Wednesday 25 May
From lifestyle to designer therapies
- Maciej Banach
Maciej BanachLodz, Poland
Prof. Maciej Banach was an Undersecretary of State at the Ministry of Science and Higher Education of the Republic of Poland (2010-2012), and a President of the Polish Mother’s Memorial Hospital – Research Institute (PMMHRI) (February 2014-March 2021). He is a Head of Cardiovascular Research Centre at University of Zielona Gora, full Professor of Cardiology at the Medical University of Lodz (MUL) and PMMHRI, Head of Foreign Affairs Office (2012-2014), Head of Department of Preventive Cardiology and Lipidology at the Medical University of Lodz and Professor in the Department of Nephrology, Hypertension and Family Medicine, Chair of Nephrology and Hypertension, at the WAM University Hospital in Lodz, Poland (2009-).
He is a Secretary of the European Atherosclerosis Society (EAS) (2021-2024) and member of the Scientific and Health Policy Advisory Group of the FH Europe. He is a Founder and Head of the Polish Lipid Association (PoLA) (2011-) and Lodz Chapter of Polish Society of Hypertension (2009-). He is the founder of the Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC; lbpmcgroup.umed.pl) Group (2012-) – a group of over 150 worldwide experts aimed to investigate the most important issues in the field of lipid disorders, hypertension, nutrition and cardiovascular risk, as well as the International Lipid Expert Panel (ILEP; ilep.eu) (2015-), currently with >50 national society members, which has been founded to prepare recommendations in the area of preventive cardiology in the most debatable issues that have not been covered in the existing guidelines. He is also a member of the REPROGRAM Consortium – a group of experts challenging with Covid-19 pandemic, member of 2 largest worldwide databases – the Global Burden of Disease (GDB) (University of Washington, Seattle, US) and Non-Communicable Diseases Risk Factor Collaboration (NCD-RisC, Imperial College of London, UK). He is also Founder and President of the foundation – Think-Tank “Innovation for Health”, which gathers six main health research institutes and over 40 medical business representatives in Poland with main aim to make innovations in the medical area in Poland. He is a Visiting Professor of University of Alabama at Birmingham (UAB) and University of Medicine and Pharmacy Victor Babes in Timisoara, Romania, and University of California at Irvine.
Prof. Banach has published over 1000 original articles, reviews, editorials, and book chapters in the field of hypertension, dyslipidemia, cardiology, and risk stratification. His combined IF (for only full-text manuscripts) is over 10,000 pts, number of citations: 39,090 (acc. Web of Science Core Collection/Publons with >14,000 citations for year 2021), 40,228 (acc. SCOPUS; with >15,000 citations for year 2021), 49,601 (acc. ResearchGate), and 59,898 (acc. Google Scholar; with >21,000 citations for year 2021), Hirsch’s Index = 75 (WoS/Publons), 75 (SCOPUS), 88 (ResearchGate) and 93 (i10-index: 598) (Google Scholar) – being within 1% the highest cited scientists in the world (in the research area of Clinical Medicine and Pharmacology and Toxicology) according to Essential Science Indicators by Clarivate (with 42 TOP Papers). Prof. Banach is also within top 10 worldwide experts according to ExpertScape in the field of lipids (9), statins (2), dyslipidemias (6), cholesterol (5), lipoproteins (12), LDL cholesterol (9), lipoproteins LDL (6), HDL cholesterol (5), and dietary supplements (15). He is also a 1% Top Reviewer in the areas of Clinical Medicine and Cross-Field (in 2018 and 2019) by Publons/Clarivate and Publons Academy Mentor.
He is Founder (2005) and Editor-in-Chief of the Archives of Medical Science (IF2020 = 3.318), Archives of Medical Science – Civilization Diseases, and Archives of Medical Science – Atherosclerotic Diseases, Deputy Editor of European Heart Journal Open, Editor in Chief of the Cardiology Section in Journal of Clinical Medicine, Section Editor of Current Atherosclerosis Reports, Scientific Coordinator of the HeartBeat Journal (2012-2018), Regional Associate Editor of European Heart Journal – Quality of Care and Clinical Outcomes, Co-Founder and Deputy Editor of Thyroid Research (2007-2012), Associate/Section Editor of BMC Medicine, Scientific Reports, Recent Patents on Cardiovascular Drugs Discovery & Biomed Research International, and member of Editorial Advisory Board of over 60 international medical journals. Guest Editor (2010-) among others in BMC Medicine, Expert Opinion on Pharmacotherapy, Nutrients, Current Hypertension Reports, Journal of Diabetes Research, Current Vascular Pharmacology, Current Pharmaceutical Design, Current Medicinal Chemistry and Frontiers in Digital Public. He is also a Faculty member of F1000 prime. He is Reviewer of over 80 international journals, including New England Journal of Medicine, European Heart Journal, JACC, Circulation, JAMA-Cardiology, JAMA Network Open, Lancet Diabetes & Endocrinology, Circulation Research, and British Medical Journal; editor or author of 31 books (102 chapters). He was also a Scientific President (2016-2020) of the Termedia Publishing House, being responsible for the indexation and developing of over 50 scientific journals, including 9 journals with IF.
Participation in clinical trials since 2005: (1) IPDACS Trial (Incidence and Predictors of Delirium After Cardiac Surgery) (NCT00784576) (study coordinator [SC]); (2) ACT 2 Trial with RSD1235 – vernakalant (principal investigator [PI]); (3) The Influence of Atorvastatin on the Parameters of Inflammation and the Function of Left Ventricle (NCT01015144) (PI); (4) SWEEP TRIAL (Study to Evaluate the Efficacy, Safety and Immunogenicity of Subcutaneous HX575 in the Treatment of Anemia Associated With Chronic Kidney Disease) (PI); (5) SWEEP OLE Trial (PI); (6) STIPPARE Trial (Simvastatin in the Treatment of Isolated arterial hyPertension and Prevention of cARdiovascular Events) (NCT01017835) (PI); (7) FIRST Trial (Ferumoxytol Compared to Iron Sucrose Trial: A Randomized, Multicenter Trial of Ferumoxytol Compared to Iron Sucrose for the Treatment of Iron Deficiency Anemia in Adult Subjects with Chronic Kidney Disease); (8) FER-CKD Trial (An open-label multicentre, randomised 3-arm study to investigate the comparative efficacy and safety of intravenous ferric carboxymaltose versus oral iron for the treatment of iron deficiency anaemia in subjects with non-dialysis-dependent chronic kidney disease) (Co-Investigator [CPI]); (9) FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk) trial (PI); (10) ENSURE-AF (national PI [NPI]); (10) BetOnMACE trial (RVX222-CS-015) (NPI); (11) ODDYSEY APPRISE Trial (LPS14245) (NPI); (12) CLEAR Harmony trial (Evaluation of Long-Term Safety and Tolerability of ETC-1002 in High-Risk Patients With Hyperlipidemia and High CV Risk) (PI); (13) CLEAR Harmony OLE Trial (PI); (14) CLEAR Outcomes Study (1002-043) (NPI); (15) Da Vinci Study (co-NPI), ODDYSEY Kids (NPI), (16) VESALIUS-REAL Trial with evolocumab (NPI), (17) LIPIDOGRAM & LIPIDOGEN study (co-PI), (18) FHSC Registry (NPI), (19) TERCET Registry; (20) VESALIUS-CV Trial with evolocumab (PI), and (21) Lp(a)HORIZON with TQJ231 (PI), (22) ORION-16 with inclisiran (PI), (23) Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (PI).
