BUILDING A VESSEL WALL: FROM DEVELOPMENTAL BIOLOGY TO PHYSIOLOGICAL AND PATHOLOGICAL REMODELING IN ADULT LIFE
Mark Majesky is an internationally recognized expert in the field of stem cell biology. He is currently Professor of Pediatrics at the University of Washington, Associate Director of the Center for Tissue and Cell Sciences, and Director of the Myocardial Regeneration Initiative at Seattle Children's Research Institute.
Dr. Majesky’s research is centred on understanding basic mechanisms of formation and repair of blood vessels. A key focus concerns the development and fate of vascular stem/progenitor cells that reside in the adventitial layer of the artery wall.
Coronary progenitors found in the pro-epicardium are the forerunners for the endothelium, smooth muscle and adventitial cells of the coronary vasculature. Defining the mechanisms involved in the differentiation of the embryonic vasculature may provide insights into the formation, regression, remodelling and repair of blood vessels in later life.
Emerging evidence suggests that the adventitia provides a niche-like signalling environment for progenitor stem cells in the artery wall with the capacity to respond to arterial injury. Studies have shown that progenitor cells can be mobilized to differentiate to mural-like cells in vitro, and may promote angiogenesis in vivo. The adventitia is also involved in immune surveillance, inflammation and via the vasa vasorum, acts as a gateway for migration of macrophages and leukocytes into the intima. These findings suggest a potential role for the adventitia in coronary artery repair, remodelling and disease.
Understanding the role of the adventitia may have important application in stem and progenitor cell-based therapies, as well as in the management of congenital heart defects and other cardiac abnormalities.
Majesky MW, Dong XR, Hoglund V, Mahoney WM Jr, Daum G. The adventitia: a dynamic interface containing resident progenitor cells. Arterioscler Thromb Vasc Biol 2011;31:1530-9.
Majesky MW, Dong XR, Regan JN, Hoglund VJ. Vascular smooth muscle progenitor cells: building and repairing blood vessels. Circ Res 2011;108:365-77.
Hoglund VJ, Majesky MW. Patterning the artery wall by lateral induction of notch signaling. Circulation 2012;125:212-5.
ENDOTHELIAL FUNCTION AND DYSFUNCTION: THE KEYS TO CORONARY AND PERIPHERAL CIRCULATION
Ulf Landmesser is Professor of Cardiology, Head, Acute and Invasive Cardiology and Head of Cardiovascular Research at the Department of Cardiology of the University Hospital Zurich.
A key focus of his research is progenitor cell-mediated repair capacity in cardiovascular disease.
Prof Landmesser is Deputy Editor, European Heart Journal, and a member of the ESC Congress Program Committee (2010-2012), the Science and Guidelines committee, EACPR and the Nucleus Exercise, Basic and Translational Science, EACPR.
Endothelial dysfunction underlies the development and progression of atherosclerosis and its clinical complications. In particular reduced endothelial availability of nitric oxide (NO), in part due to increased vascular oxidant stress, promotes a pro-inflammatory and prothrombotic phenotype of the endothelium. Clinical studies have shown close association between the degree of endothelial dysfunction and risk of future cardiovascular events. The development of novel methods for evaluating endothelial function offers the possibility for detecting endothelial dysfunction before overt coronary and peripheral vascular disease.
Cardiovascular risk factors reduce the number and impair the function of circulating endothelial progenitor cells, thereby impairing their repair capacity. Understanding these mechanisms may offer a potential therapeutic strategy in ischaemic heart disease. Approaches have been aimed at maintaining stem cell niche function and targeting mobilization/recruitment of specific stem/progenitor cell populations to preserve vascular and cardiac function. Although small studies suggest that cell-based therapy may improve cardiac function on top of standard therapy, there remain limitations and uncertainties.
Ultimately such approaches, combining emerging tools such as cell priming, bionanotechnology and tissue engineering, may offer the opportunity for a combined biological approach to ischaemic tissue repair.
