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Research Highlights 2018 Inside this issue. . .

P2 CRY International Conference P3 European Conferences P4-9 Interviews P10 Papers/Articles P11 Presentations P12 CRY’s Research Programme

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


Conferences

CRY International Medical Conference

Just as CRY’s screening programme continues to grow, so too does our standing in the medical community. Our International Medical Conference is always a terrific event, giving our doctors an opportunity to present their latest research and for us to connect with other leading experts. Professor Sanjay Sharma (right) introduced the conference and gave the opening talk about the role of CT coronary angiography in veteran athletes. CRY myheart cardiologist Dr Michael Papadakis looked at hypertrophic cardiomyopathy (HCM). All individuals are different, but Dr Papadakis discussed exercise recommendations for athletes with HCM and the ideal amounts of aerobic and static exercise. He made a few strong closing points, including that there is “no clear association between HCM and exercise as a trigger of arrhythmias.” Several previous and current CRY Research Fellows gave fantastic presentations, including Dr Sabiha Gati (management of athletes with myocarditis); Dr Gherardo Finocchiaro (idiopathic left ventricular hypertrophy); Dr Stathis Papatheodorou (sudden adult death syndrome and research from CRY’s Centre for Inherited Cardiac Conditions); Dr Aneil Malhotra (sudden cardiac death in football players being a bigger issue than previously thought); and Dr Hamish MacLachlan (CRY’s screening programme, what has developed and what we have learned). This year we had a number of highly renowned international speakers contribute at the conference. This was a first for Professor Antonio Pelliccia from Rome, Italy, and the 12th time for Professor Domenico Corrado from Padova, Italy, who has only missed one conference since the first one in 2006. These are two of the most influential cardiologists in the world of cardiac screening and sports cardiology. Professor Jonathan Drezner, Seattle, USA, attended for the second time, almost a decade since he last presented, during which time there have been significant changes in the US and internationally. Professor Pelliccia spoke about exercise for athletes with cardiomyopathies and how recommendations vary depending on different diagnoses and risk profiles. Professor Mats Börjesson, Gothenburg, Sweden, also looked at exercise recommendations for athletes, but for those with ischaemic heart disease.

After the first break of the day, Professor Corrado gave a presentation on myocardial fibrosis in athletes. Dr Belinda Gray followed, discussing some of her research into SADS and the use of molecular autopsy. Professor Drezner gave the longest talk and shared some of his expertise from working with a variety of sports teams, such as the Seattle Seahawks of the NFL. It was extremely encouraging to hear of the growing argument in the USA for using cardiac screening. Professor Drezner discussed how screening can prevent deaths in young people, and research on the rate of deaths in athletes, especially black athletes, being higher. For instance, men’s basketball (a high-risk sport for those with a condition due to its intensity and explosive movements) accounts for only 4% of male National Collegiate Athletic Association (NCAA) athletes, but nearly 20% of all NCAA SCD cases. Following the day’s presentations, the case sessions panelled by Professor Sharma, Professor Corrado, Professor Pelliccia, Professor Drezner, Professor Börjesson and Dr Maite Tome were the next integral part of the conference. The case sessions on electrical disease, cardiomyopathies and structural disease were a brilliant way to bring discussion into the conference centre, test those in attendance, and see how different experts would approach specific conditions in young people. These sessions put theory into practice, adding a valuable dynamic after the morning’s talks. We are incredibly proud of our CRY Research Fellows, past and present, for all the work they do to further our understanding of young sudden cardiac death. CRY’s research and position in the medical community couldn’t progress without it. Thank you to all of them for their presentations, and to all of our international speakers for making the effort to join us and share their insight. Finally, many thanks to our sponsors Equivital and Radcliffe Cardiology, and also to our exhibitors GE Healthcare, Sanofi and Rightangled.

Professor Corrado, Professor Pelliccia, Professor Drezner, Dr Papadakis, Professor Börjesson and Professor Sharma

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Research Highlights 2018

For videos of all the presentations, sponsored by Radcliffe Cardiology, visit www.c-r-y.org.uk/cryinternational-conference

Cardiac Risk in the Young


European Conferences EuroPrevent

BCS Conference – By Dr Steven Cox

The 2018 EuroPrevent conference was held in Ljubljana, Slovenia, between April 19th and 21st. CRY was well represented by current and former Research Fellows who gave excellent presentations on a number of topics. Dr Papadakis gave a superb presentation titled “Apical HCM and mild phenotype HCM in athletes: Common and benign? Let them play?”. It considers whether we are too restrictive with athletes identified with certain cardiac conditions. More detail is needed when using statistics of the increased likelihood of death during exertion for those with an underlying issue. Dr Papadakis made it clear that different conditions and sports will vary in terms of the risk they pose. For instance, exercise recommendations for those with hypertrophic cardiomyopathy in particular could be more lenient than we have previously thought. This prompts the need for more specificity with different conditions, rather than grouping them all under the same worrying statistics. Former CRY Research Fellow Dr Gati gave a brilliant talk on weighing the balance between physiology and pathology in left ventricular hypertrabeculation in athletes. There were also several excellent poster presentations given by our doctors. Dr Joyee Basu presented her research “The effect of ethnicity on left ventricular adaptation to exercise”, which aimed to “assess the effect of black ethnicity on LV geometry in healthy male and female athletes.” Dr Gemma Parry-Williams looked at some of the impacts of years of high-level exercise athletes sustain with her poster entitled “Master endurance athletes: Too much pressure?”. Dr Stathis Papatheodorou also examined athletes with his research “Comparison of different ECG Criteria in the interpretation of the veteran athlete’s ECG”, while Dr Aneil Malhotra presented his study “The efficacy of the Ziopatch patch novel leadless prolonged ECG monitoring in athletes.” Professor Sharma was involved with a very interesting panel on cardiac disease in women. Specifically, that research is currently disproportionately focused on men, and the panel debated whether this is because women suffer less from these conditions or because research is so Dr Finocchiaro and Dr Parry-Williams heavily focused on men to begin with that we don’t have sufficient female data. A highlight of the event was former CRY Research Fellow Dr Chris Miles winning the Young Investigator of the Year award for his work studying ARVC in athletes, “Sudden death and competitive sport in arrhythmogenic cardiomyopathy: A postmortem study of young athletes.”