He is a fellow of the Council for High Blood Pressure Research of the American Heart Association (FAHA), National Lipid Association (FNLA), American Society of Angiology (FASA), European Society of Cardiology (FESC), Royal Society for Public Health (FRSPH) and Society of Geriatric Cardiology (FSGC; 2008-2010). He is a member of the working-core of Alliance for Biomedical Research/European Council for Health Research (2011-2013 and 2016- being as a EAS representative), steering committee of European Innovation Partnership in Active and Healthy Ageing (2010-2012) at the European Commission, member of the European Commission’s Scientific Panel for Health (SPH) (2014-2017), and steering committee of Centre for Good Aging / Healthy Ageing Research Center (HARC) at the Medical University of Lodz, member of Committee for Public Health of the Polish Academy of Sciences, member of the Scientific Board of Institute of Sport in Warsaw, Poland, and the Presiding Board of Scientific Committee of the Polish Ministry of Health (2015-). He is an expert of the European Medicines Agency (EMA, 2018-), and member of prestigious EU Academy of Sciences (EUAS; 2018-).
He is a laureate of several prizes and award, including: Doctor Honoris Causa of the Medical University in Kosice, Slovak Republic (2020), on Top-100 List of the most influential scientists in medicine in Poland for year 2020 (position 8), 2019 (10), and 2018 (9), Doctor Honoris Causa of the Carol Davila University of Medicine and Pharmacy in Bucharest, Romania, “Gold Scalpel” Distinction in 2019 for the Innovation (Smart Hospital); Honorary Member of the Romanian Society of Cardiology (2019), Doctor Honoris Causa of the Institute of Cardiology in Kiev (2018), and the University of Medicine and Pharmacy Victor Babes in Timisoara (2017); Gold Honorary Medal for scientific achievements of the Medical Faculty of Medical University in Kosice, Slovak Republic (2018), The Manager of the Year 2016 – Public Entities (2017), “Innovator of the Year – Science Category” by Wprost journal (2017); “Gold Scalpel” Distinction in 2016 for the Innovation; The Personality of the Year 2013 in Poland for the development of science in the field of healthcare – founded by the Heath Manager journal (Termedia Publishing House), Super-Talent in Medicine 2012 Award – the winner of the competition for young scientists in medicine (up to 40) founded by Puls Medycyny journal; scientific awards of Ministry of Health of Republic of Poland for the cycle of publications (2009, 2011), >40 individual and group scientific awards of President of Medical University of Lodz (2009-2020); START Award (2008) and Conferences Awards (2005, 2007) of Foundation for Polish Science, Polityka journal Awards for Young Scientists (2006), and Travel Grants of European Society of Hypertension (2007) and Heart Failure Association of ESC (2005, 2007).
His main area of scientific interests concerns hypertension aspects (risk stratification, prehypertension, new biomarkers, optimal level of BP – J-curve phenomenon, pharmacotherapy/combined therapy, prevention, complications), lipid disorders (risk stratification, new biomarkers, diagnosis, rare diseases), dyslipidemia therapy (statins, new drugs, combined treatment) and new drugs in CVD therapy.
- Christoph Binder
Christoph BinderVienna, Austria
Christoph J. Binder (born 1973) received his MD degree from the University of Vienna, Austria, in 1997 and his PhD degree in Molecular Pathology from the University of California San Diego (UCSD), USA, in 2002. Following postdoctoral training at the Department of Medicine of UCSD, he established his own research group at the Medical University of Vienna in 2005. In 2009 he was appointed Full Professor of Atherosclerosis Research at the Medical University of Vienna. He is a specialist in Laboratory Medicine and currently Deputy Head of the Department of Laboratory Medicine at the Medical University of Vienna. He is also PI of the Austrian Familial Hypercholesterolemia Registry. Since 2014 Christoph Binder acts as a referee and board member of the Austrian Science Fund. From 2016 until 2019 he was a member of the Executive Committee and since 2021 he is Vice President of the European Atherosclerosis Society. Christoph Binder’s research interests span vascular biology, lipid oxidation, and immunity. His group is investigating immune mechanisms of atherosclerosis with a special focus on the role of innate and humoral immunity and how this can be exploited for the treatment of cardiovascular disease. Christoph Binder has authored >150 original and review papers in important international journals, including Nature Medicine and Nature. He is Co-Editor of Atherosclerosis and Section Editor of Thrombosis & Haemostasis.
Artificial Intelligence assisted diagnostics of atherosclerotic vascular disease
Artificial intelligence (AI) has the potential to transform the diagnosis and management of atherosclerotic cardiovascular disease (ASCVD), with imaging one key area where it is likely to impact markedly. In part this has been enabled by improvement in the quality and precision of imaging approaches, as well as wider access. With expanding imaging capabilities, AI offers a solution to the need for operational efficiency and focus on precision medicine.
One area where AI offers promise is in coronary computed tomography (CT) technology. Application of AI provides opportunities to improve the process of image acquisition, interpretation, and decision-making, as well as enhance the reproducibility of technical protocols. Two distinct approaches have been investigated: classical machine learning approaches using clinical and/or pre-computed image features, and deep learning. Integration of anatomical, functional, and biological information relating to the coronary circulation aids risk stratification of patients, so that preventive therapeutic strategies can be targeted more specifically to those individuals likely to benefit most, a key aim underpinning personalised medicine. Before AI can be adopted into routine practice, however, several challenges need to be addressed, in particular, defining how best to apply this technology to address outcome needs for patients. As a tool to improve the application of precision medicine, AI solutions in cardiac imaging will undoubtedly impact the entire healthcare system.
Antonopoulos AS, Angelopoulos A, Papanikolaou P, Simantiris S, Oikonomou EK, Vamvakaris K, Koumpoura A, Farmaki M, Trivella M, Vlachopoulos C, Tsioufis K, Antoniades C, Tousoulis D. Biomarkers of vascular inflammation for cardiovascular risk pPrognostication: a meta-analysis. JACC Cardiovasc Imaging 2021:S1936-878X(21)00698-7.
Antoniades C, Oikonomou EK. Artificial intelligence in cardiovascular imaging-principles, expectations, and limitations. Eur Heart J 2021;doi: 10.1093/eurheartj/ehab678.
Kotanidis CP, Antoniades C. Perivascular fat imaging by computed tomography (CT): a virtual guide. Br J Pharmacol 2021;178(21):4270-4290.
Charalambos Antoniades, Oxford, United Kingdom
Charis Antoniades is a Professor of Cardiovascular Medicine and Consultant Cardiologist. He was awarded his PhD title with hons on the genetics of premature myocardial infarction, and during his PhD studies he won multiple Young Investigator award competitions, including those of the European Society of Cardiology (ESC) twice, the ISHR and others. He has been awarded the Outstanding Achievement Award of the basic Cardiovascular Science Council of the European Society of Cardiology in 2016, a National clinical excellence award in 2020 and has given various named lectures. He is the Director of Acute Vascular Imaging Centre of the University of Oxford, the Deputy Head of the Division of Cardiovascular Medicine and director of the Oxford Academic cardiovascular CT programme (and Oxford Academic Cardiovascular CT Core Lab). He is also the Chair of the British Atherosclerosis Society.
His research is focused on the study of the cross-talk between adipose tissue and the cardiovascular system, with specific interest in the non-invasive imaging of inflammation. He directs the Oxford Heart Vessels and Fat programme, and coordinates large national flagship programmes (such as the UK C19-CRC) and international multicentre studies (e.g. ORFAN study). His research has led to the development of novel imaging biomarkers using Computed Tomography, with major role in cardiovascular risk prognosis.