Landmesser U, Hornig B, Drexler H. Endothelial function: a critical determinant in atherosclerosis ? Circulation 2004; 109(Suppl 1): II27-II33
Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, Kremastinos D, Landmesser U, Protogerou A, Stefanadis C, Tousoulis D, Vassalli G, Vink H, Werner N, Wilkinson I, Vlachopoulos C. Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Eur J Cardiovasc Prev Rehabil 2011;18:775-89.
Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, Mueller M, Akhmedov A, Daniil G, Manes C, Templin C, Wyss C, Maier W, Tanner FC, Matter CM, Corti R, Furlong C, Lusis AJ, von Eckardstein A, Fogelman AM, Lüscher TF, Landmesser U. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693-708.
Tongers J, Losordo DW, Landmesser U. Stem and progenitor cell-based therapy in ischaemic heart disease: promise, uncertainties, and challenges. Eur Heart J 2011;32:1197-206.
IMMUNITY IN ATHEROSCLEROSIS
Göran Hansson is Professor of Cardiovascular Research at the Karolinska Institute and Head of the Cardiovascular Research Laboratory in the Center for Molecular Medicine at Karolinska University Hospital in Stockholm, Sweden. He is a previous recipient of the Anitschkow Prize from the European Atherosclerosis Society, as well as other prestigious awards. The focus of his research is immune and inflammatory mechanisms in atherosclerosis.
Atherosclerosis is a chronic inflammatory disease, elicited by cholesterol accumulation in the artery wall. The atherosclerotic plaque contains macrophages, T cells and other cells of the immune response, as well as cholesterol derived from low-density lipoprotein (LDL). Much progress has been made in understanding the immune mechanisms involved in atherosclerosis. Studies using gene-targeted mouse models have suggested that both immune modulation and immunization may reduce the progression of atherosclerotic disease.
T cells, present at all stages of atherosclerosis, play key roles in both initiation and progression of atherosclerotic plaque. Targeting T cells is attractive because of the antigen-specific, clonal nature of these cells.
Recent research has focused on identifying peptide fragments of apolipoprotein B100 (apoB100) which act as antigenic epitopes in triggering T cell activation. Conversely, blocking the immunological response involved in T cell recognition of apoB100 inhibits T cell activation and the secretion of proinflammatory cytokines, and also reduces atherosclerosis. These findings suggest therapeutic possibilities for the development of agents that selectively target T cells specific for a certain epitope.
1. Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol 2011;12:204-12.
2. Hermansson A, Johansson DK, Ketelhuth DF, Andersson J, Zhou X, Hansson GK. Immunotherapy with tolerogenic apolipoprotein B-100-loaded dendritic cells attenuates atherosclerosis in hypercholesterolemic mice. Circulation 2011;123:1083-91.
3. Klingenberg R, Lebens M, Hermansson A, Fredrikson GN, Strodthoff D, Rudling M, Ketelhuth DF, Gerdes N, Holmgren J, Nilsson J, Hansson GK. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 2010;30:946-52.
Professor Gerard Pasterkamp
UNDERSTANDING THE VULNERABLE PLAQUE – BASIS FOR TREATMENT OPTIONS
Gerard Pasterkamp is Professor of Experimental Cardiology, Division Heart and Lungs, University Medical Centre Utrecht (UMCU), The Netherlands. His research has focused on arterial remodelling in atherosclerotic disease. He is the initiator and project leader of Athero-Express BioBank Studies, a longitudinal atherosclerotic plaque biobank from more than 2,000 patients.
Identifying individuals at risk of plaque rupture and subsequent clinical events remains a clinical challenge, given the limitations of risk stratification based on traditional markers and histological characteristics of the vulnerable plaque.
The Athero-Express project aims to identify novel local plaque markers, specifically genetic and molecular markers, that will aid in identification of individuals at risk. The premise underlying this approach is that atherosclerosis is a systemic disease and therefore all plaques in the vascular system provide information about the stability of the atherosclerotic lesions irrespective of their location.
