Monday 27 May
METABOLIC DYSFUNCTION IN CARDIOVASCULAR DISEASE
Klaus Ley, La Jolla, USA
Klaus LeyLa Jolla, USA
Klaus Ley is Professor and Head of the Division of Inflammation Biology at the La Jolla Institute for Allergy and Immunology and Adjunct Professor of Bioengineering at the University of California, San Diego, USA. He trained at Julius-Maximilians-Universität in Würzburg, Germany and was a Professor of Bioengineering at the University of Virginia from 1994 to 2007. His research focuses on chronic inflammatory diseases such as atherosclerosis, specifically the role of myeloid leukocytes. Professor Ley is the recipient of AHA Distinguished Scientist , the 2010 Malpighi Award from the European Society for Microcirculation, and the 2008 Bonazinga Award from the Society for Leukocyte Biology.
Manipulating adaptive immunity to curb atherosclerosis
Atherosclerosis is a chronic inflammatory disease that is driven by subendothelial accumulation of low-density lipoprotein in the arterial wall. The retained lipoproteins provoke a series of maladaptive immune responses that in turn promote plaque progression and eventually rupture. Monocytes are important mediators of the inflammatory responses involved in atherosclerosis progression. Their differentiation to macrophages, and phenotypic characterization of these macrophages, can be modulated by microenvironmental signals within the artery wall, including oxidized lipids, Toll-like receptor ligands, hematopoietic growth factors, cytokines, and chemokines. Dynamic modulation of macrophage phenotypes affects atherosclerosis progression by modulating the inflammatory responses within the vessel wall. On this basis, therefore, macrophage phenotype modulation represents an attractive therapeutic target.
Atherosclerotic plaques contain T cells, most of which are CD4+ T cells in humans. A key step in the immune response is the activation of T cells by antigens. Peptide epitopes from apolipoprotein B (apoB) have been shown to act as atherosclerosis-related autoantigens, by binding to major histocompatibility complex class II molecules and inducing specific T cell responses. Recently, apoB peptide18 was identified as the first regulatory T cell epitope in human atherosclerosis. In animal models, vaccination with p18 prevented atherosclerosis. Other studies have focused on the role of myeloid epsins, a family of ubiquitin-binding endocytic adaptors, in the regulation of atherogenicity. These epsins appear to promote atherogenesis by facilitating proinflammatory macrophage recruitment and inhibiting efferocytosis. Therefore, manipulating the adaptive immune system by vaccination or immunomodulatory strategies may offer future therapeutic potential in preventing and treating atherosclerosis.
Wolf D, Ley K. Immunity and inflammation in atherosclerosis. Circ Res 2019;124:315-27.
Ley K, Hoffman HM, Kubes P, Cassatella MA, Zychlinsky A, Hedrick CC, Catz SD. Neutrophils: New insights and open questions. Sci Immunol 2018;3(30). pii: eaat4579.
Kimura T, Kobiyama K, Winkels H, Tse K, Miller J, Vassallo M, Wolf D, Ryden C, Orecchioni M, Dileepan T, Jenkins MK, James EA, Kwok WW, Hanna DB, Kaplan RC, Strickler HD, Durkin HG, Kassaye SG, Karim R, Tien PC, Landay AL, Gange SJ, Sidney J, Sette A, Ley K. Regulatory CD4+ T cells recognize major histocompatibility complex class II molecule-restricted peptide epitopes of apolipoprotein B. Circulation 2018;138:1130-43.
Helen Hobbs, Dallas, USA
Helen HobbsDallas, USA
Helen H. Hobbs, M.D., is an Investigator of the Howard Hughes Medical Institute and a Professor of Internal Medicine and Molecular Genetics at the University of Texas Southwestern Medical Center. She holds the Dallas Heart Ball Chair in Cardiology Research, the Philip O’Bryan Montgomery Jr., M.D., Distinguished Chair in Developmental Biology, and the Eugene McDermott Distinguished Chair for the Study of Human Growth and Development. She obtained her undergraduate degree from Stanford University prior to attending Case Western Reserve University School of Medicine.
After completing an internship in internal medicine at Columbia-Presbyterian Medical Center, she moved to Dallas, Texas where she finished her clinical training and served as chief resident in internal medicine at Parkland Memorial Hospital. She worked as a postdoctoral fellow in the laboratory of Drs. Michael Brown and Joseph Goldstein before joining the faculty of UT Southwestern in 1987.
Currently, Professor Hobbs is Director of the McDermott Center for Human Growth and Development, which serves as the Center for Human Genetics at UT Southwestern. She is also Director of the Dallas Heart Study, a longitudinal, multiethnic, population-based study of Dallas County. Her professional affiliations include the Arteriosclerosis, Thrombosis and Vascular Disease Council of the American Heart Association, the Association of American Physicians, the American Society of Human Genetics and the American Society of Clinical Investigation. Professor Hobbs has received numerous awards, most recently the Passano Award (with Jonathan Cohen) in 2016, and the Breakthrough Prize in Life Sciences and Pearl Meister Greengard Prize, Rockefeller University, both in 2015.
Lipids, lipases and fatty liver disease
World-wide, the escalating prevalence of nonalcoholic fatty liver disease (NAFLD) poses a major challenge, with estimates suggesting that over one billion individuals are currently affected. Although obesity and insulin resistance are the most prevalent risk factors, genetic factors also play a role in determining both risk for and clinical manifestations of NAFLD.
