CRY Research Highlights 2020

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Registered Charity No. 1050845

Research Highlights 2020 Inside this issue. . .

P2 Conferences and Webinars P6 Interviews P11 Papers/Articles P13 CRY’s Research Programme

Offering help and support to affected families @CRY_UK CardiacRiskintheYoung www.c-r-y.org.uk


Conferences & Webinars

CRY’s online International Medical Conference

Similarly to the rest of CRY’s events and fundraising during 2020 due to the COVID-19 pandemic, the CRY Conference had to move online, with presentations being broadcast live through the day. For the first time, on October 16, our annual conference was a virtual event, which offered delegates the opportunity to sign up to watch talks from some of the world’s leading experts in sports cardiology and young sudden cardiac death. While this was rather different from our typical annual conference in London, we still had a fantastic day of talks, with those watching getting involved during presentations by taking part in polls and answering questions, too. As always, we were pleased to share the insight and research of many leading experts, including some of CRY’s present and past Research Fellows. CRY Consultant Cardiologist Professor Sanjay Sharma began the day with his presentation, “Athlete’s heart or dilated cardiomyopathy; The role of exercise imaging”. Professor Sharma discussed methods of differentiating physiological increases in heart size from dilated cardiomyopathy (DCM).

As he pointed out to begin his talk, there is a lot of data about how this is done when dealing with hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, but there is little data covering DCM. Professor Sharma looked at this topic in extensive detail, and discussed the value of using stress echocardiography due to

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Research Highlights 2020

its better diagnostic ability. Professor Thijs Eijsvogels from Nijmegen, Netherlands, who is an associate professor at the Radboud University medical centre, gave the second presentation of the day. Professor Eijsvogels looked closely at troponin release following endurance exercise in athletes and what it means. He discussed how exercise-induced increases in troponin are very common following endurance exercise even though the degree of increase can vary significantly depending on the individual, as well as some findings that require more research. Next, former CRY Research Fellow Dr Aneil Malhotra talked about the challenges of screening in athletes, focusing on the black athlete’s heart. As Dr Malhotra noted at the beginning of his presentation, T-Wave inversion affects one in 30 young athletes and is six times more common in black athletes. T-Wave inversion is present in cardiomyopathy, which increases the risk of exercise-induced sudden cardiac death threefold.

Furthermore, as CRY research has shown, young sudden cardiac deaths are six times more common in young black footballers. This disparity is a problem, and Dr Malhotra went on to look at other conditions and research, as well as what studies need to be completed to help us truly understand the long-term implications of electrical and structural differences in the hearts of black, white and mixed race athletes. The next presentation of the day came from Professor Domenico Corrado, who has frequently spoken at the CRY Conference for many years now. Professor Corrado gave a

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CRY’s online International Medical Conference talk entitled “Ventricular Ectopy in Athletes Made Simple” and focused on how to interpret different conditions and examine the risks involved for athletes. He concluded that the risk stratification of athletes with ventricular arrhythmias has evolved to the current perspective that prognosis is related to the morphology, complexity and response to exercise, rather than to the number of premature ventricular beats. Uncommon ventricular arrhythmia morphology (mostly right bundle branch block/superior axis) and worsening with exercise could be associated with concealed myocardial fibrosis.

Professor Mats Börjesson’s presentation, “The veteran athlete’s coronary arteries: What to expect,” followed. Professor Börjesson first defined what a veteran athlete is, explaining that they are typically over 50 years of age and take part in competitive sports (mainly endurance events). Regular physical activity has plenty of health benefits, but the problem is that high intensity activity can also be associated with an increased risk for those with an underlying cardiovascular condition. Professor Börjesson explained that you can expect the presence of subclinical coronary artery disease in veteran athletes, which means that risk evaluation should be completed for all veteran athletes to look at their level of exercise and sports participation. For veteran athletes who are known to have coronary artery disease, an anatomical and functional evaluation should be completed before they participate in high-intensity sports. Former CRY Research Fellow Dr Sabiha Gati spoke as well, and discussed “The assessment of athletes post myocarditis.

What does CMR add?” Dr Gati discussed the subject in plenty of detail, covering everything from the natural history of myocarditis, to the role of cardiovascular magnetic resonance imaging (CMR) is used in both the diagnosis and determining prognosis in myocarditis. The precise incidence and prevalence of myocarditis is unknown. However, we do know that it accounts for 5-15% of all sudden cardiac deaths in young athletes and 20% of sudden deaths in military recruits, which, as Dr Gati noted, suggests that exercise is an important trigger in myocarditis. Dr Gati went on to discuss methods that can be used to diagnose myocarditis, and concluded that CMR is the most effective non diagnostic method of diagnosis acute myocarditis.

Dr Michael Papadakis gave the final presentation of the day, “COVID-19 and the athlete’s heart.” Dr Papadakis tackled this important subject, and outlined the effects of COVID on the heart, advice for exercising during the COVID-19 era, and provided the rationale for who should have cardiac investigations. Dr Papadakis began by discussing symptoms of COVID and how different individuals can be affected, including potential impacts on the heart (for example, research showed that up to 30% of those admitted to hospital have elevated troponin, which usually indicates more severe disease). After covering the benefits of exercise, advice and how to return to exercise after testing positive for COVID-19, he laid out a detailed framework for completing cardiac investigations for different individuals. We are grateful to everyone who followed the conference on the day, and to all of our speakers for giving such fantastic presentations on a range of topics.

