NATURE AND NURTURE - IMPACT OF TRADITIONAL RISK FACTORS, ENVIRONMENT AND GENES
- François Mach
Gregory Roth, Seattle, USA
Global perspectives of cardiovascular disease, and impact of risk factors
The Global Burden of Disease Study, established over two decades ago, estimates disability and death from a multitude of causes worldwide. The study has clearly shown that cardiovascular disease (CVD) is a major contributor to the escalating 21st century pandemic of non-communicable chronic disease, responsible for nearly two-thirds of all global deaths. Indeed, much of the continuing burden from CVD has shifted to low- and middle-income countries, due to sociodemographic transition in these regions. However, it is also recognised that with the ongoing global epidemics of obesity and type 2 diabetes, CVD mortality rates have plateaued and are no longer declining for high-income regions. These trends underline the importance of increased investment in prevention and treatment of CVD for all regions of the world.
Integration of data relating to incidence, prevalence, and mortality has established poor diet, physical inactivity, tobacco use and excessive alcohol use as key contributors to CVD, via their association with hypertension, hyperglycaemia, hypercholesterolaemia and type 2 diabetes mellitus. In addition, the Global Burden of Disease Study has been instrumental in identifying other risk factors that are precursors of CVD.
The Global Burden of Disease study provides a novel platform for tracking changes in CVD epidemiology linked to demographic and socioeconomic change. Findings from the study will be critical to improving health systems to reduce or eliminate disparities in CVD prevention across the globe.
Key references
Thomas H, Diamond J, Vieco A, Chaudhuri S, Shinnar E, Cromer S, Perel P, Mensah GA, Narula J, Johnson CO, Roth GA, Moran AE. Global Atlas of Cardiovascular Disease 2000-2016: the path to prevention and control. Glob Heart 2018;13:143-63.
Murphy A, Johnson CO, Roth GA, Forouzanfar MH, Naghavi M, Ng M, Pogosova N, Vos T, Murray CJL, Moran AE. Ischaemic heart disease in the former Soviet Union 1990-2015 according to the Global Burden of Disease 2015 Study. Heart 2018;104:58-66.
Prabhakaran D, Singh K, Roth GA, Banerjee A, Pagidipati NJ, Huffman MD. Cardiovascular diseases in India compared with the United States. J Am Coll Cardiol 2018;72:79-95.
Anne Tybjærg-Hansen, Copenhagen, Denmark
Anne Tybjærg-Hansen
Copenhagen, DenmarkAnne Tybjærg-Hansen is Chief Physician at the Department of Clinical Biochemistry, Section for Molecular Genetics, at Rigshospitalet, Copenhagen University Hospital, Copenhagen, as well as Professor of Clinical Biochemistry with Focus on Translational Molecular Cardiology at the University of Copenhagen, Copenhagen, Denmark. After completing her medical degree at the University of Copenhagen, she undertook additional studies at the University of Copenhagen and the Lipid Clinic at Righospitalet, Hagedorn Research Laboratory, Gentofte, Denmark, and the British Heart Foundation’s Molecular Biology Research Group, London, UK. Professor Tybjaerg-Hansen has made major contributions to the understanding of the genetics of lipoproteins and their association with atherosclerotic cardiovascular disease. She is a member of the steering committees of the Copenhagen City Heart Study and the Copenhagen General Population Study, and a member of the European Atherosclerosis Consensus Panel, contributing to statements on familial hypercholesterolaemia, hypertriglyceridaemia, triglyceride-rich lipoproteins and high-density lipoprotein, and lipoprotein(a). Professor Tybjaerg-Hansen was the recipient of the Anitschkow Award presented by the European Atherosclerosis Society in 2018.
Can polygenic scores reach clinical practice?
Advances in genomic research, biobank resources and computational methodologies offer the tantalising prospect of personalised genomic medicine to facilitate more appropriate medical interventions to reduce the burden of disease. Recent efforts have been directed to investigating the clinical utility of polygenic risk profiling to identify groups of individuals who could benefit from the knowledge of their likely susceptibility to disease.
The polygenic risk score is based on the premise that multiple gene variants with weak associations with disease risk collectively may enhance disease predictive value in the population. Information from the increasing number of biobanks has been instrumental in the development of very large longitudinal cohorts that are needed to verify and test polygenic risk scores. Translation to the clinic, however, poses several challenges. Consideration of the contribution of the genetic component to the underlying mechanisms of the disease is critical, as are appropriate selection of variants for use in the risk score and their weighting. Importantly, the disparity in precision between those of European descent and other ethnicities, a direct consequence of Eurocentric biases in genome-wide association studies, highlights an urgent need for greater diversity in genetic studies. Integration of the use of polygenic risk profiling with other tools and metrics for disease diagnosis and prognosis is also critical.
Key references
Benn M, Tybjærg-Hansen A, Nordestgaard BG. Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality. J Am Coll Cardiol 2019;73:3102-14.
Marott SCW, Nordestgaard BG, Tybjærg-Hansen A, Benn M. Causal associations in type 2 diabetes development. J Clin Endocrinol Metab 2019;104:1313-24.
Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general population cohort. Eur Heart J 2019. doi: 10.1093/eurheartj/ehz402.
Nicole Probst-Hensch, Basel, Switzerland
Nicole Probst-Hensch
Basel, SwitzerlandNicole Probst-Hensch is Professor and Head of Epidemiology and Public Health at the Swiss Tropical and Public Health Institute, Basel, Switzerland. After completing postdoctoral studies at the University of California and University of Southern California, USA, Dr. Probst-Hensch was Head, Zürich Cancer Registry and Department of Molecular Epidemiology, University of Zürich (2002-2008) and in 2008 was appointed Professor, School of Medicine, University of Zürich. From 2008 to 2009 she was Director, National Institute of Cancer Epidemiology and Registration, University of Zürich & Head, Department of Chronic Disease Epidemiology, University of Zürich, Switzerland, before her current appointment. Among other memberships and consultancies, Professor Probst-Hensch is a Fellow of the Swiss School of Public Health, and a Founding Member of the Public Health Genomics Task Force Switzerland. Her associations include the American Association for Cancer Research; the Society for Epidemiologic Research; and the European Respiratory Society. She is a member of the editorial board of Public Health Genomics and Environmental Health Perspectives.
What is the environment doing to cardiovascular health?
Much of the focus in cardiovascular disease (CVD) prevention has been on the major established risk factors. It is increasingly recognised, however, that environmental factors pose additional risks with health implications. For example, in Europe, current estimates suggest that environmental factors are responsible for up to 20% of the disease burden, with CVD the largest component of this burden.
Air and noise pollution are environmental health risks with a wide-ranging impact on CVD. A wealth of epidemiologic studies has linked exposure to air pollutants including particulate matter, nitrogen oxides, and carbon monoxide to subclinical CVD and clinical cardiovascular outcomes, with the greatest impact in individuals already at risk. While the underlying mechanisms require further elucidation, pathways implicated include inflammation, oxidative stress, and vascular (endothelial) dysfunction, which can facilitate the development of hypertension, diabetes, and atherosclerosis.
Public policies are essential to protect health and, ultimately, to reduce the burden of CVD. Good evidence supports better urban and transport planning to promote physical activity and reduce levels of air and noise pollution. Moreover, a switch to clean, renewable energy sources has been estimated to more than halve the attributable CVD mortality rate in Europe by over 50%.
Key references
Meier-Girard D, Delgado-Eckert E, Schaffner E, Schindler C, Künzli N, Adam M, Pichot V, Kronenberg F, Imboden M, Frey U, Probst-Hensch N. Association of long-term exposure to traffic-related PM10 with heart rate variability and heart rate dynamics in healthy subjects. Environ Int 2019;125:107-16.
Vienneau D, Héritier H, Foraster M, Eze IC, Schaffner E, Thiesse L, Rudzik F, Habermacher M, Köpfli M, Pieren R, Brink M, Cajochen C, Wunderli JM, Probst-Hensch N, Röösli M; SNC study group. Façades, floors and maps – Influence of exposure measurement error on the association between transportation noise and myocardial infarction. Environ Int 2019;123:399-406.
Thiesse L, Rudzik F, Spiegel K, Leproult R, Pieren R, Wunderli JM, Foraster M, Héritier H, Eze IC, Meyer M, Vienneau D, Brink M, Probst-Hensch N, Röösli M, Cajochen C. Adverse impact of nocturnal transportation noise on glucose regulation in healthy young adults: Effect of different noise scenarios. Environ Int 2018;121(Pt 1):1011-23.
Jan van Deursen, Rochester, USA
Jan van Deursen
Rochester, USAJan Van Deursen is Vita Valley Professor of Senescence at Mayo Clinic, where he chairs the Department of Biochemistry and Molecular Biology, and Professor of Pediatrics at The Mayo Clinic, Rochester, Minnesota, USA. Dr van Deursen holds a BSc in Biology, MSc in Molecular Biology, and PhD in Cell Biology from the University of Nijmegen, the Netherlands. He is an Honorary Professor at the University of Groningen, the Netherlands and serves on numerous national and international grant review panels. Professor Van Deursen has a longstanding interest in questions related to cell cycle control and cellular responses to stress. He helped establish the concept that, with ageing and development of age-related disease, wasteful transformed cells that cannot divide – “senescent cells”- litter tissues and demonstrated that clearance of these cells extends both health span and lifespan. He established that BubR1 (an essential mitotic checkpoint protein) is causally implicated in cancer and ageing and provided the first in vivo evidence that p16-positive senescent cells drive ageing and age-related disease. Dr Van Deursen has been recognised by numerous awards, and has a strong commitment to supporting the successful careers of young up-and-coming scientists.