Studies have shown that variants in a number of genes including PNPLA3 (palatin-like phospholipase domain-containing 3) and TM6SF2 (transmembrane 5 superfamily member 2) genes increase the heritability of NAFLD. One of the most important genetic risk factors is a missense mutation in PNPLA3 (PNPLA3-148M), which been shown to influence both hepatic fat accumulation and susceptibility for more severe liver damage. Experimental studies indicate that the mechanism(s) involved may include disruption of ubiquitylation and proteasomal degradation of PNPLA3, resulting in impaired mobilization of triglycerides from lipid droplets. Concomitant adiposity has been shown to amplify clinical manifestation of this variant on liver fat content and hepatic transaminases. Another variant in TM6SF2 (TM6SF2-167K) was associated with increased risk for hepatic fibrosis independent of age, obesity, diabetes, and PNPLA3 genotype.
Insights from genetic studies, together with improved understanding of the molecular basis of NAFLD, may provide a basis for the development of effective therapies so far lacking. Genetic screening in obese individuals may also help to identify those at highest risk of progression to more severe manifestations of NAFLD.
Mitsche MA, Hobbs HH, Cohen JC. Patatin-like phospholipase domain-containing protein 3 promotes transfer of essential fatty acids from triglycerides to phospholipids in hepatic lipid droplets. J Biol Chem 2018;293:6958-6968.
Banfi S, Gusarova V, Gromada J, Cohen JC, Hobbs HH. Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice. Proc Natl Acad Sci U S A 2018;115:E1249-58.
BasuRay S, Smagris E, Cohen JC, Hobbs HH. The PNPLA3 variant associated with fatty liver disease (I148M) accumulates on lipid droplets by evading ubiquitylation. Hepatology 2017;66:1111-24.
Peter Carmeliet, Leuven, Belgium
Peter CarmelietLeuven, Belgium
Peter Carmeliet is Professor at the Katholieke Universiteit Leuven and Adjunct Director of the VIB Vesalius Research Center, KU Leuven, Belgium. He is internationally renowned for his research on the growth and functioning of blood vessels, with key findings including identification of which signalling molecules play a role in the formation of new blood vessels, as well as investigation of vascular growth in tumours. His research interests also include investigating the molecular basis of endothelial cell dysfunction and regeneration. Professor Carmeliet was awarded the 2018 Heineken Prize for Medicine for his pioneering research on blood vessel formation, elected a foreign member of the Royal Netherlands Academy of Arts and Sciences in 2017, and the recipient of the 2016 Anitschkow Award from the European Atherosclerosis Society.
Angiogenesis Revisited: Role and (Therapeutic) Implications of Endothelial Metabolism
Endothelial cells are critical to the regulation of organ growth, regeneration and stem cell function and therefore play a key role in the pathophysiology of diseases such as atherosclerosis, diabetes and hypertension. Within the same organ, endothelial cells may have different origins, heterogeneous properties and functional specialization. Distinct gene expression patterns influence the function of endothelial cells including their angiogenic potential, together with the tissue environment and epigenetic factors.
Insights into endothelial metabolism have indicated the importance of glycolysis, a key metabolic pathway, in the regulation of endothelial cell function. Other pathways have also been implicated, including fatty acid oxidation and, more recently, glutamine/asparagine metabolism. Targeting endothelial cell metabolism and metabolic crosstalk may therefore offer a means of limiting oxidative stress and hyperglycaemia-induced endothelial dysfunction that underpin the development of diabetes-related vascular complications. However, as hyperglycaemia-induced endothelial cell dysfunction varies across different vascular beds, and diabetes preferentially affects endothelial cells in some but not in all vascular beds, further study is needed. Investigation of the consequences of over- or underexpression of a specific target in endothelial cells could ultimately provide future therapeutic potential.
Eelen G, Dubois C, Cantelmo A, Goveia J, Brüning U, DeRan M, Jarugumilli G, van Rijssel J, Saladino G, Comitani F, Zecchin A, Rocha S, Chen R, Huang H, Vandekeere S, Kalucka J, Lange C, Morales-Rodriguez F, Cruys B, Treps L, Ramer L, Vinckier S, Brepoels K, Wyns S, Souffreau J, Schoonjans L, Lamers WH, Wu Y, Haustraete J, Hofkens J, Liekens S, Cubbon R, Ghesquière B, Dewerchin M, Gervasio FL, Li X, van Buul JD, Wu X, Carmeliet P. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. Nature 2018;561:63-9.