For videos of all the presentations from CRY’s International Medical Conferences, sponsored by Radcliffe Cardiology, visit www.c-r-y.org.uk/cryinternational-conference

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Research Highlights 2020

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Conferences & Webinars

CRY shares new research developments at ESC Congress 2020

Dr Michael Papadakis has been a key member of the CRY team for years after first joining the charity when he started his training as a CRY Research Fellow in 2007. He’s continued to develop education in the sports cardiology field by building educational material for the European Society of Cardiology (ESC) and launched a novel degree in sports cardiology, which was the first post graduate qualification of its kind. Dr Papadakis has also transformed CRY’s myheart network. He serves as our myheart cardiologist and has created over 60 videos to explain various cardiac conditions and procedures, with the network continuing to expand to over 530 young members who have been diagnosed with a condition. In addition, over the past 10 years Dr Papadakis has provided his expertise at many myheart meetings for young people aged 18-35 who have been diagnosed with an inherited cardiac condition. We are now thrilled to say that Dr Papadakis has received an extremely well deserved position. He is the new President Elect of the European Dr Papadakis at a CRY myheart meeting in 2014. Association of Preventive Cardiology (EAPC), a community of the ESC. Dr Papadakis has proven himself as a leading expert in his field and an invaluable part of both CRY and the ESC, first as the Chair of the Sports Cardiology and Exercise section of the EAPC and now in his new role. “It is fantastic to see Dr Papadakis to be appointed to this prestigious role,” CRY Chief Executive Dr Steven Cox says. “This is a brilliant achievement and highlights the tremendous impact that CRY’s doctors are having, through producing ground breaking research, through education and through leadership on the international stage.” On the subject of the ESC and CRY’s research, the ESC Congress 2020 was rather different due to the COVID-19 pandemic. Like many various events all over the world, this year’s conference went online. However, it was a recordbreaking occasion. This year’s ESC Congress went on from August 29 to September 1, with 116,000 healthcare professionals from 211 countries joining the wide range of online presentations from some of the world’s leading cardiologists.

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Research Highlights 2020

CRY was well represented by a number of our doctors. CRY Research Fellow Dr Joyee Basu gave a presentation about her research, “Safety and outcomes of a structured exercise programme in young patients with hypertrophic cardiomyopathy: The SAFE-HCM trial,” which had fantastic engagement on the day as well as after the talk when the results were shared on social media. This study was generously funded by Heather Reid and the fundraising completed by her family and friends in support of CRY, in memory of Heather’s daughter, Alex. 67 individuals with HCM, aged 16-60, completed Dr Basu’s study. They were randomised to a 12-week supervised exercise programme or usual activity, and baseline investigations were repeated at 12 weeks. The participants underwent baseline testing with ECG, echocardiography, blood testing, exercise testing, 48-hour ECG and psychological assessment to see how they responded. This study highlighted the need for a personalised approach to ‘safe exercise’ for young people living with heart conditions, and suggests that personalised exercise regimes should be ‘prescribed.’ There were also considerable gains in cardiorespiratory fitness and psychological outcomes for the HCM patients in the study. The results ultimately indicate that high intensity exercise in patients is not as unsafe as previously thought, and could pave the way for further research leading to a new national framework. Professor Mary Sheppard from the CRY Centre for Cardiac Pathology (CRY CCP) also spoke at this year’s conference and gave a presentation entitled “Autopsy investigation and the need of uniform protocols in sudden cardiac death.” The CRY CCP is now the largest pathology unit dealing with sudden cardiac death in the world, and more than 80 Professor Mary Sheppard at the CRY CCP. percent of UK coroners are now routinely referring to the centre. Professor Sheppard and her team at CRY’s centre have carried out more than 3,500 expert cardiac post-mortems on young people, which has made the CRY CCP the world’s largest database of expert cardiac investigations. Along with her contribution to over 100 journals on cardiac pathology and contributions to research projects around the world, Professor Sheppard has had a tremendous impact on CRY’s research and the field of cardiac pathology in general. It is always excellent for this work to be shared at conferences like the ESC Congress.

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Guidance for ‘safe exercise’ in the COVID era and how to prepare for a return to sport Consultant Cardiologist Professor Sanjay Sharma. Professor Sharma’s presentation, entitled “Exercise in the COVID-19 era: Facts and Fiction,” looked at the effects of COVID-19 on the heart, the effects of exercise on the susceptibility to infection, the effects and consequences of myocarditis in athletes, and much more.

As in-person meetings and physical conferences were not an option, to continue to share research and the expertise of CRY’s doctors during 2020, we held webinars for the first time. Like our virtual CRY Conference, these gave people a chance to hear from experts and ask questions. On June 15, we held our first webinar, covering how athletes can continue exercising safely during the COVID-19 pandemic and how to prepare for a return to sport. This webinar featured three talks, beginning with CRY

Next, Professor Mat Wilson, the head of sport and exercise medicine at the Institute for Sport Exercise and Health, gave his presentation “Going back to exercise; A roadmap to retraining.” Professor Wilson provided his insight on how to understand the contextual factors – ranging from potentially being infected by COVID-19, to athletes recovering from old or new injuries – that need to be considered for athletes when returning to competitive sport following quarantine to do so as safely as possible. Dr Michael Papadakis gave the final presentation, “Cardiac evaluation prior to return to sport. One size fits all?” Dr Papadakis looked at who should receive cardiac evaluation and how, and the impact that COVID can have on the heart. To bring the webinar to a close, all of the speakers answered questions submitted by those watching live.

