European Heart Journal

Ozkan, Judy

doi: 10.1093/eurheartj/ehy447pmid: 30202966

Outgoing President of the British Cardiovascular Society (BCS), Sarah Clarke MA MD FRCP FESC FACC speaks to CardioPulse  Interventional cardiologist Dr Sarah Clarke is a full-time consultant at Royal Papworth Hospital, Cambridge, UK and highly regarded as a leader and an educator. She is known for her transformative work in health and clinical services and was recently appointed joint national cardiology lead for the Getting It Right First Time (GIRFT) programme aimed at improving quality and efficiency and ensuring consistency across the UK National Health Service (NHS). Dr Clarke, a committed member of the British Cardiovascular Society (BCS) which was founded in 1922, first joined the Society 18 years ago when she was a registrar and became the roving reporter at the annual conference, later developing the webcasting with a team recording sessions and posting live interviews on the website. This led to a role on the Education Committee, which she went on to chair. In this position, she developed a portfolio of courses for trainees and specialists. A notable initiative from this period is the ongoing ‘Year in Cardiology’ review series, published in the EHJ since 2013, aiming to provide health care professionals with the most relevant updates, advances, and developments from this fast-moving area. As Vice President of Education and Research between 2011 and 2013, Dr Clarke was elected to an officer/trustee post in the Society and joined the board of BCS. This 3-year term saw a growth in education courses as well as a rethink and reinvigoration of the BCS Annual Conference. A new agenda was introduced, and the programme was arranged into dedicated ‘tracks’ which grouped sessions together under specific categories of interest such as basic science or education for revalidation. Annual themes such as Innovation or ‘Sports Cardiology’ (during the London Olympics), were adopted to provide a specific focus on areas less well, or not covered by the curriculum. In 2018, the theme of ‘High Performing Teams’ was chosen to highlight leadership skills following requests from trainees and junior doctors for support in this area. She was elected the first female president of the BCS in 2014 and took office in 2015. During this time she embarked on a programme of transformational change. She handed over to Simon Ray, a Consultant Cardiologist at the University Hospital of South Manchester in June 2018, having completed her tenure. Of her time at the helm, she says: ‘It has been marked by a trajectory of significant change. As a Society, we needed to modernize, and professionalize our services, and develop appropriate systems infrastructure to support core functions and enable our strategic goals to be realized so as to remain fit for the future. The programme of transformation has involved significant internal scrutiny, and reviewing most of the services we provide with a strong focus on governance. We have looked at all our committees to make sure they have strong terms of reference and appropriate membership arrangements. One positive output of which was to establish trainee representatives on all BCS committees to ensure a strong trainee voice. We have also undertaken a financial review to ensure that as a charity we act according to charity commission rules and responsibly with respect to how we utilize membership income in support of the provision of core activities. At the same time, we looked at the staffing and management structure making changes to ensure optimal organizational delivery, and staff are now working more closely in teams and across functions. Along with better internal communication, staff now have regular structured appraisals and one-to-ones where we can identify any skills gaps and provide training. Our internal team of staff is now, importantly, more aligned to the strategy of the organisation’. A major innovation for 2018 is the development of a digital strategy to support the aims of the Society through a new customer relationship management system (CRM) and website overhaul which will make it easier to deliver education and to access and book training and education courses. ‘Our new IT systems will allow us to make the improvements which are essential to communicate our activities better with our members and will also future-proof us. One of our objectives was to take our education overseas as there has been a significant demand for our programmes, but we have not had the right media to engage on a global platform in a similar way to the ACC and ESC, until now. Affiliate Societies with modest funding will be able to link to, and use the new website as a template for their own activities and as such will automatically comply with General Data Protection Regulation’, Dr Clarke says. A new initiative involves a project to establish a clinical research network to enable closer collaboration at a clinical level to engage more hospitals and more patients in clinical research. ‘We’re not looking at the academic side of things, it’s more about developing a network where clinicians can come together from different specialities and different types of organizations to pool ideas for research projects that they would like to see undertaken’. A database of experts and their locations is proposed to connect professionals and facilitate more grass roots clinical research across various bodies and organizations. A further project is looking at developing a data science centre. In its early infancy, this project could potentially facilitate research and audit across the NHS and not just in cardiology. Alongside the root and branch review of structure and governance, BCS has been looking at membership categories and what they offer to members. The BCS is an umbrella organization for 18 affiliated societies covering all subspecialties of cardiology, trainees, and patients and other professional groups such as cardiac physiologists, nurses, and those in primary care, and now numbers 12 000 members in total. ‘We are the voice for all those who work in cardiovascular care and research and we also engage with patients to encourage the best possible treatment for them’. Benefits of membership include subsidized access to the BCS Annual Conference and many of the educational courses that run throughout the year. Heart, the journal of the BCS, which contains a wealth of original articles as well as educational articles and features designed to help the trainee and generalist cardiologist is free to members. Access to CardioSource and JACC come with membership and travel bursaries are available. With her extensive professional network, Dr Clarke provides a link to high profile international and global bodies such as the European Society of Cardiology (ESC) and the American College of Cardiology (ACC). Dr Clarke is a member of Council to the Royal College of Physicians (London), an elected Councillor and Board member of the ESC, Governor of the GB, and Ireland Chapter of the ACC and European Representative at the Assembly of International Governors at the ACC. With access to such a wide and informed network, BCS is able to engage at a national, European, and global level. In 2017, Dr Clarke was delighted to establish a partnership with the Virginia Chapter of the ACC, which will afford exciting opportunities in 2018 and beyond for some shared educational activities and exchange programmes. Dr Clarke is champion of Women in Cardiology and says ‘I am proud to have been part of a small but significant piece of history linked to women in medicine, and cardiology in particular, as the first female President of the British Cardiovascular Society, coinciding with the terms of Barbara Casadei as President Elect of the European Society of Cardiology, Minnow Walsh as President of the American College of Cardiology, and Jane Dacre as President of the Royal College of Physicians of London, among others. I hope such a legacy will inspire more women to enter the specialty of cardiology going forwards and to aim high when doing so’. In 2018, Dr Clarke was awarded the ACC International Service award for enhancing cardiovascular care and education throughout the world. Conflict of interest: none declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

doi: 10.1093/eurheartj/ehy448pmid: 30202965

Sarah Clarke has been involved in the work of the Society since 2000. As Vice President for Education and Research, she became the first female Officer and Trustee of the Society in 2011. She was elected President in 2015 and has taken the Society through an ambitious modernization programme to provide a better service to members and deliver key initiatives in quality improvement, education, research, and data science. Dr Clarke trained in Cambridge, UK and at the Massachusetts General Hospital, Boston, USA. She was appointed Consultant Interventional Cardiologist at Papworth Hospital in Cambridge in 2002. Then, from 2006 to 2012, she was Clinical Director for Cardiac Services and has been Clinical Director for Strategic Development since 2012. Sarah is Clinical Lead for Cardiology for the Cambridgeshire and Peterborough Sustainable Transformation Programme (STP). In 2017, she was appointed joint National Lead for Cardiology for the Getting It Right First Time (GIRFT) programme helping to improve the quality of care within the National Health Service by reducing unwarranted variations, bringing efficiencies, and improving patient outcomes. Sarah is a member of Council at the Royal College of Physicians (London), Councillor to the Board of the European Society of Cardiology (ESC) and is Chair of the ESC e-communications committee. She is Governor of the GB and Ireland Chapter of the American College of Cardiology (ACC), European Representative on the Assembly of International Governors (ACC), Co-chair of the International Centres of Excellence Programme (ACC), and a member of the Women in Cardiology Leadership Council of the (ACC). Dr Clarke is Editor for Education in Heart, the international peer-reviewed journal and Editor of the ACC International e-Newsletter. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Nicholls, Mark