Kalucka J, Bierhansl L, Conchinha NV, Missiaen R, Elia I, Brüning U, Scheinok S, Treps L, Cantelmo AR, Dubois C, de Zeeuw P, Goveia J, Zecchin A, Taverna F, Morales-Rodriguez F, Brajic A, Conradi LC, Schoors S, Harjes U, Vriens K, Pilz GA, Chen R, Cubbon R, Thienpont B, Cruys B, Wong BW, Ghesquière B, Dewerchin M, De Bock K, Sagaert X, Jessberger S, Jones EAV, Gallez B, Lambrechts D, Mazzone M, Eelen G, Li X, Fendt SM, Carmeliet P. Quiescent endothelial cells upregulate fatty acid β-oxidation for vasculoprotection via redox homeostasis. Cell Metab 2018; doi: 10.1016/j.cmet.2018.07.016. [Epub ahead of print]
Bruning U, Morales-Rodriguez F, Kalucka J, Goveia J, Taverna F, Queiroz KCS, Dubois C, Cantelmo AR, Chen R, Loroch S, Timmerman E, Caixeta V, Bloch K, Conradi LC, Treps L, Staes A, Gevaert K, Tee A, Dewerchin M, Semenkovich CF, Impens F, Schilling B, Verdin E, Swinnen JV, Meier JL, Kulkarni RA, Sickmann A, Ghesquière B, Schoonjans L, Li X, Mazzone M, Carmeliet P. Impairment of angiogenesis by fatty acid synthase inhibition involves mTOR malonylation. Cell Metab 2018; doi: 10.1016/j.cmet.2018.07.019. [Epub ahead of print]
Douglas R. Seals, Boulder, USA
Douglas R. SealsBoulder, USA
Douglas R. Seals is the Distinguished Professor, Department of Integrative Physiology, University of Colorado Boulder. After receiving his PhD in applied exercise physiology, Dr Seals undertook postdoctoral studies at the Washington University School of Medicine, St Louis, and Associate Professorships at the University of Arizona, and University of Colorado Boulder. His recent awards include a National Institute on Aging MERIT Award (2004-current), and the Edward F. Adolph Distinguished Lecturer, American Physiological Society (2013). His research interests include investigation of changes in systolic blood pressure, large artery stiffness and vascular endothelial function that occur with physiological and pathophysiological aging; biological and lifestyle factors that influence cardiovascular aging; integrative (molecular to systemic) mechanisms that mediate cardiovascular aging and its modulation by biological and lifestyle factors; and interventions to improve adverse physiological changes associated with aging, including cardiovascular dysfunction, reductions in motor performance and impairments in cognitive function.
Cardiovascular aging and mitochondia function
Mitochondrial dysfunction plays a critical role in cardiovascular aging, with crosstalk between the mitochondria and cellular signaling implicated in both cardiac and vascular effects. It is already well established that age-related changes in mitochondria function are integral to pathological alterations in the heart. Added to this, recent studies have also implicated age-related changes in the mitochondria that are associated with vascular pathophysiological changes.
Studies have shown that mitochondria-derived oxidative stress is an important mechanism underlying the development of arterial endothelial dysfunction, a precursor to the development of cardiovascular disease. There is evidence that an excess of mitochondria-derived reactive oxygen species promotes adverse structural changes, notably an increase in collagen production and elastin degradation. Additionally, studies in animal models indicate that modulation of mitochondria-derived reactive oxygen species contributes to large elastic artery stiffening. Beyond these effects, mitochondria-derived reactive oxygen species have also been implicated in exacerbating and sustaining arterial inflammation. This may further contribute to arterial stiffening via a number of mechanisms, including induction of gene expression patterns that modulate structural protein turnover, impairment of vascular endothelial function, increases in vascular smooth muscle cell tone, and exacerbation of the local proinflammatory environment in the vascular wall.
Thus, the emerging evidence suggests the possibility of novel approaches to preventing cardiovascular disease. A key consideration is whether intervention with mitochondria-targeted antioxidants earlier in life could decrease aortic stiffness, and potentially, the risk of associated cardiovascular complications. Indeed, initial clinical studies in healthy older subjects suggest that this approach offers promise for treating age-related vascular dysfunction.
Gioscia-Ryan RA, Battson ML, Cuevas LM, Eng JS, Murphy MP, Seals DR. Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol 2018;124:1194-202.
Rossman MJ, Santos-Parker JR, Steward CAC, Bispham NZ, Cuevas LM, Rosenberg HL, Woodward KA, Chonchol M, Gioscia-Ryan RA, Murphy MP, Seals DR. Chronic supplementation with a mitochondrial antioxidant (MitoQ) improves vascular function in healthy older adults. Hypertension 2018;71:1056-63.
LaRocca TJ, Martens CR, Seals DR. Nutrition and other lifestyle influences on arterial aging. Ageing Res Rev 2017;39:106-19.
Tuesday 28 May
PREVENTING CVD RISK: WHERE DO WE STAND?
Chris Packard, Glasgow, UK
Chris PackardGlasgow, UK
Chris Packard is Professor of Vascular Biochemistry and a Senior Research Fellow at the University of Glasgow. His research has focused on lipoprotein metabolism and how it is affected by diets and drugs, and he has played a key role in large scale clinical trials of lipid lowering agents. More recently, his research interests have extended to the study of emerging risk factors for coronary heart disease, the metabolic consequences of insulin resistance and the causes of the dyslipidaemia in metabolic syndrome, the health consequences of social deprivation, as well as exploration of the mechanism of action of novel lipid lowering drugs. Key contributions from his research include evaluation of the role of the low-density lipoprotein (LDL) receptor in vivo, the discovery of metabolic channelling in the apolipoprotein B lipoprotein delipidation cascade, and the formulation of models to explain the generation of small, dense LDL. Outside the laboratory, Professor Packard is active in local and national initiatives to promote health gains from medical research. He was founding chairman of NEXXUS, the West of Scotland Bioscience Network which promoted community building and knowledge exchange between life sciences industry, academia and the UK National Health Service.