The importance of CRY’s research sudden cardiac death, identifying the prevalence of serious cardiac diseases in the young population, and refining cost effective methods for identifying and treating young people with cardiac conditions. Professor Sharma began by looking at a CRY research paper published in 2009, entitled “The magnitude of sudden cardiac death in the young: a death certificate-based review in England and Wales” (Papadakis M, Sharma S, Cox S, Sheppard MN, et al. Europace, 2009). This study examined sudden cardiac deaths in England and Wales and helped further CRY’s early efforts to identify the incidence of YSCD. As CRY Chief Executive Dr Steven Cox said when introducing this presentation and Q&A session, “internationally, CRY is known as a charity which has led the way in funding research into young sudden cardiac death.” Professor Sanjay Sharma has been leading CRY’s research programme over the past 25 years, helping develop research that has transformed our understanding of the causes and prevention of young sudden cardiac death (YSCD), and the treatment of those at risk. To look at some of the developments of CRY’s research and its importance, Professor Sharma hosted a live 15-minute presentation. This covered several key areas, including how CRY’s research has shed light on the incidence of YSCD, the causes of sudden cardiac death, the interpretation of autopsy findings, the evaluation of first degree relatives of victims of

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From there, Professor Sharma looked at more studies which examined unexplained deaths in young people, and research that shows how often underlying conditions can be genetic. He added further insight on how CRY research developed our ability to detect conditions through new refined, internationally recommended ECG guidelines; protocols on how to investigate families that have suffered a sudden cardiac death, which are now used nationally to test affected families; and ultimately how vital it is to identify cardiac conditions early with the ECG, which is where CRY’s screening programme is leading the way in screening tens of thousands of young people every year and saving lives. To finish, Professor Sharma answered questions from CRY supporters. Research Highlights 2020

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How CRY’s research impacted the investigation and management of people at risk of sudden cardiac death

Webinars & Interviews

For our final webinar of the year, Dr Michael Papadakis spoke about how CRY’s research has impacted the investigation and management of people at risk of sudden cardiac death. Dr Papadakis began by looking at what CRY’s research is based on, including the 4,000 individuals with inherited cardiac conditions that are seen annually at St George’s Hospital, the 30,000 young people we typically screen every year, and the 200 hearts that are examined each year at the CRY Centre for Cardiac Pathology. The combination of these three databases gives CRY a valuable foundation of information to support research and improve our ability to prevent sudden deaths. Dr Papadakis proceeded to go into further detail on the different factors that go into preventing young sudden cardiac deaths: researching the prevalence of different conditions; indentifying individuals at risk through ECG screening and examining family history; how to determine the risks for those

who have been identified with a cardiac condition; and how to support people living with a condition through lifestyle advice and any potential medical treatments. To conclude, Dr Papadakis highlighted some areas of research that CRY’s doctors are aiming to advance in 2021. And again, everyone watching live had the opportunity to send in questions at the end.

What’s coming in 2021 1. Improving our screening programme • Optimising screening protocols

2. Differentiating benign from sinister entities • Athletic adaptation vs. disease

• Further refining ECG interpretation

3. Optimising investigative protocols

• Search for novel ECG markers of disease • Evaluate the impact of our programme on young individuals

4. Impact of COVID-19 in the heart/myocarditis 5. Exercise prescription in inherited cardiac conditions

Exercise and hypertrophic cardiomyopathy: Two incompatible entities? CRY Research Fellow Dr Joyee Basu completed a new piece of research into hypertrophic cardiomyopathy, entitled “Exercise and hypertrophic cardiomyopathy: Two incompatible entities?” which was published in Clinical Cardiology (Basu J, Malhotra A, Papadakis M, August 2020). research with us:

Dr Basu shared a brief explanation of her

“Patients with hypertrophic cardiomyopathy were historically considered to be at high risk of sudden cardiac death during exercise. However, there is emerging evidence which suggests that exercise in HCM has a favourable effect on

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Research Highlights 2020

cardiovascular remodelling, and moderate exercise programs have not raised any safety concerns. “Small studies have also revealed that athletes who choose to continue with regular competition do not demonstrate adverse outcomes when compared to those who discontinue sport. “Therefore the recently published exercise recommendations from the European Association for Preventative Cardiology account for more contemporary evidence and adopt a more liberal stance regarding competitive and high intensity sport in low risk individuals. “This review addresses the issue of exercise in individuals with HCM, and explores current evidence supporting safety of exercise in HCM, potential caveats, and areas of further research.”

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Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy Former CRY Research Fellow Dr Gherardo Finocchiaro completed a study into hypertrophic cardiomyopathy, entitled “Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy” (Finocchiaro G, Dhutia H, Gray B. Europace, April 2020). Here, he explains the key takeaways from the study: Sudden cardiac death (SCD) in apparently healthy individuals is commonly due to a diverse spectrum of inherited cardiac diseases including cardiomyopathies and channelopathies. Autopsy is an essential preliminary diagnostic step to steer the clinical evaluation of surviving relatives towards inherited structural diseases or primary arrhythmogenic syndromes. The interpretation of the autopsy results, however, is often a complex task and uncertainty may exist about the precise significance of some pathological findings and their causal relationship with SCD. Idiopathic left ventricular hypertrophy (LVH) is an increasingly recognized finding at autopsy of young decedents from SCD. The entity is used to describe unexplained LVH in the absence of myocardial disarray or secondary causes. Idiopathic LVH may be interpreted as hypertrophic cardiomyopathy (HCM) and targeted screening of first-degree relatives is recommended to detect others with quiescent disease. The significance and causal relationship of this entity with SCD is uncertain. Importantly, it is unclear whether idiopathic LVH represents the disease spectrum of HCM. Consequently, there are concerns that families of decedents with idiopathic LVH may be falsely reassured after limited evaluation with a 12-lead ECG and echocardiogram, which would be expected to identify