Proteomic studies show that local plaque proteins may have strong predictive value for future cardiovascular events in all vascular territories. Subsequent research will aim to improve risk prediction by combining multiple biomarkers to define a plaque protein signature. Novel imaging techniques using specific targeting of cell surface receptors may help in ultimately translating study findings to the primary prevention setting.
Systems biology approaches, incorporating clinical, genetic and molecular data from such large bio-bank studies, are likely to have therapeutic application, especially in the context of a personalised management approach.
1. Peeters W, Moll FL, Vink A, van der Spek PJ, de Kleijn DP, de Vries JP, Verheijen JH, Newby AC, Pasterkamp G. Collagenase matrix metalloproteinase-8 expressed in atherosclerotic carotid plaques is associated with systemic cardiovascular outcome. Eur Heart J 2011;32:2314-25.
2. Herder C, Peeters W, Illig T, et al. RANTES/CCL5 and risk for coronary events: results from the MONICA/KORA Augsburg case-cohort, Athero-Express and CARDIoGRAM studies. PLoS One 2011;6:e25734.
3. Ylä-Herttuala S, Bentzon JF, Daemen M et al. Stabilisation of atherosclerotic plaques. Position paper of the European Society of Cardiology (ESC) Working Group on atherosclerosis and vascular biology. Thromb Haemost 2011;106:1-19.
Professor Bengt Jönsson
ECONOMIC ISSUES IN CARDIOVASCULAR DISEASE: WHAT ARE THE COSTS OF PREVENTION?
Bengt Jönsson is Professor in Health Economics, Stockholm School of Economics, and Director of the Center for Health Economics. He is currently a member of the board for the Karolinska University Hospital, Stockholm, Sweden. Professor Jönsson has been a temporary adviser on many issues to the World Health Organization and a consultant to the Organisation for Economic Co-operation and Development (OECD), the World Bank and the United Nations Industrial Development Organization (UNIDO).
Despite advances in management, cardiovascular disease (CVD) remains a public health challenge. In the European Union, CVD is estimated to cost the economy €192 billion each year, accounting for about 10% of total health care expenditure. However, this does not take account of important indirect costs, due to loss of productivity and the need for informal care.
Statins remain the cornerstone of dyslipidaemia treatment for prevention of CVD. Economic evaluations based on clinical outcomes trials have shown that improved care associated with statin therapy came at a reasonable price in most risk groups. As statins come off patent, their use is associated with even greater cost savings. This poses a challenge for demonstrating the cost-effectiveness of new therapies entering the field.
Recent guidelines have redirected their focus to take account of the fundamental importance of lifestyle intervention, largely in response to the obesity/diabetes pandemic. Economic evaluations of the value of such interventions have shown that these have the potential to be highly cost-effective, and suggest that increased resources should be directed to primary care to implement such changes. However, such findings also raise a number of issues, including who will provide the necessary investment to fund programs for lifestyle intervention, and what incentives for participation should be offered to motivate those most likely to benefit.
Such issues warrant urgent evaluation given the increasing need for financial restraint in healthcare systems within Europe and beyond.
1. Jönsson B. A 3-year lifestyle intervention for adults at moderate to high risk of cardiovascular disease is cost effective when added to standard care and improves physical health-related quality of life. Evid Based Med 2011;16:70-1.
2. Lindgren P, Jönsson B. Cost-effectiveness of statins revisited: lessons learned about the value of innovation. Eur J Health Econ 2011 Apr 29. [Epub ahead of print].
3. Lindgren P, Jönsson B. From 4S to IDEAL: the health economics of the statin trials. Eur J Cardiovasc Prev Rehabil 2009;16:138-43.
Professor John Kastelein
NEW PERSPECTIVES IN HYPOLIPIDEMIC TREATMENT
John J.P. Kastelein is Professor of Medicine and chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he holds the Strategic Chair of Genetics of Cardiovascular Disease. His current research interests focus on the aetiology, diagnosis, prevention and treatment of hypertriglyceridaemia, hypercholesterolaemia and low HDL cholesterol, with a key interest in the genetic basis of dyslipidaemia.