Age, the unpreventable risk factor - targeting senescence
Cellular senescence is a process in which cells cease dividing and undergo distinctive phenotypic alterations, including profound chromatin and secretome changes. Senescent cells may only represent 1–5% of the cells in a tissue, but due to their aggressive nature they have a very profound effect on neighbouring cells. Historically, this process has been viewed as an irreversible cell-cycle arrest mechanism that acts to protect against cancer. However, recent insights indicate that, unlike a static endpoint, senescence represents a series of progressive and phenotypically diverse cellular states acquired after the initial growth arrest. Resistance of senescent cells to both extrinsic and intrinsic pro-apoptotic stimuli implies complex regulation of apoptosis. Indeed, this is a highly dynamic, multi-step process, involving morphological changes, chromatin remodelling, and metabolic reprogramming, as well as secretion of a complex mix of mostly proinflammatory factors termed the senescence-associated secretory phenotype. Epigenetic and genetic changes are important in driving these changes. Thus, these findings extend the role of cellular senescence to complex biological processes such as tissue repair, ageing and age-related disorders.
A deeper understanding of the molecular mechanisms underlying the multi-step progression of senescence and the development and function of acute versus chronic senescent cells offers nascent therapeutic potential. Given the heterogeneity of senescent cell phenotypes, characterisation of senescent cells in vivo using single-cell transcriptome and proteome profiling of tissues will be fundamental to this process. Novel senolytic therapies offer possibilities in future regenerative medicine and age-related pathologies.
Key references
van Deursen JM. Senolytic therapies for healthy longevity. Science 2019;364:636-7.
Childs B, van Deursen J. Inhibition of ‘jumping genes’ promotes healthy ageing. Nature 2019;566:46-8.
Childs BG, Li H, van Deursen JM. Senescent cells: a therapeutic target for cardiovascular disease. J Clin Invest 2018;128:1217-28.
UNDERSTANDING BIOLOGY FOR CLINICAL APPLICATION
- Alberico L. Catapano
Sotirios Tsimikas, La Jolla, USA
Sotirios Tsimikas
La Jolla, USASotirios (Sam) Tsimikas is Professor of Medicine and Director of Vascular Medicine at the University of California San Diego – School of Medicine. After completing his MD degree in 1988 at the University of Massachusetts Medical School, Dr. Tsimikas undertook Internal Medicine training at the University of Massachusetts Medical Center. He completed separate fellowships in Cardiovascular Disease, Atherosclerosis, and Interventional Cardiology at the University of California, San Diego, from 1992-1997. Dr. Tsimikas’ clinical interests are focused in his role as Director of the Vascular Medicine Program in treating a wide variety of patients across the continuum of high-risk primary prevention to endovascular intervention. Dr. Tsimikas is a Fellow of the American College of Cardiology, the American Heart Association, and the Society for Cardiac Angiography and Interventions.
The lipoprotein(a) story - from risk factor to causality to clinical trials
Lipoprotein(a) [Lp(a)] has been considered a cardiovascular risk factor for many years. In the last decade, there has been accumulating and substantial evidence from epidemiologic and Mendelian randomization studies, as well as genome-wide association studies, to support a likely causal role for elevated Lp(a) levels in cardiovascular disease. Until recently, however, the main obstacle to confirmation of causality has been the lack of treatments that specifically lower Lp(a) for testing in large-scale cardiovascular outcomes studies.
A new frontier in Lp(a) research has emerged with antisense-oligonucleotide therapy, which targets Lp(a) production at the level of mRNA translation. Antisense oligonucleotides targeting apolipoprotein(a) have shown promise in early trials. Subsequent development led to an antisense oligonucleotide containing an N-acetyl-galactosamine (GalNac3)−conjugated molecule, which was shown to be highly and selectively taken up by hepatocytes. These properties allowed the use of lower doses and longer dose intervals for this agent compared with other antisense oligonucleotides. In early clinical trials, treatment with this novel therapy was associated with dose dependent reduction in plasma Lp(a) of up to 90% or more in some patients. These advances provide the opportunity to finally test whether pharmacologically lowering elevated Lp(a) levels reduces the risk of cardiovascular events against a background of current best evidence-based therapy.
Key references
Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res 2019;124:386-404.
Tsimikas S, Gordts PLSM, Nora C, Yeang C, Witztum JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J 2019. pii: ehz310.
Tsimikas S. In search of patients with elevated Lp(a): Seek and ye shall find. J Am Coll Cardiol 2019;73:1040-2.
Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 2018;392;1311-20.
Ziad Mallat, Cambridge, UK
Ziad Mallat
Cambridge, UKZiad Mallat is the British Heart Foundation Professor of Cardiovascular Medicine at the University of Cambridge, Addenbrooke’s Hospital, UK. He received his MD and qualification in Cardiovascular Diseases from the University of Pierre et Marie Curie in 1996, and his Ph.D. in Vascular Biology, Thrombosis and Haemostasis from University of Paris-Diderot in 1999. He subsequently joined INSERM, Paris in 1998 as Assistant Research Professor, became Associate Professor in 2002 and Research Professor in 2007. His research aims to understand the role of immune responses in the development and progression of cardiovascular diseases. Professor Mallat was the first to identify a major atheroprotective role of regulatory T cells and associated anti-inflammatory cytokines, IL-10 and TGF-β. More recently, he identified selective pathogenic and protective roles for defined B cell and innate lymphoid cell subsets in atherosclerosis and cardiac remodelling following ischaemic injury. His basic science research is complemented by proof-of-concept clinical trials in patients with coronary artery disease. Professor Mallat is Associate Editor of Arteriosclerosis Thrombosis and Vascular Biology, Atherosclerosis, Consulting Editor for Cardiovascular Research, and serves on the Editorial Board of Circulation Research, and JCI Insight.