Cardiac Risk in the Young

Once again the team of CRY doctors, led by Professor Sharma, had a massive impact at the British Cardiovascular Society conference. Some of the highlights included presentations from Professor Sharma, Dr Papadakis, Dr Elijah Behr, Dr Gati and Dr Malhotra. But the real highlight for me had to be seeing CRY Research Fellow Dr Basu (above) collecting her award on the stage at the end of the conference, having won the prize for “Best of the Best” abstracts in the field. The research provided further insights into the differences in the way the heart adapts to exercise based on gender and ethnicity. Winning this award is an amazing achievement, especially considering her main competition came from Dr Miles, another CRY Fellow. Both of these were brilliant presentations, demonstrating the significant impact CRY’s research is having. It is through CRY’s research programme that we are able to continue subsidising CRY’s screening programme. Without our doctors’ commitment to research we would be unable to do the screening. That is why events like these are so important, providing a platform for CRY’s team of doctors to present research and raise awareness in the cardiology community. It is the research which is changing the way medicine is practiced and that is only possible because of all of the support we receive from families throughout the country. Every time I am told we punch above our weight when it comes to research, it gives me a great sense of pride to know everything which is done in memory of all those who have died will help to save young lives.

ESC Congress Several CRY doctors attended ESC Congress 2018. Dr Papadakis presented research papers from Dr Nabeel Sheikh (“Diagnostic Yield of Genetic Testing in Young Athletes with T-wave Inversion”) and Dr Malhotra (“Outcomes of Cardiac Screening in Adolescent Soccer Players”). Dr Finocchiaro presented research on the athlete’s heart and diagnostic conundrums, while Professor Sharma gave a presentation entitled “Athletes with low ejection fraction and a structurally normal heart: How to manage?” Research Highlights 2018

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Interviews

Interview with Dr Michael Papadakis

In this interview, Dr Michael Papadakis addresses some concerns about family testing after a SADS death, referencing research which aimed to assess the impact of systematic ajmaline testing using high right precordial leads on the diagnostic yield of Brugada syndrome in 300 SADS families. The research, entitled “The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy”, was published in the Journal of the American College of Cardiology in March 2018 (Papadakis M, Papatheodorou E, Mellor G et al). When families are referred after a SADS death to the CRY Centre for Inherited Cardiac Conditions at St George’s Hospital would they always/usually have the ajmaline test on the same day as all the other tests? Yes, we do ajmalines on the same day for the great majority. We may not if: • The PM casts doubt regarding diagnosis, i.e. there is some

structural issue but no diagnosis such as idiopathic fibrosis or idiopathic LVH when I prefer to do an MRI first prior to ajmaline.

• The investigations in any relative is suggestive of a potential

structural cause.

• Middle-aged relative with arrhythmia try to exclude coronary

disease or cardiomyopathy before ajmaline.

• Family member not keen.

It is possible to have a polygenic disorder, which Brugada probably is, that the combination of parental genes may cause the disease in the child and we have definitely seen positive ajmalines like that in our cohort but in a tiny number of cases, which, to be honest, you are not sure how to interpret them. So, given the challenges of ajmaline testing, we have taken a more pragmatic approach and we won’t offer it to children when the results of both parents are completely normal (including the ajmaline tests) and the baseline investigations of the children (ECG, echo, exercise test…) are all completely normal. We could still offer an ajmaline to a child of negative parents (on a case-by-case basis) if, for example: • The children have a suspicious looking ECG at baseline. • The ajmaline of dad or mum looks suspicious but not

diagnostic.

• A child may be ajmalined irrespective of the parent’s result

if they happen to be referred earlier, i.e. the daughter is referred first and then we see (or not sure if we will ever see) the parents, or the daughter comes with only one of the parents.

My child died of SADS 15 years ago. At the time we were not offered ajmaline tests, we just had an ECG and an echo. Should we have had these tests and what should we do now? At the CRY centre we have been routinely doing an ajmaline test after a SADS death for just over 10 years. This was not always routine practice and it has not been routine practice within some Inherited Cardiac Conditions Centres throughout the UK. We would recommend you contact the ICC centre in your region and ask them to review your original tests and to ask for them to conduct comprehensive testing on first degree blood relatives of the child who died. It is possible that 15 years ago when there was less understanding of SADS that the cause of death could have been structural (e.g. a cardiomyopathy). The post mortem should be reviewed and if there is any concern the cause of death was a structural problem then an MRI may be warranted.

CRY’s research team at St George’s tested 911 first-degree blood relatives following a SADS death, using an ECG, echocardiogram, exercise ECG test, 24 hour monitor (Holter), and an ajmaline test.