There is unequivocal evidence that a low plasma level of high-density lipoprotein (HDL) cholesterol is a cardiovascular risk factor. This has provided the rationale for the HDL hypothesis: that raising plasma HDL cholesterol levels may translate to improved cardiovascular benefit. Possible therapeutic strategies in development include cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein (apo) A-1 mimetics, and reconstituted HDL or apoA-1. Emerging data with a number of novel CETP inhibitors are promising, although there is still uncertainty regarding the extent of HDL cholesterol raising required and whether this translates to reduction in cardiovascular events.
Recently, there has been emerging evidence that the functionality of HDL, rather than plasma concentrations, may be more relevant to atheroprotection. HDL are highly heterogeneous in terms of structure, intravascular metabolism and biological activity. Thus, improving HDL functionality may offer the potential to reverse the process of atherosclerosis. Here, apoA-I mimetic peptides, either in single or tandem formulation, hold promise, given evidence that they have anti-inflammatory, antioxidant, and antiatherogenic activities.
The results of ongoing trials with these investigational agents will be fundamental to addressing outstanding uncertainties regarding the HDL hypothesis, and whether improving HDL functionality rather than plasma levels is more relevant.
1. Nicholls SJ, Brewer HB, Kastelein JJ, Krueger KA, Wang MD, Shao M, Hu B, McErlean E, Nissen SE.Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109.
2. Arsenault BJ, Barter P, DeMicco DA, Bao W, Preston GM, LaRosa JC, Grundy SM, Deedwania P, Greten H, Wenger NK, Shepherd J, Waters DD, Kastelein JJ; TNT Study Investigators. Prediction of cardiovascular events in statin-treated stable coronary patients by lipid and nonlipid biomarkers. J Am Coll Cardiol 2011;57:63-9.
3. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study Group. HDL
Dr Miranda van Eck
THE MACROPHAGE LIPOPROTEIN INTERACTIONS – FOR GOOD OR FOR BAD
Miranda van Eck is Associate Professor, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. Her research is focused upon the role of macrophage genes in the development of atherosclerosis with special emphasis on the function of genes involved in high-density lipoprorein (HDL) metabolism and reverse cholesterol transport, in particular the role of the ATP-binding cassette (ABC) transporters and scavenger receptor BI (SR-BI) in this process.
HDL-mediated cholesterol efflux from macrophage foam cells is crucial for the prevention of atherosclerosis. Key mediators for macrophage cholesterol homeostasis include scavenger receptors and the ABC transporters, ABCA1 and ABCG1, which facilitate the influx and efflux of lipids. The role of macrophage ABCG1 in the development of atherosclerosis may be more complex, as experimental studies suggest that ABCG1 may be both anti-atherogenic and pro-atherogenic, depending on the stage of atherogenesis. Furthermore, local and systemic factors, including inflammation and diabetes, also influence the expression of cholesterol transporters on macrophage foam cells.
Targeting macrophage foam cell formation by modulating ABC-transporter and SR-BI expression may have therapeutic potential for preventing atherosclerosis. Such therapies should also aim to improve both the quantity and quality of HDL. One approach is to increase hepatic SR-BI expression by activation of the nuclear receptors farnesoid X receptor and liver receptor homolog 1. Alternatively, targeting macrophage cholesterol efflux via upregulation of the expression of ABCG1 – and indirectly ABCA1 - by activation of the transcription factors liver X receptors (LXR) may be beneficial. Assuming problems of increased fatty liver can be resolved, these agents may offer therapeutic promise. Future research aims to elucidate which of these targets are viable in the clinical setting.
1. Van Eck M , Singaraja RR, Ye D et al. Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol 2006;26:929-34.
2. Van Eck M , Hoekstra M, Out R et al. Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo. J Lipid Res 2008;49:136-46.
3. Ye D, Lammers B, Zhao Y, Meurs I, Van Berkel TJ, Van Eck M , ATP-binding cassette transporters A1 and G1, HDL metabolism, cholesterol efflux, and inflammation: important targets for the treatment of atherosclerosis. Curr Drug Targets 2011;12:647-60.