He is also deputy editor of Cardiovascular Research, one of the editors of British Journal of Pharmacology and associate editor of Hellenic Journal of Cardiology. He has published more than 300 peer review scientific papers in high impact journals like the Lancet, Science Transl Med, Circulation, JACC, EHJ and others. He is one of the founders of the Scientists of Tomorrow of the ESC and has served as vice chair in the Marie Curie Fellowships panel of the European Commission. He is also founder and Chief Scientific Officer of Caristo Diagnostics, a university of Oxford spinout company.
Nonpharmacologic approaches to promote population cardiovascular health
Worldwide, cardiovascular disease (CVD) is the leading cause of death and contributes to an escalating burden of disease, aligned with trends in population growth and aging. The shift in the burden of disease, from mortality to morbidity, and its impact on cost has significant implications for public health policy. While advances in pharmacological approaches to preventive management have shown value, health economics underline the need to focus on promoting ideal cardiovascular health and healthy aging with feasible and affordable nonpharmacological strategies.
Reducing exposure to established modifiable cardiovascular risk factors is key to population health preventive strategies, supported by insights from major epidemiologic studies such as the Prospective Urban Rural Epidemiology (PURE) Study. A heart healthy diet, limiting saturated and trans fats and increasing fibre, regular physical activity, smoking cessation, and maintaining a healthy weight comprise the foundation for CVD risk reduction. Consideration of the overall dietary profile is more important as individual nutrient food groups cannot be viewed in isolation. Even when risk factors such as cholesterol are controlled with pharmacological therapy, adoption of lifestyle changes contributes to improved outcome and well-being.
Population health policies should focus on risk factors that have the greatest impact in preventing CVD and death globally, with additional emphasis on risk factors of greatest importance in specific groups of countries. This low-cost high-value approach to population‐wide prevention offers the potential to substantially impact the global CVD burden, especially among lower- and middle-income countries.
Iqbal R, Dehghan M, Mente A, Rangarajan S, Wielgosz A, Avezum A, Seron P, AlHabib KF, Lopez-Jaramillo P, Swaminathan S, Mohammadifard N, Zatońska K, Bo H, Varma RP, Rahman O, Yusufali A, Lu Y, Ismail N, Rosengren A, Imeryuz N, Yeates K, Chifamba J, Dans A, Kumar R, Xiaoyun L, Tsolekile L, Khatib R, Diaz R, Teo K, Yusuf S. Associations of unprocessed and processed meat intake with mortality and cardiovascular disease in 21 countries [Prospective Urban Rural Epidemiology (PURE) Study]: a prospective cohort study. Am J Clin Nutr 2021;114:1049-1058.
Naito R, Leong DP, Bangdiwala SI, McKee M, Subramanian SV, Rangarajan S, Islam S, Avezum A, Yeates KE, Lear SA, Gupta R, Yusufali A, Dans AL, Szuba A, Alhabib KF, Kaur M, Rahman O, Seron P, Diaz R, Puoane T, Liu W, Zhu Y, Sheng Y, Lopez-Jaramillo P, Chifamba J, Rosnah I, Karsidag K, Kelishadi R, Rosengren A, Khatib R, K R LIA, Azam SI, Teo K, Yusuf S. Impact of social isolation on mortality and morbidity in 20 high-income, middle-income and low-income countries in five continents. BMJ Glob Health 2021;6(3):e004124.
Mohan D, Mente A, Dehghan M, Rangarajan S, O’Donnell M, Hu W, Dagenais G, Wielgosz A, Lear S, Wei L, Diaz R, Avezum A, Lopez-Jaramillo P, Lanas F, Swaminathan S, Kaur M, Vijayakumar K, Mohan V, Gupta R, Szuba A, Iqbal R, Yusuf R, Mohammadifard N, Khatib R, Yusoff K, Gulec S, Rosengren A, Yusufali A, Wentzel-Viljoen E, Chifamba J, Dans A, Alhabib KF, Yeates K, Teo K, Gerstein HC, Yusuf S; PURE, ONTARGET, TRANSCEND, and ORIGIN investigators. Associations of fish consumption with risk of cardiovascular disease and mortality among individuals with or without vascular disease from 58 countries. JAMA Intern Med 2021;181:631-649.
Jenkins DJA, Dehghan M, Mente A, Bangdiwala SI, Rangarajan S, Srichaikul K, Mohan V, Avezum A, Díaz R, Rosengren A, Lanas F, Lopez-Jaramillo P, Li W, Oguz A, Khatib R, Poirier P, Mohammadifard N, Pepe A, Alhabib KF, Chifamba J, Yusufali AH, Iqbal R, Yeates K, Yusoff K, Ismail N, Teo K, Swaminathan S, Liu X, Zatońska K, Yusuf R, Yusuf S; PURE Study Investigators. Glycemic index, glycemic load, and cardiovascular disease and mMortality. N Engl J Med 2021;384:1312-1322.
Swaminathan S, Dehghan M, Raj JM, Thomas T, Rangarajan S, Jenkins D, Mony P, Mohan V, Lear SA, Avezum A, Lopez-Jaramillo P, Rosengren A, Lanas F, AlHabib KF, Dans A, Keskinler MV, Puoane T, Soman B, Wei L, Zatonska K, Diaz R, Ismail N, Chifamba J, Kelishadi R, Yusufali A, Khatib R, Xiaoyun L, Bo H, Iqbal R, Yusuf R, Yeates K, Teo K, Yusuf S. Associations of cereal grains intake with cardiovascular disease and mortality across 21 countries in Prospective Urban and Rural Epidemiology study: prospective cohort study. BMJ 2021;372:m4948.
Salim Yusuf, Hamilton, Canada
Salim Yusuf is Distinguished Professor of Medicine and Clinical Epidemiology & Biostatistics and Executive Director of the Population Health Research Institute, McMaster University, Chief Scientist at Hamilton Health Sciences, Canada, and Past-President of the World Heart Federation. His research over the last 35 years has substantially improved the prevention and treatment of cardiovascular disease, thereby benefiting millions of people. He coordinated the ISIS trial (which set the structure for future international collaborative work in cardiovascular disease) and served on the steering committees for all subsequent ISIS trials. In 1984, he moved to the National Institutes of Health, Bethesda, USA, where he developed and led the SOLVD trial (establishing the value of ACE-inhibitors in heart failure and left ventricular dysfunction) and the DIG trial (clarifying the role of digitalis). In 1992 he moved to McMaster University and as Founding Director of the Population Health Research Institute at Hamilton Health Sciences established an international programme of research in cardiovascular diseases and prevention. He currently leads the Prospective Urban Rural Epidemiology (PURE) study in 25 high, middle and low income countries in 5 continents. Dr Yusuf has received the Lifetime Research Achievement award of the Canadian Cardiovascular Society, the Paul Wood Silver Medal of the British Cardiac Society, the European Society of Cardiology Gold medal, the American Heart Association Clinical Research Award, the Eugene Braunwald Lecturer of the American College of Cardiology, as well as over 50 international and national awards for research. He has been inducted into the Royal Society of Canada and Canadian Medical Hall of Fame, appointed as an Officer of the Order of Canada, and received the Canada Gairdner Wightman Award. He was elected a Fellow of the Islamic World Academy of Sciences in 2017.
Should we target inflammation?
