsaturated fats, moderate alcohol intake and limited consumption of red meat. Adoption of a Mediterranean diet has been associated with a reduced risk for cardiovascular disease, type 2 diabetes, as well as a range of chronic diseases including rheumatoid arthritis, Parkinson's disease and Alzheimer's disease.
Recent findings from the PREDIMED study have shown substantial reduction (by 30%) in the risk of cardiovascular events, specifically stroke, in primary prevention patients at high cardiovascular risk who consumed a "Mediterranean diet" (supplemented with extra-virgin olive oil or tree nuts). Mechanistic studies show that this diet is associated with delayed progression of atherosclerotic plaque, as well as improvement in the lipoprotein profile, with a shift to a less atherogenic pattern. Other recent findings from PREDIMED have indicated benefits on blood pressure, waist circumference, and depression in individuals with type 2 diabetes.
Given these spectrum of favourable effects, it is therefore a concern that changing socioeconomic factors in Southern Europe may have detrimentally influenced adoption or adherence to the "Mediterranean diet". This was particularly evident in those individuals most likely to benefit from the "Mediterranean diet", i.e. those who were overweight, had diabetes, were less physically active, or smoked. Clearly more effort is needed to promote the benefits of the "Mediterranean diet", especially in people at increased cardiovascular risk.
Ros E, Martínez-González MA. Mediterranean diet for primary prevention of cardiovascular disease. N Engl J Med 2013;369:676-7.
Sala-Vila A, Romero-Mamani ES, Gilabert R, Núñez I, de la Torre R, Corella D, Ruiz-Gutiérrez V, López-Sabater MC, Pintó X, Rekondo J, Martínez-González MA, Estruch R,
Ros E. Changes in ultrasound-assessed carotid intima-media thickness and plaque with a Mediterranean diet: A substudy of the PREDIMED Trial. Arterioscler Thromb Vasc Biol 2013 Nov 27. [Epub ahead of print]
Damasceno NR, Sala-Vila A, Cofán M, Pérez-Heras AM, Fitó M, Ruiz-Gutiérrez V, Martínez-González MÁ, Corella D, Arós F, Estruch R,
Ros E. Mediterranean diet supplemented with nuts reduces waist circumference and shifts lipoprotein subfractions to a less atherogenic pattern in subjects at high cardiovascular risk. Atherosclerosis 2013;230:347-53.
Mika Kivimäki, UK: Socioeconomic stress
Mika Kivimäki holds the Chair of Social Epidemiology, Department of Epidemiology & Public Health, University College London School of Life and Medical Sciences, UK. His research aims to increase understanding of modifiable risk factors and prognostic factors for adult-onset chronic diseases of public health relevance. He is also interested in determinants of functional limitations in later life.
Socioeconomic stress influences health behaviours and disease morbidity and mortality in a population. Inequalities across socioeconomic groups with respect to the patterning of unhealthy behaviours have important implications for public health policy. If health behaviours are key mediators of socioeconomic stress, as shown for the Whitehall II cohort, there is likely to be greater uptake of healthy behaviours among individuals who are more socially advantaged. Consequently, targeting unhealthy behaviours in socially disadvantaged groups is likely to reduce potential social inequalities in health and favourably impact population health. However, as the link between health behaviours and socioeconomic stress differs across cohorts, there needs to be better understanding of the underlying mechanisms, taking into account cultural differences.
In addition, there is emerging recognition of the impact of socioeconomic stress in early life on the development of a 'vulnerable' phenotype at subsequent increased risk for disease. For example, recent research has shown inflammation may be a contributing factor to explain the association between duration of exposure to socioeconomic stress and increased incidence of type 2 diabetes, meriting further investigation of the underlying mechanisms. Such findings offer support for targeting socioeconomic differences that influence inflammatory factors (such as weight management, physical activity, and smoking cessation), as well as potential for pharmacotherapeutic intervention.
Heikkilä K, Fransson EI, Nyberg ST, Zins M, Westerlund H, Westerholm P, Virtanen M, Vahtera J, Suominen S, Steptoe A, Salo P, Pentti J, Oksanen T, Nordin M, Marmot MG, Lunau T, Ladwig KH, Koskenvuo M, Knutsson A, Kittel F, Jöckel KH, Goldberg M, Erbel R, Dragano N, DeBacquer D, Clays E, Casini A, Alfredsson L, Ferrie JE, Singh-Manoux A, Batty GD,
Kivimäki M, IPD-Work Consortium. Job strain and health-related lifestyle: findings from an individual-participant meta-analysis of 118,000 working adults. Am J Public Health 2013;103:2090 - 2097.
Sulkava S, Ollila HM, Ahola K, Partonen T, Viitasalo K, Kettunen J, Lappalainen M,
Kivimäki M, Vahtera J, Lindström J, Härmä M, Puttonen S, Salomaa V, Paunio T. Genome-wide scan of job-related exhaustion with three replication studies implicate a susceptibility variant at the UST gene locus. Hum Mol Genet 2013;22:3363 – 3372.
Kivimaki M. Stress and cardiovascular disease: an update of current knowledge. Annual Review of Public Health 2013;34:337 – 354.