Professor Alan Tall
NOVEL ANTI-ATHEROGENIC FUNCTIONS OF HDL
Alan Tall is Tilden Weger Bieler Professor of Medicine, at Columbia University, New York USA. He is internationally recognized for his work in plasma lipoprotein metabolism and atherosclerosis, in particular the regulation and metabolism of plasma high density lipoproteins (HDL). His research identifying mutations in the cholesteryl ester transfer protein (CETP) gene associated with markedly elevated HDL levels established a key role for CETP in the regulation of HDL levels. More recently, his research has focused on the molecular mechanisms of cellular cholesterol efflux, mediated by the ATP binding cassette transporters, ABCA1 and ABCG1.
The functionality of HDL is relevant to its ability to promote cholesterol efflux from macrophage foam cells. Although multiple mechanisms are likely to be involved, these effects may in part be related to the role of the ABC transporters, ABCA1 and ABCG1, in cholesterol efflux. Further investigation has led to elucidation of a class of specialised transcription factors (LXRs) that co-ordinate the regulation of cellular cholesterol efflux and reverse cholesterol transport.
HDL possess other beneficial activities including inhibition of LDL oxidation, smooth muscle cell migration and platelet aggregation. ABCG1 and, to a lesser extent, ABCA1, may play a role in preserving endothelial function.
Finally, HDL exhibit anti-inflammatory properties in endothelial cells and macrophages that may be relevant to their atheroprotective effects. Accumulating evidence links these anti-inflammatory effects to cholesterol efflux pathways. Studies suggest that the ABCA1 transporters are implicated in the control of hematopoietic stem cell proliferation, monocytosis and neutrophilia, as well as activation of monocytes and neutrophils.
Thus, the ABC transporters ABCA1 and ABCG1 have important effects in reducing macrophage foam cell formation, inflammation, and atherosclerosis. Pharmacologic approaches for increasing cholesterol efflux may offer therapeutic potential for preventing atherosclerosis.
1. Tall AR, Yvan-Charvet L, Terasaka N, Pagler T, Wang N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab 2008;7:365-75.
2. Tall AR. Functions of cholesterol ester transfer protein and relationship to coronary artery disease risk. J Clin Lipidol 2010;4:389-93.
3. Terasaka N, Westerterp M, Koetsveld J, Fernández-Hernando C, Yvan-Charvet L, Wang N, Sessa WC, Tall AR. ATP-binding cassette transporter G1 and high-density lipoprotein promote endothelial NO synthesis through a decrease in the interaction of caveolin-1 and endothelial NO synthase. Arterioscler Thromb Vasc Biol 2010;30:2219-25.
4. Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M, Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, Yvan-Charvet L, Tall AR. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J Clin Invest. 2011 Oct;121(10):4138-49. PubMed PMID: 21968112; PubMed Central PMCID: PMC3195472.
5. Tsuchiya K, Banks AS, Liang CP, Tabas I, Tall AR, Accili D. Homozygosity for an allele encoding deacetylated FoxO1 protects macrophages from cholesterol-induced inflammation without increasing apoptosis. Arterioscler Thromb Vasc Biol. 2011 Dec;31(12):2920-8. Epub 2011 Sep 22. PubMed PMID: 21940942; PubMed Central PMCID: PMC3220790.
Professor ESTHER LUTGENS
Prof. Esther Lutgens, The Netherlands
Esther Lutgens is Professor of Vascular Immunopathology, Academic Medical Center, University of Amsterdam, The Netherlands. Her research group is focused on the role of the immune system in atherosclerosis. She has shown that the inhibition of specific inflammatory responses can counteract the complications of atherosclerosis. Her current research interests include the role of the CD40-CD40 ligand signalling system in atherosclerosis development and progression.