Systemic vascular inflammation plays a central role in all stages of atherosclerosis, from initiation to the progression and destabilization of atheroma, and consequent development of acute coronary syndromes. Although understanding of the underlying biology of inflammation has increased, translation into effective therapies has proved challenging. The CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) provided proof of the concept that targeting IL (interleukin)-1β, an major cytokine involved in activation of proinflammatory signalling pathways, reduced cardiovascular events in high-risk patients with established atherosclerotic disease. Subsequent to CANTOS, clinical trials have confirmed the benefits of another anti-inflammatory therapy, colchicine in patients with a recent myocardial infarction or with chronic coronary syndromes. However, not all trials have been positive. In CIRT (Cardiovascular Inflammation Reduction Trial), treatment with low-dose methotrexate, a widely used therapy for inflammatory conditions, was not associated with fewer cardiovascular events than placebo due to lack of effect on levels of interleukin-1β, interleukin-6, or C-reactive protein.
Taken together these findings imply considering both the relevance of the patient population – targeting treatment to patients with sufficiently elevated inflammation – and the diversity of inflammatory pathways involved in atherosclerosis. Thus, while residual inflammatory risk is increasingly recognised as a viable therapeutic target, identifying which inflammatory pathways are preferable targets for intervention requires clarification. Moreover, despite evidence for the clinical utility of high-sensitivity C-reactive protein, it may not be the ideal target for anti-inflammatory therapies.
Recent insights suggest that targeting the NLRP3 inflammasome pathway, which plays a central role in atherosclerosis and the pathogenesis of heart disease, may offer therapeutic potential. Animal models have demonstrated protective effects from NLRP3 inflammasome inhibition, and early clinical data for selective inhibitors of the NLRP3 inflammasome supported this as a feasible and effective strategy. Realizing the promise of targeting inflammation will likely require more individualized approaches targeting different contributors to residual inflammatory risk.
Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M; RESCUE Investigators. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021;397:2060-2069.
Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021;128:1728-1746.
Adamstein NH, MacFadyen JG, Rose LM, Glynn RJ, Dey AK, Libby P, Tabas IA, Mehta NN, Ridker PM. The neutrophil-lymphocyte ratio and incident atherosclerotic events: analyses from five contemporary randomized trials. Eur Heart J 2021;42:896-903.
Paul Ridker, Boston, USA
Paul M. Ridker is Director of the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital and the Eugene Braunwald Professor of Medicine at Harvard School of Medicine (HMS). His clinical interests include coronary artery disease and the underlying causes and prevention of atherosclerotic disease. His research focuses on inflammatory mediators of heart disease and the molecular and genetic epidemiology of haemostasis and thrombosis, with particular interests in biomarkers for coronary disease, “predictive” medicine, and the underlying causes and prevention of atherosclerotic disease.
Targeting non-coding RNAs
Non-coding RNAs do not encode proteins but are instead involved in the regulation of complex biological processes, including cellular lipid metabolism. Accumulating evidence indicates that these non-coding RNAs are functionally active in major regulatory gene expression networks at epigenetic, transcriptional, and even post-transcriptional levels.
Non-coding RNAs, can be classified as either small non-coding RNAs such as microRNAs or long non-coding RNAs, with >200 nucleotides. Over the last decade, research focused on microRNAs which have been shown to act mainly in post-transcriptional control. Specific microRNAs were identified as potent regulators of cholesterol homeostasis through their ability to repress the expression of genes in the integrated pathways of cholesterol and fatty acid biosynthesis, reverse cholesterol transport, and lipid storage. Increasingly, however, attention has been directed to long-coding RNAs, given associations with atherosclerosis and cardiovascular disease, and aided by high-throughput sequencing technologies. Recent studies in primates identified a novel long-coding RNA (CHROME, (Cholesterol Homeostasis Regulator of MiRNA Expression) involved in the maintenance of cholesterol homeostasis, via upregulation of cholesterol efflux and high-density lipoprotein biogenesis. Moreover, CHROME also inhibited specific miRNAs , implying a coordinated and flexible mechanism to counter post-transcriptional repression of the cholesterol efflux pathway.
Elucidation of the functional significance of non-coding RNAs remains a major challenge. Despite this, emerging evidence suggests a role in modulating gene expression at multiple levels of regulatory pathways involved in cellular and systemic cholesterol homeostasis, which may offer future therapeutic potential.
van Solingen C, Moore KJ. Two birds, one stone: NFATc3 controls dual actions of miR-204 in foam cell formation. Eur Heart J 2021;doi: 10.1093/eurheartj/ehab640
Afonso MS, Sharma M, Schlegel M, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Rahman K, Giannarelli C, Li H, Brown EJ, Khodadadi-Jamayran A, Fisher EA, Moore KJ. miR-33 silencing reprograms the immune cell landscape in atherosclerotic plaques. Circ Res 2021;128:1122-1138.
Sansbury BE, Corr EM, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Lafaille JJ, Spite M, Loke P, Fisher EA, Moore KJ. Regulatory T cells license macrophage pro-resolving functions during atherosclerosis regression. Circ Res 2020;127:335-353.
Kathryn Moore, Boston, USA
Dr. Kathryn Moore is the Jean and David Blechman Professor of Cardiology, and the Director of the Cardiovascular Research Center at New York University Grossman School of Medicine. She is internationally recognized for her research on the molecular pathogenesis of cardiometabolic diseases, and the roles that non-coding RNAs and dysregulated immune responses play in those settings. By forging new links between lipids, metabolism and innate immunity, her discoveries have revealed fundamental insights into pathways that regulate cholesterol homeostasis and vascular inflammation.
Dr. Moore’s contributions to the fields of innate immunity and vascular biology have been recognized by numerous awards, including the NIH’s Outstanding Investigator Award, the American Heart Association’s Distinguished Scientist Award, and election to the National Academy of Sciences USA.
Tuesday 24 May
Lipoproteins revisited: what has changed?
- Maurizio Averna
- Lale Tokgözoğlu
Lale TokgözoğluAnkara, Turkey
S. Lale Tokgözoğlu, MD, FACC, FESC is Professor of Cardiology at Hacettepe University, Ankara, Turkey. She is currently the immediate Past-President of the European Atherosclerosis Society and Deputy Editor of the European Heart Journal. She chaired the ‘Atherosclerosis and Vascular Biology Working Group of the European Society of Cardiology’ between 2008 and 2010. Prof. Tokgözoğlu has served on the Board of the Turkish Society of Cardiology and was elected to be the first female President of the Society in its history, between 2014-2016. During that time, she worked with the Ministry of Health to develop ‘Heart Health policies’ and strategies. She also chaired the Dyslipidaemia Working Group of the Turkish Society of Cardiology. She has contributed to several Guidelines and Consensus Papers on dyslipidaemia and Preventive Cardiology both in Europe and nationally. She was a member of the Steering Committee of the EUROASPIRE III-V studies which were the landmark studies defining preventive measures in Europe. She has also served on the Board of the Prevention Association as well as different committees of the European Society of Cardiology including the Fellowship and Training Committee, the Education Committee and currently the Research and Grants Committee. She is a member of the Science Academy and a founding member of the Atherosclerosis Research and Education Society in Turkey. She is also a founding member of the Department of Noncommunicable diseases in Hacettepe University. She serves on the Scientific and Research Council of Turkey Working Group on women researchers.
Metrodora Award Global Leader in Science and Health 2020
Istanbul Medical Association Science Award in 2019
Paul Dudley White Science team award AHA 2017
Prof. Dr. Şeref Zileli Resident of the Year” Award in 1987
Young Investigator Award of the Turkish Society of Cardiology in 1994
ApoB – friend and foe
Cholesterol-rich apolipoprotein (apo) B-containing lipoproteins, of which low-density lipoprotein (LDL) is the archetypal representative, play a fundamental role in the genesis and promotion of atherosclerosis. Mechanistic and genetic studies suggest that assessment of the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) rather than their lipid content may be a better predictor of cardiovascular risk. Alternatively, with accumulating evidence that apoB is integral to lipoproteins exerting their causal effect on risk for cardiovascular disease, measurement of apoB may be preferable.