Immune modulation in atherosclerosis
Atherosclerosis is well recognised as a chronic inflammatory disease of the arterial wall, responsible for most ischaemic cardiovascular events. Moreover, inflammation may account for a substantial proportion of the residual risk for cardiovascular disease that persists in high risk patients on current therapies. Both innate and adaptive immune responses are involved in all stages of atherosclerosis. If adaptive immune responses occur early during the disease process, then despite reduction in risk factors such as low-density lipoprotein (LDL) cholesterol, there may be sustained production of pathogenic effectors.
T cell and B cell responses play prominent roles in atherosclerotic lesion development and inflammation. T cells are found within coronary atherosclerotic plaques at many stages of disease progression. Indeed, various functional T cell subsets have been associated with cardiovascular disease, whereas levels of regulatory T cells, which dampen immune responses in many ways, are reduced. B cells control cellular immune responses through cell-cell contact, antigen presentation, and cytokine production, and thereby participate in systemic and local immune responses in atherosclerotic arteries. To date, both proatherogenic and antiatherogenic properties have been assigned to B cells, depending on subsets and how they are functionally targeted.
Deciphering the role of specific subtypes of immune cells in atherosclerotic plaque development offers the potential for novel and specific therapeutic strategies to limit progression of atherosclerosis and reduce residual cardiovascular risk.
Key references
Zhao TX, Mallat Z. Targeting the immune system in atherosclerosis: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:1691-706.
Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol 2019;16:180-96.
Zhao TX, Kostapanos M, Griffiths C, Arbon EL, Hubsch A, Kaloyirou F, Helmy J, Hoole SP, Rudd JHF, Wood G, Burling K, Bond S, Cheriyan J, Mallat Z. Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial. BMJ Open 2018;8(9):e022452.
Stefano del Prato, Pisa, Italy
Stefano del Prato
Pisa, ItalyStefano Del Prato is Professor of Endocrinology and Metabolism at the School of Medicine, University of Pisa and Chief of the Section of Diabetes, University Hospital of Pisa, Italy. He graduated from the University of Padova, Italy and undertook postgraduate specialisation in Endocrinology and Internal Medicine. Professor Del Prato’s main research interests focus on the physiopathology and therapy of type 2 diabetes and insulin resistance. He is a member of many societies and associations including the European Association for the Study of Diabetes (EASD) and the American Diabetes Association. Professor Del Prato is past Vice-President of the EASD, past President and Honorary President of the Italian Society of Diabetology, and the current Chairman of the European Foundation for the Study of Diabetes (EFSD). Professor Del Prato is the recipient of many awards including the Prize of the Italian Society of Diabetology for outstanding scientific activity and the Honorary Professorship at the Universidad Peruana Cayetano Heredya in Lima.
Prevention of cardiovascular diseases by glucose lowering drugs
Individuals with type 2 diabetes are at greater risk for cardiovascular disease and associated mortality than those without diabetes. Previous clinical studies had consistently showed that improving glycaemic control in patients with type 2 diabetes had minimal effect, or at best, only a modest effect in reducing the risk of cardiovascular events. However, the growing armamentarium of glucose-lowering therapies has yielded new insights. Clinical trials with the glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown a favourable benefit-risk balance in mitigating cardiovascular risk in high-risk patients with type 2 diabetes. Both empagliflozin and liraglutide also showed reduction in all-cause mortality in diabetic patients with cardiovascular disease. These benefits were independent of the glucose-lowering effects of these agents and improvement in traditional cardiovascular risk factors. European guidelines on diabetes, pre-diabetes and cardiovascular disease now recommend GLP‑1 receptor agonists and SGLT2 inhibitors as first-line treatments in type 2 diabetes patients with established cardiovascular disease or at high/very high risk of cardiovascular disease.
These recommendations herald a new paradigm for the management of patients with type 2 diabetes to improve cardiovascular outcome. With the increasing prevalence of obesity and diabetes globally, the advent of pharmacotherapies with proven efficacy in reducing cardiovascular outcomes makes it imperative to understand the underlying mechanisms for these cardiovascular benefits, to inform clinicians for the best approach for combination glucose-lowering therapy in patients with type 2 diabetes.
Key references
Del Prato S. Heterogeneity of diabetes: heralding the era of precision medicine. Lancet Diabetes Endocrinol 2019;7:659-66.
Del Prato S. Rational combination therapy for type 2 diabetes. Lancet Diabetes Endocrinol 2019;7:328-9.
Hernandez AF, Green JB, Janmohamed S, D’Agostino RB Sr, Granger CB, Jones NP, Leiter LA, Rosenberg AE, Sigmon KN, Somerville MC, Thorpe KM, McMurray JJV, Del Prato S; Harmony Outcomes committees and investigators. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-29.