Professor ZIAD MALLAT
Prof. Ziad Mallat, UK
Ziad Mallat is currently British Heart Foundation Professor of Cardiovascular Medicine, University of Cambridge, UK. His research group is focused on regulation of the immuno-inflammatory response in atherosclerosis. Specifically, his group has shown that defective clearance of apoptotic cells impairs the regulatory immune response in atherosclerosis and accelerates lesion development. Current research activities include the role of the regulatory immune response in the prevention and/or treatment of plaque vulnerability.
Atherosclerosis is a chronic inflammatory disease which is driven by innate and adaptive immune responses. Inflammation controls the development and the destabilisation of arterial plaque. Regulatory T cells play a critical role by inhibiting vascular inflammation, thereby protecting against lesion development and inflammation. Cytokines play a dual role in this process mediating both proinflammatory and antiinflammatory effects. Thus, induction of a specific regulatory T cell response to atherosclerosis-relevant antigens would be an attractive strategy to limit the development and progression of atherosclerosis through the promotion of immune tolerance.
In addition, the CD40-CD40 ligand (CD40L) signalling axis plays a key role in immunological pathways implicated in atherosclerosis. In an experimental model, inhibition of the CD40-CD40L system promoted the development of a stable atherosclerotic plaque. Therefore, targeting specific components of the CD40-CD40L pathway may offer the potential for reduced atherosclerosis and improved plaque stability. In addition, recognition that self DNA (i.e. released from dying cells or neutrophil extracellular traps) may stimulate autoimmune activation and atherosclerosis lesion formation, may provide a basis for novel therapeutic targets in the future.
Understanding Innate and adaptive immunity in atherosclerosis remains a key focus of research directed at promoting protective immune responses in atherosclerosis.
Döring Y, Manthey H, Drechsler M, Lievens D, Megens R, Soehnlein O, Busch M, Manca M, Koenen RR, Pelisek J, Daemen MJ, Lutgens E, Zenke M, Binder CJ, Weber C, Zernecke A. Auto-antigenic protein-DNA complexes stimulate plasmacytoid dendritic cells to promote atherosclerosis. Circulation 2012 [Epub ahead of print]
Engel D, Beckers L, Wijnands E, Seijkens T, Lievens D, Drechsler M, Gerdes N, Soehnlein O, Daemen MJ, Stan RV, Biessen EA, Lutgens E. Caveolin-1 deficiency decreases atherosclerosis by hampering leukocyte influx into the arterial wall and generating a regulatory T-cell response. FASEB J 2011;25:3838-48.
Herbin O, Ait-Oufella H, Yu W, Fredrikson GN, Aubier B, Perez N, Barateau V, Nilsson J, Tedgui A, Mallat Z. Regulatory T-cell response to apolipoprotein b100-derived peptides reduces the development and progression of atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2012;32:605-12.
Van Vré EA, Ait-Oufella H, Tedgui A, Mallat Z. Apoptotic cell death and efferocytosis in atherosclerosis. Arterioscler Thromb Vasc Biol 2012 [Epub ahead of print].
Workshop: Saturday, May 26, 2012, 11:00–12:30
LIPIDS, LIPOPROTEINS AND LIPID METABOLISM:
Intestinal flora as regulator of lipid metabolism
Prof. Nathalie Delzenne, Belgium
Nathalie Delzenne is Head of the Research Group in Metabolism and Nutrition, Louvain Drug Research Institute Université catholique de Louvain, Brussels, Belgium. Her research interests focus on the role of the gut microbiota in the modulation of glucose and lipid metabolism and inflammation, and how these effects can be influenced by functional foods including prebiotic-type nutrients.
Prof. Antonio Gasbarrini, Italy
Antonio Gasbarrini is Professor of internal medicine and gastroenterology at the Universita' Cattolica, Rome, Italy. His research interests focus on diseases of the liver and biliary tract and the organic and functional diseases of the digestive system. He is a member of the EAGEN – European Association of Gastroenterology, Endoscopy and Nutrition.
Increasing evidence suggests a strong link between the gut microbiota and the development of obesity and related metabolic disorders. Not only is obesity associated with changes in the composition and metabolic function of the gut microbiota, but there is also less diversity and changes in the metabolic pathways in the gut microbiota of obese individuals. A high-fat has also been shown to modulate the microbiota, independently of the obese state.