Biomarkers predicting CVD
The morbidity and disability associated with nonfatal cardiovascular complications are major contributors to the societal burden of cardiovascular disease. With increasing financial pressures on healthcare systems, it is therefore critical to identify susceptible individuals so as to prevent new events. Much of the focus of previous guidelines for cardiovascular disease prevention has been on traditional modifiable risk factors; however, it is evident that these risk factors do not explain all risk, as there are individuals who have events who do not fit the traditional definition of “high risk”. Consequently, there has been a drive to identify and validate novel biomarkers that may be of relevance.
Investigation of this question has offered a diversity of biomarker candidates. One example is troponin I, a specific marker of myocardial injury and an independent predictor of cardiovascular mortality in patients with and without cardiovascular disease. Analyses from the West of Scotland Coronary Prevention Study also showed that serial troponin I measurement has therapeutic potential as a dynamic biomarker of cardiovascular disease risk. To date, however, there is no ‘one’ biomarker that can be recommended. Furthermore, while incorporation of multiple biomarkers in one multimodal marker can improve predictive ability, the costs entailed can limit the gains of this approach.
More recently, attention has also focused on the potential of small non-coding microRNAs (miR) as biomarkers of disease, given their regulatory roles in gene expression. For example, miR-30 has been suggested as one possibility given evidence of a positive association with total- and low-density lipoprotein cholesterol, implicating regulatory functions in lipid homeostasis. Studies also implicate miR‑30c-5p as a promoter of early atherosclerosis. These novel miR may therefore offer promise as non-invasive biomarkers in diagnosis and cardiovascular disease risk stratification, providing information complementary to traditional markers and established clinical variables. As with other potential biomarker candidates, however, there are a range of issues to consider, including changes in the utility of the biomarker in different clinical settings, the extent of intra-individual variability over time, as well as practical requirements. If validated, the use of such novel biomarkers, either alone or in combination, may offer opportunities for tailoring treatment to the individual, as well as monitoring efficacy, consistent with the concept of personalized cardiovascular disease medicine.
Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest risk-highest benefit’ strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J 2018;39:2546-50.
Packard CJ, Young R, Ross K, Ford I, Ambegaonkar BM, Brudi P, McCowan C. Modelling total coronary heart disease burden and long-term benefit of cholesterol lowering in middle aged men with and without a history of cardiovascular disease. Eur Heart J Qual Care Clin Outcomes 2017;3:281-8.
Sodi R, Eastwood J, Caslake M, Packard CJ, Denby L. Relationship between circulating microRNA-30c with total- and LDL-cholesterol, their circulatory transportation and effect of statins. Clin Chim Acta 2017;466:13-19.
Heribert Schunkert, Munich, Germany
Heribert SchunkertMunich, Germany
Heribert Schunkert, MD is Professor of Cardiology of the Technische Universitaet Munich, Director of the Cardiology Department and Medical Director of the German Heart Centre Munich. He completed a research fellowship at Brigham and Women,s Hospital, Boston, USA and clinical fellowships at Beth Israel Hospital and at the Universitaetsklinikum, Regensburg and the Massachusetts General Hospital, Boston, USA. From 2002-2012 Prof. Schunkert was Director of Internal Medicine and Cardiology at the University of Luebeck. He conducts research in the molecular genetics of multifactorial cardiovascular disease.He coordinates several EU- and BMBF-sponsored projects as well as the European-American Leducq network CADgenomics to identify the genetic roots of myocardial infarction. He served in the Board of Directors of the German Societies of Hypertension (DHZ) as well as Cardiology (DGK). He is the author of more than 500 publications in international journals.
The genetic burden in CVD
Cardiovascular disease is multifactorial with a diversity of underlying causative factors. While clinical, biochemical, and imaging parameters have been used to stratify cardiovascular risk and, potentially, to tailor therapy, further insights into the pathophysiology of atherosclerosis is now needed to improve preventive strategies. Consideration of genetic susceptibility to cardiovascular disease suggests a way forward.
Methodological advances together with collaborative efforts have improved understanding of the heritability of coronary artery disease. There is now evidence that genetic susceptibility accounts for a proportion of the risk for coronary artery disease, as demonstrated in reproducible findings from genome-wide association studies (GWAS) in extremely large cohorts. GWAS have identified over 50 genetic variants associated with coronary artery disease and myocardial infarction; almost all of these loci are commonly found in European populations. While there are rare variants with a strong impact on disease risk, in the majority of cases, polygenic effects, i.e. the combined small effects of hundreds of thousands of variants are more typical.
Understanding of the biology and pathways which mediate the effects of these loci, and the interplay between multiple genes and non-genetic factors, such as lifestyle factors, lags behind. Improved elucidation of the translation of human genetics to functional biology is fundamental to the development of a simple, clinically meaningful genetic risk score which would provide complementary prognostic information, with the ultimate aim of providing personalized management of coronary artery disease risk and treatment strategies.
van der Laan SW, Siemelink MA, Haitjema S, Foroughi Asl H, Perisic L, Mokry M, van Setten J, Malik R, Dichgans M, Worrall BB; METASTROKE Collaboration of the International Stroke Genetics Consortium, Samani NJ, Schunkert H, Erdmann J, Hedin U, Paulsson-Berne G, Björkegrenn JLM, de Borst GJ, Asselbergs FW, den Ruijter FW, de Bakker PIW, Pasterkamp G. Genetic susceptibility loci for cardiovascular disease and their impact on atherosclerotic plaques. Circ Genom Precis Med 2018;11(9):e002115.
Vilne B, Schunkert H. Integrating genes affecting coronary artery disease in functional networks by multi-OMICs pproach. Front Cardiovasc Med 2018;5:89.