My child died from SADS. Both of us (the parents) and our child were referred for further testing. Should all family members have had an ajmaline test? We used to ajmaline everyone in the past and we definitely offered it to most people in the paper published in March 2018. As a result of our and others’ research, our practice has changed.

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Research Highlights 2018

Is SADS the same as young sudden cardiac death? If someone dies young from cardiomyopathy, is this called SADS? If a young person dies from cardiomyopathy, this is considered a young sudden cardiac death. However, it is not considered a SADS death. A SADS death is when the cause of death is unascertained but all possible causes of death are excluded, leaving the probable cause of death to be cardiac. SADS deaths are usually caused by conditions like long QT, Brugada, CPVT and WPW. SADS is due to an electrical problem and after the death there is no evidence of structural changes to the heart.

Cardiac Risk in the Young


My child died of hypertrophic cardiomyopathy. Should family members have been offered an ajmaline test? No. If the cause of death was established as a structural problem, then the further tests of family members should focus on that specific condition. This may include an ECG, echo, exercise test, Holter monitor and in the case of cardiomyopathy an MRI. Genetic cascade testing may also be offered. If the individuals who are at risk for having Brugada when they have the ajmaline infusion, what response does that infusion mimic in terms of an in-life response? Does it represent a phase when resting? Does it represent a phase when scared or alerted? What ajmaline does is block some of the sodium ion channels. These are the same channels that are defective in Brugada syndrome. In most individuals ajmaline will cause some ECG changes, but nowhere near enough to mimic the diagnostic Brugada ECG pattern as they have “normal” sodium channels and they are able to cope/compensate. In those with Brugada syndrome the ion channels are defective and by adding a sodium channel blocker you provoke the ECG pattern, as they do not have the normal reserves. So, in a way, ajmaline makes the situation temporarily worse (makes the electricity of the heart more unstable) to allow us to diagnose the condition. As it is a very short acting drug it is out of the system within minutes. Ajmaline is not a stress test, i.e. it does not mimic exercise or anxiety. How do you not know that for every 10 or 20 healthy individuals an ajmaline test just happens to cause a benign ECG pattern that’s only seen when given this chemical? Are there any studies suggesting a clear response to a selected portion in terms of Brugada and ajmaline? This is an excellent point and it is possible that some of our

positive results represent what we would call a false-positive, i.e. the test is positive but the individual does not have the condition. We know that no test in medicine is 100% accurate. There are always a few false positives or even false negatives even with accurate tests. In the past few years, concerns have been raised about the specificity of the ajmaline test which have been predominantly based on a Turkish study, i.e. having a high false positive rate; in other words, a positive test not indicating disease. Our estimate is that the ajmaline test may be falsely positive in 1 in 20 individuals we test (5%) and we think this is the worst case scenario. However, it is important to remember that it is different to do the test in an otherwise “healthy” population and difficult to ignore in a family who just lost someone. In addition, you can look at other clues such as multiple family members in the same family being the most important. This point is discussed extensively in our paper. Once the individual has gone through a negative result from ajmaline, does this necessarily mean they are Brugada free? This is an excellent point and it is possible that some of our negative results represent what we would call false-negatives, i.e. the test is negative but the individual has the condition. We know that no test in medicine is 100% accurate. There are always a few false negatives or even false positives even with very accurate tests. It is important to emphasise that we always advise families that should they experience any new symptoms they should come back to us and not be reassured by their negative screening. However, it is also important to emphasise that we are extremely reassuring to individuals with a completely negative screening. Even if one assumes that an ajmaline test is falsely positive, the risk of that individual would be extremely small.

Cardiac Risk in the Young

Research Highlights 2018

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Interviews

Interview with Dr Aneil Malhotra

How did you conduct your study? This study sought to investigate the incidence and causes of sudden cardiac death in adolescent football players in the UK. The English Football Association cardiac screening programme enabled us to study a well-defined population of over 11,000 scholar footballers in a systematic way. The study itself was conducted across three sites: St George’s University, Wembley stadium and St George’s Park in Burton-on-Trent. Between 1996 and 2016, we evaluated 11,168 adolescent athletes aged 16 years, the vast majority of whom were males (95%). They had all undergone cardiac screening with a health questionnaire, physical examination, ECG and echocardiogram. We were not only able to report the number of conditions identified, but also the number of sudden cardiac deaths that ensued, which were confirmed with autopsy reports. The main findings of this study were: • During screening, 42 (0.38%) athletes were found to have

cardiac disorders associated with sudden cardiac death. A further 225 (2%) minor cases of congenital and valvular abnormalities were identified. • Following screening, there were 23 deaths from all causes, of which 8 (35%) were attributed to cardiac disease. • Cardiomyopathies accounted for 7 (88%) sudden cardiac deaths. • 6 (75%) athletes who suffered sudden cardiac death demonstrated a normal cardiac screen at the age of 16 years. • The mean time between screening and sudden cardiac death was 6.8 years. • Based on a total of 118,351 person-years, the incidence of sudden cardiac death in previously screened adolescent soccer players was 1/14,794 person-years. While 1 in 266 of the footballers having a condition may sound concerning, how much of this is due to a high rate of Wolff-Parkinson-White syndrome in this group? While a WPW ECG pattern accounted for the largest proportion of serious conditions among football players, the prevalence of a WPW pattern among our study population was 0.23% (26/11,168) which is similar to that reported in the general population which is between 0.1-0.3% (see reference). (Ehtisham J, Watkins H. Is Wolff-Parkinson-White syndrome a genetic disease? J Cardiovasc Electrophysiol. 2005 Nov; 16 (11): 1258-62.) Does this research help confirm what we already knew, that athletes are more at risk than the general population? The focus of the study was on the conditions identified that can be associated with exercise-induced sudden cardiac death. While all those who died did so during exercise, this is an association rather than causality, which is more difficult to prove without a control group of non-exercising individuals with a cardiac condition.