Stanley Hazen, Cleveland, USA
Stanley Hazen
Cleveland, USAStanley Hazen, MD, PhD, is chair of the Department of Cellular & Molecular Medicine in the Lerner Research Institute and section head of Preventive Cardiology & Rehabilitation in the Miller Family Heart & Vascular Institute at Cleveland Clinic. He holds the Jan Bleeksma Chair in Vascular Cell Biology and Atherosclerosis. Dr. Hazen obtained a Bachelor degree and dual MD /PhD degree in Biophysical Chemistry and Molecular Biology, with subsequent clinical training in Internal Medicine in the subspecialty of Diabetes, Endocrinology and Metabolism at Washington University School of Medicine, St Louis. He has made seminal discoveries linking gut microbial pathways to cardiovascular disease and metabolic diseases, including atherosclerosis, thrombosis, heart failure and chronic kidney disease. Dr. Hazen has received numerous awards, including election to the American Federation for Medical Research, the American Society for Clinical Investigation, the Association of American Physicians, and the National Academy of Medicine. He is a Fellow of the American Association for the Advancement of Science. In 2017, he was named as a Distinguished Scientist by the American Heart Association.
Taming the gut microbiota
The gut microbiota act collectively as an integrated organ, regulating multiple biological functions that can modulate cardiovascular risk factors and the pathogenic mechanisms of this process. These activities are mediated by various metabolites that can act locally in the gut, as well as travel systemically to affect host physiology. Changes in the composition of the gut microbiota are identified as contributing factors in the development of atherosclerosis and cardiometabolic disease. In particular, three main classes of gut microorganism-dependent metabolites have been linked to cardiovascular health – trimethylamine N-oxide (TMAO), short chain fatty acids and secondary bile acids. If these pathways are dysregulated, there is the potential for exacerbation of risk for cardiovascular disease.
Perhaps the most compelling evidence for the role of the gut bacterial metabolites in cardiometabolic diseases is provided by TMAO. At the molecular level, TMAO has been shown to activate inflammatory gene expression, increase uptake of modified low-density lipoprotein by macrophages, and predispose to increased aggregation and thrombosis. In population-based and intervention studies, increased plasma levels of TMAO were associated with risk of type 2 diabetes mellitus, cardiovascular disease and incident thrombosis.
Short chain fatty acids produced by the gut microbiota are critical in multiple regulatory roles in energy homeostasis, insulin sensitivity, and glucose and lipid metabolism. Studies consistently show that these metabolites are associated with a reduced risk of cardiovascular and metabolic diseases. The secondary bile acids, deoxycholic acid and lithocholic acid, are the main ligands for TGR5, a G protein-coupled receptor, implicated in weight maintenance and glucose metabolism.
Further understanding of the gut microbe pathways involved in the biosynthesis of cardiovascular-related metabolites, in particular characterisation of their cellular receptors and signalling pathways, may offer potential therapeutic application for managing cardiac health and preventing cardiovascular disease.
Key references
Li XS, Obeid S, Wang Z, Hazen BJ, Li L, Wu Y, Hurd AG, Gu X, Pratt A, Levison BS, Chung YM, Nissen SE, Tang WHW, Mach F, Räber L, Nanchen D, Matter CM, Lüscher TF, Hazen SL. Trimethyllysine, a trimethylamine N-oxide precursor, provides near- and long-term prognostic value in patients presenting with acute coronary syndromes. Eur Heart J 2019;40:2700-9.
Tang WHW, Bäckhed F, Landmesser U, Hazen SL. Intestinal microbiota in cardiovascular health and disease: JACC State-of-the-Art Review. J Am Coll Cardiol 2019;73:2089-105.
McMillan A, Hazen SL. Gut microbiota involvement in ventricular remodeling post-myocardial infarction. Circulation 2019;139:660-2.
Koeth RA, Lam-Galvez BR, Kirsop J, Wang Z, Levison BS, Gu X, Copeland MF, Bartlett D, Cody DB, Dai HJ, Culley MK, Li XS, Fu X, Wu Y, Li L, DiDonato JA, Tang WHW, Garcia-Garcia JC, Hazen SL. l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans. J Clin Invest 2019;129:373-87.
Stephanie Dimmeler, Frankfurt, Germany
THE CHANGING LANDSCAPE IN ATHEROSCLEROTIC VASCULAR DISEASE - BRAVE NEW WORLD
- Ruth Frikke-Schmidt
Johan Björkegren, Stockholm, Sweden
Johan Björkegren
Stockholm, SwedenJohan Björkegren is currently Professor of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA. He obtained his MD at the Karolinska University Hospital, and his PhD at the Karolinska Institutet, Sweden. His early work explored the role of triglyceride-rich lipoproteins in coronary artery disease, and postdoctoral studies in mouse models established the hepatic gene microsomal triglyceride transfer protein as a key target to lower plasma cholesterol levels and reduce atherosclerosis. His subsequent research has focused on the use of multi-modal big data analysis to create reliable network models of human biology and cardiovascular disease. This has been achieved using a range of clinical datasets that combine detailed clinical characteristics, including imaging, genomics, and proteomics data. Together with Dr. Arno Ruusalepp, Tartu University Hospital, Estonia, Dr. Björkegren initiated the Stockholm-Tartu Atherosclerosis Reverse Network Engineering Task (STARNET) biobank from coronary artery disease (CAD) patients undergoing cardiac surgery. Subsequent work using this biobank has led to identification of RNA sequence data from up to nine CAD-relevant tissues, which will be critical to generating network models that predict the risk for and clinical outcomes of CAD.