Li Y, Wang DW, Chen Y, Chen C, Guo J, Zhang S, Sun Z, Ding H, Yao Y, Zhou L, Xu K, Song C, Yang F, Zhao B, Yan H, Wang WJ, Wu C, Lu X, Yang X, Dong J, Zheng G, Tian S, Cui Y, Jin L, Liu G, Cui H, Wang S, Jiang F, Wang C, Erdmann J, Zeng L, Huang S, Zhong J, Ma Y, Chen W, Sun J, Lei W, Chen S, Rao S, Gu D, Schunkert H, Tian XL. Genome-wide association and functional studies identify SCML4 and THSD7A as novel susceptibility genes for coronary artery disease. Arterioscler Thromb Vasc Biol 2018;38:964-75.
Schunkert H. Genetics of CVD in 2017: Expanding the spectrum of CVD genetics. Nat Rev Cardiol 2018;15:77-8.
Ian Graham, Dublin, Ireland
Ian GrahamDublin, Ireland
Ian Maklim Graham FRCPI, FESC, FTCD Biographical note Ian Graham is Professor of Cardiovascular Medicine in Trinity College, Dublin, and Professor Emeritus of Preventive Cardiology at the Royal College of Surgeons in Ireland. He is a member of the Board of the European Society of Cardiology, Chairman of the Adelaide Health Foundation and of its Health Policy Initiative. He is a member of the 6th Joint European Societies Task Force on the Prevention of Cardiovascular Disease in clinical practice and of its Prevention Implementation Committee, having Chaired the 4th Task Force. He is co-Chair the 2016 European Guidelines on the management of dyslipidaemias. Prof Graham studied medicine at Trinity College in Dublin, and worked in Dublin and Cambridge before becoming Head of Cardiology at Tallaght Hospital in Dublin and Vice-Chair of its Board of management. He was Director of Research at St Vincent’s Hospital and at the Irish Heart Foundation. He is past President of the Irish Heart Foundation, the Dublin University Biological Association and the Irish Hyperlipidaemia Association. He founded the Irish National Cardiac Surgery register. He is an honorary Fellow of Trinity College in Dublin, and recipient of the Stokes Medal of the Irish Cardiac Society, and the Sir Thomas and Lady Dixon Medal from the Royal Victoria Hospital in Belfast. He held a Medical Research Council Fellowship, a EU travelling Fellowship at Erasmus University in Rotterdam and an ISFC Cardiovascular Epidemiology Fellowship. Prof Graham is Project leader of the EU Concerted Action Project SCORE (Systematic COronary Risk Evaluation) and of its electronic derivative, HeartScore. He is a member of the EuroAspire risk factor audit, and Project Leader of a simplified international audit, SURF (Survey of Risk Factors). Research interests include the natural history of coronary heart disease, cardiovascular risk estimation, homocysteine and vascular disease, health policy and planning and the evaluation of therapies. He has written extensively in these areas. email@example.com
Thomas Lüscher, Zurich, Switzerland
Thomas LüscherZurich, Switzerland
Professor Lüscher studied medicine at the University of Zurich and obtained the board certification in internal medicine and cardiology. He trained in cardiovascular research and in cardiology and specifically in echocardiography at the Mayo Clinic in Rochester, MN, USA and was later Professor of Pharmacotherapy at the University of Basel, then Professor of Cardiology at the University of Berne, before assuming a position as Professor and Chairman of Cardiology and Director of the University Heart Center at the University Hospital Zurich and Director of the Center for Molecular Cardiology at the University of Zurich, Switzerland. He is now Director of Research, Education & Development and Consulting Cardiologist at the Royal Brompton & Harefield Hospital Trust and the Imperial College in London.
Clinical Competence and Activity:
Professor Lüscher is an active general and interventional cardiologist with a broad clini-cal scope and large experience in prevention, coronary and valvular heart disease, percutaneous interventions and heart failure. He has sucessfully taken care of cardiac patients for many years from many countries.
Professor Lüscher has been a mentor of numerous physicians and scientists from many countires. His research is translational in nature and focuses on coronary artery disease, specifically on the role of endothelium-derived mediators in the regulation of vascular tone and structure, platelet-vessel wall interactions, coagulation in aging, hy-pertension, lipid disorders and atherosclerosis. More recently, inflammatory pathways in coronray artery disease and particularly in acute coronary syndromes has been at the center of his interest. Professor Lüscher has published extensively, authoring or co-authoring over 500 original research articles and more than 200 reviews, book chapters and monographs including the ESC Textbook of Cardiovascular Medicine.
Recognition and Awards:
By the Institute for Scientific Information he has been rated as one of the 0.5% most cited scientists worldwide. He has obtained numerous research prizes and prestigious lecturerships worldwide. He is a member of many editorial boards and was Associate Editor Europe of Circulation (Journal of the American Heart Association) from 2004 to 2008. Since 2009 he is chairman of the publications committee of the European So-ciety of Cardiology (ESC) and an ex-officio member of the ESC board as well as editor-in-chief of the European Heart Journal.