Bart Staels, France: Transcriptional regulators
Bart Staels is Professor in the Faculty of Pharmacy at the University of Lille 2, Lille, France. His research focuses on the molecular pharmacology of cardiometabolic disease, specifically the role of nuclear receptors (such as the peroxisome proliferator-activated receptors [PPAR], farnesoid X receptor, Rev-erba and RORa) in the control of inflammation and lipid and glucose homeostasis and the transcriptional mechanisms involved. Research by Professor Staels and his group has identified the PPAR transcription factors as potential drug targets for the treatment of diabetes, dyslipidaemia and cardiovascular disease.Professor Staels is the President of the Nouvelle Société Française d'Athérosclérose (NSFA) since 2009; and a member of the International Atherosclerosis Society, the ALFEDIAM (French Association for the Study of Diabetes and Metabolic Diseases), the American Heart Association, the American Diabetes Association and the European Association for the Study of Diabetes.
Nuclear receptors play a fundamental role in the regulation and coordination of lipid metabolism. Their mode of action in modulating transcription involves transactivation and transrepression activities targeting specific genes, either by a direct, DNA binding-dependent mechanism or via crosstalk with other transcriptional regulators. In addition, nuclear receptors can be the targets of other signalling pathways under the control of transcription factors that modify the receptor or their transcriptional comodulators post-translationally. Thus, nuclear receptors can control transcriptional events both directly and non-directly to promote coordinated regulation of key aspects of cellular and whole-body cholesterol homeostasis, including absorption, lipoprotein synthesis and remodelling, lipoprotein uptake by peripheral tissues, reverse cholesterol transport, and bile acid synthesis and absorption.
The advent of high throughput genomic, epigenetic and proteomic techniques has provided insights into nuclear transcriptional regulators with therapeutic potential. One example is the peroxisome proliferator-activated receptor (PPAR) family, which plays a role in the expression and control of genes involved in lipid metabolism, as well as the insulin/insulin-like growth factor signalling pathway. Ongoing research is focused on the role of PPAR agonism in the settings of cardiometabolic disease, including non-alcoholic fatty liver disease. In addition, research has identified the role of liver X receptors (LXRs) and the farnesoid X receptor (FXR), in promoting the storage, transport, and catabolism of sterols and their metabolites. These findings suggest potential for the LXRs as therapeutic targets for the treatment of lipid disorders, although translation to the clinical setting has been less successful due to adverse effects.
Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K,
Staels B, Lüscher TF, Matter CM. The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. Eur Heart J 2014 Mar 6. [Epub ahead of print]
Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, Baron M, Lucas A, Tailleux A, Hum DW, Ratziu V, Cariou B, Hanf R. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 2013;58:1941-52.
Oger F, Dubois-Chevalier J, Gheeraert C, Avner S, Durand E, Froguel P, Salbert G,
Staels B, Lefebvre P, Eeckhoute J. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes. J Biol Chem 2014;289:708-22.
Ectopic fat as a cardiovascular risk factor
Sven Francque, Belgium: The role of non-alcoholic fatty liver disease in cardiovascular disease
Sven Francque is Professor, Department of Gastroenterology and Hepatology, University Hospital Antwerp and his Research group is based in the Department of Experimental Medicine and Paediatric Medicine, Antwerp University, Antwerp, Belgium. His key research interests include liver and systemic haemodynamic alterations, non-invasive diagnostic markers and potential pathophysiological mechanisms for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
NAFLD is a major health concern, affecting about 30-40% of the adult population, higher in patients with type 2 diabetes. NAFLD may progress to fibrosis, cirrhosis and its complications like hepatocellular carcinoma and liver failure. Not only is the link between NAFLD and insulin resistance well established, but there is also accumulating evidence that NAFLD is an independent risk factor for cardiovascular disease.
Several factors may explain the increased atherogenic risk associated with NAFLD. These include increased secretion of very low-density lipoproteins, hyperglycaemia arising from hepatic overproduction of glucose, increased secretion of inflammatory factors such as fibrinogen and C reactive protein, as well as quantitative and qualitative changes in plasma lipoproteins, including high-density lipoprotein. Recent studies also suggest that NAFLD may predispose to a prothrombotic state, with the severity of NAFLD shown to be an independent contributor to an increase in plasminogen activator inhibitor type 1 levels.
Elucidation of the mechanisms underlying the association between NAFLD and increased cardiovascular disease risk is critical. Not only will this help to identify specific biomarkers which would enable clinicians to target those patients at increased cardiometabolic risk for invasive testing and treatment, but further insights will offer the potential for therapeutic approaches for clinical management.
Francque S, Mertens I, Prawitt J, Caron S, Hubens G, Van Marck E, Staels B, Michielsen P, Van Gaal L. Prothrombotic factors in histologically proven nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology 2014;59:121-9.
Vonghia L, Michielsen P,
Francque S. Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 2013;14:19867-90.
Francque S, Laleman W, Verbeke L, Van Steenkiste C, Casteleyn C, Kwanten W, Van Dyck C, D'Hondt M, Ramon A, Vermeulen W, De Winter B, Van Marck E, Van Marck V, Pelckmans P, Michielsen P. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Lab Invest 2012;92:1428-39.