Implementing systems biology to personalise medicine
Genome-wide association studies (GWAS) have led to the identification of over two hundred genetic loci that modulate inherited risk for CAD. However, given the complexity of the underlying molecular disease processes, it is evident that CAD cannot be understood nor cured by targeting isolated genes. Instead a focus on the regulatory-gene networks that control these processes is needed, to capture the combined effects of many genetic and environmental risk factors. These networks offer a framework to identify novel risk genes and study the molecular interactions within and across disease-relevant tissues leading to CAD.
Systems genetics offers a means to identify disease-driving networks and their genetic regulation, using genomic activity measures to define the underlying molecular processes and to integrate these with GWAS datasets. One innovative approach is transcriptome-wide association studies (TWAS), which offers the opportunity to prioritize candidate causal genes and tissues underlying GWAS loci, to identify gene-trait associations and likely causal genes in CAD.
Therefore, network models have enormous potential to improve the ability to predict CAD risk, and in turn to improve the application of precision medicine – the preventive and individual care of patients – in clinical practice. In addition, these models can also provide information to identify new therapeutic targets, and to monitor the effects of treatment for CAD.
Key references
Zeng L, Talukdar HA, Koplev S, Giannarelli C, Ivert T, Gan LM, Ruusalepp A, Schadt EE, Kovacic JC, Lusis AJ, Michoel T, Schunkert H, Björkegren JLM. Contribution of gene regulatory networks to heritability of coronary artery disease. J Am Coll Cardiol 2019;73:2946-57.
Glicksberg BS, Amadori L, Akers NK, Sukhavasi K, Franzén O, Li L, Belbin GM, Akers KL, Shameer K, Badgeley MA, Johnson KW, Readhead B, Darrow BJ, Kenny EE, Betsholtz C, Ermel R, Skogsberg J, Ruusalepp A, Schadt EE, Dudley JT, Ren H, Kovacic JC, Giannarelli C, Li SD, Björkegren JLM, Chen R. Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. BMC Med Genomics 2019;12(Suppl 6):108.
Eales JM, Maan AA, Xu X, Michoel T, Hallast P, Batini C, Zadik D, Prestes PR, Molina E, Denniff M, Schroeder J, Bjorkegren JLM, Thompson J, Maffia P, Guzik TJ, Keavney B, Jobling MA, Samani NJ, Charchar FJ, Tomaszewski M. Human Y chromosome exerts pleiotropic effects on susceptibility to atherosclerosis. Arterioscler Thromb Vasc Biol 2019;39:2386-401.
Jörg Menche, Vienna, Austria
Jörg Menche
Vienna, AustriaJörg Menche is Principal Investigator at the CeMM Research Center for Molecular Medicine in Vienna, Austria. Dr. Menche obtained his PhD at the Max-Planck-Institute for Colloids and Interfaces in Potsdam, specializing in network theory, before undertaking postdoctoral studies at Northeastern University and at the Center for Cancer Systems Biology at Dana Farber Cancer Institute, USA. In close collaboration with Joseph Loscalzo from Harvard Medical School and Marc Vidal from Dana Farber Cancer Institute he applied tools and concepts from network theory to elucidate the complex machinery of interacting molecules that constitutes the basis of (patho-)physiological states. At CeMM, Dr. Menche applies diverse computational approaches to help understand and interpret the large datasets derived from a broad range of post-genomic technologies, ranging from next-generation sequencing of genomes, epigenomes and transcriptomes, to high-throughput proteomics and chemical screening. Two major areas of interest of his research group are network-based approaches to rare diseases and understanding the basic principles of drug-drug interactions.
AI in CVD & beyond
Cardiovascular disease poses major clinical and socioeconomic challenges. Technological advances such as whole-genome-sequencing provide complex data to aid in personalized patient care, but these data also require sophisticated interpretation. It is evident that new strategies are needed to address this. Artificial intelligence (AI), also known as machine intelligence, is a branch of computer science that mimics the human mind process, and its application may offer potential to improve clinical management. Specific areas of interest for the use of AI in cardiovascular medicine include the development of diagnostic tools, clinical decision support, quantitative analysis tools and computer-aided detection. In studies, AI has shown promise in automated imaging interpretation and clinical risk prediction, although further refinement and evaluation are still needed.
The integration of AI and cardiovascular medicine requires professional skills, advanced technologies and substantial investment. Despite advances in AI technology, it is imperative that clinicians are the mainstay of management; AI should be viewed as having an enabling role by provision of a set of tools to augment clinical knowledge and experience. AI will drive improved patient care by improving the ability of clinicians to interpret more data and to a greater depth.