Kausik Ray, London, UK
Kausik RayLondon, UK
Kausik Kumar Ray is currently Professor of Public Heath, Deputy Director of Imperial Clinical Trials Unit and Head of Commercial Trials within the Department of Public Health and Primary Care, School of Public Health, Imperial College London. Professor Ray received his medical education (MB ChB, 1991) at the University of Birmingham Medical School, his MD (2004) at the University of Sheffield, a postdoctoral fellowship at Harvard Medical School and finally an MPhil in epidemiology (2007) from the University of Cambridge. A Fellow of the American College of Cardiology, the European Society of Cardiology, the American Heart Association and the Royal College of Physicians, Kausik Ray is also a member of the British Cardiovascular Society and European Atherosclerosis Society also serving on the EAS Consensus panel. Professor Ray has been the national lead investigator (SC or EC member) for several major medical trials, and is currently involved in 8 ongoing trials in lipids and diabetes and the PI for ORION 1 assessing PCSK9 inhibition through RNA interference and BETONMACE assessing BET protein inhibition in patients with ACS. Professor Ray’s research interests have focused on the prevention of coronary disease with a focus on lipids, diabetes, biomarkers and risk prediction. He has an H index of 59, an i10 of 123 and over 26,000 citations overall, including over 170 publications in journals including NEJM, Lancet, JAMA, Archives of Internal Medicine, Circulation, the Journal of the American College of Cardiology, and the European Heart Journal. Key original contributions which have influenced European and American guidelines include demonstrating the early benefits of statin therapy post ACS, the impact of more/less intensive glycaemic control on CVD and the risks/benefits of aspirin therapy in primary prevention. Recently, his work on statins and diabetes risk led to a global label change for statins by the FDA and EMEA. Currently Professor Ray leads the EAS FH Studies collaboration which is the first global registry of FH and includes 68 countries, as well as being the Senior PI for the TOGETHER study looking at cardiometabolic risk in the vascular health checks in 250,000 people in London.
Wednesday 29 May
LOOKING TO THE FUTURE - NOVEL TREATMENT STRATEGIES
Matthias Nahrendorf, Boston, USA
Matthias NahrendorfBoston, USA
Matthias Nahrendorf, MD PhD, is a Professor at Harvard Medical School and a Principal Investigator at the MGH Center for Systems Biology. He studies the function, supply and production of leukocytes, and the signals that regulate hematopoiesis after injuries such as myocardial infarction or stroke. He described that after MI, the spleen releases a large population of ready-made leukocytes that travel to the ischemic heart (Science 2009). He further found that MI and chronic stress increases sympathetic nerve activity in the bone marrow. This modulates the hematopoietic stem cell niche, activating migration and proliferation of myeloid progenitor cells (Nature 2012, Nat Med 2014). Resident macrophages, on the other hand, do not derive from circulating cells and promote steady state functions such as cardiac conduction (Cell 2017). The laboratory also develops and employs imaging to sample biology non-invasively, using MR, nuclear, optical and microscopic modalities. Dr. Nahrendorf is an editorial board member of the European Heart Journal, JACC, Circ Res, ATVB, Circulation, Cardiovascular Research and The Journal of Nuclear Medicine. He published >200 peer reviewed articles, was given the MGH Research Scholar Award in 2014, the Basic research Award of the German Society of Cardiology in 2015 and the NHLBI Outstanding Investigator Award in 2018.
The immune system: The next game-changer?
Development of atherogenesis involves a complex interplay between lipids, inflammatory stress and cellular immune responses. Circulating monocytes have been shown to have a pivotal role in plaque inflammation, infiltrating the plaque where they differentiate into macrophages, and further exacerbate the inflammatory environment. Recent studies have implicated that the ‘neural-hematopoietic’ inflammatory axis as a key driver of atherogenesis. Imaging approaches may hold the key to understanding vascular changes in the bone marrow during acute inflammation and help to identify novel therapeutic targets.
Monocytes and monocyte-derived macrophages also play a key role in the immune response to cardiac ischaemia associated with myocardial infarction (MI). In particular, pro-inflammatory monocytes dominate the early acute period after MI, with neutrophils the first immune cells present at the site of injury in response to danger-associated molecules released by necrotic tissue. Although neutrophils initially help to clear cellular debris, their inflammatory mediators can lead to tissue damage and further leucocyte recruitment. Monocytes and monocyte-derived macrophages release inflammatory cytokines, proteases, and reactive oxygen which together perpetuate inflammation. There is emerging evidence, however, that neutrophils may also have a protective role in MI, as the lack of neutrophil -derived mediators impacts the ability of cardiac macrophages to clear cellular debris, and promotes a reparative phenotype. Identification of novel targets that restrict the local inflammatory monocyte response and potentiate cardioprotective properties may offer therapeutic potential for immunomodulatory approaches to healing post-MI.
Vandoorne K, Rohde D, Kim HY, Courties G, Wojtkiewicz GR, Honold L, Hoyer FF, Frodermann V, Nayar R, Herisson FE, Jung Y, Désogère P, Vinegoni C, Caravan P, Weissleder R, Sosnovik DE, Lin CP, Swirski FK, Nahrendorf M. Imaging the vascular bone marrow niche during inflammatory stress. Circ Res 2018; doi: 10.1161/CIRCRESAHA.118.313302. [Epub ahead of print]
Honold L, Nahrendorf M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ Res 2018; 122:113-27.
