EAS Newsletter

​​​​​​​Focus on EAS Glasgow 2015 
Plenary speakers​

Session I: A New Look at the Vascular Wall
Zahi Fayad, USA:  Imaging of atherosclerosis

 Zahi Fayad.jpgZahi Fayad is Professor of Radiology and Medicine (Cardiology) at the Mount Sinai School of Medicine, as well as Director of the Translational and Molecular Imaging Institute, Director and Founde​r of the Eva and Morris Feld Imaging Science Laboratories and Director of Cardiovascular Imaging Research at the Mount Sinai School of Medicine and Mount Sinai Medical Center. Dr. Fayad is a leader in the development and use of multimodality cardiovascular imaging and molecular imaging to study cardiovascular disease. Recent research has focused on the use of in vivo non-invasive multimodality imaging methods for the early detection of atherosclerosis in humans and for cardiovascular events and outcomes prediction. These approaches permit assessment of the morphology and composition of the vessel walls, even at the cellular and molecular level. Dr Zayad is a Fellow of the American Heart Association and the American College of Cardiology, and a member of the NIH's National Lung, and Blood Institute Cardiovascular Strategic Planning Working Group on Vascular Disease and Hypertension. He is the recipient of multiple prestigious awards, including recently the John Paul II Medal from Krakow, Poland.
An acute coronary event is often the first presentation of coronary disease in asymptomatic patients. Therefore the challenge for clinicians is to better identify patients at risk before such events occur. Increasing evidence shows that characteristics of plaque morphology, notably the fibrous cap, inflammatory factors and necrotic core size, are better indicators of risk for coronary events than the extent of luminal stenosis.
Imaging of vulnerable or culprit plaques can be performed either by noninvasive or invasive methods. While intravascular ultrasound (IVUS) is commonly used for assessing plaque burden, it does have practical limitations and does not allow for assessment of the thickness of the fibrous cap or imaging of microfeatures. Instead, strategies such as optical coherence tomography (OCT) and near-infrared spectroscopy may be used for assessment of high-risk plaque phenotype. For example, with advances in OCT technology there is the possibility of determining the collagen content and smooth muscle cell density in the fibrous cap, which in turn provides insights into the mechanical stability of the fibrous cap. The use of near-infrared spectroscopy to characterise the necrotic core of vulnerable plaques may offer potential for determining their susceptibility for rupture. The ongoing natural history PROSPECT II study is using this imaging modality to identify susceptible non-flow obstructing vulnerable plaques.
Finally, developments in multimodality imaging or molecular imaging using targeted tracers enable imaging of plaque morphology, composition, and detection of plaque inflammation. Such approaches may help in understanding the mechanisms of vascular inflammation and its role in plaque destabilisation. Ultimately, the use of multimodality cardiology imaging may offer the tantalising possibility of identifying the most opportune time for mechanical intervention to avert the clinical consequences of vulnerable plaque rupture.
Key references
Garcia-Garcia HM, Jang IK, Serruys PW, Kovacic JC, Narula J, Fayad ZA. Imaging plaques to predict and better manage patients with acute coronary events. Circ Res 2014;114:1904-17.
Millon A, Canet-Soulas E, Boussel L, Fayad Z, Douek P. Animal models of atherosclerosis and magnetic resonance imaging for monitoring plaque progression. Vascular 2014;22:221-37.
Giannarelli C, Alique M, Rodriguez DT, Yang DK, Jeong D, Calcagno C, Hutter R, Millon A, Kovacic JC, Weber T, Faries PL, Soff GA, Fayad ZA, Hajjar RJ, Fuster V, Badimon JJ. Alternatively spliced tissue factor promotes plaque angiogenesis through the activation of HIF-1α and VEGF signaling. Circulation. 2014 Aug 12. pii: CIRCULATIONAHA.114.006614. [Epub ahead of print]
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Martin Bennett, UK: Cell senescence and atherosclerosishttp://www.med.cam.ac.uk/bennett/files/2011/10/martin-bennet-portrait.jpg

 Martin Bennett.jpgMartin Bennett holds the British Heart Foundation Chair of Cardiovascular Sciences at the University of Cambridge, with Honorary Consultant Cardiologist positions at both Addenbrooke's and Papworth Hospitals, and heads the Division of Cardiovascular Medicine in Cambridge. His major research interests are the vascular biology of atherosclerosis, angioplasty and stent stenosis. In particular, his work has identified the mechanisms by which human vascular smooth muscle cells (VSMCs) undergo apoptosis in atherosclerosis and stent stenosis, and the consequences of smooth muscle cell apoptosis. His research aims to understand the regulation of cell accumulation and interactions in vascular disease, using both human and mouse cells in vitro and models of atherosclerosis with genetic manipulation. Recent work has focussed on the protective mechanisms that ensure survival in VSMCs, their defects in disease, and triggers for VSMC apoptosis and cell senescence. Professor Bennett is currently on the editorial board of Circulation Research, Heart and Biochemical Pharmacology, and the Scientific Councils of the American Heart Association and the European Society for Cardiology. He is a founder member of the European Vascular Genomics network, a network of excellence funded by the EEC, and the European Vascular Biology Organisation.​

There is growing evidence that cellular senescence, defined as the irreversible loss of the ability of cells to divide, contributes to the pathogenesis of human atherosclerosis. Whereas there is extensive proliferation of VSMCs in early atherosclerotic lesions, there is much less in advanced atherosclerotic plaques, suggesting that VSMCs in the plaque might be senescent. 