Dr Finocchiaro presenting at the CRY Conference in 2017.

the majority of individuals with HCM. With this CRY-funded study, we aimed to investigate the significance of idiopathic LVH in decedents who experienced SCD through comprehensive clinical evaluation of their firstdegree relatives and by conducting molecular autopsy in the decedents. Clinical evaluation of 125 first-degree relatives of 46 decedents with idiopathic LVH did not reveal a single case of HCM despite comprehensive clinical evaluation, including CMR imaging, exercise testing, and prolonged ECG monitoring, which would be expected to identify even milder phenotypes of HCM. In contrast with none of the first-degree relatives being diagnosed with HCM, we found a 24% clinical diagnostic yield of inherited arrhythmia syndromes in family members of decedents with idiopathic LVH and a 14% yield of pathogenic variants in genes encoding cardiac myocyte ion channels at molecular autopsy. Specifically, Brugada syndrome was the most common diagnosis, followed by long QT syndrome.

Dr Gherardo Finocchiaro presenting some of his research on ARVC at the 2019 CRY Conference.

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In summary, in this study, none of the family members of decedents with idiopathic LVH showed phenotypic features of HCM following comprehensive cardiovascular evaluation. Similarly, molecular autopsy in 14 decedents failed to reveal pathogenic variants in genes encoding sarcomeric proteins, which are commonly implicated in HCM. Therefore, idiopathic LVH and HCM are likely to represent two distinct pathological entities. The familial diagnosis of other cardiomyopathies and channelopathies in some families suggests that the presence of idiopathic LVH should prompt comprehensive assessment of families to encompass the broader spectrum of inherited structural heart disease and channelopathies. Research Highlights 2020

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Interviews

A qualitative analysis of psychosocial needs and support impacts in families affected by young sudden cardiac death: The role of community and peer support

A team of researchers from the Departments of Psychology at the universities of Kingston, Roehampton and Surrey have completed the first ever interview-based study on the psychological support needs of families tragically affected by young sudden cardiac death. This study – which was completed by Dr Edith Maria Steffen, Dr Lada Timotijevic and Professor Adrian Coyle, and published in the European Journal of Cardiovascular Nursing – highlighted the importance of peer-to-peer support following a tragedy, and was funded by CRY. For the study, detailed interviews were completed with 19 people who had suffered the sudden loss of a young family member due to a previously undiagnosed cardiac condition. The researchers held one-to-one interviews with five individuals, and three focus groups with the other affected family members. Audio recordings of the interviews and focus groups were then studied and thematic analysis was completed of the participants’ psychological needs. Three key themes were identified in the paper:

1. “YSCD community support as offering a place of safety. 2. “YSCD community support as fostering sensemaking. 3. “YSCD community support as facilitating finding new meaning.” As the lead author Dr Steffen explains, ensuring that families receive the necessary support after the tragedy of a young sudden cardiac death, in addition to determining the cause of death, is essential. “In essence, our research concluded that whilst the immediate clinical pathway following a sudden death will always focus on determining the cause of death and diagnosis of a condition, in the case of YSCD, an additional step should be integrated into the patient pathway whereby families are made aware of patient representative groups that can offer additional and ongoing support,” Dr Steffen says. “This should involve informational and emotional support and would ideally include access to families with prior support experience of YSCD. It should be ensured that patients are aware of any such available resources when they leave the clinical appointment. “Through our personal, honest and very moving interviews as part of this project, our team found that YSCD-affected families can truly benefit from having access to YSCD-sensitive peer and

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CRY’s series of “Grief” booklets.

community support. Whilst YSCD trauma and the associated experiences of loss are often characterised by their uniqueness and isolating consequences, the concept of ‘recovery’ seems to be based in social relationships. “What is particularly important is the rebuilding of a sense of belonging through a community that can provide an anchor. Clinicians need to be aware that this is an essential part of patient care.” CRY Chief Executive Dr Steven Cox explains why this research is important and how CRY continues to develop the bereavement support we offer. “Since 1995, CRY has received thousands of calls from families wanting to speak to others who have suffered similar tragedies to them – and we know from these desperately difficult calls over the years, that this grief can be an incredibly lonely and isolating experience,” Dr Cox says. “As referenced in this insightful and pertinent new research, many people tell us they feel ‘afraid of going mad’ and that the only thing that helped them in their attempts to understand their turmoil – which in itself is an entirely normal response – was to make contact with someone with a shared experience. “I feel very proud that CRY’s Bereavement Support Network already serves to connect families and individuals knowing that it literally offers a life line to many who feel lost, angry, bereft and confused having been totally blindsided by the tragedy of a young, sudden cardiac death. “Recently, we’ve also introduced more informal platforms for bereaved families and friends to connect and share memories, through our closed Facebook groups – providing a safe and empathetic space for meaningful and positive peer support.” As this research highlighted, and as CRY’s support team knows, bereavement support is vital for those who have been affected by a young sudden cardiac death.