Jean Pierre Després, Canada: Obesity and cardiovascular risk
Jean Pierre Després is Professor, Department of Social and Preventive Medicine, Université Laval, Quebec City, Québec, Canada. He has been the Director of Research at the Québec Heart Institute in Québec City since 1999, and Scientific Director of the International Chair on Cardiometabolic Risk at Laval University since 2005. The research interests of Professor Després encompass the assessment and management of obesity and body fat distribution, lipid metabolism, diabetes, metabolic syndrome, exercise, nutrition and the prevention and treatment of coronary heart disease risk factors. Professor Després is a Fellow of the International Atherosclerosis Society and the American Heart Association, and is a member of the WHO Expert Committee on Physical Status. In 2006, he was the recipient of the Prix Pierre et Céline Lhermite, Académie nationale de médecine, France and the Prix des fondateurs Jean-Davignon et Paul-Lupien, Société québécoise de lipidologie, de nutrition et de métabolisme (SQLNM). He was Editor of the International Journal of Obesity from 1992 to 2000, and is currently a member of the editorial boards of several scientific journals, including Diabetologia, Diabetes and Nutrition, Metabolism and Cardiovascular Diseases.
Clinicians are facing the challenge of a global obesity pandemic, fuelled by energy-dense diet and increasingly sedentary lifestyle. This is clearly a major concern, given clear evidence linking obesity with health outcomes including cardiovascular disease. However, there is considerable interindividual heterogeneity in regional body fat distribution, especially visceral adipose tissue/liver fat accumulation. Moreover, the metabolic properties of visceral adipose tissue differ from those of subcutaneous adipose depots. Visceral adipose tissue has active endocrine and paracrine functions with the secretion of various pro-inflammatory chemokines which adversely affect vascular biology, and potentially contribute to atherosclerosis progression.
While visceral adiposity and liver fat are key drivers of cardiometabolic risk, other ectopic fat depots also appear to play a role. Due to their close anatomic association with the myocardium, epicardial and perivascular adipose tissues contribute to the pathogenesis of cardiovascular disease beyond that of visceral fat. In the obese individual, these tissues expand, resulting in an increase in macrophage infiltration, T-cell accumulation and adipokine production; in addition, lipid overload accompanying obesity may promote cardiomyocyte apoptosis, cardiac fibrosis, and/or impairment in the contractile function of the heart. Clearly, further study is needed to elucidate the local molecular pathways and inflammatory mediators of epicardial adipose tissue, and their cross-talk between adjacent tissues. Such findings may offer the potential for new therapeutic approaches to reduce cardiovascular disease risk.
Bastien M, Poirier P, Lemieux I,
Després JP. Overview of epidemiology and contribution of obesity to cardiovascular disease. Prog Cardiovasc Dis 2014;56:369-81.
Després JP, Koh KK. Perivascular adipose tissue in the pathogenesis of cardiovascular disease. Atherosclerosis 2013;230:177-84.
Després JP. Body fat distribution and risk of cardiovascular disease: an update. Circulation 2012;126:1301-13.
Luis Masana, Spain: Treatment of adults with FH
Lluís Masana is Professor of Medicine, Head of Vascular Medicine and Metabolism and Director of the Lipid and Arteriosclerosis Research Unit, and Research Director, University Hospital Sant Joan, University Rovira & Virgili (Reus-Tarragona). His research interests include lipid metabolic diseases, lipids, arteriosclerosis and diabetes, the pathogenesis of arteriosclerosis, vascular medicine and metabolism, lipoprotein oxidation, the molecular biology of hyperlipidaemia, metabolic syndrome and endothelial function, and subclinical arteriosclerosis. Professor Masana is a founder member of several Research Foundations, including Juan Abelló, Nucis, FEA and F-IRCIS. He was a Member of the Executive Committee of the European Lipoprotein Club, the Scientific Council of the International Arteriosclerosis Society (2002-2004), and the Executive Committee of the European Society of Arteriosclerosis (2009- 2012). He is on the Editorial Board and/or reviewer of numerous journals including Atherosclerosis, Metabolism, Nutrition and Cardiovascular Diseases, European Heart Journal and Diabetologia.
Based on current estimates, up to 34 million people worldwide may be affected by familial hypercholesterolaemia (FH), although most remain undetected. Yet even among those diagnosed, treatment is often suboptimal. Clearly, there is a need for urgent action to educate and improve diagnosis of FH; these unmet needs have been recently highlighted by the European Atherosclerosis Society Consensus Panel Position Statement on FH.1
The EAS Consensus Panel recommends cascade screening of family members of known FH cases based on measurement of plasma levels of low-density lipoprotein (LDL) cholesterol as the most cost-effective screening method for identifying new FH subjects. Index cases can be identified by opportunistic or targeted screening in primary care or in hospital settings. Ideally, screening should centrally co-ordinated by a specialised centre and based on both plasma lipid profiles and genetic testing, although if genetic testing is not available, plasma lipid levels alone may be used. The Dutch Lipid Clinic Network Criteria are recommended for clinical diagnosis in adults, after exclusion of secondary causes of hypercholesterolaemia.