doi: 10.1093/eurheartj/ehy449pmid: 30202968

With an over-arching theme of High Performing Teams, the British Cardiovascular Society conference in Manchester 4–6 June saw an extensive programme of speakers, presentations, keynote lectures, hot-topic sessions, and awards. In high-profile presentations, Professor Pamela Douglas examined the shift towards precision testing for chest pain while Professor Martin Cowie posed the question why it takes 20 years to develop new therapies. In keeping with the conference theme, one session looked at what cardiology could learn from motorsport and Porsche, while Former Royal Air Force Tornado pilot Mandy Hickson spoke about operating in hostile environments. Precision testing for chest pain A one-size-fits-all test may no longer be the best option for assessing risk of cardiac events. Professor Pamela Douglas, who is leading a shift towards more precision testing for patients who may be at risk of a myocardial infarction or cardiovascular disease, argued the case in delivering the Thomas Lewis Lecture at the British Cardiovascular Society conference. With a focus often on high-risk patients in cardiology, she suggested in her presentation ‘Evaluating Stable Chest Pain patients: evolving evidence for precision testing’, that there is an area of growing thought that those at low risk should also be attracting the attention of cardiology. Looking at patients, with a 17% chance of cardiac event in the next 10 years, the question was what should the cardiologist do next? ‘What is the best test for stable chest pain?’ asked Professor Douglas, who is the Ursula Geller Professor of Research in Cardiovascular Diseases in the Department of Medicine at Duke University and Director of the Multimodality Imaging Program at Duke Clinical Research Institute. ‘We hypothesize for precision testing rather than one size fits all’. She reflected on the hypothesis up until 2015 a single test was best, but in the 3 years since with the SCOT-HEART and PROMISE trials delivering mixed results, the view is changing. ‘Studies in 2015 offered a mix of results but now in 2018 after 3 years of dissecting the data, we have realized it is perhaps not so simple. Many questions are being asked in a chest pain work-up’, said Professor Douglas, who is a former President of the American College of Cardiology and has been among the pioneers in a number of areas including heart disease in women, sports cardiology, and cardio-oncology. ‘Now, the “best test” is selective use of different test modalities. Different tests provide different types of information’. Following on from SCOT-HEART and PROMISE, she said: ‘We are going beyond “one test is best” and to the stage where very low risk patients might be considered for deferred testing, though we know that not testing means we may miss left main and/or 3-vessel disease (LM/3VD) and there is a for and against’. ‘In cardiology, it is always about high risk, but we wanted to know about low risk, which was about a quarter of those in the PROMISE study’. During her 30+ years of experience, she has led several landmark studies and clinical trials and is renowned for her scientific and policy work in improving the quality and appropriateness of imaging in clinical care, clinical trials, and registries. In summary, she presented evidence favouring a primary role for computed tomography angiography (CTA), that it offers: better preventive care; 29% reduction in MR (meta-analysis); both CTA and stress testing fail to predict most events and while CTA is more sensitive it is less specific; offers better triage to invasive testing; offers additional prognostic information such as non-obstructive coronary artery disease and high-risk plaque features; fewer false positive test results in women than stress testing; and improves outcomes in diabetics. ‘So, the evidence for precision testing is strong, but there are still some questions’, said Professor Douglas, who concluded by announcing the launch of the PRECISE trial, a Prospective Randomised Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularisation. Speeding up the innovation process The length of time it takes to deliver new drugs and treatments to patients was examined in detail during the keynote British Cardiovascular Society Lecture 2018. Professor Martin Cowie posed the question: ‘From evidence to implementation: does it need to take 20 years?’ He made the point that access to innovation for all, regardless of the ability to pay, was a key goal from the earliest years of the National Health Service (NHS) and that has been emphasized more recently by being enshrined within the NHS Constitution. However, the evidence suggests that it takes between 15 and 20 years for a new concept to move to full-scale implementation, and even then, there is marked variation in adoption of new medicines, diagnostics, and devices across the regions in the UK. He said the modern approach of ‘Evidence-based medicine’, with a hierarchical approach to the assessment of the quality of evidence, is a scientific-bureaucratic approach that does not lead to rapid and even implementation of innovation. Martin Cowie, who is Professor of Cardiology at the National Heart & Lung Institute at Imperial College London and Consultant Cardiologist at the Royal Brompton Hospital, London, said: ‘Many studies suggest that the value of evidence is often contested—often because the randomized trial is considered a poor representation of the “real world,” yet professionals continue to demonstrate a significant level of autonomy, and clinical knowledge is largely considered tacit and experiential’. A founding member and past-chairman of the British Society for Heart Failure, Professor Cowie quoted examples of implementation of innovation from cardiology, looking at treatment of heart failure with beta-blockers, cardiac resynchronization therapy, and the use of non-vitamin K oral anticoagulants. It is clear that although robust evidence from randomized trials is required, it is insufficient on its own to drive rapid implementation. A positive decision from the National Institute for Health and Care Excellence (NICE) is supposedly the gateway to rapid adoption in England, but it and other organizations are concerned that the ‘postcode lottery’ appears to be alive and well. The recent Accelerated Access Review has looked at the barriers to adoption of innovation and has made some far-reaching suggestions that apply to medicines, med tech and diagnostics, and digital technologies. These proposals have to be viewed in the political context of modernizing the NHS, speeding up access to true innovation, and the need to encourage the innovators, and the life-science industry, said Professor Cowie. He pointed to the vision of patients, clinicians, and charities being key drivers in the development, prioritization, evaluation, and adoption of innovation and how a new Accelerated Access Partnership, including NICE, will bring together key parts of the health system to provide a single source of national-level guidance to oversee the innovation pathway and to identify where implementation has failed. He was optimistic that innovation would remain at the heart of the NHS, and that the postcode lottery would be under constant attack, allowing clinicians and patients access to the world’s best therapies and care no matter where they lived. Key take-home messages were that innovation in cardiovascular care is often slow and patchy; that evidence-based medicine and guidelines are necessary but not sufficient to ensure rapid adoption of innovation, or disinvestment from things that do not work; and that NICE will remain central to advising the NHS on the value of innovation but is likely to increase its role in monitoring and rewarding implementation. Life in the fast lane With an over-riding theme of high performance teams, one of the conference sessions focused on what lessons cardiology can learn from motorsport and the Porsche experience. Speakers included Richard Tuthill, managing director of Tuthill Porsche, which runs rally cars in high-endurance events such as the Safari Rally; Jack Wilson, Head of Sport and Exercise Science at the Porsche Human Performance Centre at Silverstone; and Dr Harj Chaggar, who sits on the Fédération Internationale de l’Automobile (FIA), the world governing body of motorsport medical commission and is Professor of motor sport medicine. Mr Tuthill outlined the demands of working under pressure and using video footage of the 2013 Safari Rally across Tanzania and Kenya, he focused on planning an event in an extreme environment, running 17 cars across 5000 km over 18 days in 2013. ‘One of the things we can guarantee is that at some point, something is going to go wrong’, he said. ‘We advise our clients that we expect problems and will deal with those problems as they arise—we do not want small problems to become big problems’. As well as mechanical issues, there are human factors such as fatigue. ‘We average 6 h sleep per night over 3 weeks, walk 20 km per day, heart rate is high, and blood pressure probably high at times, so we work closely with our doctors and paramedics to keep everybody healthy’. He emphasized that preparation is