While LDL cholesterol is conventionally used as a predictor of cardiovascular risk, its use is not without issues, especially when calculated measures of LDL cholesterol are used. In individuals with diabetes or metabolic syndrome, LDL cholesterol levels may not reflect the atherogenicity of the abnormal lipid profile associated with elevated triglyceride-rich lipoproteins. In these patients, apoB is a more accurate measure of risk rather than the concentration of cholesterol contained in lipoproteins. Evidence from epidemiologic studies also supports apoB as a better predictor of cardiovascular risk and response to treatment than measurement of LDL cholesterol. These findings make a case for considering apoB as a priority lipid target in prevention of cardiometabolic disease.
Although improvement in standardization and accessibility is needed, the totality of evidence supports apoB for both risk assessment and as a treatment target in routine clinical practice.
Zanoni P, Panteloglou G, Othman A, Haas JT, Meier R, Rimbert A, Futema M, Abou-Khalil Y, Nørrelykke SF, Rzepiela A, Stoma S, Stebler M, Dijk FV, Wijers M, Wolters JC, Dalila N, Huijkman N, Smit M, Gallo A, Carreau V, Philippi A, Rabès JP, Boileau C, Visentin M, Vonghia L, Weyler J, Francque S, Verrijken A, Verhaegen A, Van Gaal LF, van der Graaf A, van Rosmalen BV, Robert J, Velagapudi S, Yalcinkaya M, Keel M, Radosavljevic S, Geier A, Tybjærg-Hansen A, Varret M, Rohrer L, Humphries SE, Staels B, van de Sluis B, Kuivenhoven JA, Von Eckardstein A. Posttranscriptional regulation of the human LDL receptor by the U2-spliceosome. Circ Res 2021;doi: 10.1161/CIRCRESAHA.120.318141.
Loaiza N, Hartgers ML, Reeskamp LF, Balder JW, Rimbert A, Bazioti V, Wolters JC, Winkelmeijer M, Jansen HPG, Dallinga-Thie GM, Volta A, Huijkman N, Smit M, Kloosterhuis N, Koster M, Svendsen AF, van de Sluis B, Hovingh GK, Grefhorst A, Kuivenhoven JA. Taking one step back in familial hypercholesterolemia: STAP1 does not alter plasma LDL (Low-Density Lipoprotein) cholesterol in mice and humans. Arterioscler Thromb Vasc Biol 2020;40:973-985.
Rimbert A, Dalila N, Wolters JC, Huijkman N, Smit M, Kloosterhuis N, Riemsma M, van der Veen Y, Singla A, van Dijk F; Biobank-Based Integrative Omics Studies Consortium, Frikke-Schmidt R, Burstein E, Tybjærg-Hansen A, van de Sluis B, Kuivenhoven JA. A common variant in CCDC93 protects against myocardial infarction and cardiovascular mortality by regulating endosomal trafficking of low-density lipoprotein receptor. Eur Heart J 2020;41:1040-1053.
Jan Kuivenhoven, Groningen, The Netherlands
Jan Albert Kuivenhoven started with an MSc degree in molecular biology and finished his PhD on the genetics of human high-density lipoprotein at the Academic Medical Center (AMC). After a postdoc appointment at the Department of Biology, Massachusetts Institute of Biology, he established his own research group at the AMC. His current research is focused on identifying novel lipid genes using an extreme genetics approach.
Emerging therapies for dyslipidemia
Low-density lipoprotein cholesterol (LDL-C) is undoubtedly the priority target for lipid lowering therapy to prevent atherosclerotic cardiovascular disease (ASCVD). However, despite maximally tolerated LDL-C lowering, including PCSK9-directed therapies, residual cardiovascular risk persists. Advances in human genetics enabling the identification of rare genetic variants with strong effects on ASCVD risk not only accelerated the development of therapies for severe dyslipidaemia, but also led to identification of novel pathways involved in the metabolism of other atherogenic lipoproteins, most notably triglyceride rich lipoproteins. These insights were critical to the application of a Mendelian randomization design to establish elevated plasma levels of these lipoproteins, as well as lipoprotein(a) [Lp(a)], as independent causal risk factors for ASCVD and thus potential contributors to residual risk. Understanding the underlying genetic and cell machinery has also provided impetus in treating rare dyslipidaemias.
The development of novel antisense therapies, including oligonucleotides and short interfering RNA-based strategies, addresses several unmet medical needs in lipidology. Among these treatments, those targeting apolipoprotein C-III or angiopoietin-like protein 3 have demonstrated substantial lowering of plasma triglycerides in the setting of moderate to severe hypertriglyceridaemia.
Despite the potential efficacy of these new therapies in ASCVD prevention, cost is likely to be prove a major obstacle to their clinical use. Affordability and access are therefore the key challenges facing the next generation of lipid-lowering agents in the era of precision medicine.
Ginsberg HN, Packard CJ, Chapman MJ, Borén J, Aguilar-Salinas CA, Averna M, Ference BA, Gaudet D, Hegele RA, Kersten S, Lewis GF, Lichtenstein AH, Moulin P, Nordestgaard BG, Remaley AT, Staels B, Stroes ESG, Taskinen MR, Tokgözoğlu LS, Tybjaerg-Hansen A, Stock JK, Catapano AL. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; doi: 10.1093/eurheartj/ehab551.
Ahmad Z, Pordy R, Rader DJ, Gaudet D, Ali S, Gonzaga-Jauregui C, Ponda MP, Shumel B, Banerjee P, Dunbar RL. Inhibition of Angiopoietin-Like Protein 3 with evinacumab in subjects with high and severe hypertriglyceridemia. J Am Coll Cardiol 2021;78:193-195.
Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O’Dea LSL, Stroes ESG, Tsimikas S, Witztum JL; COMPASS study group. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021;9:264-275.
Daniel Gaudet, Montreal, Canada
Dr. Gaudet is affiliated to the Department of Medicine, Université de Montréal (UdeM). He is the scientific director of the UdeM Community Genetic Medicine Center and its Clinical Lipidology and Rare Lipid Disorders Unit. He is currently president and scientific director of ECOGENE-21, a non-for profit organization devoted to access to innovation in precision medicine. His main clinical and academic activities aim at investigating rare dyslipidemias and translating new knowledge issued from extreme phenotypes to more common forms of diseases. Over the years, he has coordinated more than 200 studies involving the development of screening tools, technologies or therapies for severe dyslipidemias or related disorders, in collaboration with biotechs, pharmas, or academic partners. He authored more than 300 scientific publications in peer-reviewed journals, including several tens in very highly rated Journals (NEJM, Lancet, Nature Medicine, Nature Genetics) as well as >500 scientific communications or book chapters.
Lp(a): The next frontier
Following decades of debate, lipoprotein(a) [Lp(a)] is now recognised as a causal risk factor for atherosclerotic cardiovascular disease and aortic valvular stenosis, supported by evidence from genetic, epidemiological and mechanistic studies. Until recently, however, final proof of causality has proved elusive as the available lipid lowering therapies either have minimal effect on Lp(a) or effects on multiple lipoproteins. The emergence of novel antisense treatments that specifically inhibit the synthesis of apolipoprotein(a) offers the key to addressing this enigma.