In addition to lifestyle intervention, statins are first-line treatment, and patients with FH should be initiated on maximal doses of potent statins at first consultation. However, it is recognised that most patients will not achieve LDL cholesterol goals and will require additional pharmacotherapy. Although the majority of patients with FH can be managed in primary care, or a 'shared care' approach between primary care and specialised lipid or FH clinics, patients who are statin intolerant, with established coronary heart disease or who remain refractory to treatment (including homozygous FH patients), require specialist management. Finally, the advent of novel therapies that are effective in further lowering LDL cholesterol against a background of statin therapy has driven renewed focus on the management of FH.
1. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN,
Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a.
Masana L, Civeira F, Pedro-Botet J, de Castro I, Pocoví M, Plana N, Mateo-Gallego R, Jarauta E, Pedragosa À. [Expert consensus on the detection and clinical management of familial hypercholesterolemia]. Clin Investig Arterioscler 2013;25:182-93.
Plana N, Ferré R, Merino J, Aragonès G, Girona J, Heras M,
Masana L. Heterozygous familial hypercholesterolaemic patients have increased arterial stiffness, as determined using the augmentation index. J Atheroscler Thromb 2011;18:1110-6.
Albert Wiegman, The Netherlands: Children and adolescents with
Albert Wiegman is a paediatrician and paediatric cardiologist at the Academic Medical Center (AMC), Amsterdam, The Netherlands. His work focuses on the care of children and adolescents with familial hypercholesterolaemia and other dyslipidaemias. He is a member of the EAS Consensus Panel on FH, as well as the International FH Foundation, which has recently published guidance on the management of FH patients.
It is critical to identify and treat FH in children as early as possible. Indeed, recent research shows that differences in measures of subclinical atherosclerosis, such as carotid intima-media thickness between children with FH and their unaffected siblings may be significant as early as age 8 years. Clearly, screening is a priority, with current strategies focusing on either universal screening or case finding to search for children at risk. In most cases, FH is diagnosed on the basis of plasma low-density lipoprotein (LDL) cholesterol concentration and family history; detection of a FH mutation in a child is the gold standard for confirming a diagnosis of FH. Diagnostic tools such as the Dutch Lipid Clinic Network and Simon Broome criteria are not validated for use in children and adolescents. The issue of consent from patients and their carers prior to genetic testing is critical, and information should be tailored to the child's level of comprehension and the family's level of literacy.
Lifestyle intervention is an important first step in management. However, is it recognised that most patients will require treatment with a statin (in accordance with regulatory advice) as first-line pharmacotherapy. Other pharmacological options are ezetimibe or bile acid sequestrants. These agents have all proven to be safe and effective in lowering LDL cholesterol levels and improving surrogate markers of cardiovascular disease. The magnitude of reduction in LDL cholesterol concentration in FH children need not be as low as in FH adults; indeed, evidence for an absolute target does not exist. While children with uncomplicated and well controlled FH may be managed in primary care, those with very high LDL cholesterol levels, multiple cardiovascular risk factors or complications of pharmacologic therapy, or with homozygous FH require specialist management.
Finally, whether it is safe to initiate treatment at a young age to prevent cardiovascular disease in later life is a key question which warrants further investigation by long-term follow-up studies. There is a clear need for more data concerning myopathy and risk of diabetes in young FH patients treated with statins for many years.
Watts GF, Gidding S, Wierzbicki AS, Toth PP, Alonso R, Brown WV, Bruckert E, Defesche J, Lin KK, Livingston M, Mata P, Parhofer KG, Raal FJ, Santos RD, Sijbrands EJ, Simpson WG, Sullivan DR, Susekov AV, Tomlinson B,
Wiegman A, Yamashita S, Kastelein JJ. Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation. Int J Cardiol 2014;171:309-25.
Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res 2014;114:307-10.
Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC,
Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-90a.
Gene environment interactions and epigenetics
Florian Kronenberg, Austria: Gene-environment interactions
Florian Kronenberg is Professor and Head of Department, GenEpi, Department of Medical Genetics, Innsbruck Medical University, Austria. His research focuses on genetic epidemiology, lipoprotein metabolism, and the genetics of atherosclerosis, kidney disease and diabetes mellitus. He is a member of the Executive Board of the Austrian Society of Human Genetics, and the Organization Committee of the European Lipoprotein Club. Professor Kronenberg is associate editor of Atherosclerosis and PLOS One, and a member of the editorial board of numerous other journals.
Genetic variability, environmental components and biochemical indices are all implicated in the pathophysiology of atherosclerosis and cardiometabolic disease. However, it is only recently that research strategies have begun to investigate the interplay of environmental and genetic factors in disease risk. Such strategies have been aided by insights from studies of the genetic basis underlying lipid and lipoprotein metabolism. Indeed, there is now compelling evidence that a complex interplay between genetic determinants and environmental factors is responsible for large inter-individual variation in susceptibility to atherosclerosis and coronary heart disease.