Hoogeveen RM, Nahrendorf M, Riksen NP, Netea MG, de Winther MPJ, Lutgens E, Nordestgaard B, Neidhart M, Stroes ESG, Catapano AL, Bekkering S. Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases. Eur Heart J 2017 doi: 10.1093/eurheartj/ehx581. [Epub ahead of print]
Laszlo Nagy, Florida, USA
Laszlo NagyFlorida, USA
László Nagy is Professor of Biochemistry and Molecular Biology, University of Debrecen (since 2006), Head of the Center for Clinical Genomics and Personalized Medicine Hungary (since 2000) and Director of Genomic Control of Metabolism Program and Professor of the Diabetes & Obesity, Research Center Sanford Burnham Prebys Medical Discovery Institute at Lake Nona (since 2013). After completing his medical degree and PhD at the University Medical School, Debrecen, Hungary he undertook postdoctoral research at the University of Texas Medical School, Houston, USA (1992 – 1995). Subsequent appointments included International Research Scholar of the Howard Hughes Medical Institute (2001-2011), a Wellcome Trust International Senior Research Fellow (2005-2010), and a Fulbright Scholar Visiting Scientist, The Salk Institute for Biological Studies (2010-2011). His affiliations include the Endocrine Society (USA), American Society of Biochemistry and Molecular Biology, American Association of Immunologists, and the American Physiological Society. He is a founding member of the Hungarian Society for Bioinformatics. Professor Nagy is the recipient of numerous awards, most recently the ESCI Award for Excellence in Biomedical Investigation (2008), Academia Europaea (2012), Scientist of the Year 2012 (City of Debrecen, Dehir), and the Béla Tankó prize (2014).
System-level analyses of inflammatory and repair macrophages reveal an integrated circuitry of lipid and epigenomic changes
Systems biology provides a holistic collaborative approach when investigating complex cellular processes, integrating data from many scientific areas to predict how these systems change over time and under varying conditions. A combination of high-throughput, multiplexed, quantitative methods with computational modelling and statistical approaches is required, especially relevant in the context of macrophage function, given the versatility, plasticity and multiple roles of macrophages in the innate immune system.
The rapid re-programming required for the plasticity of macrophage function depends on the changing microenvironment and metabolic processes. Understanding the transcriptional regulation of macrophage-specific responses to environmental cues has been aided by recent progress in genomics, both for transcriptional activation and, more recently, transcriptional repression. Mechanistic models that explain how transcription factors control macrophage activation and function provide an interpretative framework for the impact of genetic variability on macrophage-specific gene expression. Future systems analysis of the regulation of specific genes involved in macrophage activation in response to different stimuli is likely to represent the next frontier for this field.
Czimmerer Z, Daniel B, Horvath A, Rückerl D, Nagy G, Kiss M, Peloquin M, Budai MM, Cuaranta-Monroy I, Simandi Z, Steiner L, Nagy B Jr, Poliska S, Banko C, Bacso Z, Schulman IG, Sauer S, Deleuze JF, Allen JE, Benko S, Nagy L. The Transcription Factor STAT6 mediates direct repression of inflammatory enhancers and limits activation of alternatively polarized macrophages. Immunity 2018;48:75-90.
Czimmerer Z, Horvath A, Daniel B, Nagy G, Cuaranta-Monroy I, Kiss M, Kolostyak Z, Poliska S, Steiner L, Giannakis N, Varga T, Nagy L. Dynamic transcriptional control of macrophage miRNA signature via inflammation responsive enhancers revealed using a combination of next generation sequencing-based approaches. Biochim Biophys Acta 2018;1861:14-28.
Czimmerer Z, Nagy ZS, Nagy G, Horvath A, Silye-Cseh T, Kriston A, Jonas D, Sauer S, Steiner L, Daniel B, Deleuze JF, Nagy L. Extensive and functional overlap of the STAT6 and RXR cistromes in the active enhancer repertoire of human CD14+ monocyte derived differentiating macrophages. Mol Cell Endocrinol 2018;471:63-74.
Erik S. Stroes, Amsterdam, The Netherlands
Erik S. StroesAmsterdam, The Netherlands
Erik Stroes is Professor and Chair of the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. Professor Stroes received his medical degree from the University of Rotterdam in 1991, and subsequently trained in internal medicine at the University Medical Center of Utrecht. His major research interest over the last two decades has been the role of the vessel wall in atherogenesis, especially the contributions of lipid disorders and inflammation. Recent research has focused on targeting epigenetic changes in innate immune cells in atherosclerosis that may offer future potential for imaging, biomarkers and therapies. Professor Stroes is a member of the Council for Basic Science, the American Heart Association, the International Atherosclerosis Society and Chair of the Dutch Society of Atherosclerosis. He has authored more than 300 scientific publications associated with his research interests.
New lipid drugs: Is LDL done, ready for new targets?
Much of the emphasis on novel treatments in atherosclerosis has been on apolipoprotein (apo)B-containing lipoproteins, especially in view of the indisputable causality of low-density lipoprotein (LDL) for atherosclerotic cardiovascular disease. Cardiovascular outcomes studies with proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibody therapy represent the pinnacle of this avenue, showing that lowering LDL cholesterol levels, beyond those attained on intensive statin therapy, reduced cardiovascular events in very high risk patients. Moreover, there was no evidence to suggest any threshold in LDL cholesterol lowering for associated clinical benefit.
Yet despite the availability of these highly efficacious LDL cholesterol lowering treatments, very high risk patients continue to experience cardiovascular events. This implies the need to address other targets that contribute to this residual cardiovascular risk. Lipoprotein(a) [Lp(a)] is a key contender, given evidence from epidemiologic and genetic studies for a causal role in atherosclerotic cardiovascular disease. Insights from cardiovascular outcomes studies with the PCSK9 inhibitors add further support, showing that patients with higher baseline Lp(a) levels gained greater cardiovascular benefit from PCSK9 inhibition.