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Research Highlights 2018

Seeing as 74% of those diagnosed with a condition were able to continue playing, can this research reassure other footballers and athletes? The majority of these players consisted of those with WPW who underwent a curative procedure. Some with structural abnormalities such as anomalous coronary artery origins and valvular disease also underwent corrective operations and returned to play. This is encouraging for players who have been diagnosed with a condition in that this often does not signify the end of their sporting career. How important is this research in reinforcing the value of cardiac screening, as it’s clear that all athletes need multiple screenings to ensure their safety? Of the 42 cases identified in this study, only 2 experienced symptoms. Of the 8 deaths none were symptomatic. Therefore, some form of screening procedures need to exist to detect the vast majority of conditions associated with sudden cardiac death. Despite identifying 42 cases, this study shows that some athletes who are predisposed to developing cardiomyopathy in the future will not be identified at 16 years of age. Therefore, serial evaluations are advised. Can this research help put better preventative measurements in place, with the FA making a proactive commitment to improve the rates of cardiac screening? In 86% of all serious diseases identified, the ECG was abnormal. This suggests that screening should be implemented not just across the upper echelons of football, but potentially across grassroots football. We should also highlight that screening is not a substitute for emergency response facilities, including AED provision and usage. Our group recently showed that emergency response facilities, including primary and secondary prevention strategies across professional football clubs in England (see reference), was of a higher standard when compared with European counterparts. Training staff and ensuring AEDs are maintained are crucial in ensuring safety of athletes on the pitch too. (Malhotra A, Dhutia H, Gati S, Yeo TJ, Finocchiaro G, Keteepe-Arachi T, Richards T, Walker M, Birt R, Stuckey D, Robinson L, Tome M, Beasley I, Papadakis M, Sharma S. Br J Sports Med. 2017 Jun 14. pii: bjsports-2016-097440.) What research needs to be done to further these findings? There are a number of avenues to explore based on the findings of this study. There was a 6-fold higher incidence of sudden cardiac arrest among black footballers compared to white footballers. Although there were many more white (90%) than black subjects, this corroborates with findings in the USA among black basketball players. The reasons behind this ethnic variation should be explored further. The paper also highlighted over 250 athletes with abnormal ECG findings but a structurally normal heart. Re-evaluation of these athletes will help further our understanding as to how many of these may have developed a cardiomyopathy. Finally, longitudinal prospective serial evaluation of footballers will help shed light onto the issue of if and when a cardiomyopathy may manifest. The FA recommendations of an ECG at 18, 20 and 25 years of age, following an ECG and echo at 16 years, will provide data to help investigate this.

Cardiac Risk in the Young


Interview with Dr Sabiha Gati After publishing research in Heart, entitled “Exercise recommendations in patients with valvular heart disease” (Gati S, Malhotra A, Sharma S. September 2018), former CRY Research Fellow Dr Sabiha Gati offers advice about exercising with valvular heart disease. Why is valvular heart disease important in the young population? Valvular heart disease affects approximately 3% of young individuals, many of whom aspire to partake in competitive sport or high intensity recreational exercises. Research supported by CRY’s screening programme has shown that 1 in 100 individuals have a minor cardiac structural abnormality, such as bicuspid valve disease or mitral valve prolapse, which requires surveillance throughout life. Therefore, early identification may prevent future heart complications. Why does valve disease progress with exercise? Reports on the natural history of valvular heart disease in exercising individuals are limited. However, there is a theoretical possibility that a large blood volume pumped out by the heart during exercise associated, vigorous heart contractions may accelerate valve problems and may subsequently cause changes in the heart structure, function, electricity and even lead to sudden death.

1. Symptomatic detection: Warning symptoms of progressive disease

Aortopathy

Functional deterioration

Pulmonary hypertension

Adverse cardiac remodelling

Arrhythmias

Myocardial Ischaemia

How is valvular heart disease managed in exercising individuals? The management of exercising individuals with valvular heart disease requires a structured approach which incorporates: 1) Assessment of symptoms such as chest pain, breathlessness, dizziness and fluttering in the chest. 2) Assessment of functional capacity. 3) Type and nature of valve disease. Is it a left sided or right sided valve problem and is the valve narrowed or leaky?

2. Risk of infective endocarditis. Ensure good dental hygiene

General advice for all patients with valvular heart disease 3. Avoid tattoos and body piercings

The potential effects of adrenergic surges and increased haemodynamic load associated with exercise in individuals with valvular heart disease

4. Surveillance with 1-2 yearly clinical evaluation

4) The impact on the heart structure and function. Which valve abnormalities are common in young individuals? Mitral valve prolapse and bicuspid aortic valves are the most common valvular abnormalities in young exercising individuals. The good news is that the risk of adverse events is low but both valve abnormalities can be associated with important complications that require monitoring with an ultrasound scan of the heart. Young people with minor valve abnormalities can compete in any sport. Those with moderate level of disease will require some further tests, including an exercise treadmill test, to assess how they do. What advice would you give to exercising individuals with valve disease?