For successful plaque repair, VSMCs must be able to proliferate and synthesise matrix. Studies in culture and in plaques have shown that both properties are altered by cellular senescence. These cells therefore show increased propensity to undergo cell death, elevated DNA damage, and extensive telomere shortening and dysfunction. This may be due to both replicative senescence of cells forming the plaque, and stress-induced premature senescence, such as that induced by oxidative stress. The reduced ability for DNA repair results in accumulation of both nuclear and mitochondrial DNA damage, leading to cellular dysfunction and vascular stiffness and loss of elasticity. DNA damage may also interact with epigenetic modifications to regulate genes that themselves regulate cell proliferation, cell senescence, and apoptosis. In addition, the release of multiple cytokines by senescent VSMCs augments the pre-existing inflammation and further promotes the development of atherosclerosis. Thus, senescence of VSMCs in the fibrous cap may be implicated in inefficient plaque repair and consequent plaque instability. Ultimately, understanding the mechanisms contributing to such changes may offer potential for therapeutic targets in atherosclerosis.​

Key references

Warboys CM, de Luca A, Amini N, Luong L, Duckles H, Hsiao S, White A, Biswas S, Khamis R, Chong CK, Cheung WM, Sherwin SJ, Bennett MR, Gil J, Mason JC, Haskard DO, Evans PC. Disturbed flow promotes endothelial senescence via a p53-dependent pathway. Arterioscler Thromb Vasc Biol 2014;34:985-95.

Gorenne I, Kumar S, Gray K, Figg N, Yu H, Mercer J, Bennett M. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation 2013;127:386-96.

Wang JC, Bennett M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 2012;111:245-59. 

Christine Mummery, The Netherlands: Using stem cells to model human vascular disease

 Christine Mummery.jpgChristine Mummery is Professor and Chair of Developmental Biology at Leiden University Medical Centre, The Netherlands. Dr. Mummery pioneered studies characterising cardiomyocytes from human embryonic stem cells.  Her recent work has focused on creating cardiac and vascular disease models based on induced pluripotent stem cells and their potential use in drug discovery. Dr Mummery serves on the Medical and Ethical Councils of the Netherlands Ministry of Health, and is a member of the Royal Netherlands Academy of Arts and Science (KNAW), and the International Society for Stem Cell Research (ISSCR. She also serves on the boards of the KNAW and the Netherlands Medical Research Council (ZonMW). 

With increased understanding of stem cell biology, there is much interest in their potential application for regenerative medicine and as treatments for chronic disease, including diabetes and vascular disease.  Protocols have been developed to ensure the development of fully functional human-induced pluripotent stem cells (hPSC) for use in disease modelling.
Derivation of cardiomyocytes from hPSC is an area of growing interest as a platform for drug discovery and toxicity. Studies have shown that combinations of drugs or specific genetic backgrounds modelled using cardiomyocytes from patient-derived hPSC predispose to increased sensitivity to drugs affecting potassium channels. More recently, a human disease model based on cardiomyocytes from human embryonic stem cells showed that repression of PGC-1α, an important regulator of energy metabolism, decreased mitochondrial content and activity and levels of reactive oxygen species and increased the calcium transient amplitude.  These findings suggest potential application in cardiac physiology relevant to vascular disease.  Additionally, studies have indicated the possibility of modulating endocrine cell plasticity with implications for islet development, physiology, and regeneration.
For the long-term, optimising the inflammatory response, and investigating possibilities for the formation of new vessels from the heart itself, may offer the best hope of attaining benefit from the application of stem cell biology in vascular disease.
References
Orlova VV, Drabsch Y, Freund C, Petrus-Reurer S, van den Hil FE, Muenthaisong S, Dijke PT, Mummery CL. Functionality of endothelial cells and pericytes from human pluripotent stem cells demonstrated in cultured vascular plexus and zebrafish xenografts. Arterioscler Thromb Vasc Biol 2014;34:177-86.
Birket MJ, Casini S, Kosmidis G, Elliott DA, Gerencser AA, Baartscheer A, Schumacher C, Mastroberardino PG, Elefanty AG, Stanley EG, Mummery CL. PGC-1α and reactive oxygen species regulate human embryonic stem cell-derived cardiomyocyte function. Stem Cell Reports 2013;1:560-74.
Mummery CL, Lee RT. Is heart regeneration on the right track? Nat Med 2013;19:412-3.


Matthias Nahrendorf, USA: ​Crosstalk between invading and resident cells in atherosclerosis