Genotype by environmental interaction studies have been used to interpret and quantify this relationship. Studies to date have highlighted gene-obesity interaction effects on high density lipoprotein (HDL) using genetic predisposition scores. The cumulative effect of genetic variants that raise HDL cholesterol was shown to be attenuated by increasing levels of obesity-relevant parameters. Additionally, low adiponectin levels have been associated with an increased risk of coronary artery disease in observational studies; recent studies have revealed common variants that influence both adiponectin levels and coronary risk. In contrast, family history of diabetes, an important risk factor for pre-diabetes, appears to have greater impact in subjects who are not obese.
As prospective interventional studies to investigate gene-environment interactions are difficult for ethical and practical reasons, genotype by environmental interaction studies currently offer the best means of studying these effects, and may ultimately provide new potential for therapeutic approaches.
Kronenberg F. Genetic determination of lipoprotein(a) and its association with cardiovascular disease: convenient does not always mean better. J Intern Med 2014; doi: 10.1111/joim.12207. [Epub ahead of print].
Dastani Z, Johnson T,
Kronenberg F, Nelson CP, Assimes TL, März W; CARDIoGRAM Consortium; ADIPOGen Consortium, Richards JB. Dastani Z, Johnson T, Kronenberg F, Nelson CP, Assimes TL, März W; CARDIoGRAM Consortium; ADIPOGen Consortium, Richards JB. Atherosclerosis 2013;229:145-8.
Thun GA, Imboden M, Künzli N, Rochat T, Keidel D, Haun M, Schindler C,
Kronenberg F, Probst-Hensch NM. Follow-up on genome-wide main effects: Do polymorphisms modify the air pollution effect on lung function decline in adults? Environ Int 2013;64C:110-115.
Thomas Thum, Germany: MicroRNAs in heart disease
Thomas Thum is Full Professor and Director of the Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Medical School Hannover, Germany. His key areas of interest are transcription factors and microRNAs that are involved in the complex genetic networks in individual cells crucial for cardiovascular homeostasis and disease. His research group developed the first therapeutic use of microRNA antagonists to prevent cardiac fibrosis in various mouse models of cardiac stress. Professor Thum is a Fellow of the European Society of Cardiology, and a member of the American Heart Association. He is a member of the Editorial Boards forArteriosclerosis, Thrombosis, and Vascular Biology and the Journal of Molecular Cell Cardiology among other journal affiliations.
Despite significant progress over the last decade, cardiovascular disease remains the major challenge facing clinicians. Emerging research has highlighted a potential role for microRNAs, small, noncoding RNAs that control expression of complementary target mRNAs (miRNAs), in the pathophysiology of cardiovascular disease. Functional studies have shown that miRNAs are implicated in cardiac fibrosis, hypertrophy, angiogenesis, and heart failure. An array of in vivo animal models and even human miRNA-based approaches validate miRNAs as a possible therapeutic target.
Interest has focused on a potential role for miRNA therapeutics targeting atherosclerosis. Studies have implicated miRNAs, notably miR-122, miR-370, miR-378/378, miR-335, miR-125a-5p and miR-33, in the regulation of lipid metabolism. For example, miR-122 is involved in the control of cholesterol metabolism, as well as modulation in vitro and in vivo of genes implicated in liver metabolism, fatty acid synthesis and oxidation. Additionally, miR-33 has been shown to regulate several genes involved in cholesterol uptake and synthesis, with key targets identified to date including ABCA1 and HDL biosynthesis. Such findings in animal models may ultimately pave the way for the development of miRNA therapeutics and investigation of their potential in cardiovascular disease management.
Thum T. Non-coding RNAs in cardiac remodeling and heart failure. Circ Res 2013;113:676-89.
Heymans S1, Corsten MF, Verhesen W, Carai P, van Leeuwen RE, Custers K, Peters T, Hazebroek M, Stöger L, Wijnands E, Janssen BJ, Creemers EE, Pinto YM, Grimm D, Schürmann N, Vigorito E,
Thum T, Stassen F, Yin X, Mayr M, de Windt LJ, Lutgens E, Wouters K, de Winther MP, Zacchigna S, Giacca M, van Bilsen M, Papageorgiou AP, Schroen B. Macrophage microRNA-155 promotes cardiac hypertrophy and failure. Circulation 2013;128:1420-32.
Raizman JE1, Diamandis EP, Rayner K, Dimmeler S, Calin GA,
Thum T. Novel Biomarkers for Acute Myocardial Infarction: Is MicroRNA the New Kid on the Block? Clin Chem 2013 Nov 8. [Epub ahead of print].
Lipid and lipoprotein metabolism
Cheryl Wellington, Canada: HDL and ABCA1 in the brain
Cheryl Wellington is Professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia, Vancouver, Canada. Subsequent to completing her PhD in Microbiology at University of British Columbia, she undertook postdoctoral training at Harvard Medical School, University of Calgary, and University of British Columbia. Her research focuses on lipid and lipoprotein metabolism in the brain and how this relates to neurological disorders. Dr. Wellington’s group has made key contributions to the understanding of the role of apolipoprotein E (apoE) in Alzheimer’s disease and traumatic brain injury.
Cerebrovascular dysfunction contributes to the clinical presentation and aetiology of Alzheimer's disease. Risk factors, such as hypertension, cardiovascular disease, diabetes and dyslipidaemia are all implicated in the increased risk for Alzheimer's disease. These comorbidities are also characterised by low and/or dysfunctional high-density lipoprotein (HDL), which itself is a risk factor for Alzheimer's disease.