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To provide more detail about this research and the importance of peer to peer support, author Dr Edith Maria Steffen spoke with us and answered a few questions. What is peer to peer support and why is it important? The broad definition of Peer Support is when two or more people with similar experiences get together to share their experiences, to give each other hope, and to support each other. The CRY support programme has identified the importance of peer support and formalised it in a way (through trained bereavement supporters who are peers) where it can be provided to those in need in a more formal way. Peer to peer support has actually been around for a long while, however in recent years the focus moved to more formal support structures. CRY’s programme evolved very naturally through trying to identify the best ways to support families. I think CRY is at the forefront of what we are starting to see more in clinical and counselling psychology, the role of peer to peer support as a broader support framework for individuals in need. How did you conduct the study? Why were the research methods important? We conducted a qualitative study through in-depth, semistructured interviews organised through focus groups and one-on-one. There are two broad types of research methods: quantitative and qualitative methods. The first deals with statics and numbers, looking at how people respond to questionnaires. The second focuses on understanding the meaning people attach to their experiences and deeper analysis of the spoken and written data... It is fair to say that often the preference for scientific journals is to focus on quantitative analysis that examines the prevalence of the phenomenon under study or models the relationship between measurable factors, but often it is not possible to truly get inside an issue through this methodology. Through in-depth analysis of interviews and transcripts we can identify issues which would not have been possible through quantitative research. How did you find the process of interviewing CRY families? The families were very kind to be so open and honest about their experiences. For good quality research you need this and the CRY families were incredible. It is not easy to have someone “observe” you while you are opening up about something which is so horrendous. It is impossible not to be moved and affected by the stories which really reinforces why it is so important to do research like this, so hopefully more people who need this type of support are offered it. How do you feel about the research being referenced in the

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most recent European guidelines ,“2020 APHRS/HRS Expert Consensus Statement on the Investigation of Decedents with Sudden Unexplained Death and Patients with Sudden Cardiac Arrest, and of Their Families”? This is fantastic news for a number of reasons. I hope the families who supported this research can see the impact they have had. Also, we need clinicians to be aware of studies like these as it will encourage them to introduce signposting to peer to peer support within their protocols. Everyone who is part of the patient pathway is there to help the family, when they see a study like this be published and realise this is how they can better help their patients they will think twice when the patient asks them when they leave their clinic saying, “is there anything else I need to know?”. You have done a lot of work with bereavement. How does this area compare to other areas? This is a unique aspect of bereavement. YSCD has a devastating effect on families. Not only is there a heightened risk of posttraumatic stress and prolonged grief, but families may also find themselves at risk of YSCD. Furthermore, the genetic implications of these conditions may have an enduring impact within extended families and often, there will be uncertainty about the conditions and causes of death. I think it is probably because of these many different aspects of this grief which reinforce why peer to peer support is so important in this context.

Concluding comments from CRY Chief Executive Dr Steven Cox It is not always possible for the public, outside universities, to have access to full academic papers. We very much appreciate the authors of this paper contacting the journal to ask for this to be open access for all to read. You can read the full paper here. This was such a vital paper because it focused on the bereavement support programme that Alison has developed over many years, working with CRY families who have given so much to support other bereaved families. The paper has really helped to highlight some of the ways in which peer to peer and community support can help families after a tragedy. Research is so important because it helps us to systematically evaluate our actions and understand the impact of those actions. The findings of this paper have significant implications for clinical practice, whereby clinicians can see the value of referring families to patient representative groups where community and peer to peer support can be accessed. In time this will become a routine part of the referral pathways for families after a young sudden cardiac death.

To learn more about the various resources that CRY’s Bereavement Support Programme offers, you can go to: www.c-r-y.org.uk/support

Research Highlights 2020

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Morphometric characterization of collagen and fat in normal ventricular myocardium

Interviews

Former CRY Research Fellow Dr Chris Miles’ new research helped demonstrate how new computer software can help identify and analyse abnormalities in the heart that we may not be able to see otherwise. Dr Miles’ paper, entitled “Morphometric characterization of collagen and fat in normal ventricular myocardium” (Miles C, Westaby J, Ster I C, et al. Cardiovascular Pathology, May, 2020), looked at 29 noncardiac death cases referred to the CRY Centre for Cardiac Pathology. This study aimed to examine the structure of heart tissue and collagen content using automated digital pathology software, finding that automated image analysis is a useful tool for cardiac tissue qualification. Dr Miles provided us with an explanation of his study, and why

new technology is important: “Detailed examination of the heart is crucial in determining the cause of an initially unexplained sudden death. Over recent years, specialist computer software has emerged as a useful tool in helping identify abnormalities in the heart, which may not be appreciated under the microscope. “In this study, we examined hearts from a group of individuals who had died from non-cardiac causes. Image analysis software was used to investigate the composition of normal heart tissue, providing an accurate measurement of the proteins and cells required for the heart to function. “The results from this study demonstrate how novel technology can complement traditional methods of diagnosis, allowing comparisons to be made with suspected abnormalities that can be difficult to discern with the human eye.” If you want to find out more and see the research in full, you can read the paper here.