5. Familial evaluation for first-degree relatives of athletes with bicuspid aortic valve/mitral valve prolapse

Cardiac Risk in the Young

Exercising individuals with valve abnormalities should undergo yearly to 2 yearly assessments depending on the severity of valve disease they may have and we should inform them about the warning symptoms of progressive deterioration of valve disease. Research Highlights 2018

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Interviews

moving forward.

Interview with Dr Chris Miles

In this interview former CRY Research Fellow Dr Chris Miles discusses the arrhythmogenic cardiomyopathy research that he presented at EuroPrevent 2018 (“Sudden death and competitive sport in arrhythmogenic cardiomyopathy: A post-mortem study of young athletes”) that led to his Young Investigator of the Year award, and what his research aims are

Why did you choose to research arrhythmogenic cardiomyopathy in athletes?

suggesting that ACM affects the whole heart independently of changes that occur in the right ventricle during sustained exercise. What are the other key takeaways from your research? Over a third of young sudden death victims diagnosed with arrhythmogenic cardiomyopathy at expert post-mortem were engaged in competitive sport, principally sports with a high dynamic component such as football. Young athletes who had died suddenly from arrhythmogenic cardiomyopathy most often died during physical exertion, primarily while participating in their sport.

There is still much for us to learn about arrhythmogenic cardiomyopathy, in particular understanding more about why the condition arises and how it can be detected. This is especially relevant in young athletes, where competitive sport is an established trigger for heart rhythm disturbances.

They also had evidence of enlargement of the right ventricle alongside increased weight of the heart, consistent with the changes we see in the heart following prolonged athletic training.

Appearances of the diseased heart may also overlap with adaptive processes we see in the healthy athlete; it has been proposed that exercise may be enough to ‘trigger’ emergence of the condition in those with an underlying genetic susceptibility.

How did it feel to win the Young Investigator of the Year award at EuroPrevent?

Why is finding evidence of disease affecting the left ventricle so important?

I was deeply honoured to receive the Young Investigator Award in Sports Cardiology. This competition provides an excellent opportunity to Dr Miles with Professor Sharma present work at an international level and is well recognised by colleagues within the field.

The overwhelming majority of our arrhythmogenic cardiomyopathy sudden death group had evidence of disease involving the left ventricle, a significant finding given its classical description as a right ventricular disorder (arrhythmogenic right ventricular cardiomyopathy). There was also no difference in the presence of left ventricular involvement between young athletes and non-athletes,

I would like to thank my peers and supervisors Dr Elijah Behr and Professor Mary Sheppard, in addition to Cardiac Risk in the Young for its essential role in funding the CRY Centre for Cardiac Pathology. CRY is supported by hundreds of families affected by young sudden cardiac death and we hope to continue to make important progress into researching one of its important causes. What do you intend to focus on in your research next? I will continue my research into arrhythmogenic cardiomyopathy and also study the overlap with another rare disorder that affects the heart’s rhythm, Brugada syndrome. Dr Miles presenting his research at EuroPrevent 2018

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Research Highlights 2018

My PhD will investigate the pathological and genetic basis of these conditions.

Cardiac Risk in the Young


Dr Nabeel Sheikh discusses the role of genetic testing when evaluating athletes with abnormal ECG results In this article former CRY Research Fellow Dr Sheikh details his research “Diagnostic Yield of Genetic Testing in Young Athletes with T-Wave Inversion.” (Sheikh N, Papadakis M, Wilson M et al. Circulation, May 2018). Regular intensive exercise is associated with a number of changes in the heart which include enlargement of the chambers, thickening (hypertrophy) of the muscle, and slowing of the heart rate. These changes can be detected on an athlete’s electrical tracing (ECG) and ultrasound scan (echocardiogram). In the vast majority of athletes, such changes are well within what we would class as normal for a highly athletic individual. However, a small number of athletes and particularly those of African/Afro Caribbean (black) ethnicity exhibit changes on their ECG called T-wave inversion (TWI) which are commonly seen in several inherited (genetic) heart conditions implicated in exercise-related sudden death. The presence of TWI on an athlete’s ECG therefore invariably raises concerns and prompts several investigations to ensure the athlete does not harbour one of these inherited heart conditions. Up until now, studies have shown that in a small number of athletes with TWI, a heart condition is indeed found, either after initial routine tests or after subsequent tests during followup over a number of years. This is important to determine, as affected individuals can then be given the appropriate treatment and advice about whether to exercise or not, as well as treatment and lifestyle advice that can lower the risk of sudden cardiac death (SCD). However, in the vast majority of athletes with TWI, a cardiac condition is not found, despite comprehensive investigations and follow-up. This results in uncertainty about whether these athletes have a sinister heart condition or not.