 Matthias Nahrendorf.jpgMatthias Nahrendorf is Associate Professor and Director, Mouse Imaging Program, Center for Systems Control, Massachusetts General Hospital, Boston, USA.  Current research by his team is focused on investigation of the molecular processes during the healing phase after myocardial infarction, specifically the role of immunity in atherosclerosis and heart failure. His laboratory also develops and employs non-invasive imaging approaches to investigate the underlying biology of these process​es.
Atherosclerosis is a chronic inflammatory disease which may progress to the clinical complications of myocardial infarction (MI) and stroke. Leukocytes are important players in the disease process, with emerging research implicating maladaptive leukocyte function.
There is evidence that leukocytes belong to an organ network that accelerates the progression of atherosclerosis after MI. Communication within this network is mediated by processes that elicit activation, differentiation and migration. After MI, increased sympathetic nervous signalling releases noradrenaline in the bone marrow microenvironment, which in turn results in hematopoietic stem cell activity and retention and production of leukocytes. Increased production of leukocytes leads to further recruitment of monocytes to the atherosclerotic plaque, thus accelerating plaque growth and inflammation. This crosstalk may offer insights into why secondary infarcts are so common in patients.
The ultimate goal is to target leukocytes so as to treat atherosclerotic cardiovascular disease. However, there are still unanswered questions relating to leukocyte biology before this is possible. Further understanding of the triggers for leukocyte participation and activation, as well as key connecting points for crosstalk between the different organ systems, is needed. Such insights offer the possibility of re-focusing the leukocyte response to ensure optimal healing of the infarct.
References
Heidt T, Sager HB, Courties G, Dutta P, Iwamoto Y, Zaltsman A, von Zur Muhlen C, Bode C, Fricchione GL, Denninger J, Lin CP, Vinegoni C, Libby P, Swirski FK, Weissleder R, Nahrendorf M. Chronic variable stress activates hematopoietic stem cells. Nature Med 2014;20:754-758 -
Leuschner F, Courties G, Dutta P, Mortensen LJ, Gorbatov R, Sena B, Novobrantseva TI, Borodovsky A, Fitzgerald K, Koteliansky V, Iwamoto Y, Bohlender M, Meyer S, Lasitschka F, Meder B, Katus HA, Lin C, Libby P, Swirski FK, Anderson DG, Weissleder R, Nahrendorf M. Silencing of CCR2 in myocarditis. Eur Heart J 2014;ePub - PMID: 24950695.


Session II: Novel insights into the regulation of lipid and lipoprotein metabolism

Thomas ​Willnow, Germany: Sortilin as a Regulator of Lipoprotein Metabolism

​​Thomas Willnow.jpg Thomas Willnow is Head of Research, Max-Delbrück-Center for Molecular Medicine, and Full Professor, Charité, Berlin, Germany. His research focuses on the functional characterisation of orphan endocytic receptors of the low-density lipoprotein (LDL) receptor and Sortilin gene families, in particular, their roles in the cardiovascular and nervous systems. His research team uses transgene technologies to generate model organisms with altered receptor expression to study the consequences for organ function in vivo, so as to unravel the underlying molecular mechanisms of receptor activity. Professor Willnow has received numerous awards for his research, including the Research Award of the Alzheimer Research Initiative, Cologne (2006), the Butenandt Award of the Ernst Schering Research Foundation (2000) and the Heinrich Wieland Award (2008). In 2013 he received an ERC Advanced Grant for research into type 2 diabetes and obesity as major risk factors for Alzheimer`s Disease.

Sortilin is a sorting receptor that directs proteins through secretory or endocytic pathways of cells. Not only do these receptors play key roles in regulating protein transport in neurons and controlling neuronal viability, but recent data suggest that they also have important functions in the control of lipoprotein metabolism.

Genome-wide associations studies (GWAS) indicated a strong association of hypercholesterolaemia and myocardial infarction with single nucleotide polymorphisms on the human chromosome 1p13.3, the locus for three genes: SORT1, CELSR2, and PSRC1. Subsequent mechanistic studies supported a role for sortilin, encoded by SORT1, as an important regulator of lipoprotein metabolism. Sortilin was shown to act as an intracellular sorting receptor for apolipoprotein (apo) B100 in the Golgi, facilitating the formation and hepatic export of apoB100-containing lipoproteins, and therefore regulating plasma low-density lipoprotein (LDL) cholesterol levels.

These findings indicate a novel pathway involving sortilin as a regulator of hepatic lipoprotein metabolism.  The involvement of sortilin in dual mechanisms, influencing both hepatic APOB secretion and LDL catabolism, explains the very strong association between increased hepatic sortilin expression and reduced plasma LDL cholesterol levels in man. Furthermore, these insights provide a basis for explaining how altered trafficking pathways may represent a major risk factor for dyslipidaemia and atherosclerosis.

References

Carlo AS, Nykjaer A, Willnow TE. Sorting receptor sortilin-a culprit in cardiovascular and neurological diseases. J Mol Med (Berl) 2014;92:905-11.

Breiderhoff T, Christiansen GB, Pallesen LT, Vaegter C, Nykjaer A, Holm MM, Glerup S, Willnow TE. The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain. J Neurosci 2013;33:358-70.

Nykjaer A, Willnow TE. Sortilin: a receptor to regulate neuronal viability and function. Trends Neurosci 2012;35:261-70.

Peter Tontonoz, USA: Regulation of Cellular Lipid Homeostasis​ ​

 Peter Tontonoz.jpgPeter Tontonoz  is currently Professor of Pathology and Laboratory Medicine and an Investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles. The focus of his research team is the control of gene expression by lipids and the role of nuclear receptors in lipid metabolism. His major research contributions include delineation of the role of peroxisome proliferator-activated receptors (PPAR) and liver X receptors (LXR) in adipogenesis and atherosclerosis, and elucidation of mechanisms of crosstalk between metabolism, inflammation and immunity. Dr. Tontonoz is the recipient of the Richard. E. Weitzman Award from the Endocrine Society, the Jeffrey M. Hoeg Award for Basic Science and Clinical Research from the American Heart Association, and a Bristol Myers-Squibb Freedom to Discover Award in Cardiovascular Disease. He is the Vice-President of the American Society for Clinical Investigation. Dr. Tontonoz serves on a number of editorial boards and is an Editor of Molecular and Cellular Biology.

Systemic cholesterol homeostasis reflects a finely tuned balance between uptake, transport, and excretion. Cholesterol levels are tightly regulated through the coordinated action of the liver X receptor (LXR) and sterol regulatory element–binding protein (SREBP) transcription factors. The nuclear receptors LXRα and LXRβ work in a complementary fashion with SREBPs to maintain cholesterol homeostasis, via integration of lipid and inflammatory signalling pathways.