Differentiation between athlete’s heart and dilated cardiomyopathy in athletic individuals Former CRY Research Fellow Dr Lynne Millar recently completed a study into dilated cardiomyopathy in athletes, entitled “Differentiation between athlete’s heart and dilated cardiomyopathy in athletic individuals” (Millar L, Fanton Z, Finocchiaro G, et al. Heart, July 2020). This paper intended to distinguish the difference between dilated cardiomyopathy and typical, healthy changes that can occur in an athlete’s heart, and came up with an array of tests to help achieve this. These varied depending on the condition of the individual, but the tests involved in the study included N-terminal pro-brain natriuretic peptide (NT-proBNP) measurement, ECG, exercise echocardiography, cardiovascular magnetic resonance (CMR) and Holter monitoring. This research is best explained by Dr Millar herself: “We know around 11% of highly trained athletes have a heart that mimics a heart muscle condition called dilated cardiomyopathy or ‘DCM’ for short due to the changes in the heart from athletic training. We also know that DCM can be

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serious and previous CRY research has shown around 1-2% of athletes die from this condition. “It is therefore incredibly important that we differentiate these two conditions to ensure those with DCM are properly diagnosed, given appropriate treatment and that family members are screened if necessary. “Additionally, we don’t want to incorrectly label someone with a DCM if in fact they are healthy as this would have potential serious implications for their life and exercise. “In this study we were able to come up with a comprehensive set of tests to distinguish athletic adaption from DCM with a high level of accuracy. Specifically the use of exercise stress echocardiography (a heart scan performed at rest and during exercise) was particularly useful to differentiate these two conditions. These tests can be then easily used by doctors when faced with this clinical problem. “To date there has been little research in this field and we believe this paper will help inform our understanding of DCM and the athlete’s heart.” If you would like to learn more about this study, from the tests used to exact findings, you can read the paper on the Heart website here.

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Papers/Articles

Research •  “The electrocardiogram in the diagnosis and management of patients with hypertrophic cardiomyopathy.” Finocchiaro G, Sheikh N, Biagini E, et al. Heart Rhythm, January 2020. “In the present review, we discuss the current role of the ECG in the diagnosis and management of HCM, focusing on various clinical settings where its appropriate use and interpretation can make a difference.” •  “The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy.” Lahrouchi N, Raju H, Lodder EM, et al. European Journal of Human Genetics, January 2020. “This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy.” • “Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening.” Bhuva AN, D’Silva A, Torlasco C, et al. Journal of the American College of Cardiology, January 2020. “Training for and completing a marathon even at relatively low exercise intensity reduces central blood pressure and aortic stiffnessequivalent to a ~4-year reduction in vascular age. Greater rejuvenation was observed in older, slower individuals.” • “Left bundle branch block-induced cardiomyopathy: a diagnostic proposal for a poorly explored pathological entity.” Sanna GD, Merlo M, Moccia E, et al. International Journal of Cardiology, January 2020. “In this review the complex relationship between LBBB and left ventricular non-ischaemic dysfunction is described. Furthermore, a multiparametric approach based on clinical, electrocardiographic and imaging red flags, is provided in order to allow an early detection of the LBBB-induced cardiomyopathy.” • “Exercise and hypertrophic cardiomyopathy: Two incompatible entities?” Basu J, Malhotra A, Papadakis M. Clinical Cardiology, February 2020. “This review addresses the issue of exercise in individuals with HCM, and explores current evidence supporting safety of exercise in HCM, potential caveats, and areas of further research.” • “Subclinical coronary artery disease in veteran athletes: is a new preparticipation methodology required?” Dores H, de Araújo Gonçalves P, Monge J, et al. British Journal of Sports Medicine, March 2020. “Conventional methodology used in preparticipation evaluation of veteran athletes, based on clinical CV risk factors and exercise testing, was poor at identifying significant subclinical CAD. The inclusion of more objective markers, particularly data derived from cardiac CT, is promising for more accurate CV risk stratification of these athletes.” • “The effects of endurance exercise on the heart: panacea or poison?” Parry-Williams G, Sharma S. Nature Reviews. Cardiology, March 2020. • “Determinants of the athlete’s heart: a cardiovascular magnetic resonance imaging study.” Gati S, Sharma S. European Journal of Preventive Cardiology, March 2020. • “Cardiovascular Remodeling Experienced by Real-World, Unsupervised, Young Novice Marathon Runners.” D’Silva A, Bhuva AN, van Zalen J, et al. Frontiers in Physiology, March 2020. “Previous studies have highlighted concerning transient myocardial dysfunction and biomarker release immediately after the race. Whether this method of increasing physical activity is beneficial or harmful remains a matter of debate. We examine in detail the realworld cardiovascular remodeling response following competition in a first marathon.” • “Sudden Death and Left Ventricular Involvement in