Advances in antisense oligonucleotide development, notably conjugation with N-acetylgalactosamine to direct the therapy specifically to hepatocytes, has resulted in improved affinity and selectivity. In phase 2 trials, this agent reduced Lp(a) levels by up to 80%, providing a basis for further development to investigate the impact of Lp(a) lowering on cardiovascular events. The major outcomes study Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) with the apolipoprotein (a) antisense oligonucleotide pelacarsen is testing the Lp(a) hypothesis in secondary prevention patients with elevated Lp(a) levels and optimally managed of low-density lipoprotein cholesterol levels. This trial will be pivotal to bridging the final frontier: Is Lp(a)-associated risk abolished by potent Lp(a) lowering? If proven, the results of Lp(a)HORIZON will be crucial for the development of paradigms aiming to improve awareness, diagnosis, and management of elevated Lp(a).
Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol 2021;77:1576-1589.
DeFilippis AP, Trainor PJ, Thanassoulis G, Brumback LC, Post WS, Tsai MY, Tsimikas S. Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis. Eur Heart J 2021: doi: 10.1093/eurheartj/ehab600.
Karwatowska-Prokopczuk E, Clouet-Foraison N, Xia S, Viney NJ, Witztum JL, Marcovina SM, Tsimikas S. Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen. Atherosclerosis 2021;324:102-108.
Sotirios Tsimikas, San Diego, USA
Dr. Tsimikas is Professor of Medicine and the Director of Vascular Medicine at the University of California San Diego School of Medicine. His education and training included obtaining his MD degree from the University of Massachusetts Medical School, Internal Medicine training at the University of Massachusetts Medical Center, and separate fellowships in Cardiovascular Medicine, Atherosclerosis and Molecular Medicine and Interventional Cardiology at the University of California San Diego (UCSD) Medical Center. Dr. Tsimikas is the Founding Director of the Vascular Medicine Program withing the Cardiovascular Medicine Division. In 2014, he established the concpet of a dedicated “Lp(a) Clinic” at UCSD. Dr. Tsimikas’ research interests are translational in scope and focus on two major areas: 1-“biotheranostics”- biomarkers, molecular imaging and therapeutics targeted to oxidation-specific epitopes, and 2- Lp(a) pathophysiology and therapeutics. He has published in all of the major medical journals, including NEJM, Lancet, Nature, Cell and has over 300 original manuscripts, review articles and book chapters. He currently has a dual appointment at University of California San Diego Medical School and as Senior Vice President of Global Cardiovascular Development at Ionis Pharmaceuticals, Carlsbad, CA. He is co-inventor of 13 issued patents, and co-founder of Oxitope, Inc, Kleanthi Diagnostics and Covicept Therapeutics.
Trigylcerides: From systemic to cellular metabolism
Whether elevated triglycerides, a surrogate for triglyceride [TG]-rich lipoproteins and their remnants, are associated with risk for cardiovascular disease, has engendered much debate over the decades. Current thinking, largely driven by insights from genetic studies, supports this association although definitive proof is still lacking from major outcomes studies. In addition, the underlying mechanisms of the atherogenicity of TG-rich lipoproteins merit further study. Given that lipoprotein lipase (LpL) plays a central role in TG metabolism, and those genes that modulate its activity correlate with the risk of cardiovascular disease events, research has focused on LpL biology to address this latter question.
ElucidatIon of the structure of the LpL active protein and its interaction with other post-translational regulators has been an important step. Studies showing that LpL is active as a monomer challenged thinking that LpL inhibitors like angiopoietin-like 4 (ANGPTL4) and stabilizers like lipid maturation factor 1 (LMF1) act by disrupting or maintaining LpL in dimer form. These insights prompted interest in developing targets to block LpL to reduce circulating TG levels.
Involvement of LpL in the intravascular hydrolysis of TG-rich lipoproteins on the surface of capillary endothelial cells has driven research into the multiple pathways that mediate endothelial transit of lipids into tissues. There is evidence to suggest a role for receptor-mediated processes in the movement of lipoproteins into the sub-endothelial space. In addition, studies have identified factors that may influence endothelial barrier integrity and thus delivery of lipids.
Taken together, it is evident that improved understanding of TG regulation at the cellular level may offer new therapeutic potential for the management of elevated TG to reduce residual risk.
Goldberg IJ, Cabodevilla AG, Samovski D, Cifarelli V, Basu D, Abumrad NA. Lipolytic enzymes and free fatty acids at the endothelial interface. Atherosclerosis 2021;329:1-8.
Cabodevilla AG, Tang S, Lee S, Mullick AE, Aleman JO, Hussain MM, Sessa WC, Abumrad NA, Goldberg IJ. Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation. J Clin Invest 2021;131:e145800.
Abumrad NA, Cabodevilla AG, Samovski D, Pietka T, Basu D, Goldberg IJ. Endothelial cell receptors in tissue lipid uptake and metabolism. Circ Res 2021;128:433-450.
Ira Goldberg, New York, USA
Dr. Goldberg received his undergraduate degree from MIT and his medical degree from Harvard Medical School. After fellowships in endocrinology and metabolism, and atherosclerosis and metabolism, he was appointed to the faculty of the Department of Medicine at Columbia University in 1983 and was Chief of the Division of Preventive Medicine and Nutrition and the Dickinson Richards Professor of Medicine. He is currently the Clarissa and Edgar Bronfman, Jr. Professor and Chief of the Division of Endocrinology, Diabetes and Metabolism at New York University School of Medicine.
Dr. Goldberg has published over 200 articles, as well as numerous book chapters, editorials, and reviews. His research has focused on abnormalities of lipoprotein metabolism, macrovascular disease in diabetes, and the role of triglycerides in atherosclerosis. Among Dr. Goldberg’s honors is a MERIT Award from the National Heart, Lung, and Blood Institute. He was chosen to give the 2007 Robert Levy Lecture of the NPAM Committee of the American Heart Association, the Edwin Bierman Lecture on diabetes and heart disease at the 2010 American Diabetes Association Meeting, and the 2017 George Lyman Duff Lecture of the ATVB council.
Monday 23 May
Personalised approach to ASVD: The future is here
- Alberico Catapano
Alberico CatapanoMilan, Italy
Full Professor of Pharmacology, Director of the Center of Epidemiology and Preventive Pharmacology (SEFAP) as well as Director of the Laboratory of Lipoproteins, Immunity and Atherosclerosis at the University of Milan (Department of Pharmacological and Biomolecular
Sciences) and PhD coordinator from 2017 to 2020.
Moreover he is Director of the Center for the Study, Prevention and Therapy of Atherosclerosis of the University of Milan, at the Bassini Hospital, Head of Cardiovascular Research Line at Multimedica IRCCS Sesto San Giovanni (Mi), President of the Italian Society of Clinical and Sperimental Therapy (SITeCS) and General Director of the SISA Foundation
His main research, from 1972, interests include the study of atherosclerosis, lipids, lipoproteins and genetic dyslipidaemias, and he has made landmark observations regarding heat shock proteins and pentraxins in atherogenesis, on high-density lipoproteins in the modulation of the immune response, and on the identification of possible therapeutic targets by exploiting genetic information. Past President of the European Atherosclerosis Society (EAS), Professor Catapano is currently Co- Chairman of the EAS/European Society of Cardiology (ESC) guidelines for the treatment of dyslipoproteinaemias. Editor of Atherosclerosis Supplements, Co-editor of Atherosclerosis and Associate Editor of other scientific journals, he has authored more than 590 scientific papers in peer-reviewed journals (I.F. 10.929) and is among the highly cited scientists in 2019, 2020 and 2021 according to Clarivate
- Kausik Ray
Kausik RayLondon, United Kingdom
Kausik Ray is currently Professor of Public Health, Deputy Director of Imperial Clinical Trials Unit and Head of Commercial Trials within the Department of Public Health and Primary Care, School of Public Health, Imperial College London, Consultant Cardiologist and Chief Clinical Officer and Head of Trials –Discover Now as well as NIHR ARC National Lead of Cardiovascular Disease. Professor Ray received his medical education (MB ChB, 1991) at the University of Birmingham Medical School, his MD (2004) at the University of Sheffield, a post-doctoral fellowship at Harvard Medical School and finally an MPhil in epidemiology (2007) from the University of Cambridge.
