Wednesday, 25 May
From lifestyle to designer therapies – AI assisted diagnostics of ASCVD
Charalambos Antoniades, Oxford, United Kingdom
Charis Antoniades is Professor of Cardiovascular Medicine and Director of the Acute Vascular Imaging Centre, University of Oxford, the Deputy Head of the Division of Cardiovascular Medicine and Director of the Oxford Academic cardiovascular clinical trials programme. He is also Chair of the British Atherosclerosis Society. His research is focused on studying 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 a major role in cardiovascular risk prognosis. Dr Antoniades was awarded the Outstanding Achievement Award of the basic Cardiovascular Science Council of the European Society of Cardiology in 2016, and a National Clinical Excellence award in 2020. 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.
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.
References
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.
Nonpharmacologic approaches to promote population cardiovascular health
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.
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.
References
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.
Should we target inflammation?
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.
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.
References
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.
Targeting non-coding RNAs
Kathryn Moore, Boston, USA
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.
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.
References
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.