The LXR signalling pathway also exerts a strong influence on the cellular uptake of cholesterol through the LDLR, a process mediated by E3 ubiquitin ligase MYLIP, subsequently renamed IDOL. IDOL expression is controlled at the transcriptional level by LXR. In response to rising cellular sterol levels, activated LXR induces IDOL production, thereby limiting further uptake of exogenous cholesterol through the LDLR pathway. The LXR-IDOL-LDLR mechanism for feedback inhibition of cholesterol uptake is independent of the SREBP pathway. Moreover, there is also evidence that IDOL is expressed and responsive to LXR activation in other metabolically active tissues, including adipose tissue, the intestine and in macrophages.

Such insights suggest possibilities for pharmacological manipulation of LXRs and their target genes in the management of atherosclerotic cardiovascular disease, to complement statin therapy, as well as other diseases in which lipids have a central role, such as Alzheimer's disease.

References

Calkin AC, Lee SD, Kim J, Van Stijn CM, Wu XH, Lusis AJ, Hong C, Tangirala RI, Tontonoz P. Transgenic expression of dominant-active IDOL in liver causes diet-induced hypercholesterolemia and atherosclerosis in mice. Circ Res 2014;115:442-9.

Rong X1, Albert CJ, Hong C, Duerr MA, Chamberlain BT, Tarling EJ, Ito A, Gao J, Wang B, Edwards PA​, Jung ME, Ford DA, Tontonoz P. LXRs regulate ER stress and inflammation through dynamic modulation of membrane phospholipid composition. Cell Metab 2013;18:685-97.

Beaven SW, Matveyenko A, Wroblewski K, Chao L, Wilpitz D, Hsu TW, Lentz J, Drew B, Hevener AL, Tontonoz P. Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance. Cell Metab 2013;18:106-17.​

Jan Borén, Sweden: Lipoprotein Retention

 Jan Borén.jpgJan Borén is Professor of Cardiovascular Medicine at the Department of Medicine, Sahlgrenska Academy at Göteborg University and Director of the Wallenberg Laboratory for Cardiovascular Research. His research interests focus on defining the mechanisms that regulate secretion and metabolism of atherogenic lipoproteins; the development of strategies to prevent retention of atherogenic lipoproteins so as to identity novel biomarkers for cardiovascular disease; and understanding how cardiac uptake of lipoproteins induces lipotoxicity and insulin resistance. Professor Borén is actively involved in the activities of the EAS and the International Atherosclerosis Society.  He is the recipient of numerous honours and awards including the Irvine H. Page Atherosclerosis Research Awards for Young Investigators (AHA, 1997) and the Göran Gustafsson Prize in Medicine from the Swedish Royal Academy of Sciences (2004).​​

Atherogenesis is initiated by subendothelial accumulation (i.e. retention) of apolipoprotein B (apoB)-containing lipoproteins. Lipoprotein retention only occurs in specific vascular areas and is mediated by artery wall proteoglycans in the innermost layer of the artery (the arterial intima). In particular, proteoglycans with elongated glycosaminoglycan chains seem to play a crucial role in this process. The retained lipoproteins subsequently provoke an inflammatory response that ultimately leads to atherosclerosis.

Atherogenic lipoproteins specifically locate in areas of intimal hyperplasia, characterised by accumulation of vascular smooth muscle cells and extracellular matrix. This thickened intima appears to act as a depot for extracellular lipids in the earliest initial stages of atherosclerosis. Furthermore, accumulation of apoB-containing triglyceride-rich lipoproteins in the postprandial state promotes the retention of remnant particles in the artery wall, in turn leading to accelerated atherosclerosis and cardiovascular disease (CVD).

Emerging evidence indicates that myocardial lipid accumulation also causes cardiac dysfunction independently of coronary artery disease in individuals with diabetes. This cardiac lipid accumulation induces a series of destructive responses after infarction, including apoptosis and loss of muscle cells, which exacerbate functional impairment in the heart and limit its adaptive capacity for compensatory remodelling. In recent studies, accumulation of lipids in the cardiomyocytes was dependent on expression of the very low-density lipoprotein (VLDL) receptor, with a positive association between VLDL receptor expression and lipid droplet content in ischaemic hearts.

Thus, understanding of the mechanisms that underlie the retention of lipoproteins in the arterial wall and in the myocardium may offer the potential for new therapeutic targets for prevention of atherosclerosis and cardiovascular disease.

References

Borén J, Matikainen N, Adiels M, Taskinen MR. Postprandial hypertriglyceridemia as a coronary risk factor. Clin Chim Acta 2014;431:131-42.

Sayin VI, Khan OM, Pehlivanoglu LE, Staffas A, Ibrahim MX, Asplund A, Agren P, Nilton A, Bergström G, Bergo MO, Borén J, Lindahl P. Loss of one copy of Zfp148 reduces lesional macrophage proliferation and atherosclerosis in mice by activating p53. Circ Res 2014 Sep 11. [Epub ahead of print].

Akhmedov A, Rozenberg I, Paneni F, Camici GG, Shi Y, Doerries C, Sledzinska A, Mocharla P, Breitenstein A, Lohmann C, Stein S, von Lukowicz T, Kurrer MO, Borén J, Becher B, Tanner FC, Landmesser U, Matter CM, Lüscher TF. Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo. Eur Heart J 2014 Jan 12. [Epub ahead of print].