ABCA1 is a cholesterol transporter that is widely expressed throughout the body, including cells of the central nervous system. Recent studies have shown that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, the major apolipoprotein in the brain. ApoE has also been shown to mediate repair pathways after several forms of acute brain injury. In vivo, deficiency of ABCA1 results in reduction in apoE levels in whole brain, hippocampus and striatum. These findings therefore implicate glial ABCA1 as a key influence in apoE metabolism in the brain, and potentially in the pathogenesis of Alzheimer's disease. Ongoing studies are investigating whether deficiency or overexpression of ABCA1 affects Alzheimer's disease in vivo.
Translation of the results of these studies has the potential for important impact both for the patient and society as a whole, given projections for the prevalence of Alzheimer's disease. For example, in 2012 in the UK,1 800,000 people had dementia and the cost for caring for such patients exceeded £23 billion. This societal cost will exponentially increase as the proportion of elderly patients increases, unless studies are able to identify new therapeutic possibilities.
1 Alzheimer's Society. Statistics. http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=341.
Stukas S, Robert J,
Wellington CL. High-density lipoproteins and cerebrovascular integrity in Alzheimer's disease. Cell Metab 2014. pii: S1550-4131(14)00009-6.
Fan J, Shimizu Y, Chan J, Wilkinson A, Ito A, Tontonoz P, Dullaghan E, Galea LA, Pfeifer T,
Wellington CL. Hormonal modulators of glial ABCA1 and apoE levels. J Lipid Res 2013;54:3139-50.
Karasinska JM, de Haan W, Franciosi S, Ruddle P, Fan J, Kruit JK, Stukas S, Lütjohann D, Gutmann DH,
Wellington CL, Hayden MR. ABCA1 influences neuroinflammation and neuronal death. Neurobiol Dis 2013;54:445-55.
Hypolipidaemic drugs - present and future
Rafael Carmena, Spain: State of the art in lipid lowering therapy
Rafael Carmena is Emeritus Professor of Internal Medicine and Endocrinology at the University of Valencia and former Chief of the Endocrine and Nutrition Service at the University Hospital in Valencia, Spain. His main clinical research interests are lipid metabolism and insulin resistance states, treatment of insulin resistance, metabolic syndrome, genetics of dyslipidaemias and treatment of dyslipidaemia in diabetes. Professor Carmena is a Fellow of both the American College of Physicians and the Royal College of Physicians of Edinburgh. He is a member of the Spanish Royal Academy of Medicine, both the International and the Spanish Society of Internal Medicine, the American Diabetes Association, the European Association for the Study of Diabetes, and the European Atherosclerosis Society. In 2006 he was elected Chairman of the International Task Force for the Prevention of Coronary Heart Disease. In 2007 he was nominated as a Distinguished Fellow of the International Arteriosclerosis Society, and in 2012 he was nominated Honorary Professor of Medicine at the Universidad Peruana Cayetano Heredia, in Lima (Perú), and Doctor Honoris Causa at the University of Murcia (Spain).
Lowering low-density lipoprotein (LDL) cholesterol has a key role in preventing cardiovascular disease (CVD). Despite optimal therapy, however, it is clear from the EUROASPIRE III survey that more than 50% of patients with or at high risk of CVD do not attain guideline-recommended LDL cholesterol targets.1 While combination lipid-modifying therapy is recommended to improve goal attainment, there is so far no large cardiovascular outcomes study demonstrating clinical benefits over statin monotherapy with this approach. This scenario highlights the need for additional therapeutic approaches.
Novel therapeutic compounds targeting LDL cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol are in development. Emerging options that focus on LDL cholesterol include those targeting production of LDL, such as the microsomal transfer protein inhibitor lomitapide, and mipomersen, an antisense oligonucleotide which inhibits hepatic synthesis of apolipoprotein B-100, an essential component of the LDL particle. Both are approved in the US for the management of patients with homozygous familial hypercholesterolemia (HoFH), and lomitapide is also approved for management of HoFH in Europe. Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9), a post-translational regulator of LDL receptor activity, is another strategy generating much interest. In heterozygous FH patients, PCSK9 monoclonal antibody therapies in development have been shown to reduce LDL cholesterol in excess of 50% when combined with statin therapy, and to be similarly effective in individuals who unable to tolerate statins. Cholesterol ester transfer protein (CETP) inhibitors allow the possibility of both substantially raising HDL cholesterol, as well as lowering LDL cholesterol. Furthermore, agonists of peroxisomal proliferator-activated receptors target different areas of dysmetabolism, and are of potential interest in the setting of nonalcoholic fatty liver disease. Modulators of inflammation, for example, phospholipase inhibitors, also offer promise. The results of ongoing trials with these agents will be crucial in identifying which of these lipid-modifying options are both safe and effective in reducing CV risk.
1 Reiner Ž, De Bacquer D, Kotseva K et al; EUROASPIRE III Study Group. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: findings from the EUROASPIRE III survey. Atherosclerosis 2013;231:300-7.