Experimental studies primarily in animal models have shown that transplantation of the microbiota of either obese or lean mice influences body weight in the germ-free recipient mice. Furthermore, there is evidence that the gut microbiota may regulate body weight by influencing metabolic, neuroendocrine and immune functions. Imbalances in the gut microbiota and increases in plasma lipopolysaccharide may act as inflammatory factors predisposing to the development of atherosclerosis, insulin resistance and body-weight gain. Such evidence has led to the development of the concept of MicrObesity (i.e. Microbes and Obesity). Research has shown that modulation of specific gut microbiota has beneficial effects on glucose and lipid metabolism, oxidative stress, and low-grade inflammation, in obese and diabetic mice. Although these findings need to be confirmed in humans, they suggest that the gut may play a previously unrecognised role in the development of obesity.
Thus, profiling the gut microbiota may identify putative bacterial targets influencing host lipid metabolism, which may be of potential relevance to the management of obesity and related metabolic disease.
Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, Possemiers S, Van Holle A, François P, de Vos WM, Delzenne NM, Schrenzel J, Cani PD. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011;60:2775-86.
Delzenne NM, Cani PD. Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr 2011;31:15-31.
Scarpellini E, Campanale M, Leone D, Purchiaroni F, Vitale G, Lauritano EC, Gasbarrini A. Gut microbiota and obesity. Intern Emerg Med 2010;5 Suppl 1:S53-6.
Professor Robert Hegele
GENETICS OF ATHEROGENIC DYSLIPIDEMIAS
Robert Hegele is Director of the Blackburn Cardiovascular Genetics Laboratory at the Robarts Research Institute, London, Ontario, Canada. He is also Professor of Medicine and Biochemistry at The University of Western Ontario. His laboratory has focussed on research into the genetic basis of diabetes, atherosclerosis, hypertension and obesity in Canadian sub-populations and aboriginal communities. Research from his laboratory has been instrumental in identifying more than 100 mutations contributing to dyslipidaemia, diabetes and atherosclerosis in man.
The development of atherosclerosis and cardiovascular disease is the result of multiple intermediate disease processes, which individually have genetic and environmental determinants. There has been extensive interest in potential genetic contributions to atherogenic dyslipidaemia, a feature of cardiometabolic disease. The driving force behind this dyslipidaemia is hypertriglyceridaemia. Several experimental strategies have helped in understanding the genetics of hypertriglyceridaemia, including studies of monogenic dyslipidaemias, resequencing, phenomic analysis and, more recently, genome-wide association studies (GWASs) and analysis of metabolic networks. Recent GWASs have identified both known and novel loci associated with plasma triglyceride levels.
However, the genetics of plasma triglycerides is still far from clear. Genetic variation at these loci explains only a proportion (10%) of variation in triglyceride levels within the population. Rare variant sequencing studies and evaluation of animal models may be relevant for expanding the understanding of the genetics of atherogenic dyslipidaemia.
Elucidation of the genetics of hypertriglyceridaemia has potential application in diagnosis and prognosis, as well as the development of more effective therapeutic strategies.
1. Johansen CT, Kathiresan S, Hegele RA. Genetic determinants of plasma triglycerides. J Lipid Res 2011;52:189-206.
2. Johansen CT, Wang J, Lanktree MB et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat Genet 2010;42:684-7.
3. Hegele RA. Plasma lipoproteins: genetic influences and clinical implications. Nature Reviews Genetics 2009;10:109-21.
Professor Henry Ginsberg
ARE LIPOPROTEIN REMNANTS A REASONABLE TARGET FOR THERAPY?
Henry N. Ginsberg is the Irving Professor of Medicine at Columbia University College of Physicians and Surgeons, Associate Dean for Clinical and Translational Research, and Director of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center in New York, New York, USA. His research interests focus on the regulation of plasma cholesterol and triglyceride blood levels, particularly the metabolism of apolipoprotein B–containing lipoproteins.