S​otirios T​simikas, USA: The Role of Oxidized Phospholipids on Lp(a) in Mediating CVD and Aortic Stenosis

 Sotirios Tsimikas.jpgSotirios Tsimikas is Professor of Medicine and Director of Vascular Medicine at the University of California San Diego. His clinical interests are in line with his role as Director of the Vascular Medicine Program, with areas of interest including the evaluation and treatment of patients with elevated lipoprotein(a) [Lp(a)] levels. Professor Tsimikas's research interests focus on defining the mechanisms of atherosclerosis progression and regression, plaque rupture, acute coronary syndromes, percutaneous coronary intervention and the benefits of therapeutic cardiovascular agents. Professor Tsimikas has well-established programmes in "biotheranostics" that seek to develop biomarkers, molecular imaging and therapeutics related to diagnosis and treatment of cardiovascular disease. Professor Tsimikas has published widely including in NEJM, Nature, JACC, JCI, Circulation, Circ Res, ATVB, and EHJ. He is a Fellow of the American College of Cardiology, the American Heart Association and the Society for Cardiac Angiography and Interventions. He is also Deputy Editor of the Journal of the American College of Cardiology and Associate Editor of JACC Cardiovascular Interventions.

Lipoprotein oxidation plays an important role in the pathogenesis of atherosclerosis. Oxidized phospholipids (OxPLs), present mainly on Lp(a), are significant predictors of the presence and extent of carotid atherosclerosis, development of new lesions, and increased risk of cardiovascular events. Furthermore, Lp(a) is also associated with risk of peripheral arterial disease. Studies investigating the underlying mechanisms have shown that OxPLs on Lp(a) modulate monocyte trafficking, implying a key role of OxPL in the pathophysiology of atherosclerosis mediated by Lp(a).  Indeed, recent insights that suggest a link between pro-inflammatory interleukin-1 genotype, oxidation of phospholipids, Lp(a), and predisposition to coronary artery disease and cardiovascular events offer the possibility of a novel therapeutic treatment target.

Given this accumulating evidence, there is a clear rationale for investigating possibilities for OxPL biomarkers present on Lp(a) in diagnosing and monitoring cardiovascular disease. Biomarker assays measuring OxPL present on Lp(a) predict the development of cardiovascular disease events. Infusion or overexpression of oxidation-specific antibodies reduces the progression of atherosclerosis by potentially neutralising and clearing oxidation-specific epitopes and preventing foam cell formation Translational studies are now investigating therapeutic possibilities for human oxidation-specific antibodies following validation in animal models. These suggest the potential for more rational targeted diagnostic and therapeutic modalities.

References

Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, Clopton P, Brilakis E, Kornman KS, Witztum JL. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 2014;63:1724-34.

Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, Xu Q, Mayr A, Willeit J, Tsimikas S. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): Prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014;64851-60.

Hung MY, Witztum JL, Tsimikas S. New therapeutic targets for calcific aortic valve stenosis: the lipoprotein(a)-lipoprotein-associated phospholipase A2-oxidized phospholipid axis. J Am Coll Cardiol 2014;63478-80.​

Session III: Future Challenges and Opportunities in the Prevention and Treatment of CVD 

John Deanfield, UK: Heart Disease Risk in Children and Adolescents​

 John Deanfield.jpgJohn Deanfield is the British Heart Foundation Vandervell Professor of Cardiology at University College Hospital London, the Director of the National Centre for Cardiovascular disease Prevention and Outcomes at University College London, which incorporates the National Databases for Cardiovascular Outcomes (NICOR), and Consultant Cardiologist at the Heart Hospital and Great Ormond Street Hospital, London. Professor Deanfield chairs the current Joint British Societies (JBS3) new National Guidelines for Cardiovascular Disease Prevention. His principal interests are vascular medicine, opportunities for lifetime management of cardiovascular risk and large scale cardiovascular outcomes research. Professor Deanfield serves on many international advisory boards and is a member of the editorial boards of several major cardiovascular journals.​

The alarming global increase in the occurrence of obesity in the latter parts of the 20th century, most notably in children, is a major cause for concern. Not only is this scenario likely to translate to future increases in adult obesity and associated cardiometabolic disease, but there is also evidence to suggest that childhood obesity is associated with deleterious effects on the atherosclerotic process, which are likely to be cumulative.
The public health challenges of childhood obesity are numerous. There is a clear need for action to reverse the widespread decline in physical activity, as well as to rebalance diet quality and quantity. To achieve real change, a concerted collaborative effort is necessary, not just for the individual and his/her family level but also for change at societal and government levels to implement changes in public health policy. Yet even with the successful implementation of measures aimed at countering childhood obesity, it is likely to be at least one generation in most countries before such changes will impact society.  
Much of the existing evidence to support public health policy changes is from an era in which the balance of chronic disease risk factors differs from the current situation. Clearly, therefore, there is a need for additional trials involving the use of surrogate endpoints for vascular disease. In addition, given that assessment of absolute risk is less relevant in younger individuals, a shift to consideration of lifetime risk rather than absolute risk, is certainly justified. Indeed, this risk estimation strategy has been incorporated within the latest Joint British Societies guidelines for cardiovascular disease prevention.
References
Johnson W, Kuh D, Tikhonoff V, Charakida M, Woodside J, Whincup P, Hughes AD, Deanfield JE, Hardy R; NSHD Scientific and Data Collection Teams. Body mass index and height from infancy to adulthood and carotid intima-media thickness at 60 to 64 years in the 1946 British Birth Cohort Study. Arterioscler Thromb Vasc Biol 2014;34:654-60.
JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 2014;100:ii1-ii67.
Charakida M, Jones A, Falaschetti E, Khan T, Finer N, Sattar N, Hingorani A, Lawlor DA, Smith GD, Deanfield JE. Childhood obesity and vascular phenotypes: a population study. J Am Coll Cardiol 2012;60:2643-50.