heart condition or not. Some of the drawbacks with gene testing are that it is very expensive to do and that the results can take a long time to process. In addition, when results do arrive, in some cases they can be difficult to interpret because changes of uncertain significance are uncovered. In our study, we added genetic testing to the comprehensive routine clinical evaluation of 50 black and 50 white athletes to see whether this would help us find out the cause of TWI in those athletes whose clinical investigations were all normal. The results from our study show that firstly, comprehensive clinical evaluation can result in a diagnosis over one fifth of athletes with TWI (21%) after a first evaluation. From this perspective, cardiac MRI appears to be the most useful investigation and athletes with TWI in the lateral ECG leads appear to be the ones who harbour a cardiac condition. In addition, cardiac conditions are identified in more than twice the number of white athletes with TWI compared to black athletes with TWI (30% versus 12%). Conversely, the results of genetic testing are only positive in 10% of athletes yet triple the cost of evaluation: routine clinical testing alone costs $1,084 per athlete evaluated, but the addition of genetic testing put this cost up to $3,267 per athlete. Furthermore, genetic testing contributed to additional diagnoses beyond routine clinical testing in only 2.5% of athletes with T-wave inversion despite the substantial cost, and caused diagnostic uncertainty in a minority of athletes. The results from our study provide the answer to a long awaited question: whether genetic testing can help in the evaluation of athletes with TWI. Our study shows that such a strategy is not useful in day-to-day clinical practice and that routine clinical investigation alone (particularly cardiac MRI) outperforms genetic testing in determining the cause of TWI in athletes. Our study also shows that TWI is associated with cardiac disease in 20% of athletes.

So far, all of the studies investigating athletes with TWI have used routine clinical tests such as an echocardiogram and cardiac MRI scan to try to detect whether an athlete has a heart condition. However, as mentioned, most of the heart conditions associated with TWI are genetic, meaning they arise due to a spelling mistake in a gene containing information about the heart’s structure. Therefore, one unanswered question has been whether searching for these spelling mistakes by gene testing athletes will help us determine whether their TWI is due to a genetic

Cardiac Risk in the Young

Research Highlights 2018

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Research

Papers/Articles •  “Response by Merghani et al to Letters Regarding Article, ‘Prevalence of Subclinical Coronary Artery Disease in Masters Endurance Athletes With a Low Atherosclerotic Risk Profile.’” Merghani A, Maestrini V, Rosmini S et al. Circulation, January 2018.

•  “The Role of Cardiovascular Magnetic Resonance Imaging in the Assessment of Highly Trained Athletes.” Gati S, Sharma S, Pennell D. Journal of American Cardiology, February 2018.

step in the right direction, based on these simple elements, is the most important. We here review arrhythmic presentations of rare or relatively rare diseases, and suggest a simple ‘rule out–rule in’ approach to help direct clinical suspicion and minimize risk of neglect.” •  “Role of Doppler Diastolic Parameters in Differentiating Physiological Left Ventricular Hypertrophy from Hypertrophic Cardiomyopathy.” Finocchiaro G, Dhutia H, D’Silva A et al. Journal of the American Society of Echocardiography, May 2018.

“Cardiac magnetic resonance plays an increasingly important role in helping to establish an accurate diagnosis in these individuals. This review highlights the role of cardiac magnetic resonance in differentiating physiological adaptation in athletes from pathology.”

“Reduced septal and lateral E’ are rarely observed in young elite athletes. Tissue Doppler velocities tend to decrease with increasing age and LV size, and values representative of supernormal diastolic function are found in less than one-third of young athletes. Cutoff thresholds for Doppler parameters of diastolic function should be corrected for multiple demographic and clinical variables to differentiate cardiac adaptation to exercise from HCM in young individuals.”

•  “The Diagnostic Yield of Brugada Syndrome After Sudden Death With Normal Autopsy.” Papadakis M, Papatheodorou E, Mellor G et al. Journal of American Cardiology, March 2018.

•  “Diagnostic Yield of Genetic Testing in Young Athletes with T-wave Inversion.” Sheikh N, Papadakis M, Wilson M et al. Circulation, May 2018.

“Systematic use of ajmaline testing with high RPLs increases substantially the yield of BrS in SADS families. Assessment should be performed in expert centers where patients are counselled appropriately for the potential implications of provocation testing.”

“Up to 10% of athletes with TWI revealed mutations capable of causing cardiac disease. Despite the substantial cost, the positive diagnostic yield from genetic testing was one half that from clinical evaluation (10% versus 21%) and contributed to additional diagnoses in only 2.5% of athletes with TWI in the absence of a clear clinical phenotype, making it of negligible use in routine clinical practice.”

•  “Obesity and sudden cardiac death in the young: Clinical and pathological insights from a large national registry.” Finocchiaro G, Papadakis M, Dhutia H et al. European Journal of Preventive Cardiology, March 2018. “Various conditions underlie sudden cardiac death in obesity, with a prevalence of sudden arrhythmic death syndrome, left ventricular hypertrophy and coronary artery disease. The degree of left ventricular hypertrophy measured by heart weight is excessive even after correction for body size. Almost one in four young obese sudden death patients show some degree of coronary artery disease, underscoring the need for primary prevention in this particular subgroup.” •  “Put out to pasture: What is our duty of care to the retiring professional footballer? Promoting the concept of the ‘exit health examination’ (EHE).” Carmody S, Jones C, Malhotra A et al. British Journal of Sports Medicine, March 2018. “The aim of this editorial is to highlight the health issues faced by players in retirement, to advance the concept of the ‘exit health examination’ (EHE) and to promote the duty of care that clinicians, clubs and governing bodies have to ensure that the risk of poor longterm health outcomes is minimised.” •  “A guideline update for the practice of echocardiography in the cardiac screening of sports participants: A joint policy statement from the British Society of Echocardiography and Cardiac Risk in the Young.” Oxborough D, Augustine D, Gati S et al. Echo Research and Practice, March 2018. “Echocardiography is a primary investigation utilized in the pre-participation setting and in 2013 the British Society of Echocardiography and Cardiac Risk in the Young produced a joint policy document providing guidance on the role of echocardiography in this setting. Recent developments in our understanding of the athlete’s heart and the application of echocardiography have prompted this 2018 update.” •  Comment in “Cardiac Arrest During Competitive Sports.” D’Silva A, Papadakis M, Sharma S. New England Journal of Medicine, April 2018. “In their study, Landry et al. (Nov. 16 issue) found that only 20% of young athletes who had sudden cardiac arrest during participation in competitive sports in Ontario, Canada, had a disorder that could have been detected by preparticipation screening electrocardiography (ECG). We question the generalizability of these conclusions because of the small sample size (16 athletes).” •  “Common presentation of rare cardiac diseases: Arrhythmias.” Olivotto I, Finocchiaro G, Maurizi N et al. International Journal of Cardiology, April 2018. “Advanced imaging and laboratory testing at experienced referral centers is then necessary to reach a final diagnosis, but the first