A Fellow of the American College of Cardiology, the European Society of Cardiology, the American Heart Association and the Royal College of Physicians, Kausik Ray is also a member of the British Cardiovascular Society and President of the European Atherosclerosis Society, also serving on the EAS Consensus panel and EAS Executive Committee. Professor Ray has either been the National Lead Investigator, Principal Investigator, or served on committees for several major medical trials, as well as international registries and is currently involved in 8 ongoing trials in lipids and diabetes and the PI for ORION 1, 3, 11 assessing PCSK9 inhibition through RNA interference and BETONMACE assessing BET protein inhibition in patients with ACS.
Professor Ray’s research interests have focused on the prevention of coronary disease with a focus on lipids, diabetes, biomarkers and risk prediction. He has an H index of 87, an i10 of 220 and over 92,000 citations for his work in journals such as New England Journal of Medicine, The Lancet, JAMA, European Heart Journal, Circulation and JACC. He has also been included in the Clarivate Analytics’ list of the top 1% most cited authors in all of global medicine in 2018, 2019 and 2020. Key original contributions which have influenced European and American guidelines include demonstrating the early benefits of statin therapy post ACS, the impact of more/less intensive glycaemic control on CVD and the risks/benefits of aspirin therapy in primary prevention. Recently, his work on statins and diabetes risk led to a global label change for statins by the FDA and EMEA. Currently Professor Ray leads the EAS FH Studies collaboration which is the first global registry of FH which includes 70 countries and 62,000 cases, as well as being the Senior PI for the TOGETHER study looking at cardiometabolic risk in the vascular health checks in 250,000 people in London.
Deep phenotyping of disease
Systems approaches encompassing genomics, lipidomics and metabolomics have advanced understanding of the biology of atherosclerosis. Application of deep phenotyping of gene transcriptional and regulatory effects of lipid associated loci, together with ‘cloud’ computing power and ‘big data’, have also identified novel targets with therapeutic potential.
A key focus is inflammation, given its involvement at all stages of atherosclerosis, and evidence that anti-inflammatory interventions reduce the risk of adverse cardiovascular events in patients with recent acute myocardial infarction. Until recently, research has targeted systemic inflammation; however, the emergence of single-cell technologies offers the capability for multi-dimensional profiling of human atherosclerotic plaques, providing insights into novel immune alterations in the plaque microenvironment that are associated with the clinical manifestations of atherosclerosis, as well as key cell-cell signalling networks contributing to progression of atherosclerosis. Single-cell omics can therefore have value in identifying precise interventions that restore the function of immune cellular and molecular networks acting within the circulation and in atherosclerotic lesions in the same patient, with the ultimate goal of reducing both systemic and plaque inflammation.
For the future, the integration of single-cell omics studies in humans with relevant functional experimental models will provide a framework for the development of personalised immunotherapies targeting specific groups of patients who will derive most benefit.
Hill CA, Fernandez DM, Giannarelli C. Single cell analyses to understand the immune continuum in atherosclerosis. Atherosclerosis 2021;330:85-94.
Afonso MS, Sharma M, Schlegel M, van Solingen C, Koelwyn GJ, Shanley LC, Beckett L, Peled D, Rahman K, Giannarelli C, Li H, Brown EJ, Khodadadi-Jamkaran A, Fisher EA, Moore KJ. miR-33 silencing reprograms the immune cell landscape in atherosclerotic plaques. Circ Res 2021;128:1122-1138.
Fernandez DM, Giannarelli C. Mapping transplant arteriosclerosis cell-by-cell: a path to new immune insights. Circ Res 2020;127:994-996.
Chiara Giannarelli, New York, USA
Dr. Giannarelli is an Associate Professor of Cardiology, Medicine and Associate Professor of Pathology at the New York University (NYU) Langone Health and the NYU Grossman School of Medicine in New York City. She is a physician scientist with years of experience in the field of vascular biology and atherosclerosis. She has published original research spanning from preclinical models to clinical studies in the areas of endothelial dysfunction, arterial stiffness, hypertension, angiogenesis, and atherosclerosis. Dr. Giannarelli currently focuses on translational and patient-oriented research using systems biology and drug repurposing approaches. Her laboratory was the first to integrate Cytometry by time of flight (CyTOF), single cell RNA sequencing (scRNAseq), and Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) to map the composition and molecular states of circulating and plaque-derived immune cells from CVD patients and to establish their role in plaque progression and clinical cardiovascular events.
Imaging and biomarkers: Targeting the right patient for the right treatment
Personalised medicine, in which medical therapy is tailored to specific patient characteristics, is now a clinical reality. Imaging and biomarkers are two of the tools that can help in precisely defining disease mechanisms so that treatments are targeted to patients likely to benefit most.
Imaging already has a pivotal role in diagnosis and risk stratification in atherosclerotic cardiovascular disease (ASCVD) prevention. Multimodal cardiovascular imaging can identify vulnerable plaque and may anticipate the beneficial effect of pharmacological agents on clinical endpoints and patients’ potential responsiveness to these agents. Leveraging artificial intelligence and machine learning provides objective assessment of the potential clinical benefit to the individual, and thus aids transition to personalised delivery of precision cardiovascular medicine.
Identification and validation of novel biomarkers also provide opportunities for personalising therapy, moving beyond the use of a single marker such as apolipoprotein B/LDL-C to simultaneously target other drivers of atherosclerotic risk. For example, mechanistic studies have shown an interplay between inflammatory processes within the arterial wall or systemic circulation and the cholesterol pathway, linked by activation of the NLRP3 inflammasome. Prevailing evidence suggests that targeting the NLRP3 inflammasome pathway may help to refine phenotypic screening, improve risk stratification, and guide treatment eligibility. Combining multiple markers into a multiplex panel could further improve the application of personalised approaches to ASCVD prevention.
Taken together, integrating information from ‘omics’ technologies with traditional risk factors and imaging data, using artificial intelligence approaches will aid the implementation of specific treatment strategies for precision cardiovascular medicine.
Sujana C, Salomaa V, Kee F, Costanzo S, Söderberg S, Jordan J, Jousilahti P, Neville C, Iacoviello L, Oskarsson V, Westermann D, Koenig W, Kuulasmaa K, Reinikainen J, Blankenberg S, Zeller T, Herder C, Mansmann U, Peters A, Thorand B; BiomarCaRE Consortium. Natriuretic peptides and risk of type 2 diabetes: results from the biomarkers for cardiovascular risk assessment in Europe (BiomarCaRE) Consortium. Diabetes Care 2021;44:2527-2535.
Batra G, Ghukasyan Lakic T, Lindbäck J, Held C, White HD, Stewart RAH, Koenig W, Cannon CP, Budaj A, Hagström E, Siegbahn A, Wallentin L; STABILITY Investigators. Interleukin 6 and cardiovascular outcomes in patients with chronic kidney disease and chronic coronary syndrome. JAMA Cardiol 2021:e213079.
Wallentin L, Eriksson N, Olszowka M, Grammer TB, Hagström E, Held C, Kleber ME, Koenig W, März W, Stewart RAH, White HD, Åberg M, Siegbahn A. Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study. PLoS Med 2021;18(1):e1003513.