key, as at the end of the race it can come down to the finest margins. Mr Wilson, who heads a multi-disciplinary team of doctors and therapists concentrating on strength and diet of racers from F1 drivers to 13-year-old go-karters and rally drivers, explained how to get drivers fit to meet the physical demands of elite motor sport. ‘An F1 driver is 185 cm tall, has a typical body weight of 68 kg, with 8–13% body fat and’, he said. ‘In terms of cardiovascular fitness, they will show high heart rates—a driver’s in-car average is 186 bpm and can be 220 bpm—they suffer heat stress as it can be 50°C cockpit temperature and they can lose 3 kg in body weight’. G-forces of 6.5 G occur on some 450 corners during a race so drivers need to be strong but also have excellent cognitive and psychomotor abilities with small margins for error, postural integrity, and spinal health. ‘It is not just preparation to be fit, they need strength when involved in a crash’, added Mr Wilson. Preparing a driver for 21 races over 8 months sees 20 h a week training in the closed season with activities including cycling, running, strength, flexibility, mobility and rest, along with yoga and pilates, and activities such as tennis for hand to eye co-ordination. During the season, training is 5 h a week. He said: ‘The lessons we have learned are: adhere to evidence-based practice; have a fundamental coach–athlete relationship and good communication with drivers; use outcome-based innovation; good planning and preparation; reflect desired traits of the individual; and emphasize education and promote autonomy so the driver can be as self-sustaining as possible in their training and preparation’. Dr Chaggar said it is not just about getting a driver fit to race, but ensuring they are ‘fit to crash’. ‘Human tolerance to crash survivability includes factors such as age, health, gender, and physical condition’, he said. But personal preparation, equipment (clothing/helmet), working environment (the car), accident management, and extrication (takes six people to get an F1 driver out of a car) are also critical. He said that getting the basics right—communication, a team approach, innovation, diversity, and perspective—is paramount. Quoting F1 champion Mario Andretti from 1978 when the driver said, ‘if everything is under control you’re not going fast enough’, Dr Chaggar added: ‘Motor sport medicine has a similar concept’. Aging and senescence in the cardiovascular system Researchers are unlocking the mysteries of aging on the cardiovascular system via discovering some of the secrets of cell senescence. Senescent cells can become old, can no longer divide, do not function properly, and also induce inflammation, which is critical for development of atherosclerosis. The subject was at the heart of a Basic Science session at the conference entitled ‘Aging and senescence in the cardiovascular system’. Focussing on the consequences of cell senescence in atherosclerosis, looking at a range of markers and the difficulties in using them, Professor Martin Bennett said: ‘We know that senescent cells occur in atherosclerosis, but the question is how much there is, and does it matter, i.e. are there particularly bad consequences and are there treatments that could stop detrimental effects, could we remove senescent cells or prevent them becoming pro-inflammatory’. Speaking outside of the session, he said the evidence now suggests that senescent cells are detrimental and promoting senescence results in more atherosclerosis. ‘There is also now evidence that if you prevent or remove those senescent cells then you might slow the development of atherosclerosis and promote plaque stability’, he continued. ‘The really fascinating area at present is the development of drug treatment that might be able to do that. We know there are specific drugs that are being developed to target just senescent cells, and we also know that drugs like statins work in part by preventing development of senescent cells and preventing inflammation’. The area has become particularly topical because researchers have now established what causes senescence and the pathways that lead to cell senescence. Martin Bennett, who is British Heart Foundation (BHF) Chair of Cardiovascular Sciences at the University of Cambridge, said: ‘Scientists have found that cell senescence is widespread and is associated with many diseases associated with aging, including heart disease, kidney disease, arthritis, dementia, liver disease, and with cancer, so potential for a drug that can remove these cells from all of these organs means that you might improve health span. We have also found what controls senescence and what controls inflammation induced by senescence, but the other major step forward is we have discovered how detrimental these senescent cells are in a large number of tissues’. His team at the University of Cambridge, and others across the world, are now focusing on senescence, and it has attracted attention from industry as a potential therapeutic target because of the potential for use in multiple diseases. With BHF funding to investigate the role of cell senescence on atherosclerosis and coronary artery disease, his team is progressing it in human systems and models. ‘Ultimately, we are looking for pathways that we can design treatments both to prevent and also reverse detrimental effects of cell senescence’, he said. ‘The key take-home message is that senescence is present in human atherosclerosis, it promotes development of atherosclerotic plaques and promotes features of instability. It is therefore a target for drug development, although we still have a number of major unanswered questions…but we are seeking to answer those questions’. However, he stressed that while the work has promise and potential in terms of therapeutic significance, a drug for widespread use in patients is at least a decade away. Other speakers were Dr Bennett Childs (‘Promoting cardiovascular health and extending healthy lifespan by eliminating senescent cells’), Dr Jorge Erusalimsky, Professor of Biomedical Sciences at Cardiff Metropolitan University (Vascular endothelial senescence: from mechanisms to pathophysiology), and Dr Jesus Gil, Professor of Cell Proliferation at Imperial College London (Novel regulatory mechanisms of paracrine senescence). New biomarkers for cardiovascular disease A range of new biomarkers and diagnostics for precision cardiovascular medicine were outlined by speakers from the King’s College London British Heart Foundation Centre. Presentations looked at how mass spectrometry allows clinicians to measure large numbers of proteins simultaneously, discussed a new biomarker for cardiac ischaemia that was discovered by a proteomics approach, highlighted a diagnostic structure-function atlas for titin mutations in inherited heart disease, and with first phase ejection fraction outlined a marker for left ventricular (LV) diastolic dysfunction. In his presentation ‘A multi-omics approach to cardiovascular risk in the era of precision medicine’, Professor Manuel Mayr highlighted the advantages of mass spectrometry in allowing scientists to measure a large number of proteins simultaneously and to apply the technique to longitudinal cohorts so they can associate biomarker measurements with onset of disease or disease progression. While basic measurements to evaluate cardiovascular risk have not changed that much, with mass spectrometry researchers can now measure a wide range of proteins and lipid species, he said. Prof. Mayr suggested that the time was right to take advantage of mass spectrometry profiling in clinical research and expand measurements from just monitoring total triglycerides, HDL, and LDL cholesterol to deliver better cardiometabolic phenotypes of patients. ‘Using mass spectrometry, we can simultaneously measure an unprecedented number of apolipoproteins in a single analysis rather than measuring ApoB-100 and Apo-A1 as surrogate for LDL and HDL cholesterol’, added Professor Mayr who holds the British Heart Foundation Chair of Cardiovascular Proteomics at King’s College London. In a recent study, his group demonstrated that three VLDL-associated apolipoproteins, ApoE, Apo-CII, and Apo-CIII, were associated with a higher risk of CVD and outperformed ApoB-100 in the Bruneck Study—a cohort with widespread use of statins. He discussed in detail the benefits of measuring a panel of apolipoproteins by mass spectrometry and said that the strong associations of certain triglyceride species and VLDL-associated apolipoproteins with incident CVD support the concept of targeting triglyceride-rich lipoproteins to further reduce risk of CVD in the statin era. ‘Currently, we just monitor lipid classes (total cholesterol, total triglycerides) as well as HDL and LDL cholesterol. The focus is on “quantity” rather than “molecular composition.” Targeting certain triglycerides and triglyceride-rich lipoproteins can be a future strategy to reduce residual cardiovascular risk’, he said. His research group has also set up a proteomics method to look for extracellular proteins in atherosclerotic plaques and highlighted the differences between plaques from symptomatic and asymptomatic patients. He noted