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Research Highlights 2018

•  “Diet and Nutrition after the PURE study.” Malhotra A, Sahdev N, Sharma S. European Heart Journal, May 2018. “The PURE study provides an interesting and thought-provoking view on the impact of macronutrients on total mortality. Whether the study calls for a radical change in the current ESC recommendations is debatable.” •  “The relationship between left ventricular structure and function in the elite rugby football league athlete as determined by conventional echocardiography and myocardial strain imaging.” Forsythe L, MacIver DH, Johnson C et al. International Journal of Cardiology, June 2018. “The aims of this study were to establish the left ventricular (LV) phenotype in rugby football league (RFL) athletes and to mathematically model the association between LV size, strain and ejection fraction (EF).” •  “Recommendations for participation in leisure time or competitive sports in athletes-patients with coronary artery disease: a position statement from the Sports Cardiology Section of the European Association of Preventive Cardiology (EAPC).” Börjesson M, Dellborg M, Niebauer J et al. European Heart Journal, July 2018. “This article presents an update of earlier recommendations from the Sports Cardiology section of the European Association of Preventive Cardiology (EAPC) on sports-participation in patients with coronary artery disease (CAD), coronary artery anomalies (CAAs), or spontaneous dissection of the coronary arteries (SCAD), all entities being associated with myocardial ischaemia.” •  “Outcomes of Cardiac Screening in Adolescent Soccer Players.” Malhotra A, Dhutia H, Finocchiaro G et al. New England Journal of Medicine, August 2018. “We sought to investigate the incidence and causes of sudden cardiac death among adolescent soccer players in the United Kingdom.” •  “Electrocardiographic differentiation between ‘benign T-wave inversion’ and arrhythmogenic right ventricular cardiomyopathy.” Finocchiaro G, Papadakis M, Dhutia H et al. Europace, August 2018. “The ECG is frequently abnormal in patients with ARVC [arrhythmogenic right ventricular cardiomyopathy] and anterior TWI [T-wave inversion] is the most common feature. Anterior TWI is usually accompanied by other abnormalities in ARVC, which are uncommon in healthy individuals.” •  “Cardiac Screening of Young Athletes: a Practical Approach to Sudden Cardiac Death Prevention.” Dhutia H, MacLachlan H. Current Treatment Options in Cardiovascular Medicine, August 2018. “We aim to report on the current status of cardiovascular screening of

Cardiac Risk in the Young


Papers/Articles athletes worldwide and review the up-to-date evidence for its efficacy in reducing sudden cardiac death in young athletes.” •  “Exercise recommendations in patients with valvular heart disease.” Gati S, Malhotra A, Sharma S. Heart, September 2018. “Asymptomatic individuals with minor valvular abnormalities may engage in all forms of competitive sport, whereas those with lesions of moderate severity may exercise intensively if an exercise stress test tailored to the relevant physical activity reveals good functional capacity without myocardial ischaemia, haemodynamic disturbances or arrhythmia.” •  “Predictors of poor clinical outcomes in patients with acute myocardial infarction and non-obstructed coronary arteries (MINOCA).” Ciliberti G, Coiro S, Tritto I et al. International Journal of Cardiology, September 2018. •  “Unravelling the mystery behind sudden death in the young: a wake up call for nationwide autopsy-based approach.” Finocchiaro G, Sharma S, Sheppard MN. Europace, September 2018. •  “Recommendations for participation in competitive sports of athletes with arterial hypertension: a position statement from the sports cardiology section of the European Association of Preventive Cardiology (EAPC).” Niebauer J, Börjesson M, Carre F et al. European Heart Journal, October 2018. “Despite its undisputed multitude of beneficial effects, competitive athletes with arterial hypertension may be exposed to an increased risk of cardiovascular events. This document is an update of the 2005 recommendations and will give guidance to physicians who have to decide on the risk of an athlete during sport participation.” •  “Incidental identification of stent migration in the ascending aorta: a cautionary tale.” Samways J, MacLachlan H, Ramasamy A et al. Hellenic Journal of Cardiology, October 2018. •  “The Female Athlete’s Heart: Facts and Fallacies.” Simone CS, Colombo S, Finocchiaro G. Current Treatment Options in Cardiovascular Medicine, November 2018. “Undoubtedly, males and females exhibit many biological, anatomical, and hormonal differences, and cardiac adaptation to exercise is no