Cardiac Risk in the Young

Arrhythmogenic Cardiomyopathy.” Miles C, Finocchiaro G, Papadakis M, et al. Circulation, April 2020. “Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort.” • “Diagnostic yield of hypertrophic cardiomyopathy in first-degree relatives of decedents with idiopathic left ventricular hypertrophy.” Finocchiaro G, Dhutia H, Gray B, et al. Europace, April 2020. “Idiopathic LVH appears to be a distinct disease entity from HCM and is associated with fatal arrhythmias in individuals with primary arrhythmia syndromes. Family screening in relatives of decedents with idiopathic LVH should be comprehensive and encompass the broader spectrum of inherited cardiac conditions, including channelopathies.” • “Reaping the rewards of exercise: it is never too late to start.” Sharma S, Malhotra A. European Heart Journal, April 2020. • “The electrocardiogram in the diagnosis and management of patients with dilated cardiomyopathy.” Finocchiaro G, Merlo M, Sheikh N, et al. European Journal of Heart Failure, April 2020. “In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.” • “Exercise and Coronary Atherosclerosis: Observations, Explanations, Relevance, and Clinical Management.” Aengevaeren VL, Mosterd A, Sharma S, et al. Circulation, April 2020. “This review describes the effects of physical activity and exercise training on coronary atherosclerosis in athletes who are middle-aged and older and aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries.” • “Brief recommendations for participation in leisure time or competitive sports in athletes-patients with coronary artery disease: Summary of a Position Statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC).” Borjesson M, Dellborg M, Niebauer J, et al. European Journal of Preventive Cardiology, May 2020. • “Age matters: differences in exercise-induced cardiovascular remodelling in young and middle aged healthy sedentary individuals.” Torlasco C, D’Silva A, Bhuva AN, et al. European Journal of Preventive Cardiology, June 2020. “Medium-term, unsupervised physical training in healthy sedentary individuals induces measurable remodelling of both heart and vasculature. This amount is age dependent, with predominant cardiac remodelling when younger and predominantly vascular remodelling when older.” • “Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part 2: ventricular arrhythmias, channelopathies, and implantable defibrillators.” Heidbuchel H, Arbelo E, D’Ascenzi F, et al. Europace, June 2020. • “Differentiation between athlete’s heart and dilated cardiomyopathy in athletic individuals.” Millar LM, Fanton Z, Finocchiaro G, et al. Heart, July 2020. “Comprehensive assessment using a cascade of routine investigations revealed that exercise stress echocardiography has the greatest discriminatory value in differentiating between grey-zone athletes and asymptomatic patients with DCM. Our findings require validation in larger studies.” • “The metabolic signature: an emerging paradigm in cardiovascular nutritional health research?” Sharma S, Parry-Williams G, Gati S. European Heart Journal, July 2020. • “Left ventricular remodeling in elite and sub-elite road cyclists.” Brown B, Millar L, Somauroo J, et al. Scandinavian Journal of Medicine & Science in Sports, July 2020.

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Papers/Articles “This study aimed to describe structural, functional, and mechanical characteristics of the cyclists’ LV, based on clearly defined performance levels.” • “Myocardial Infarction With Nonobstructed Coronary Arteries and Sudden Cardiac Death: A Clinical and Pathological Perspective.” Ciliberti G, Finocchiaro G, Papadakis M, et al. Circulation. Arrhythmia and Electrophysiology, July 2020. • “Infographics. Football-specific strategies to reduce COVID-19 transmission.” Carmody S, Ahmad I, Gouttebarge V, et al. British Journal of Sports Medicine, August 2020. “This article considers the evolving science pertinent to professional footballers in the context of COVID-19, with the overarching purpose to ensure the health and safety of players, staff, their families and the general public. The primary focus of this article is on strategies to reduce the risk of human-to-human transmission during football activity, aspects of which will be relevant to other sports.” • “Exercise: The ultimate treatment to all ailments?” Kasiakogias A, Sharma S. Clinical Cardiology, August 2020. • “2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease.” Pelliccia A, Sharma S, Gati S, et al. European Heart Journal, August 2020. • “Exercise in the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) era: A Question and Answer session with the experts Endorsed by the section of Sports Cardiology & Exercise of the European Association of Preventive Cardiology (EAPC).” Bhatia RT, Marwaha S, Malhotra A, et al. European Journal of Preventive Cardiology, August 2020. • “The Impact of Ethnicity on Cardiac Adaptation.” Ozo U, Sharma S. European Cardiology, August 2020. “Ethnicity is an important determinant of cardiac adaptation to exercise and should be considered during cardiac evaluation of an athlete. Black athletes from middle and west Africa and the Caribbean appear to develop the most profound electrical and structural changes. An awareness of these ethnic variants will prevent over investigation of healthy athletes and potentially unwarranted exclusion from competitive sports.” • “Mavacamten: treatment aspirations in hypertrophic cardiomyopathy.” Papadakis M, Basu J, Sharma S. Lancet, September 2020. • “Cardiorespiratory considerations for return-to-play in elite athletes after COVID-19 infection: a practical guide for sport and exercise medicine physicians.” Wilson MG, Hull JH, Rogers J, et al. British Journal of Sports Medicine, September 2020. “To support safe RTP, we provide sport and exercise medicine physicians with practical recommendations on how to exclude cardiorespiratory complications of COVID-19 in elite athletes who place high demand on their cardiorespiratory system. As new evidence emerges, guidance for a safe RTP should be updated.” • “Morphometric characterization of collagen and fat in normal ventricular myocardium.” Miles C, Westaby J, Ster IC, et al. Cardiovascular Pathology: The official journal of the Society for Cardiovascular Pathology, September 2020. “Our findings provide location and sex-specific proportions of myocardial histological tissue composition that may aid quantitative evaluation of pathology in future studies.” • “Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.” D’Silva A, Captur G, Bhuva AN, et al. International Journal of Cardiology, September 2020.