the inflammatory signature identified in symptomatic carotid endarterectomy samples could be measured in plasma. The plasma signature was not associated with the early stages of atherosclerosis but was associated with progression of early atherosclerosis to advanced atherosclerosis and cardiovascular diseases. Professor Mayr concluded: ‘Inflammatory biomarkers identified by a multi-omics approach in human symptomatic atherosclerotic plaques predict progression of atherosclerosis to manifest CVD. ‘Using a tissue-based proteomics approach to identify inflammatory plaque biomarkers could reveal novel companion diagnostics for anti-inflammatory and aggressive lipid lowering therapy. With a shift in risk factors and the advance of novel treatment strategies, there may be a need to expand on the current cardiovascular biomarkers’. In other presentations, Professor Michael Marber discussed cardiac myosin binding protein C as a novel biomarker for cardiac ischaemia; Professor Matthias Gautel spoke about ‘A diagnostic structure-function atlas for titin mutations in inherited heart disease’, and Professor Philip Chowienczyk spoke on ‘First phase ejection fraction—a marker for LV diastolic dysfunction’. Record entry for young investigator award The Young Investigator Award proved more popular than ever in 2018 and attracted a record entry, with four finalists going before the judges to present their work for the coveted prize. Organized by the British Atherosclerosis Society and the British Society for Cardiovascular Research in association with the British Cardiovascular Society conference in Manchester, it saw Laurienne Edgar take first place. Currently in her final year of a BHF-sponsored cardiovascular science DPhil at the University of Oxford Cardiovascular Medicine Department, she presented a study entitled ‘Diabetes-induced innate immune memory drivers inflammation and atherosclerosis, despite restoration of normoglycaemia’. The study hypothesized that (i) hyperglycaemia alters cellular metabolism; (ii) these changes drive pro-inflammatory responses, which remain altered after glucose normalization; and (iii) these increase atherosclerosis in vivo. In conclusion, the study found: ‘Diabetes hyperglycaemia alters haematopoietic stem cell (HSC) and macrophage metabolism to induce epigenetic change, which increase their pro-inflammatory responses and drives atherosclerotic disease in vivo. PU.1, CTCP, and RUNX1 have been previously associated to chromatin priming elements. This novel demonstration of immunological memory may help to explain why targeting elevated glucose is often ineffective in reducing cardiovascular risk in diabetes’. After beating more than 30 entries to the award, Laurienne said: ‘I am completely overwhelmed and still can’t really believe I won. The fact the competition was so outstanding, and with it being a record entry year, makes it feels even more special. I am honoured and proud to have been chosen. I am really passionate about this research area, and think it represents an important unmet clinical need, so to have won this prestigious award with this research I think highlights how important it is. It personally means so much to have all the hard work you’ve put into a project recognized and I know it will help springboard me into a long and successful career in science’. She chose this line of research because she saw that with an aging population and a steep increase in obesity levels, the prevalence of those suffering with diabetes is only due to grow. ‘It means that this line of research, trying to understand reasons underlying why current therapies that lower blood glucose aren’t always reducing diabetic cardiovascular disease risk, is so important and is going to affect a lot of people,’ added Laurienne, who was keen to thank her supervisors, Professor Robin Choudhury and Dr Naveed Akbar for their support and dedication in making research possible. Now that the team is starting to understand and characterize a mechanism for hyperglycaemic memory in innate immune cells, she explained the next step in the research lies in investigating whether it can be inhibited and ultimately reversed therapeutically. The four finalists presented their work before an audience and judges and were questioned on their study before the winner was chosen and presented with the award at the British Cardiovascular Society (BCS) dinner. The three other finalists were Dr Tom Kaier from Kings College London (From bench to improved diagnosis of AMI—cardiac myosin binding protein C); Dr Ify Mordi, clinical lecturer and speciality registrar in cardiology at the University of Dundee (Repurposing the diabetes drug metformin for treatment of adverse LV remodelling in cardiovascular disease); and Claire Raphael from the NIHR Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital, London (Perfusion abnormalities in hypertrophic cardiomyopathy: mechanisms and prognostic importance). Growing role of nanomedicine in cardiovascular diagnosis Nanomedicine is set to play an increasingly important role in the future diagnosis and treatment of cardiovascular disease. The subject was explored in detail by four expert speakers and the conference heard that the technology—dealing with dimensions and tolerances of less than 100 nm especially the manipulation of individual atoms and molecules—is a critical component in increasingly more precise and detailed approaches in cardiology. Speakers tackled areas such as nanomaterials for cardiovascular repair and regeneration, magnetic nanoparticles for atherosclerosis and the development of novel magnetic resonance imaging (MRI) tools assessing atheromatous plaque inflammation and stress analysis. Professor Dave Newby focused on ‘magnetic nanoparticles in clinical cardiovascular disease’ and highlighted how MRI agents have an application to cardiovascular disease, predominantly with macrophages. ‘Macrophages are important in lots of cardiovascular diseases—plaque rupture, heart attacks, and aneurysm, for example—and resolution of injury and inflammation within that,’ said Professor Newby, who is Professor of Cardiology at the University of Edinburgh. Nanomedicine and advanced imaging to look at biology are particularly topical at the moment. ‘It is not just structure of the body’, he continued, ‘but it is also about what the tissue in the body is actually doing. Nanoparticles can tell us about where there is active inflammation and where macrophages are active. That can be useful because it helps us understand disease biology; where injury is happening, how diseases are occurring and how the body heals’. Experts are using MRI, positron emission tomography (PET), and other technologies to exploit the role of nanomedicine in this field as they assess blockages in the artery and the size of the disease. ‘What we need to know is whether the biology is dormant, is it just going to lie there and stay unchanged for the next 10 years and never cause a problem or is there a heart attack around the corner and what can we do to stop it happening?’ Professor Newby outlined work he is conducting in identifying ongoing inflammation using ultra-small superparamagnetic iron oxides (USPIOs) to identify hot areas within the aneurysm that are growing. The work showed that if the aneurysm lights up with the MR agent, it will grow bigger and there will be a need for surgery, or the likelihood of the aneurysm bursting increased. In his presentation, he also described how the heart heals after myocardial infarction and how, via iron nanoparticles, imaging can show how much inflammation there is in the heart and how this activity relates to the resolution and scarring of the heart attack. He said: ‘We do not know yet whether modifying cellular inflammation will make things better or worse, because it could go either way. If a heart does not heal well, it can burst and rupture but if it overdoes it and heals too much then you get remodelling and heart failure’. Prof. Newby said the work with nanomedicine in this area is ‘the first steps towards trying to understand how the heart is responding to the injury of the heart attack’. Other speakers were: Dr Iwona Cicha from the University Hospital Erlangen, Germany (Magnetic nanoparticles for atherosclerosis—in vitro and in vivo preclinical studies); Professor Patrick Hsieh, research fellow and affiliate attending surgeon at the Institute of Biomedical Sciences, Academia Sinica, Taiwan (Nanomaterials for cardiovascular repair and regeneration); and Professor Jonathan Gillard, Professor of Neuroradiology at the University of Cambridge (Development of novel MRI tools assessing atheromatous plaque inflammation and stress analysis). New approaches to ischaemia imaging Advances and benefits of various approaches to ischaemia imaging were outlined by leading experts in the session ‘Detection of ischaemia by cardiac imaging in 2018’. Comparisons were made between solid-state single-photon emission computed tomography (SPECT) cameras, whether spatial resolution or visual assessment was of the greater importance, if computed tomography-derived fractional flow reserve (CT-FFR) offered advantages over CT perfusion, and the challenges in defining a gold standard of imaging ischaemia. Speaking about ‘Advances in nuclear ischaemic testing, from SPECT to PET and beyond’, Dr Kshama Wechalekar, Head of Nuclear medicine and PET at the Royal Brompton Hospital in London, told delegates that advances in nuclear imaging with solid state technology offered improved ability to detect ischaemia. ‘There is improved spatial resolution from multiple solid state Cadmium Zinc Telluride (CZT) detectors and therefore sensitivity is very high,’ she said. ‘You can reduce the acquisition time at least by half with excellent quality and the equipment has a small footprint. The advantages of solid-state detector cameras is that you can reduce the radiation dose by one-third, have high sensitivity and resolution, an open design suitable for claustrophobic patients and have good image quality, even in obese patients.’ She said the recent studies have shown ability to do dynamic imaging offering potential in quantitative myocardial perfusion with SPECT. SPECT is less expensive than current PET and MRI, said Dr Wechalekar, who is President of the British Nuclear Cardiology Society (BNCS). In conclusion, she said: ‘The future of SPECT Nuclear cardiac imaging is in solid state technology. Dynamic imaging, although technically challenging, can add value to myocardial perfusion imaging (MPI) in detection of ischaemia. While PET is the most accurate imaging technique for ischaemia assessment and prognosis, it remains expensive and less accessible’. She also felt that the new tracer Flurpiridaz, with results of phase III trials in the UK pending, may change the future of PET MPI. One area of concern was how to persuade more people to train in nuclear cardiology and she said the BNCS Council is working hard to address this. Dr Chiara Bucciarelli-Ducci, Consultant Senior Lecturer in Cardiology/non-Invasive Imaging Bristol Heart Institute, University of Bristol, explored the issue of quantitative vs. visual assessment in cardiac magnetic resonance (CMR) stress perfusion. She explained that stress CMR is now included in the ESC guidelines, based on evidence using visual assessment of ischaemia, rather than quantitative and discussed pros and cons of both visual and quantitative assessment, limitations and opportunities of increasing spatial resolution, and very recent studies showing that there is no difference in diagnostic accuracy visual vs quantitative. Dr Bucciarelli-Ducci concluded: ‘CMR perfusion (visual) is a good clinical tool already but can get better while quantitative CMR perfusion is evolving into faster and robust tools. While several methods are available, more in vivo and clinical validation is needed with a number of studies in the pipeline.’ Dr Marc Dweck, BHF Reader in Cardiology and Consultant Cardiologist at the University of Edinburgh and the Edinburgh Heart Centre, posed the question ‘CT-FFR/CT perfusion—neither or both?’ In conclusion, he outlined how CT is a powerful imaging technique that informs about coronary artery anatomy (plaque burden, stenosis severity, plaque characteristics) but emphasized that the addition of functional technique to the scan protocol can improve its specificity for identifying obstructive stenosis providing a comprehensive assessment of anatomy and function. With CT perfusion, there is increased radiation dose, while CT-FFR has increased cost, though CT-FFR potentially fitted in better with patient work flows. Professor Darrel Francis, Professor of Cardiology, Imperial College London, discussed the problems of computed tomography with a presentation called ‘Ischaemia detection—are all our ideas completely wrong?’ Women in Cardiology A key conference session brought together five high-profile women to discuss gender imbalances and pay gaps in the world of cardiology. Under the heading ‘Women in cardiology: The successful team—challenging stereotypes and supporting colleagues’, the session raised issues affecting women in the profession. Dr Sarah Clarke, in her last presentation before her 3-year tenure as BCS President ended, made the point that in cardiology women are ‘under-represented, underestimated, and undervalued’, noting that 57% of doctors in training are female but only 13% of cardiology consultants are women. ‘With women in the profession paid 18% less than men, she looked at discrimination, a perception that women will leave to have a family, sexual bias, sexual harassment, and too few role models. She outlined ‘how to successfully navigate a career in cardiology’ with advice to women to ‘set yourself apart, commit to a specialty, identify support, share a vision, find a good mentor, present research at meetings, and always finish what you start’. The session heard that one of the problems was that cardiology is still traditionally seen as a male-dominated specialty. Consultant cardiothoracic surgeon Professor Farah Bhatti, who is chair of the Women in Surgery Forum at the Royal College of Surgeons to encourage, enable, and inspire women to fulfil their surgical potential, said work is under way to establish why only 12% of consultant surgeons in the UK are women. In her presentation, Challenging stereotypes #LookLikeASurgeon, she said there are also myths such as ‘that you cannot be a surgeon if you are pregnant, have a family and want a work-life balance.’ Professor Catherine Otto, editor of BCS journal Heart, spoke on how to succeed as a woman physician scientist and issues in the USA of pay gaps and the difficulty of women getting in key positions. Her advice was that to succeed in cardiology, women need to be an expert, have a favoured area of interest, and contribute to research, teaching, and clinical activities. ACC Past-President, Dr Mary Norine Walsh pointed to low levels of women in cardiology in the USA (13% compared to 37% in internal medicine) and how other sub-specialties are rising but cardiology is not. With a significant pay gap in the USA, she said the ACC had formed a task force on diversity to look at the key issues. The final speaker, Royal College of Physicians President Professor Jane Dacre, said prejudice and a pay gap remained an issue and her society was undertaking qualitative studies to ‘get underneath the data. ‘She noted there were eight female royal college presidents but made the point that while women find themselves in leading ‘elected’ roles, the numbers in key ‘appointed’ roles remain low. Hypertension: key concepts for practising cardiologists The issue of diet and exercise in tackling blood pressure was debated during a session exploring key concepts for practising cardiologists on hypertension. Consultant cardiologist and past-president of the British and Irish Hypertension Society Professor Adrian Brady expressed concern that most people simply pay lip service to diet and exercise without looking at the detail. He is also an advocate of moving away from the term hypertension and concentrating on the phrase high blood pressure—‘because everybody knows what high blood pressure means’. Avoiding added salt with food and losing weight, he said, remain the critical elements in affecting blood pressure. ‘How weight loss affects blood pressure has been well shown in surveys carried out among American nurses about 15 years ago,’ said Professor Brady. ‘Every kilogram you lose, you lose about 1–1.5 mm mercury per kilogram. Losing 10 kg, which is manageable for many people, is 15 mm. That is two drugs—and is a fantastic health message, much safer than any drug. ‘Exercise is good so long as you do not drop dead when you are doing it. It is about exercising to about 80% of maximum, and if you can still talk, your heart rate is about right. If you cannot talk you are overdoing it’. He cited the success of his project in Scotland, aimed at encouraging men aged 35–65 to exercise and diet and how that was bolstered by linking it to the country’s major football teams. ‘It was an obvious thing to do’, he said. ‘If you attach a health programme to a football club, you have a sustained benefit, as people are passionate for that club’. Professor Brady said the take-home message from his session was that people with high blood pressure should restrict salt intake and promote weight loss. Professor Brady is a clinical cardiologist at Glasgow Royal Infirmary, past-Chairman of the Guidelines Committee of the British Cardiovascular Society and has represented the UK on the ESC Guidelines Development Group. His current research is in diet and exercise in blood pressure and non-invasive measurement of blood pressure. The BCS session also heard from Professor Neal Uren, Professor of Interventional Cardiology at the Edinburgh Heart Centre (Interventional therapy for high blood pressure) and Dr Nigel Beckett (Too high or too low?—Blood pressure in older people). Conflict of interest: none declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Bjornsson, Thorsteinn; Thorolfsdottir, Rosa B; Sveinbjornsson, Gardar; Sulem, Patrick; Norddahl, Gudmundur L; Helgadottir, Anna; Gretarsdottir, Solveig; Magnusdottir, Audur; Danielsen, Ragnar; Sigurdsson, Emil L; Adalsteinsdottir, Berglind; Gunnarsson, Sverrir I; Jonsdottir, Ingileif; Arnar, David O; Helgason, Hrodmar; Gudbjartsson, Tomas; Gudbjartsson, Daniel F; Thorsteinsdottir, Unnur;