Kausik Ray, UK: Where to in Clinical Trials of CHD Prevention?

Kausik Ray.jpg Kausik Ray is Professor of Public Health at Imperial College London and a honorary consultant cardiologist.  He is the lead for the global European Atherosclerosis Society FH Studies Collaboration which is collating data across Europe, Asia, Africa, South America and the Asia Pacific Region. He also leads the TOGETHER study assessing cardiometabolic risk factors in the UK vascular health checks in about 250 000 people. Professor Ray's research interests focus on cardiometabolic risk, preventative cardiology, cardiovascular epidemiology and clinical trials. In this capacity, he serves as the national lead or member of the steering committee of several large international trials looking at novel drug interventions and their effects on cardiovascular disease outcomes. Professor Ray is a member of the European Atherosclerosis Society Consensus panel, an expert member of the European Atherosclerosis Society Therapeutics Committee, fellow of the American College of Cardiology, the European Society of Cardiology, and the American Heart Association, and a member of the British Cardiovascular Society and the Independent Doctors Federation. He is a peer reviewer for the Medical Research Council and the Wellcome Trust and external expert for the National Institute for Health and Clinical Evidence (NICE). 

Undoubtedly, coronary heart disease (CHD) mortality in developed countries has markedly decreased over the last 40–50 years. Pharmacotherapeutic intervention trials and better care in the acute coronary setting underpin this decrease. However, improvement has plateaued more recently implying the need to consider other potential mediators of coronary risk.  Indeed, given the complex processes involved in plaque progression and instability, involving interaction between inflammation, coagulation, thrombogenesis and dyslipidaemia for example, additional targets are implicated.

The changing patient profile, as a result of world-wide epidemics in obesity and diabetes, is one focus of investigation. So far there is no definitive evidence from trials targeting non-LDL lipoproteins, although Mendelian randomisation studies provide a rationale for targeting atherogenic apolipoprotein B-containing triglyceride-rich lipoproteins and their remnants. The potential of intervention against inflammatory mediators is being addressed by ongoing clinical trials.

Epigenetic considerations are also relevant. Each of the processes that underpin coronary artery disease may be under the control of a complex set of genes, which in turn is influenced by environmental factors. Indeed, recent research suggests a biological link between pro-inflammatory interleukin-1 genotype, oxidation of phospholipids, lipoprotein(a), and genetic predisposition to coronary artery disease. Thus, trials targeting gene-gene and gene-environmental interactions may offer future possibilities. Such studies require large samples and access to diverse populations, emphasising the need for collaborative international strategies.

References

Ray KK, Kastelein JJ, Boekholdt SM, Nicholls SJ, Khaw KT, Ballantyne CM, Catapano AL, Reiner Ž, Lüscher TF. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014;35:960-8.

Ray KK. Interleukin-1 revisited: further insights into its role in atherosclerosis and as a potential therapeutic target for treatment. J Am Coll Cardiol 2014;63:1735-8.

Ray KK, Ditmarsch M, Kallend D, Niesor EJ, Suchankova G, Upmanyu R, Anzures-Cabrera J, Lehnert V, Pauly-Evers M, Holme I, Štásek J, van Hessen MW, Jones P; dal-ACUTE Investigators. The effect of cholesteryl ester transfer protein inhibition on lipids, lipoproteins, and markers of HDL function after an acute coronary syndrome: the dal-ACUTE randomized trial. Eur Heart J 2014;35:1792-800.

Sek Kathiresan, USA: GWAS and Mendelian Randomization:  What Comes Next?

Sek Kathiresan.jpg Sekar Kathiresan, a clinical cardiologist and human geneticist, is the Director of Preventive Cardiology at Massachusetts General Hospital, an Associate Member in the Broad Institute’s Program in Medical and Population Genetics, and an Associate Professor of Medicine at Harvard Medical School. His research is focused on identifying genes responsible for inter-individual differences in risk for myocardial infarction, so as to further understanding of the molecular mechanisms and ultimately translate these genetic and functional insights to improved preventive cardiac care.

Although recent genome-wide association studies (GWAS) and Mendelian randomisation studies have identified variants associated with coronary artery disease (CAD), understanding the underlying biology remains a challenge. Given that CAD has a highly complex and multifactorial genetic basis, there is the possibility that beyond cholesterol metabolism and transport, other processes such as immune response, inflammation, coagulation, and vascular wall function may play a causal role in the pathogenesis of CAD. To elucidate the relevance of potential CAD-related processes, the integration of regulatory and functional data on the molecular phenotypes is essential. The combination of human genetics, functional genomics, tissue-specific gene networks from empirical data, and biological knowledge within an integrative genomics framework provides a means to study both known and so far unidentified pathogenic processes that are relevant for CAD.
Findings from recent studies using this integrative approach suggest that a critical mass of causal variants within many of the genes in these pathways, even if the pathway includes some genes that have no causal role in the pathogenesis of CAD, may be needed to impact coronary risk. Novel biological processes such as neuroprotection, cell cycle and proteolysis may be also implicated in the genetics of CAD, supported by functional evidence. Thus, more integrative approaches to understanding CAD susceptibility will significantly enhance identification of key driver genes beyond what could be achieved by genetic association studies alone, and ultimately may suggest novel targets for therapeutic intervention.
References
Smith JG, Luk K, Schulz CA, Engert JC, Do R, Hindy G, Rukh G, Dufresne L, Almgren P, Owens DS, Harris TB, Peloso GM, Kerr KF, Wong Q, Smith AV, Budoff MJ, Rotter JI, Cupples LA, Rich S, Kathiresan S, Orho-Melander M, Gudnason V, O'Donnell CJ, Post WS, Thanassoulis G; for the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Extracoronary Calcium Working Group. Association of Low-Density Lipoprotein Cholesterol-Related Genetic variants with aortic valve calcium and incident aortic stenosis. JAMA 2014 [Epub ahead of print].
Tada H, Won HH, Melander O, Yang J, Peloso GM, Kathiresan S. Multiple associated variants increase the heritability explained for plasma lipids and coronary artery disease. Circ Cardiovasc Genet 2014 [Epub ahead of print].
TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R, Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K, Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J, North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W, Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP, O'Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O, Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ, Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG, Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S, Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.​