exception. The increasing participation of women in sports should stimulate the scientific community to develop large and longitudinal studies aimed at a better understanding of cardiac adaptation to exercise in female athletes.” •  “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, November 2018. •  “Exercise testing and coronary disease: pushing fitness to higher peaks.” Sharma S, Malhotra A. European Heart Journal, November 2018. •  “What is the role of gene testing in athletes with T-wave inversion?” Sahdev N, Sheikh N, Sharma S. European Heart Journal, November 2018. •  “Prevalence and significance of T-wave inversion in Arab and Black paediatric athletes: Should anterior T-wave inversion interpretation be governed by biological or chronological age?” McClean G, Riding NR, Pieles G et al. European Journal of Preventive Cardiology, November 2018. •  “Interpreting the Athlete’s ECG: Current State and Future Perspectives.” Basu J, Malhotra A. Current Treatment Options in Cardiovascular Medicine, November 2018. “This review aims to describe the evolution of the current knowledge on ECG interpretation as well as future directions.” •  “Cardiac Magnetic Resonance Imaging in Athletes: Acquiring the Bigger Picture.” Sharma S, Malhotra A. Journal of the American College of Cardiology, December 2018. •  “Right ventricular structure and function in senior and academy elite footballers.” Popple E, George K, Somauroo J et al. Scandinavian Journal of Medicine and Science in Sports, December 2018. •  “12-Lead Electrocardiography Parameters for Differentiating Athlete’s Heart From Arrhythmogenic Right Ventricular Cardiomyopathy.” Sharma S, Haugaa KH. Journal of the American College of Cardiology, December 2018.

Presentations at ESC Congress, BCS and EuroPrevent • “Athletes with low ejection fraction and a structurally normal heart: How to manage?” Sharma S, ESC Congress, 2018. • “Diagnostic Yield of Genetic Testing in Young Athletes with T-wave Inversion.” Papadakis M, ESC Congress, 2018. • “Outcomes of Cardiac Screening in Adolescent Soccer Players.” Malhotra A, ESC Congress, 2018. • “Aetiologies of sudden death in young athletes compared with nonathletes. Data from a large pathology registry.” Finocchiaro G, ESC Congress, 2018. • “Sudden death in myocarditis. Data from a large pathology centre.” Finocchiaro G, (poster) ESC Congress, 2018. • “Molecular changes in a case of exercise-induced arrhythmogenic cardiomyopathy.” Papatheodorou E, ESC Congress, 2018. • “Noncompaction cardiomyopathy: Diagnostic criteria for a mysterious entity.” Gati S, ESC Congress, 2018. • “Etiology of Sudden Death in Sports: Insights from a United Kingdom Regional Registry.” Sharma S, BCS, 2018. • “Sudden death and competitive sport in arrhythmogenic cardiomyopathy: A post-mortem study of young athletes.” Miles C, BCS, 2018.

• “Sudden death and competitive sport in arrhythmogenic cardiomyopathy: A post-mortem study of young athletes.” Miles C, EuroPrevent, 2018. • “The effect of ethnicity on left ventricular adaptation to exercise.” Basu J, (poster) EuroPrevent, 2018. • “Anomalous coronary artery origin and sudden cardiac death during exercise. Data from a large regional registry.” Finocchiaro G, EuroPrevent, 2018. • “What can we learn from the athletes? Exercise parameters in men and women.” Sharma S, EuroPrevent, 2018. • “Master endurance athletes: Too much pressure?” Parry-Williams G, (poster) EuroPrevent, 2018. • “The efficacy of the Ziopatch patch novel leadless prolonged ECG monitoring in athletes.” Malhotra A, (poster) EuroPrevent, 2018. • “Comparison of different ECG Criteria in the interpretation of the Veteran Athlete’s ECG.” Papatheodorou E, (poster) EuroPrevent, 2018. • “Apical HCM and mild phenotype HCM in athletes: common and benign? Let them play?” Papadakis M, EuroPrevent, 2018. • “Hypertrabeculation in athletes - ignore and move on?” Gati S, EuroPrevent, 2018.

For a full list of CRY’s research visit www.c-r-y.org.uk/research/crys-contribution-to-research Cardiac Risk in the Young

Research Highlights 2018

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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 April 2019 there are 7 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, 21 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’s research improves our understanding of the incidence, prevention, assessment and management of cardiac conditions that can cause young sudden cardiac death (YSCD). 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) • 80% of SADS deaths occur at rest or during sleep (Mellor G et al. 2014) • ARVC is the cardiac condition most likely to cause sudden death during exercise (Finocchiaro G et al. 2016)

• Management of those at increased risk of YSCD

• Prevalence of cardiac conditions in young people • Incidence of YSCD

• Exercise prescription

• Causes of YSCD

• Psychological adjustment

• Circumstances of YSCD

• Identification of those at increased risk of YSCD

• Risk stratification of those identified

• Screening

• Monitoring those identified

• Symptoms • Family history

26.5% of CRY’s Funding Supports Research Fundraising 14% Governance 2.5%

Screening 35%

Awareness 15% Support 7%

Research 26.5%

• The Matthew Cragg Memorial Fund

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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

Research Highlights 2018

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 2018 the following ringfenced funds made significant contributions to support CRY’s research team at St George’s Hospital: • The Joseph Kellogg Memorial Fund • The Alan Lumley Memorial Fund

• The Rosie Mitchell Memorial Fund • The Alex Reid Memorial Fund

Cardiac Risk in the Young

Profile for Cardiac Risk in the Young

CRY Research Highlights 2018  

CRY Research Highlights 2018