Stiller, Barbara; Schunkert, Heribert

doi: 10.1093/eurheartj/ehy230pmid: 29697798

Abstract View largeDownload slide View largeDownload slide This editorial refers to ‘A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta’†, by T. Bjornsson et al., on page 3243. Recent breakthroughs in genomic research have clarified that genetic and environmental factors jointly contribute to the aetiology of many cardiovascular diseases. The identification of genes or, even better, genetically driven disease mechanisms involved in this process are crucial steps for improving risk prediction and developing better treatments. In monogenic disorders, the identification of genetic factors was boosted by next-generation sequencing (NGS), specifically if large affected families were available for co-segregation analyses. For common diseases, which are believed to result from multiple variants with small but additive effects, genome-wide association studies (GWAS) led to numerous discoveries. As an example, more than 250 susceptibility loci and causal mutations have been identified for coronary artery disease within the last 10 years, yielding astonishing insights into the disease mechanisms.1–3 The blind spot in all these efforts are less common or even rare diseases without classical Mendelian inheritance. On the one hand, their sporadic occurrence precludes co-segregation analyses; on the other hand, the number of cases is often too small for conventional GWAS analyses, which need large sample sizes in order to account for statistical punishment for multiple testing. Congenital heart diseases (CHDs) are a good example of such challenges. Although their genetic underpinnings are well documented,4 the low prevalence, phenotypic diversity, and usually mild penetrance has hampered the successful identification of underlying mutations for CHD.5,6 Bjornsson and co-workers from deCODE genetics have now merged the advantages of NGS and GWAS into a single big experiment and have successfully discovered a variant that is responsible for one out of five cases of coarctation of the aorta (CoA).7 They studied the entire Icelandic population, which has a very special standing in the field of genetics. First, this is because it is a ‘founder population’, which means that is goes back in history to a rather small number of ancestors. On the one hand, the smaller gene pool reduces genetic variation, while on the other hand, otherwise rare variants may be found more frequently. The founders of the Icelandic population were predominantly settlers of Norwegian origin.8 Second, the Icelandic healthcare system allows for an extensive collection of medical records and the merging of these in the deCODE genetics database. The third important aspect is the Íslendingabók, the book of Icelanders, which offers comprehensive genealogical information on the Icelandic population. This treasure, dating back to the founders of the population in the 9th century, has made the tremendous efforts on sequencing, genotyping and analysing the genetic codes of almost the entire Icelandic population worthwhile. Initially, Bjornsson and co-workers sequenced 15 220 individuals with NGS in order to detect and localize the vast spectrum of genetic variants, rare and common, in the population. Next, they genotyped 151 677 individuals with a GWAS array in order to link all mutations in the genome to a single nucleotide polymorphism (SNP) or haplotype. Thereby, the scientists submerged the entire information of the costly sequencing experiment (1500€ per individual plus enormous storage costs) into the more affordable information obtained with a GWAS array (25€ per individual). Long-range phasing of the chip-genotyped individuals and imputation from variants identified by NGS, including SNPs as well as insertions and deletions, led to the identification and annotation of 32.5 million sequence variants. By using a subtle approach to impute these variants into first- and second-degree relatives using genealogic information from the Book of Icelanders,9 the authors further increased the cohort by more than 200% for cases (to 120) and by over 150% for controls (to 355 166) without the need to obtain DNA from these individuals. Thus, by genealogical workup and genotyping, the authors extrapolated their sequencing data into the entire Icelandic population (Take home figure). Their sophisticated study design allows the analysis of variants with a frequency of 2 in 10 000 for association with disease. One of these rare variants ultimately appeared to cause one out of five non-syndromic cases of CoA. Take home figure View largeDownload slide Study design of the genome-wide association study that Bjornsson and co-workers performed on coarctation of the aorta. The study was performed on 32.5 million variants obtained by whole-genome sequencing and imputed into chip-typed and long-range phased individuals, along with their first- and second-degree relatives. With a cohort of 120 coarctation of the aorta cases and 355 166 controls, Bjornsson and co-workers successfully discovered a variant that is responsible for one out of five cases of coarctation of the aorta (the Manhattan plot is taken from the original publication by Bjornsson and co-workers). CoA, coarctation of the aorta; GWAS, genome-wide association study; OR, odds ratio; WGS, whole-genome sequencing; WT, wild-type. Take home figure View largeDownload slide Study design of the genome-wide association study that Bjornsson and co-workers performed on coarctation of the aorta. The study was performed on 32.5 million variants obtained by whole-genome sequencing and imputed into chip-typed and long-range phased individuals, along with their first- and second-degree relatives. With a cohort of 120 coarctation of the aorta cases and 355 166 controls, Bjornsson and co-workers successfully discovered a variant that is responsible for one out of five cases of coarctation of the aorta (the Manhattan plot is taken from the original publication by Bjornsson and co-workers). CoA, coarctation of the aorta; GWAS, genome-wide association study; OR, odds ratio; WGS, whole-genome sequencing; WT, wild-type. Among the different CHD subtypes, CoA represents 1 in 2500 live births,10 or about 4% of all cases. Together with aortic valve stenosis and hypoplastic left heart, CoA constitutes a mechanistically defined subgroup of congenital heart defects, the left-ventricular outflow tract obstruction malformations, for which there is substantial evidence of a genetic component.11 However, despite some reports on familial clustering,12 Mendelian inheritance is rarely observed such that our understanding of the precise causes of non-syndromic CoA remains rather patchy. Using the unique wealth of the genetic data acquired for the Icelandic population, Bjornsson and co-workers have now found a genome-wide significant association signal with CoA on chromosome 14q11. The top SNP of the association finding was located in exon 18 of the coding region of the MYH6 gene, leading to an amino acid change on position 721 from arginine to tryptophan. The variant occurs with an allele frequency of 0.34% in the Icelandic population and associates with CoA with an odds ratio of 44 (!). Indeed, the MYH6 p.Arg721Trp variant was prevalent in 20% of all Icelandic CoA cases. Whether it plays a similar role outside of the island remains unclear, a disadvantage when a founder population is being analysed. In fact, it is barely present in other genetic variation databases compiling publicly available sequencing data. The MYH6 gene codes for the alpha heavy chain subunit of cardiac myosin and the p.Arg721Trp variant is located in the highly conserved myosin motor domain.13 Cardiac myosin is the major component of the sarcomere, which facilitates cardiac muscle contraction. Based on computational predictions, the amino acid change might alter the protein’s function. However, it appears that the gene is not expressed in the aorta. Thus, one can only speculate on the mechanism by which this variant could induce CoA. Indeed, if the prediction holds true and if there is a gain or a loss of function of the protein, the mechanism that links this variant to CoA needs solid experimental analysis. In vitro experiments thus far have shown that overexpression of the p.Arg721Trp variant in neonatal rat ventricular cardiomyocytes leads to the disruption of sarcomere integrity.14 However, since Bjornsson and colleagues identified the p.Arg721Trp variant not only in CoA cases but also in healthy subjects, it seems that the p.Arg721Trp variant is not sufficient to induce CoA by itself and that other factors may contribute as well. This suggests that other variants or the conjunction of exogenous factors facilitate the actual disease risk in an affected individual.15 Besides the novel association with CoA, the p.Arg721Trp MYH6 variant has been previously associated with sick sinus syndrome in the Icelandic population.16 In their current work, Bjornsson and colleagues further enlarged the search for association with other phenotypes (phenome screen). Indeed, they found associations of the MYH6 p.Arg721Trp variant with other CHDs as well. Perhaps more importantly, the mutation was also associated with heart failure and ischaemic stroke, i.e. common diseases, pointing to high variability in the phenotypic outcome of the p.Arg721Trp mutation. A final word of caution comes back to the issue of studying a founder population. In such analysis, the subjects sharing the MYH6 variant may also share larger chunks of DNA at this specific locus. Here, other mutations may be hidden that could indeed be the causative ones. In this respect, it is reassuring that other MYH6 mutations were found in a few familial cases as well as sporadic cases of CHDs, also presenting with CoA, e.g. 4 out of 10 family members suffering from atrial septal defect and carrying a p.Ala290Pro MYH6 mutation also had CoA.17 P.Arg443Pro was also found in a family presenting with hypoplastic left heart syndrome, in which one of the four affected also showed CoA.18 A non-syndromic patient with a double outlet right ventricle, mitral atresia, and CoA carried a p.Glu98Lys variant of this gene.19 However, (further) replication and, even more importantly, the elucidation of the precise mechanism needs to be awaited before the books on MYH6 p.Arg721Trp and CoA can be closed. Despite this caveat, the paper of Bjornsson and colleagues displays an elegant approach to associating a rare variant in an isolated population to a complex disease, opening up new opportunities to study the underlying mechanism, improve risk prediction, and facilitate the development of novel therapies and interventions. Acknowledgement We would like to thank Dr Cornelia Pankalla for providing the volume rendering technique reconstruction of the computed tomography scan of the aortic CoA. Conflict of interest: none declared. Footnotes The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehy142. 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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Gentille Lorente, Delicia Inés

doi: 10.1093/eurheartj/ehy184pmid: 29617767

A previously healthy 50-year-old woman was explored because of heart murmur. An echocardiography evidenced the existence of a dilated left atrium, moderate mitral regurgitation (Panel A), normal pulmonary and central venous pressure, and the incidental finding of a significant dilatation of the pulmonary veins. Cardiac magnetic resonance imaging (MRI) ruled out the existence of congenital heart disease or an intracardiac shunt, and confirmed, just like the CT, the existence of pulmonary varicose veins (PVV): upper right 37 mm, lower right 29 mm, upper left 32 mm, and lower left 30 mm (Panels B and C). An abdominal MRI revealed the existence of a normal inferior cava vein and a double intra-abdominal venous shunt (one extrahepatic, porto-azygos-hemiazygos, and the other between left renal vein and azygos-hemiazygos territory). Cardiopulmonary catheterization was normal, and an underlying hepatopathy was ruled out after performing specific blood tests, fibrogastroscopy, fibroscan, abdominal ultrasound, suprahepatic catheterization, and brain MRI. Finally, the patient was diagnosed with multiple congenital venous malformations, and a periodic follow-up was indicated. Pulmonary varicose vein is a rare vascular abnormality characterized by a focal dilation of the vessel that exceeds 50% of its normal size (9–13 mm) and does not have an arterial connection. It can be either congenital (usually associated with hereditary haemorrhagic telangiectasia) or acquired. Patients are mostly asymptomatic, and PVV often is detected incidentally as a pulmonary mass on radiological imaging test or, exceptionally, on an echocardiography; however, haemoptysis caused by its rupture or a thrombo-embolic disease have been reported. This is the first reported case of congenital varices of the four pulmonary veins and, additionally, with an associated double intra-abdominal venous shunt. View largeDownload slide View largeDownload slide Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Lüscher, Thomas F