Other lipid targets also merit attention. Recently, the REDUCE-It trial demonstrated reduction in cardiovascular events with high dose (4-g daily) of the omega-3 oil eicosapentaenoic acid in very high risk patients with elevated triglycerides. While the magnitude of benefit (25% relative risk reduction) implies the involvement of mechanisms beyond lipid-lowering, the study is pivotal in supporting the importance of targeting elevated triglycerides, a characteristic of the atherogenic dyslipidaemia associated with type 2 diabetes. Beyond lipids, findings from the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) provide proof of principle for targeting inflammatory risk to reduce cardiovascular events.
The search for other novel targets will undoubtedly continue. In the future, this will undoubtedly include the opportunity to ‘re-programme’ aberrant changes in the control of gene expression with epigenetic treatments for cardiovascular disease prevention.
O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Češka R, Ezhov MV, Jukema JW, Jensen HK, Tokgözoğlu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and cardiovascular risk. Circulation 2019;139:1483-92.
Stiekema LCA, Stroes ESG, Verweij SL, Kassahun H, Chen L, Wasserman SM, Sabatine MS, Mani V, Fayad ZA. Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment. Eur Heart J 2018 Dec 18. doi: 10.1093/eurheartj/ehy862. [Epub ahead of print]
Kastelein JJP, Stroes ESG. FISHing for the miracle of eicosapentaenoic acid. N Engl J Med 2019;380:89-90.
Nicorescu I, Dallinga GM, de Winther MPJ, Stroes ESG, Bahjat M. Potential epigenetic therapeutics for atherosclerosis treatment. Atherosclerosis 2019;281:189-97.
M. John Chapman, Paris, France
M. John ChapmanParis, France
M. John Chapman is Research Professor at the University of Pierre and Marie Curie, and Director Emeritus of the National Institute for Health and Medical Research (INSERM), Pitié-Salpétrière University Hospital, Paris, France. Together with Professor Henry Ginsberg (University of Columbia, New York, USA) he has led the EAS Consensus Panel initiative (for full details of the Consensus Panel papers see https://www.eas-society.org/page/consensus_papers ). Professor Chapman undertook his undergraduate studies at Aberdeen University and the Middlesex Hospital Medical School, University of London. He subsequently trained in cardiovascular lipidology at the Cardiovascular Research Institute of the University of California Medical Center, and the Gladstone Foundation for Cardiovascular Disease, San Francisco, USA. He is the recipient of the 2014 European Lipid Science Award and the 2015 Antonio M. Gotto Jr Prize for Atherosclerosis Research from the International Atherosclerosis Society. Present research interests include the relationship of the lipidome and proteome to the functionality of high-density lipoprotein (HDL) particles in health and cardiometabolic disease, and on the development of new anti-atherosclerotic therapeutics targeted to HDL.
The HDL story: time to reconsider?
The relationship between HDL and cardiovascular disease has had a turbulent history. Evidence from observational studies of an inverse association between HDL cholesterol levels and coronary artery disease risk prompted the notion that increasing HDL levels therapeutically would reduce atherosclerosis. The results of a number of studies involving different therapeutic approaches have, however, been largely negative and led to the demise of the ‘HDL hypothesis’. In addition, recent epidemiologic data have shown that in some clinical settings very high HDL cholesterol levels may correlate with increased atherosclerotic risk.
The key message from these findings is that HDL cholesterol is not an appropriate measure for assessing the relationship between HDL and atherosclerotic cardiovascular disease. Instead, there has been a renewed focus on HDL functionality, including protective effects of HDL on lipid oxidation, endothelial cell functions/integrity, and anti-inflammatory/antiapoptotic effects. Increased understanding of HDL particle composition with ‘omics’ technologies has also underlined the oversimplification of previous thinking. There is now increasing evidence that modification of the structure and composition of HDL particles in numerous disease states including diabetes, auto-immune disease, and cardiovascular disease, results in functionally defective particles; these changes may also indirectly enhance low-density lipoprotein atherogenicity. Taken together, evidence suggests that improving HDL particle quality rather than HDL quantity may offer alternative therapeutic approaches in the future.
Rosenson RS, Brewer HB Jr, Barter PJ, Björkegren JLM, Chapman MJ, Gaudet D, Kim DS, Niesor E, Rye KA, Sacks FM, Tardif JC, Hegele RA. HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nat Rev Cardiol 2018;15:9-19.
Feng M, Rached F, Kontush A, Chapman MJ. Impact of lipoproteins on atherobiology: emerging insights. Cardiol Clin 2018;36:193-201.
Muñoz-Hernandez L, Ortiz-Bautista RJ, Brito-Córdova G, Lozano-Arvizu F, Saucedo S, Pérez-Méndez O, Zentella-Dehesa A, Dauteuille C, Lhomme M, Lesnik P, Chapman MJ, Kontush A, Aguilar Salinas CA. Cholesterol efflux capacity of large, small and total HDL particles is unaltered by atorvastatin in patients with type 2 diabetes. Atherosclerosis 2018;277:72-9.
Chapman MJ, Orsoni A, Robillard P, Therond P, Giral P. Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP. J Clin Lipidol 2018;12:784-800.