Integration of AI offers the prospect of a major revolution in cardiovascular medicine. Societal and ethical complexities of these applications, proof of their medical utility, economic value, and development of interdisciplinary strategies are all relevant for their future application.
Key references
Caldera M, Müller F, Kaltenbrunner I, Licciardello MP, Lardeau CH, Kubicek S, Menche J. Mapping the perturbome network of cellular perturbations. Nat Commun 2019;10:5140.
Sharma A, Halu A, Decano JL, Padi M, Liu YY, Prasad RB, Fadista J, Santolini M, Menche J, Weiss ST, Vidal M, Silverman EK, Aikawa M, Barabási AL, Groop L, Loscalzo J. Controllability in an islet specific regulatory network identifies the transcriptional factor NFATC4, which regulates Type 2 Diabetes associated genes. NPJ Syst Biol Appl 2018;4:25.
Tsiantoulas D, Sage AP, Göderle L, Ozsvar-Kozma M, Murphy D, Porsch F, Pasterkamp G, Menche J, Schneider P, Mallat Z, Binder CJ. B Cell-Activating Factor neutralization aggravates atherosclerosis. Circulation 2018;138:2263-73.
Heike Bischoff-Ferrari, Zurich, Switzerland
Heike Bischoff-Ferrari
Zurich, SwitzerlandHeike Bischoff-Ferrari is Director of the Centre on Aging and Mobility at the University of Zurich, Switzerland. After completing her clinical training at the University of Basel Switzerland, Dr. Bischoff-Ferrari undertook a fellowship at the Department of Rheumatology, Immunology and Allergy at the Brigham and Women’s Hospital in Boston, and was appointed to the faculty at Harvard Medical School from 2002 until 2005. In 2002, she obtained a Master of Public Health Degree in Clinical Effectiveness, and in 2008, a Doctor of Public Health Degree from the Department of Nutrition, Harvard School of Public Health. In 2005 she took a primary faculty appointment at the Department of Rheumatology and Institute of Physical Medicine at the University Hospital in Zurich Switzerland, where she has been Head of Clinical Research since May 2007. In February 2007, she received a Swiss National Foundation Professorship and in September 2009 she started her current position. Dr. Bischoff-Ferrari’s research focuses on improving musculoskeletal health in older individuals, specifically, nutritional and exercise interventions in the prevention of falls, fractures, and osteoarthritis.
Personalised medicine in the elderly – how to avoid overtreatment
Personalized medicine offers the potential to tailor treatment using an integrative approach so as to ensure better patient care. Changing population demographics, however, mandate the need to consider issues relevant to the elderly, specifically comorbidity and polypharmacy. A particular concern is the potential for overtreatment and the associated detrimental impact on treatment tolerability and risk of drug-drug interactions, especially among elderly, frail patients. Indeed, current guidelines recommend that evidence for the effectiveness of pharmacological interventions among these individuals may be insufficient to evaluate whether the benefits of pharmacological intervention outweigh the risk of adverse outcomes. Beyond the individual, however, potential overtreatment also poses public health challenges, contributing to excessive healthcare costs and resource use.
In the era of personalized medicine, computerized tools are likely to play a role as a support to decision-making for clinicians caring for elderly patients. Recent examples include FORTA (Fit fOR The Aged), a drug classification system to optimize pharmacotherapy in the elderly, as well as TRIM (Tool to Reduce Inappropriate Medications), a data extraction tool for identifying the risk for side effects and drug-drug interactions among the elderly. Increased opportunities for clinician education and patient feedback are also relevant to the individualization of treatment and optimization of benefit versus risk among the elderly.
Recent guidelines advocate a paradigm shift to predictive, preventive and personalized medicine among the elderly, frail patient, taking into account both health and disease care. The clinical reality, however, is often a semi-personalized approach, involving a compromise between standardization and individualization of treatment.
Key references
Dent E, Morley JE, Cruz-Jentoft AJ, Woodhouse L, Rodríguez-Mañas L, Fried LP, Woo J, Aprahamian I, Sanford A, Lundy J, Landi F, Beilby J, Martin FC, Bauer JM, Ferrucci L, Merchant RA, Dong B, Arai H, Hoogendijk EO, Won CW, Abbatecola A, Cederholm T, Strandberg T, Gutiérrez Robledo LM, Flicker L, Bhasin S, Aubertin-Leheudre M, Bischoff-Ferrari HA, Guralnik JM, Muscedere J, Pahor M, Ruiz J, Negm AM, Reginster JY, Waters DL, Vellas B. Physical Frailty: ICFSR International Clinical Practice Guidelines for Identification and Management. J Nutr Health Aging 2019;23:771-87.
Ernst R, Fischer K, de Godoi Rezende Costa Molino C, Orav EJ, Theiler R, Meyer U, Fischler M, Gagesch M, Ambühl PM, Freystätter G, Egli A, Bischoff-Ferrari HA. Polypharmacy and kidney function in community-dwelling adults age 60 years and older: a prospective observational study. J Am Med Dir Assoc 2019. doi: 10.1016/j.jamda.2019.07.007. [Epub ahead of print]
Bischoff-Ferrari HA, Orav EJ, Abderhalden L, Dawson-Hughes B, Willett WC. Vitamin D supplementation and musculoskeletal health. Lancet Diabetes Endocrinol 2019;7:85.