doi: 10.1093/eurheartj/ehy574pmid: 30202969

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Although overall complications of pregnancy have declined impressively both for the mother and the child over the last century, it remains a problem for females with congenital heart, myocardial,1 valvular,2 and aortic disease. While some conditions may be known beforehand and a pregnancy can be planned after careful evaluation and management, others are only detected during pregnancy, particularly in countries with less-developed healthcare systems. In addition, some cardiac conditions such as hypertension, gestosis, coronary dissection,3 and cardiomyopathy4 may develop during pregnancy. All these diverse clinical scenarios are carefully discussed in the ‘2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy’.5 Although many aspects of these issues are not evidence-based, a few recommendations are based on randomized clinical trials, while most refer to the increasing clinical experience in the management of cardiovascular patients during pregnancy. Aortic disease is a rare but important congenital condition, as discussed in the 2014 ESC Guidelines.6 Besides Marfan syndrome7,8 and Ehlers–Danlos disease among others,9 coarctation of the aorta is also a relevant heritable aortic condition.10 Indeed, coarctation accounts for 4–8% of congenital heart defects and confers substantial morbidity despite current treatment options. In their article ‘A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta’, Hilma Holm and colleagues from deCODE Genetics Inc. in Reykjavik, Iceland11 searched a genome-wide association study involving 120 cases and 355 166 controls for sequence variants affecting the risk of coarctation. They found an association with a rare (frequency of 0.34%) missense mutation, p.Arg721Trp, in Myosin Heavy Chain 6 (MYH6) with an odds ratio of 44.2, encoding for the α-heavy chain subunit of cardiac myosin, an essential sarcomere protein. In Iceland, 20% of individuals with coarctation carry this mutation. p.Arg721Trp also associates with a bicuspid aortic valve, sick sinus syndrome, and atrial fibrillation (Figure 1). The relevance of this finding is put into perspective in an Editorial by Barbara Stiller and Heribert Schunkert from the Deutsches Herzzentrum München in Germany.12 Figure 1 View largeDownload slide Region plot for the association of variants on 14q11 with coarctation of the aorta. Shown is a 1 Mb region on chromosome 14. The strongest association is with the missense variant p.Arg721Trp in MYH6 located at position 23 396 970 on chromosome 14 (chr14: 23 396 970). The nine other variants shown are weakly correlated with p.Arg721Trp, r2 between 0.6–0.4 (green) and 0.4–0.2 (light blue) (from Bjornsson T, Thorolfsdottir RB, Sveinbjornsson G, Sulem P, Norddahl GL, Helgadottir A, Gretarsdottir S, Magnusdottir A, Danielsen R, Sigurdsson EL, Adalsteinsdottir B, Gunnarsson SI, Jonsdottir I, Arnar DO, Helgason H, Gudbjartsson T, Gudbjartsson DF, Thorsteinsdottir U, Holm H, Stefansson K. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. See pages 3243–3249). Figure 1 View largeDownload slide Region plot for the association of variants on 14q11 with coarctation of the aorta. Shown is a 1 Mb region on chromosome 14. The strongest association is with the missense variant p.Arg721Trp in MYH6 located at position 23 396 970 on chromosome 14 (chr14: 23 396 970). The nine other variants shown are weakly correlated with p.Arg721Trp, r2 between 0.6–0.4 (green) and 0.4–0.2 (light blue) (from Bjornsson T, Thorolfsdottir RB, Sveinbjornsson G, Sulem P, Norddahl GL, Helgadottir A, Gretarsdottir S, Magnusdottir A, Danielsen R, Sigurdsson EL, Adalsteinsdottir B, Gunnarsson SI, Jonsdottir I, Arnar DO, Helgason H, Gudbjartsson T, Gudbjartsson DF, Thorsteinsdottir U, Holm H, Stefansson K. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. See pages 3243–3249). Congenital heart disease has a wide spectrum of malformations, even within the same disease entity, and more biomarkers for risk assessment are in need. Of note, despite the well-known association of high-sensitivity C-reactive protein or hsCRP with cardiovascular outcomes in healthy adults13 and those with heart disease,14,15 the relevance of this inflammatory marker in adults with congenital heart disease remains unclear. In their article ‘Prospective cohort study of C-reactive protein as a predictor of clinical events in adults with congenital heart disease: results of the Boston adult congenital heart disease biobank’, Alexander Opotowsky and colleagues from the Boston Children's and Brigham and Women's Hospitals in Boston, Massachusetts in the US examined the clinical correlates and prognostic value of hsCRP in a prospective cohort study of 707 adults with congenital heart disease.16 Higher hsCRP was strongly associated with measures of functional status including New York Heart Association (NYHA) class and peak VO2, as well as with comorbidities such as atrial arrhythmias. During a follow-up of almost 3 years, 16% experienced the primary outcome, including 29 deaths. An hsCRP ≥ 2.98 mg/L compared with the lower three quartiles conferred increased risk for the primary outcome, with 30.5 vs. 11.3% and an adjusted hazard ratio of 2.00, and all-cause mortality 11.9 vs. 1.5%, (hazard ratio 4.23; Figure 2). In addition, elevated hsCRP was associated with adverse outcomes across subgroups. Thus, in adults with congenital heart disease, elevated hsCRP is not only associated with worse functional status and exercise capacity, but also greater risk for death or non-elective cardiovascular hospitalization. Figure 2 View largeDownload slide About a quarter of adults with congenital heart disease have a circulating C-reactive protein concentration above 3 mg/L. Those patients with elevated C-reactive protein are at increased risk of adverse clinical outcomes including all-cause mortality and non-elective cardiovascular hospitalization (from Opotowsky AR, Valente AM, Alshawabkeh L, Cheng S, Bradley A, Rimm EB, Landzberg MJ. Prospective cohort study of C-reactive protein as a predictor of clinical events in adults with congenital heart disease: results of the Boston adult congenital heart disease biobank. See pages 3253–3261). Figure 2 View largeDownload slide About a quarter of adults with congenital heart disease have a circulating C-reactive protein concentration above 3 mg/L. Those patients with elevated C-reactive protein are at increased risk of adverse clinical outcomes including all-cause mortality and non-elective cardiovascular hospitalization (from Opotowsky AR, Valente AM, Alshawabkeh L, Cheng S, Bradley A, Rimm EB, Landzberg MJ. Prospective cohort study of C-reactive protein as a predictor of clinical events in adults with congenital heart disease: results of the Boston adult congenital heart disease biobank. See pages 3253–3261). The editors hope that this issue of the European Heart Journal will find the interest of its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article. References 1 Goland S , van Hagen IM , Elbaz-Greener G , Elkayam U , Shotan A , Merz WM , Enar SC , Gaisin IR , Pieper PG , Johnson MR , Hall R , Blatt A , Roos-Hesselink JW. Pregnancy in women with hypertrophic cardiomyopathy: data from the European Society of Cardiology initiated Registry of Pregnancy and Cardiac disease (ROPAC ). Eur Heart J 2017 ; 38 : 2683 – 2690 . Google Scholar Crossref Search ADS PubMed 2 D'Souza R , Ostro J , Shah PS , Silversides CK , Malinowski A , Murphy KE , Sermer M , Shehata N. Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis . Eur Heart J 2017 ; 38 : 1509 – 1516 . Google Scholar Crossref Search ADS PubMed 3 Regitz-Zagrosek V , Jaguszewska K , Preis K. Pregnancy-related spontaneous coronary artery dissection . Eur Heart J 2015 ; 36 : 2273 – 2274 . 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Fifty generations of Icelanders help to explain a cause of aortic coarctation . Eur Heart J 2018 ; 39 : 3250 – 3252 . 13 Cai Y , Hansell AL , Blangiardo M , Burton PR , de Hoogh K , Doiron D , Fortier I , Gulliver J , Hveem K , Mbatchou S , Morley DW , Stolk RP , Zijlema WL , Elliott P , Hodgson S. Long-term exposure to road traffic noise, ambient air pollution, and cardiovascular risk factors in the HUNT and lifelines cohorts . Eur Heart J 2017 ; 38 : 2290 – 2296 . Google Scholar Crossref Search ADS PubMed 14 Ridker PM , Luscher TF. Anti-inflammatory therapies for cardiovascular disease . Eur Heart J 2014 ; 35 : 1782 – 1791 . Google Scholar Crossref Search ADS PubMed 15 Ridker PM. Canakinumab for residual inflammatory risk . Eur Heart J 2017 ; 38 : 3545 – 3548 . Google Scholar Crossref Search ADS PubMed 16 Opotowsky AR , Valente AM , Alshawabkeh L , Cheng S , Bradley A , Rimm EB , Landzberg MJ. Prospective cohort study of C-reactive protein as a predictor of clinical events in adults with congenital heart disease: results of the Boston adult congenital heart disease biobank . Eur Heart J 2018 ; 39 : 3253 – 3261 . Google Scholar Crossref Search ADS Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Opotowsky, Alexander R; Valente, Anne Marie; Alshawabkeh, Laith; Cheng, Susan; Bradley, Allison; Rimm, Eric B; Landzberg, Michael J