Gabriele Riccardi, Italy: State of the art of dietary recommendations for the prevention of atherosclerotic cardiovascular disease

 Gabriele Riccardi.jpgGabriele Riccardi is Professor of Endocrinology and Metabolic Diseases, and Head of the Diabetes, Nutrition and Metabolism Unit, Federico II University, Naples, Italy. He is currently President of the Italian Diabetes Research Foundation. He is an International Fellow of the American Heart Association and member of the Joint Committee of the European Society of Cardiology and the European Atherosclerosis Society for the Guidelines on Management of Dyslipidaemias. 

Diet, as part of therapeutic lifestyle intervention, underpins the prevention of atherosclerotic cardiovascular disease. Indeed, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on dyslipidaemia1 emphasise the importance of nutritional approaches, either alone or complementary to pharmacotherapy, for managing hypercholesterolaemia to reduce cardiovascular disease risk. Current recommendations focus on improving diet quality, by encouraging the consumption of a Mediterranean type diet, including fruit, vegetables, legumes, nuts, wholegrain cereals and bread, and fish (especially oily fish); substituting saturated fats with unsaturated or monosaturated fats and eliminating trans fats; replacing simple carbohydrates with complex carbohydrates with a low glycaemic index; and limiting sugar/fructose and alcohol intake. Small changes in the quality of the diet contribute to cumulative reduction in risk for cardiovascular disease events, supported by recent findings from the PrediMed Study.2
There is also emerging evidence to consider a role for ‘functional foods’ as part of the diet.  Consumption of foods with added plant sterols/ stanols, or soluble (viscous) fibre, such as in oats, have been associated with modest reductions in low-density lipoprotein cholesterol (LDL-C), and therefore may have a role in the management of patients for whom total cardiovascular risk assessment does not justify the use of pharmacotherapy. Indeed, adoption of a portfolio diet, including plant sterols, viscous fibre, soy proteins and nuts, has cumulative LDL-C lowering benefits in the region of 20-30%, and thus may represent one of the best dietary approaches for reducing the risk of cardiovascular disease.3
The key issues concerning adoption of a heart-healthy diet are 1) long-term adherence and 2) low cost. Addressing the question of how to ensure sustainable dietary change must be a priority for research. Furthermore, in the current austerity climate in Europe, cost may detrimentally influence the choice of a Mediterranean diet. Both challenges require the involvement of public health researchers and policy makers to ensure the benefits of dietary intervention are optimised.  
1. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, 1. Wood D. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
2. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J, Muñoz MA, Sorlí JV, Martínez JA, Martínez-González MA; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279-90.
3. Ramprasath VR, Jenkins DJ, Lamarche B, Kendall CW, Faulkner D, Cermakova L, Couture P, Ireland C, Abdulnour S, Patel D, Bashyam B, Srichaikul K, de SR, Vidgen E, Josse RG, Leiter LA, Connelly PW, Frohlich J, Jones PJ. Consumption of a dietary portfolio of cholesterol lowering foods improves blood lipids without affecting concentrations of fat soluble compounds. Nutr J 2014; 13:101.
References
Gylling H, Plat J, Turley S, Ginsberg HN, Ellegård L, Jessup W, Jones PJ, Lütjohann D, Maerz W, Masana L, Silbernagel G, Staels B, Borén J, Catapano AL, De Backer G, Deanfield J, Descamps OS, Kovanen PT, Riccardi G, Tokgözoglu L, Chapman MJ; European Atherosclerosis Society Consensus Panel on Phytosterols. Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. Atherosclerosis 2014;232:346-60.
International Carbohydrate Quality Consortium, Jenkins DJ, Willett WC, Astrup A, Augustin LS, Baer-Sinnott S, Barclay AW, Björck I, Brand-Miller JC, Brighenti F, Buyken AE, Ceriello A, Kendall CW, La Vecchia C, Livesey G, Liu S, Poli A, Riccardi G, Rizkalla SW, Sievenpiper JL, Trichopoulou A, Wolever TM. Glycaemic index: did Health Canada get it wrong? Position from the International Carbohydrate Quality Consortium (ICQC). Br J Nutr 2014;111:380-2.
Giacco R, Costabile G, Della Pepa G, Anniballi G, Griffo E, Mangione A, Cipriano P, Viscovo D, Clemente G, Landberg R, Pacini G, Rivellese AA, Riccardi G. A whole-grain cereal-based diet lowers postprandial plasma insulin and triglyceride levels in individuals with metabolic syndrome. Nutr Metab Cardiovasc Dis 2014;24:837-44.​