John J.P. Kastelein, Amsterdam, The Netherlands
John J.P. Kastelein
Amsterdam, The NetherlandsJohn J.P. Kastelein is Emeritus Professor of Medicine at the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam, where he held the Strategic Chair of Genetics of Cardiovascular Disease. After completing his medical studies in Amsterdam, he trained in medical genetics, lipidology and molecular biology at the University of British Columbia, Vancouver (1986-1988). Upon his return to the Netherlands, he was awarded a doctorate (Cum Laude) and in 1989 he founded the Lipid Research Clinic at AMC, which has become part of the Department of Vascular Medicine. The most important concept in Dr. Kastelein’s research career is the “extreme genetics” approach, in which the study of rare human disorders that are associated with premature coronary disease have broader relevance for the understanding of the etiology of heart disease. This approach has been very successful, most notably in familial hypercholesterolemia (FH), now recognized as the paradigm for the relationship between low-density lipoprotein cholesterol and heart disease. In 1995, Dr. Kastelein initiated a foundation for the active identification of patients with classical FH in the Netherlands (StoeH). Dr. Kastelein was president of the Dutch Atherosclerosis Society, is a member of the Royal Dutch Society for Medicine & Physics, the Council for Basic Science of the American Heart Association and the European Atherosclerosis Society, a Fellow of the European Society of Cardiology, and a board member of the International Task Force for CHD Prevention. Among his many awards, Professor Kastelein received the Anitschkow Prize from the European Atherosclerosis Society in 2014. He is ranked among the top 100 of the most influential clinical researchers globally.
New therapeutic approaches
Technological advances, especially in genomics, have provided critical insights into novel therapeutic targets, guiding drug development in the lipoprotein field. Low-density lipoprotein cholesterol (LDL-C) has been the primary focus, given overwhelming evidence that has irrefutably established LDL as causal for atherosclerotic cardiovascular disease. The discovery of PCSK9 (proprotein convertase subtilisin/kexin type 9) and elucidation of its role in the regulation of LDL particle clearance prompted the development of PCSK9 monoclonal antibody therapies. Robust LDL-C lowering (by 50% to 60%) translated to reduction in cardiovascular events in major outcomes studies in very high risk patients. Subsequent development using RNA interference resulted in inclisiran, a small interfering RNA that targets intracellular PCSK9 production. This latter approach provides similarly robust lipid lowering compared with the PCSK9 monoclonal antibodies but with the advantage of less frequent dosing; a major cardiovascular outcomes study is ongoing. Other novel approaches to PCSK9 inhibition include active immunization and gene editing. Beyond PCSK9, genetic studies have provide the foundation for development of ETC-1002 (bempedoic acid), an orally and once daily administered drug that both inhibits ACL (ATP-citrate lyase) and activates AMpK (AMP-activated protein kinase), thereby reducing hepatic cholesterol synthesis and increasing LDL receptor expression.
Attention has also focused on other lipoprotein targets, notably lipoprotein(a) and triglyceride-rich lipoproteins and their remnants, largely driven by evidence from genetic studies. Current clinical trials are investigating novel therapies directed to. The development of antisense oligonucleotides targeting apolipoprotein(a) synthesis provides an opportunity to test the ‘lipoprotein(a) hypothesis’ in major outcome studies. Fish oils (omega-3 fatty acids) have been the focus of renewed clinical development. The REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) showed significant reduction in major cardiovascular events associated with treatment with eicosapentaenoic acid in high risk patients with mixed dyslipidemia, although the extent of cardiovascular event reduction was not explained by the magnitude of triglyceride-lowering in this trial, implying the involvement of other mechanisms. Other novel approaches targeting triglyceride-rich lipoproteins and their remnants include the selective peroxisome proliferator-activated receptor alpha modulator pemafibrate, currently being tested in the PROMINENT cardiovascular outcomes study, as well as a monoclonal antibody to angiopoietin-like 3 (evinacumab) and an antisense oligonucleotide to apolipoprotein C-III.
The future holds promise for novel therapeutic approaches to dyslipidemia management with the ultimate aim of reducing major cardiovascular events in high risk patients in both primary and secondary prevention settings.
Key references
Ray KK, Stoekenbroek RM, Kallend D, Nishikido T, Leiter LA, Landmesser U, Wright RS, Wijngaard PLJ, Kastelein JJP. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA Cardiol 2019. doi: 10.1001/jamacardio.2019.3502.
Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Di Angelantonio E, Danesh J, Nicholls SJ, Bhatt DL, Sabatine MS, Catapano AL. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.
Larsen LE, Stoekenbroek RM, Kastelein JJP, Holleboom AG. Moving targets: recent advances in lipid-lowering therapies. Arterioscler Thromb Vasc Biol 2019;39:349-59.