Wolfgang Koenig, Munich, Germany
Wolfgang Koenig MD, PhD, FRCP, FACC, FAHA, FESC
German Heart Center Munich, Technical University of Munich, Munich, Germany
Wolfgang Koenig is a Professor of Medicine/Cardiology. He is a board-certified internist and interventional cardiologist and has extensive experience in the molecular epidemiology of cardiovascular diseases. A former Director of the WHO-MONICA Augsburg Myocardial Infarction Register, Professor Koenig has held multiple clinical positions at the University of Ulm Medical Center. In April 2015 he joined the German Heart Centre in Munich, where he is the Head of the Cardiometabolic Unit.
Professor Koenig`s research interest is atherosclerosis, focusing on the identification and evaluation of new biomarkers for cardiometabolic diseases, the clinical pharmacology of cardiovascular compounds, and the clinical epidemiology of cardiovascular disorders. He serves on the steering committee of multiple large, international clinical trials. He has published more than 900 papers and has an H-Index of 101. In 2014 he was given the Rudolf Schönheimer Award from the German Atherosclerosis Society, in 2019 he received the degree of Adjunct Professor from the Medical University of Vienna and in 2020 he was awarded the Paul Morawitz price from the German Cardiac Society.
Implementing genetics scores in clinical practice
Genetic risk scores offer great potential in the delivery of precision cardiovascular medicine, across primary and early secondary prevention settings, with the opportunity to intervene earlier to inform treatment choices and reduce the likelihood of clinical disease. Integration of genetic risk scores within clinical practice also has wider impact, in optimising healthcare resource use to individuals most likely to be benefit from specific interventions.
While widely applied in research studies, the clinical utility of genetic risk scores has yet to be established. There are also important challenges to their implementation. Key amongst these is the need for further validation to ensure accuracy and reliability, barriers to implementation and to the interpretation of information, education of healthcare personnel, and reimbursement issues. There are also ethical issues relating to how such information is used and the paucity of representation from different ethnicities. These challenges underline the need for further validation within each population ancestry group; definition of the added clinical value from the use of the score; consideration of benefits versus harms in research studies; and assessment of relevant social, ethical and legal issues that may impact reimbursement and health policy. Successful implementation will most likely be in personalising preventive measures and informing treatment choice.
Patel AP, Wang M, Kartoun U, Ng K, Khera AV. Quantifying and understanding the higher risk of atherosclerotic cardiovascular disease among South Asian individuals: results from the UK Biobank Prospective Cohort Study. Circulation 2021;144:410-422.
Kim MS, Kim WJ, Khera AV, Kim JY, Yon DK, Lee SW, Shin JI, Won HH. Association between adiposity and cardiovascular outcomes: an umbrella review and meta-analysis of observational and Mendelian randomization studies. Eur Heart J 2021;42:3388-3403.
Hindy G, Aragam KG, Ng K, Chaffin M, Lotta LA, Baras A; Regeneron Genetics Center, Drake I, Orho-Melander M, Melander O, Kathiresan S, Khera AV. Genome-wide polygenic score, clinical risk factors, and long-term trajectories of coronary artery disease. Arterioscler Thromb Vasc Biol 2020;40:2738-2746.
Amit V Khera, Boston, USA
Amit V Khera
Amit V. Khera, MD MSc, is a cardiologist, human geneticist, and population biologist at Massachusetts General Hospital (MGH), group leader within the MGH Center for Genomic Medicine, Associate Director of the Program in Medical and Population Genetics and Merkin Institute Fellow at the Broad Institute of MIT and Harvard, and Assistant Professor at Harvard Medical School.
He received his MD with Alpha Omega Alpha distinction from the Perelman School of Medicine at the University of Pennsylvania and went on to complete clinical training in Internal Medicine and cardiology at Brigham and Women’s Hospital and MGH. He completed a Masters of Science at the Harvard School of Public Health and a postdoctoral research fellowship with Dr. Sekar Kathiresan in human genetics at the Broad Institute of MIT and Harvard.
His research program (kheralab.org) uses genetic variation as a tool to uncover new biology and enable enhanced clinical care informed by inherited susceptibility.
He has developed expertise in epidemiology, clinical medicine, and human genetics. Among his scientific contributions, he pioneered use of a new approach to quantify genetic risk (‘genome-wide polygenic scores’) for common diseases, developed biomarkers that provide new biologic insights, and analyzed large-scale gene sequencing data to highlight key pathways driving risk and identify molecular subtypes of cardiometabolic diseases.
Dr. Khera has authored more than 90 scientific publications, including lead or senior-authored publications in the New England Journal of Medicine, Journal of the American Medical Association, Cell, Nature Reviews Genetics, Nature Genetics, Journal of the American College of Cardiology, and Circulation. His work has been recognized as among the top ten research advances by the American Heart Association (in both 2016 and 2018), and the National Human Genome Research Institute (in 2020), and he is the 2019 recipient of the Douglas P. Zipes Distinguished Young Scientist Award from the American College of Cardiology.
In tandem with his research efforts, he founded and is co-leading a Preventive Genomics Clinic at MGH to provide a clinical infrastructure for genome-first medicine.
Vascular response in atherosclerosis: From epigenetics to bone marrow
Epigenetic control is one of the most fundamental regulatory systems within the cell. Although different cells contain the same genetic material, they have different epigenomic signatures, which may be heritable or temporary, caused by dynamic responses to the environment thereby providing a link between phenotypic profile and disease risk. Epigenetic modifications, such as DNA methylation and post-translational histone processing, have emerged as important regulators of key signalling pathways that alter monocyte/macrophage phenotypes in response to environmental stimuli, and thus important factors in the pathogenesis of atherosclerosis. In contrast to adaptive immune responses, epigenetic reprogramming of transcriptional pathways mediates trained immunity, involving enhanced responsiveness to subsequent triggers. This process is likely to confer detrimental outcomes in the context of chronic inflammatory diseases, such as atherosclerosis.
Atherosclerotic plaque formation is a dynamic multi-cellular process in which the activity of the different cell types involved is essentially determined by the regulation of different genes. Epigenetic factors modulate vascular smooth muscle cell phenotype to either promote or prevent arterial remodelling. These insights have led to suggestions that atherosclerosis is an epigenetic disorder rather than a ‘lipid’, ‘metabolic’, and ‘inflammatory’ disorder. The ongoing challenge is to understand how the mechanisms of epigenetic regulation, including those mediated by intragenic epigenetic modifications and long coding RNAs, promote vascular disease. Finally, the reversibility of epigenetic modifications may suggest future potential for identifying novel therapeutic targets for atherosclerosis.
Budden CF, Gearing LJ, Kaiser R, Standke L, Hertzog PJ, Latz E. Inflammasome-induced extracellular vesicles harbour distinct RNA signatures and alter bystander macrophage responses. J Extracell Vesicles 2021;10(10):e12127.
Latz E. The inflammasome: from bench to bedside. Nat Rev Immunol 2021;21:622-623.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenvoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O’Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol 2021;22:2-6
Eicke Latz, Bonn, Germany
Eicke Latz studied medicine in Göttingen and Berlin and worked as an intensive care physician at the Charité Hospital in Berlin. Starting in 2000, he received post-doctoral training at Boston University and UMass Medical School, joining the UMass faculty in 2006. In 2010, he returned to Germany and founded the Institute of Innate Immunity at the University of Bonn.
Eicke has co-founded IFM Therapeutics, DiosCure Therapeutics, and a ‘Stealth’ biotech that translate discoveries into novel therapeutics. He has been a highly cited scientist in immunology yearly since 2014, and he has received prestigious awards, such as the Gottfried Wilhelm Leibniz Prize in 2018.