Workshop Speakers

Vascular Biology of the Arterial Wall

Sanjay Sinha, UK: Embryonic stem cells in vascular disease research

​ Sanjay Sinha.jpgDr Sinjay Sinha leads a research group investigating the regulation of vascular smooth muscle cell development and disease at the Cambridge Stem Cell Institute, affiliated with the Department of Medicine, University of Cambridge. His work focuses on the mechanisms underlying vascular smooth muscle cell (SMC) development and their relevance to cardiovascular disease and/or new vessel growth. The group has developed in vitro systems using murine and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to investigate how SMCs and their precursors initially develop from multipotent cells and how perturbation of developmental mechanisms may contribute to disease. The group's focus is on the role of the myogenic transcription factor, myocardin and transforming growth factor -β signalling, as well as other transcription factors and signalling cascades that interact with these pathways. In addition, the group is investigating whether cardiovascular progenitor cells derived from ESCs or iPSCs can revascularise ischaemic tissues in vivo and if this process can be tracked non-invasively using state-of-the-art genetic reporters​.

Embryonic stem cells (ESCs) are derived from the inner cell mass of the foetal blastula and are pluripotent, i.e. have the ability to differentiate into any cell type found in the adult body. However, given ethical and immunological concerns, the discovery that iPSCs, in common with ESCs, are not only able to self-replicate indefinitely but also have the capacity to differentiate into almost any somatic cell type, offers even greater potential for the study of disease modelling, as well as the development of novel therapies. Studies using this approach have furthered understanding of susceptibility to the development of atherosclerosis among different vascular beds, as well as the mechanisms underlying vascular injury.

However, there are priorities for further research. First, a better understanding of epigenetic alterations, transcriptional activity, and microRNA patterns associated with induction of pluripotency, and with directed differentiation, is needed. The development of tissue banks of renewable vascular cells could offer practical advantages for therapeutic development. Finally, there is a need to establish long term safety data of such cell-based systems. If these issues can be addressed, stem cell regenerative therapy offers the possibility of a paradigm shift in cardiovascular care.

Key references

Talasila A, Yu H, Ackers-Johnson M, Bot M, van Berkel T, Bennett MR, Bot I, Sinha S. Myocardin regulates vascular response to injury through miR-24/-29a and platelet-derived growth factor receptor-β. Arterioscler Thromb Vasc Biol 2013;33:2355-65.

Trigueros-Motos L, González-Granado JM, Cheung C, Fernández P, Sánchez-Cabo F, Dopazo A, Sinha S, Andrés V. Embryological-origin-dependent differences in homeobox expression in adult aorta: role in regional phenotypic variability and regulation of NF-κB activity. Arterioscler Thromb Vasc Biol 2013;33:1248-56.

Sinha S. Vascular disease in a dish: all the right ingredients? Circulation 2012;126:1676-7.


 ​Suzanne Ozanne, UK: Epigenetic programming of metabolism by diet

 Suzanne Ozanne.jpgSuzanne Ozanne is Professor of Developmental Endocrinology and a British Heart Foundation Senior Fellow, in the Department of Clinical Biochemistry, University of Cambridge. Her research interests focus on understanding the relationship between suboptimal early nutrition and later risk of diseases such as type 2 diabetes, obesity and cardiovascular disease. She has authored over 130 papers on the early origins of health and disease and is a council member of the Society for the Developmental Origins of Health and Disease. ​

Undoubtedly, lifestyle has contributed to the pandemics of obesity and type 2 diabetes. However, there is also mounting evidence that nutrition during critical stages of development in early life can "program" individuals to develop the metabolic syndrome later in life. Indeed, epidemiological data supports an association between maternal obesity and nutrition during pregnancy and obesity in the offspring. Furthermore, a number of animal models appear to consistently show a common offspring phenotype of hyperphagia, insulin resistance, and hypertension present before the development of increased adiposity, suggesting independent programming of these systems in response to maternal overnutrition.

Most recently, investigation into epigenetic mechanisms in human disease has shown that early nutrition affects epigenetic modification. There are also emerging data to support the transgenerational effects of obesity and diet. This may also help to explain increasing obesity prevalence across generations, although the underlying mechanisms have yet to be fully elucidated.

Investigating the relative contributions of both foetal and postnatal periods is clearly relevant to the development of interventional strategies. Insights from animal studies suggest that weight-loss strategies or simple dietary changes to improve the metabolic health in mothers before pregnancy can have positive impact in the offspring. Ultimately, increasing public awareness of the importance of a balanced diet before and during pregnancy, is critical for reducing the risk of cardiometabolic disease in future generations.

Key references

Tarry-Adkins JL, Fernandez-Twinn DS, Chen JH, Hargreaves IP, Martin-Gronert MS, McConnell JM, Ozanne SE. Nutritional programming of coenzyme Q: potential for prevention and intervention? FASEB J 2014 (in press).

Blackmore HL, Niu Y, Fernandez-Twinn DS, Tarry-Adkins JL, Giussani DA, Ozanne SE. Maternal diet-induced obesity programmes cardiovascular dysfunction in adult male mouse offspring independent of current body weight. Endocrinology 2014;155:3970-80.

Tarry-Adkins JL, Blackmore HL, Martin-Gronert MS, Fernandez-Twinn DS, McConnell JM, Hargreaves IP, Giussani DA, Ozanne SE. Coenzyme Q10 prevents accelerated cardiac aging in a rat model of poor maternal nutrition and accelerated postnatal growth. Mol Metab 2013;2:480-90.


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