Lipoprotein remnants are formed from the lipolysis of triglycerides in triglyceride-rich lipoproteins (TGRL). Levels of TGRL remnants reflect the balance between lipolysis and remnant uptake. In people with atherogenic dyslipidaemia, elevated triglycerides are generated by an increase in fatty acid flux to the liver. This may be due to enhanced free fatty acid release from excess visceral adipose tissue or increased remnant lipoprotein delivery of triglycerides to the liver as a result of excess caloric consumption, leading to increased hepatic lipogenesis, and in turn increased assembly and secretion of very low-density lipoproteins.
Mechanistic and genetic studies show that TGRL remnant levels are associated with increased atherogenicity compared with their precursors due to elevated cholesterol content and extended plasma residence time. Mechanistic and genetic studies also support a link between remnants and increased atherosclerosis. This has led some to suggest that lipoprotein remnants may be a preferable therapeutic target, given that the association between triglycerides and cardiovascular risk is more contentious.
To establish TGRL remnants as a therapeutic target, there is clearly a need for randomised prospective trials of lipid-lowering treatment showing reductions in clinical events predicted by reductions in TGRL remnant levels independent of other risk factors.
1. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
2. Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
3. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
Workshop: Sunday, May 27, 2012, 11:00–12:30
CARDIOVASULAR DISEASE: RISK FACTORS, GENETICS AND EPIDEMIOLOGY
Risk factors of cardiovascular diseases: a changing landscape
Prof. Kausik Ray, UK
Kausik Ray is Professor of Cardiovascular Disease Prevention at St George’s University of London. His research interests focus on cardiometabolic risk and preventive cardiology, cardiovascular epidemiology and clinical trials. He has conducted some of the most definitive analyses to date on lipid lowering and glycaemic control for the prevention of cardiovascular outcomes, which have contributed towards national and international guidelines. His aim is to develop a biobank from the unique ethnic mix of south London for identifying novel markers of risk, targets for treatment and for clinical intervention trials based on biomarkers, genotype and ethnicity.
Prof. Gerd Assmann, Germany
Gerd Assmann is the President of the Board of the Assmann-Foundation for Prevention. He is also Executive Director of the International Task Force for Prevention of Coronary Heart Disease. Professor Assmann is the lead investigator of the seminal Prospective Cardiovascular Münster (PROCAM) study. The PROCAM Study, which was initiated in 1978, is the largest prospective evaluation of cardiovascular risk markers in Europe. By July 2007, 50,000 people - 31,376 men and 18,624 women – had participated in the study. Research interests of Prof. Assmann include lipoproteins, lipid transport and metabolism, medical genetics, biotechnology, and the epidemiology of atherosclerosis.
Despite therapeutic advances, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, and is a major cause of disability affecting quality of life. The global epidemics of obesity, metabolic syndrome and type 2 diabetes have substantially impacted the landscape of CVD risk. Evidence that risk increases incrementally with each additional feature of the metabolic syndrome, highlights the need to consider other approaches beyond traditional risk factors. Increasingly, attention has focused on atherogenic dyslipidemia, the combination of elevated triglycerides and low plasma levels of high-density lipoprotein (HDL) cholesterol. Recent analyses of the PROCAM study have shown that atherogenic dyslipidemia, the combination of elevated triglycerides/ high-density lipoprotein (HDL) was an important contributor to residual coronary risk, especially in individuals who achieve low-density lipoprotein ( LDL) cholesterol goals
Additional biomarkers are implicated in this residual CV risk, given that up two-thirds of events occur in people at low to moderate risk based on conventional risk factors. Of those under investigation, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 and brain natriuretic peptide, which focus on inflammation and arterial wall stress, show most promise. However, while these have been independently associated with outcome, their addition to conventional risk factors only marginally improves risk factor prediction. Imaging variables may offer an alternative approach with the advantage of serial assessment of markers over time.
Identification of risk factors relevant to this emerging risk factor landscape, together with novel technologies and an earlier proactive approach, are key to reducing the burden of CVD
Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med 2010;170:1024-31.
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