doi: 10.1093/eurheartj/ehy362pmid: 30010900

AimsDespite the well-defined association of high-sensitivity hsCRP with cardiovascular outcomes in apparently healthy adults and those with acquired heart disease, the relevance of this inflammatory marker in adults with congenital heart disease (ACHD) remains unclear. We aimed to examine the clinical correlates and prognostic value of high-sensitivity C-reactive protein levels in ACHD.Methods and resultsWe conducted a prospective cohort study of (n = 707) outpatient ACHD (age 39 ± 14 years, 49% women), enrolled mainly at a referral centre, who had serum hsCRP measured in conjunction with a clinical assessment between 2012 and 2016. We analysed clinical correlates of hsCRP and its association with adverse events including the primary combined outcome of all-cause mortality or non-elective cardiovascular hospitalization. Higher hsCRP was strongly associated with measures of functional status including New York Heart Association class and peak V̇O2, and with comorbidities such as atrial arrhythmia. During average follow-up of 815 ± 536 days, 114 patients (16%) experienced the primary outcome, including 29 deaths. Having elevated hsCRP, in the highest (≥2.98 mg/L) compared with the lower three quartiles, conferred increased risk for the primary outcome [30.5% vs. 11.3%, adjusted hazard ratio (HR) = 2.00, 95% confidence interval (CI) 1.35–2.97; P = 0.0006] and all-cause mortality (11.9% vs. 1.5%, adjusted HR = 4.23, 95% CI 1.87–9.59; P = 0.0006). Elevated hsCRP was associated with adverse outcomes across ACHD subgroups and other patient characteristics.ConclusionAdults with congenital heart disease with elevated hsCRP have not only worse functional status and exercise capacity, but also greater risk for death or non-elective cardiovascular hospitalization. Further study is warranted to characterize the role of inflammation in the pathophysiology of ACHD.

Svensson, Lars G; Donley, Brian; Falcone, Tomosso

doi: 10.1093/eurheartj/ehy450pmid: 30202967

The US healthcare system plans to engage local UK physicians in its unique care model  Cleveland Clinic’s distinctive group practice model has been a key reason for its emergence as one of the world’s leading providers of specialized healthcare. Now the US-based integrated healthcare system is preparing to bring that model of care to a new setting—the heart of London. The plan is to work with local specialist physicians and general practitioners (GPs) to enable them to care for patients in state-of-the-art private healthcare facilities using Cleveland Clinic’s team-based, physician-led care philosophy and infrastructure. The facilities—known collectively as Cleveland Clinic London—include an outpatient medical facility to open in 2020 and a 21st-century inpatient hospital to open in early 2021. The 200-bed hospital, at 33 Grosvenor Place near Buckingham Palace, will specialize in cardiovascular disease, digestive disease, neuroscience, and orthopaedics. Care in more than a dozen other subspecialties will also be offered at the nearby outpatient space. The 330 000-square-foot hospital is being converted from an existing building, with its entire six-floor interior being rebuilt and reimagined for patient care in the decades ahead. The result will be one of the most digitally sophisticated private hospitals in the UK, with advanced-tech capabilities in virtual health and remote monitoring, alongside abundant minimally invasive procedural equipment. Cardiovascular care will be a particular focus of Cleveland Clinic London, in view of Cleveland Clinic’s long-standing reputation for leadership in the specialty, having been ranked by U.S. News & World Report as the nation’s No. 1 heart centre for more than two decades. That leadership is reflected by the latest Adult Cardiac Surgery quality ratings from the Society of Thoracic Surgeons, in which Cleveland Clinic is one of only two US programs to achieve the maximum three-star rating in all five operative categories assessed. Comprehensive services will be provided at Cleveland Clinic London for patients with heart, vascular, and thoracic conditions, including: Cardiac and thoracic surgery Interventional and diagnostic cardiology Electrophysiology Cardiac imaging Vascular surgery The hospital will include a dedicated cardiac surgery operating theatre, a hybrid theatre, a biplane catheterization lab, and a single-plane catheterization/electrophysiology lab. Advanced cardiac imaging, including CT and MRI, will be available in both the inpatient and outpatient locations. Cardiovascular patients will benefit from the hospital’s 30 intensive care beds, which will make it one of the largest private intensive therapy units in London. An interdisciplinary Heart Team approach—including GPs, when involved—will be brought to bear for all appropriate cardiovascular patients, especially in cases where percutaneous therapies are an option. The launch of this new Cleveland Clinic location is being undertaken with full recognition of the highly advanced cardiovascular healthcare system that already exists in London and the differences in healthcare culture between the USA and UK. This initiative is driven to provide high-quality outcomes and exceptional patient experience that characterize Cleveland Clinic’s philosophy of Patients First. Much of that can be achieved by reliance on the local medical and surgical community, especially in view of the UK’s rich tradition of pioneering cardiovascular care. Local surgeons and other specialists will be engaged to learn the Cleveland Clinic culture and work with the Cleveland Clinic London team to provide high-quality, collaborative care to patients in the new facilities. The roles to be filled by current Cleveland Clinic employees will be largely administrative, with most patient care being provided by clinicians with London roots who know the community. For instance, Olaf Wendler, MD, PhD, FRCS, Professor of Cardiac Surgery at King’s College London, has been enlisted to lead Cleveland Clinic London’s Heart & Vascular Institute. In addition to the promise of swifter access to care, Cleveland Clinic London offers other likely benefits: More convenient access to specialist care for Cleveland Clinic’s existing patients in the UK and Europe. Greater two-way sharing of technology and clinical best practices across borders, particularly as virtual healthcare capabilities advance. Opportunities for educational collaboration, with plans to welcome British registrars to Cleveland Ohio, USA to share their expertise and then return to London to disseminate their observations from Cleveland. The initiative also promises broader ripple effects by representing a fresh approach to the UK’s private healthcare landscape as Cleveland Clinic adapts its group practice model to a new setting. That model—in which physicians are salaried and work in collaborative care teams to devise the best management course for patients without the distraction of financial incentives—is a template that Cleveland Clinic is increasingly spreading across the globe. The dissemination began in the USA, first with regional hospitals around Cleveland in the state of Ohio, and then with Cleveland Clinic sites in Florida and Las Vegas, NV, USA. International expansion followed with the 2006 opening of Cleveland Clinic Canada, offering both publicly funded and private services in an outpatient setting in Toronto. Then came Cleveland Clinic Abu Dhabi in 2015, extending the health system’s reach to the Middle East. This 364-bed specialty hospital has since become a regional centre of medical innovation and education, forming partnerships with major academic and research institutions in the United Arab Emirates and performing the region’s first full heart transplant, first leadless pacemaker implant and first ablation procedure with zero fluoroscopy exposure. Cleveland Clinic London will join these diverse locations in a shared mission of innovative, research-based, physician-led care that is delivered efficiently and puts patients at the centre. It will also partake in the locations’ shared health information technology and evidence-based protocols. Success in London will demand world-class quality of care, exquisite attention to patient experience, the finest clinicians—and wisdom gained through experience. One such bit of wisdom is recognizing the need to pace oneself. Accordingly, Cleveland Clinic London’s Heart & Vascular Institute will start by focusing on more standard procedures and operations with local specialists before offering less common procedures, such as aortic root surgery, lung transplantation and robotically assisted mitral valve or thoracic surgery. Doing so will allow for training and development of comfort and cultural connection between local specialists and the Cleveland Clinic London team before the biggest challenges are undertaken. And given that Cleveland Clinic has signed a 123-year lease on the London hospital building at 33 Grosvenor Place, there should be plenty of time for expanding the procedural mix. Lars G. Svensson MD PhD Chairman Cleveland Clinic Heart & Vascular Institute Cleveland, Ohio, USA [email protected] Brian Donley, MD Chief Executive Officer Cleveland Clinic London Tomosso Falcone, MD Chief of Staff Chief Academic Officer Cleveland Clinic London Conflict of interest: L.G.S. is chairman of Cleveland Clinic Heart & Vascular Institute (Cleveland, OH, USA). B.D. is Chief Executive Officer, Cleveland Clinic London. T.F. is Chief of Staff, Chief Academic Officer, Cleveland Clinic London. Cardio Pulse contact: Andros Tofield, Managing Editor. Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)