Carmena R, Ascaso JF, Real JT, Masana L, Catalá M, Vendrell J, Vázquez JA, Valdés S, Urrutia I, Soriguer F, Serrano-Rios M, Rojo-Martínez G, Pascual-Manich G, Ortega E, Mora-Peces I, Menéndez E, Martínez-Larrad MT, López-Alba A, Gomis R, Goday A, Girbés J, Gaztambide S, Franch J, Delgado E, Castell C, Castaño L, Casamitjana R, Calle-Pascual A, Bordiú E. Prevalence of plasma lipid abnormalities and its association with glucose metabolism in Spain: The firstname.lastname@example.org study. Clin Investig Arterioscler 2014. pii: S0214-9168(13)00131-9. doi: 10.1016/j.arteri.2013.12.001. [Epub ahead of print]
Silbernagel G, Chapman MJ, Genser B, Kleber ME, Fauler G, Scharnagl H, Grammer TB, Boehm BO, Mäkelä KM, Kähönen M,
Carmena R, Rietzschel ER, Bruckert E, Deanfield JE, Miettinen TA, Raitakari OT, Lehtimäki T, März W. High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis. J Am Coll Cardiol 2013;62:291-9.
Genser B, Silbernagel G, De Backer G, Bruckert E,
Carmena R, Chapman MJ, Deanfield J, Descamps OS, Rietzschel ER, Dias KC, März W. Plant sterols and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J 2012;33:444-51.
Vascular biology of the arterial wall
Christoph Binder, Austria: B cells and humoral immunity in atherosclerosis
Christoph Binder is Professor of Atherosclerosis Research in the Department of Laboratory Medicine at the Medical University of Vienna, Austria. His primary area of interest is in the immune mechanisms of atherosclerosis, in particular the role and function of natural antibodies in cardiovascular disease. Current projects focus on characterisation of innate immune responses that mediate the recognition of lipid-peroxidation derived epitopes, and immune responses to malondialdehyde-epitopes. In addition, the role and function of B-cell subsets and natural antibodies are being investigated. Professor Binder is a member of the American Heart Association, the European Atherosclerosis Society, and the Austrian Atherosclerosis Society.
B cells play a crucial role in both humoral and adaptive immune responses, and in turn atherosclerosis, depending on their specific characteristics. Thus, B1 cells which are usually found in the pleural and peritoneal cavities, are involved in innate immune responses. In contrast, B2 cells which represent the main population of B cells in the spleen and lymph nodes, are not only involved in production of immunoglobulin G antibody but also function as antigen-presenting cells and cytokine producers, and therefore are able to modulate T cell responses. Recent research has also indicated a third subpopulation of B cells with regulatory properties (Breg), with a key role in autoimmune pathogenesis and restoration of tissue homeostasis.
However, it is likely that the role of B cells in regulating atherosclerosis is more complex than that proposed by these subclasses. Evidence indicates that exogenous factors may impact these B cell subsets to modify their biology, for example transforming atheroprotective B1 cells to cells which instead exacerbate atherosclerosis. Research aimed at developing B cell subset specific strategies that deplete B2 cells but do not affect B1 and regulatory B cells may offer therapeutic potential. Investigation of the mechanism(s) underlying the proposed atheroprotective role of human B‑1 cells in animal models of atherosclerosis has provided important insights; the challenge for the future is translating such findings to the clinical setting.
Karper JC, de Jager SC, Ewing MM, de Vries MR, Bot I, van Santbrink PJ, Redeker A, Mallat Z,
Binder CJ, Arens R, Jukema JW, Kuiper J, Quax PH. An unexpected intriguing effect of Toll-like receptor regulator RP105 (CD180) on atherosclerosis formation with alterations on B-cell activation. Arterioscler Thromb Vasc Biol 2013;33:2810-7.
Zouggari Y, Ait-Oufella H, Bonnin P, Simon T, Sage AP, Guérin C, Vilar J, Caligiuri G, Tsiantoulas D, Laurans L, Dumeau E, Kotti S, Bruneval P, Charo IF,
Binder CJ, Danchin N, Tedgui A, Tedder TF, Silvestre JS, Mallat Z. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med 2013;19:1273-80.
Binder CJ, Tsimikas S, Witztum JL. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. J Clin Invest 2013;123:27-36.
Asrar B.Malik, USA: Regulation of endothelial barrier integrity
Asrar B. Malik is the Schweppe Family Distinguished Professor and Head of the Department of Pharmacology, University of Illinois at Chicago, USA. In addition, he is Director of the Center for Lung and Vascular Biology, and Director of the Center for the Development of Stem Cell Therapies for Human Disease. His research focuses on the regulation of endothelial progenitor cells in vascular repair mechanisms. His affiliations include membership of the American Society of Pharmacology and Experimental Therapeutics, American Heart Association and International Society of Thrombosis and Hemostasis. He is a member of the editorial board for numerous journals including Circulation Research, Chest and the American Journal of Physiology.
Endothelial progenitor cells (EPCs) are essential to blood vessel formation, differentiate into mature endothelial cells, and promote the repair of damaged endothelium. There is also accumulating evidence that EPCs may regulate vascular repair via novel paracrine mechanisms, including the release of endothelial cell-derived microparticles or microvesicles that contain microRNAs which promote vascular repair. Furthermore, tissue-resident endothelial cells or EPCs may drive the restoration of vascular function after endothelial injury. Ongoing efforts to understand these mechanisms may offer therapeutic potential.