• “Coronary atherosclerotic burden in veteran male recreational athletes with low to intermediate cardiovascular risk.” Dores H, de Araújo Gonçalves P, Monge J, et al. Portugese Journal of Cardiology, September 2020. • “COVID-19, the heart and returning to physical exercise.” Kennedy FM, Sharma S. Occupational Medicine, October 2020. “In conclusion, the possibility of persisting low-grade cardiac injury should be considered when assessing protracted COVID-19 illness and providing fitness for work advice, particularly in the context of jobs involving strenuous physical exercise.” • “The Impact of COVID-19 on the Continuity of Cardiovascular Care.” Bhatia RT, Gati S, Papadakis M, et al. European Heart Journal, October 2020. “Given the uncertainty surrounding the duration of the COVID-19 pandemic, safe and effective integrated models of care which include remote methods of clinical management, disease surveillance and appropriate staff training should be engraved into our daily practice whilst ensuring staff wellbeing is not neglected.” • “Electrocardiographic interpretation in athletes.” Abela M, Sharma S. Minverva Cardioangiologica, October 2020. “This review will describe the normal electrical patterns of the “athlete’s heart” and provide insights into differentiation physiological electrical patterns from those observed in serious cardiac disease.” • “Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.” Corrado D, Marra MP, Zorzi A, et al. International Journal of Cardiology, November 2020. • “Recommendations for participation in competitive sport in adolescent and adult athletes with Congenital Heart Disease (CHD): position statement of the Sports Cardiology & Exercise Section of the European Association of Preventive Cardiology (EAPC), the European Society of Cardiology (ESC) Working Group on Adult Congenital Heart Disease and the Sports Cardiology, Physical Activity and Prevention Working Group of the Association for European Paediatric and Congenital Cardiology (AEPC).” Budts W, Pieles GE, Roos-Hesselink JW, et al. European Heart Journal, November 2020. • “SCN5A Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in SCN5A Families.” Wijeyeratne YD, Tanck MW, Mizusawa Y, et al. Circulation. Genomic and Precision Medicine, December 2020. • “Screening of Potential Cardiac Involvement in Competitive Athletes Recovering From COVID-19: An Expert Consensus Statement.” Phelan D, Kim JH, Elliott MD, et al. Journal of the American College of Cardiology. Cardiovascular Imaging, December 2020. “This review seeks to evaluate the current evidence regarding COVID-19–associated cardiovascular disease and how multimodality imaging may be useful in the screening and clinical evaluation of athletes with suspected cardiovascular complications of infection.” • “Highlights from the 2020 ESC guidelines on sport cardiology: practical management for safe sports and exercise in patients with cardiovascular disease.” Gati S, Drezner J, Sharma S. Heart, December 2020. • “The Labyrinth of Nomenclature in Cardiology. Eternal Dilemmas and New Challenges on the Horizon in the Personalized Medicine Era.” Finocchiaro G, Sinagra G, Papadakis M, et al. European Journal of Heart Failure, December 2020.

For a full list of CRY’s research visit www.c-r-y.org.uk/research/crys-contribution-to-research 12

Research Highlights 2020

Cardiac Risk in the Young


Professor Sanjay Sharma, CRY Consultant Cardiologist The CRY Research Programme is overseen by Professor Sanjay Sharma, Professor of Inherited Cardiovascular Disease and Sports Cardiology at St George’s Hospital, London; Virgin Money London Marathon Medical Director; and the London 2012 Olympic Cardiologist. The CRY Research Fellowship Programme funds doctors for up to three years who choose to specialise in the fields of inherited cardiac diseases, young sudden cardiac death, screening and sports cardiology. It is our unique expertise in sports cardiology and how athleticism, ethnicity and gender affect the ECG that has made CRY a leading international authority on cardiac screening. “Sports cardiology” is cardiac research and clinical practice applied to fit and healthy

young people. The knowledge gained from studying athletes better informs the diagnosis and management of all young people at risk from cardiac conditions. As of February 2021 there are 5 CRY Research Fellows at St George’s Hospital who divide their time between NHS clinics, CRY screenings and research. As well as the Fellows CRY are currently funding, 30 former Fellows have been trained as specialists by CRY and are now working in the NHS throughout the UK, and many more have received international grants to return to hospitals around the world. Professor Sharma oversees the CRY National Screening Programme in which the CRY Research Fellows play a central role. Every person that CRY tests is asked to consent to having their data used anonymously for research purposes. This has developed a symbiotic relationship between research and screening; identifying young individuals at risk whilst learning from our experience and publishing these findings.

CRY’s Research Programme CRY research has shown: • Every week in the UK at least 12 young people die of undiagnosed heart conditions (Papadakis M et al. 2009) • 1 in 300 young people that CRY tests will have a potentially life-threatening heart condition (Wilson MG et al. 2008)

Transforming the way we understand the causes and incidence of young Causes sudden cardiac death.

Transforming the way we prevent young sudden cardiac deaths Prevention and save young lives.

• 80% of SADS deaths occur at rest or during sleep (Mellor G et al. 2014)

Treatment

• ARVC is the cardiac condition most likely to cause sudden death during exercise (Finocchiaro G et al. 2016)

Transforming treatment for young people who are living with cardiac conditions.

12.5% of CRY’s funding supports research Research Awareness 12.5% 16.3% Support 10.4% Governance 2.2% Fundraising 16.1% Screening 42.6%

Due to the anticipated impact of COVID-19 on fundraising in 2020/2021 CRY reduced the number of research fellowship grants awarded.

CRY research grants fund fast-track, expert referral services at the CRY Centre for Cardiac Pathology (CRY CCP) and the CRY Centre for Inherited Cardiovascular Conditions and Sports Cardiology. CRY research grants fund original research using data gathered from the CRY Centres and through the CRY National Screening Programme. CRY research grants fund clinical doctors who are present at every CRY screening event to examine the results of young people tested and provide a consultation on the same day.

In 2020, CRY received significant contributions to support our research team in memory of: Rosie Mitchell Lewis Barry Harry Faulkner Daniel Hughes Barry Nivett Nathan Butler Anthony Fitzgerald Thomas Jeffery Suanu Saro-Wiwa Matthew Cragg Andrew Gard Bilal Kahn Philip Standing Neil Desai Ashley Goodwin Joe Kellogg Isabelle Tudisca Matthew Dewhirst Thomas Hardman Alan Lumley Fraser Vaughan

CRY also received significant contributions to support our research team from G-Research and the Robert Luff Foundation.

Cardiac Risk in the Young

Research Highlights 2020

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