This is especially relevant in the setting of diabetes mellitus, which is characterised by endothelial dysfunction. Studies have shown reduced circulating levels and impaired functionality of EPCs in diabetes patients, suggesting that these changes might have a pathogenic role in the development of diabetic complications. Various mechanisms have been proposed, including weak bone marrow mobilisation, impaired peripheral differentiation and reduced survival.
Taken together, current evidence suggests that EPCs may represent a possible target for therapeutic intervention. Of note some agents that positively affect vascular function in diabetes patients, also positively impact the function and number of EPCs. Additionally, EPC transplantation may offer another therapeutic possibility for improving vascular dysfunction. The ongoing challenge is to investigate possibilities for therapeutic targeted delivery of EPCs, which may ultimately transform the treatment of cardiovascular disease and diabetes.
Malik AB, Rehman J. Endothelial progenitor cells and vascular repair. Curr Opin Hematol 2014 Mar 15. [Epub ahead of print]
Park C, Kim TM,
Malik AB. Transcriptional regulation of endothelial cell and vascular development. Circ Res 2013;112:1380-400.
Kohler EE, Wary KK, Li F, Chatterjee I, Urao N, Toth PT, Ushio-Fukai M, Rehman J, Park C,
Malik AB. Flk1+ and VE-cadherin+ endothelial cells derived from iPSCs recapitulates vascular development during differentiation and display similar angiogenic potential as ESC-derived cells. PLoS One 2013;8:e85549.
Imaging of atherosclerosis and cardiovascular disease
Erik Stroes, The Netherlands: Novel methods of atherosclerosis mapping
Erik Stroes is Chair of the Department of Vascular Medicine, Amsterdam Medical Center, The Netherlands. His research focuses on the ‘regression’ of cardiovascular diseases by stimulating the excretion of cholesterol from the body, as well as developing new vessel wall mapping techniques, so as to study the development of arteriosclerosis more effectively. His affiliations include membership of the Vascular Biology working group, Dutch Atherosclerosis Society and Arteriosclerosis Thrombosis Vascular Biology. Amongst other accolades, Professor Stroes has received recognition for his work in the form of a Dekker fellowship from the Dutch Heart Foundation and a Career Stimulation grant from the Dutch Kidney Foundation. He has published extensively in high-impact journals such as New England Journal of Medicine, Blood, Circulation and the Journal of the American College of Cardiology.
Direct visualisation of atherosclerotic plaque morphology and activity by non-invasive imaging offers the possibility to evaluate therapeutic efficacy at earlier stages of drug development. A variety of imaging techniques for plaque morphology are now in clinical use, and ongoing research is evaluating procedures aimed at evaluation of plaque processes, such as
18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). Plaque MRI allows for noninvasive assessment of multiple biomarkers of atherosclerosis, including luminal stenosis, plaque burden, tissue composition and plaque activity. Additionally, given that liquid phase cholesteryl ester comprises a major fraction of atherosclerotic plaque, and its abundance is associated with plaque rupture and atherothrombosis, a noninvasive imaging technique to detect liquid cholesteryl ester may offer potential. These procedures therefore offer the possibility of imaging both plaque anatomy and function with contrast agents.
Increasingly, the focus of research has been on early atherosclerotic lesion formation, characterised by inflammation, endothelial dysfunction and accumulation of large amounts of lipoprotein-derived cholesterol esters in macrophages within the vessel wall. Nanoparticle-based imaging technologies which can evaluate lipoprotein metabolism or noninvasively detect lesions at a very early stage might provide a valuable therapeutic and diagnostic tool. For example, studies have indicated potential for the use of a statin-loaded reconstituted high-density lipoprotein nanoparticle to inhibit atherosclerotic plaque inflammation. Translation of such procedures to the clinical setting may prove extremely valuable in targeting the early stages of atherosclerosis and improving patient prognosis.
Kim Y, Lobatto ME, Kawahara T, Lee Chung B, Mieszawska AJ, Sanchez-Gaytan BL, Fay F, Senders ML, Calcagno C, Becraft J, Tun Saung M, Gordon RE,
Stroes ES, Ma M, Farokhzad OC, Fayad ZA, Mulder WJ, Langer R. Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis. Proc Natl Acad Sci U S A 2014;111:1078-83.
van Wijk DF, Strang AC, Duivenvoorden R, Enklaar DJ, van der Geest RJ, Kastelein JJ, de Groot E,
Stroes ES, Nederveen AJ. Increasing spatial resolution of 3T MRI scanning improves reproducibility of carotid arterial wall dimension measurements. MAGMA 2013 Sep 18. [Epub ahead of print].
Duivenvoorden R, van Wijk D, Klimas M, Kastelein JJ,
Stroes ES, Nederveen AJ. Detection of liquid phase cholesteryl ester in carotid atherosclerosis by 1H-MR spectroscopy in humans. JACC Cardiovasc Imaging 2013;6:1277-84.