CRY Research Highlights 2019

Registered Charity No. 1050845

Research Highlights 2019 Inside this issue. . .

P2 Conferences P6 Interviews P10 Marking CRY’s 25th year P12 Papers/Articles P13 Presentations P14 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

Yet again, the CRY Conference was an excellent event. We had more attendees this year, with 120 people coming to hear experts from around the world present their research.

After CRY Chief Executive Dr Steven Cox gave his introduction to the day, former CRY Research Fellow Dr Sabiha Gati presented first. between coronary artery anomaly and exercise related death,” Professor Börjesson explained early on in his presentation.

Professor Elijah Behr from St George’s Hospital spoke about “Risk stratification in athletes with Brugada syndrome – Does it matter?” Dr Behr addressed different methods of risk stratification and their different benefits and limitations.

Dr Gati tackled the subject of exercising with aortic and mitral valve disease, and provided some exercise recommendations and precautions for those with bicuspid aortic valve.

Next we were pleased to welcome Dr Maite Tome, a Consultant Cardiologist and Honorary Senior Lecturer at St George’s Hospital, London. Dr Tome’s presentation, “Athletes with dilated aorta; When to worry?”, explored how to assess these individuals, the use of genetic testing, and how elective surgery can be a life-saving process.

Dr Guido Pieles spoke about new recommendations for those with congenital heart disease participating in competitive sport. Dr Pieles discussed how new recommendations have introduced an approach to provide individual assessment and risk stratification, giving athletes advice that is better tailored to their condition and the physical strain they are undergoing.

Matts Börjesson joined us from Gothenburg, Sweden, to talk about coronary artery anomalies.

“We can clearly say that there is a strong association

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Professor Antonio Pelliccia joined us again from Italy to give a presentation on “Lateral and inferior-lateral T-Wave inversion: search for cardiac disease.” Professor Pelliccia had several key take-home messages, including the fact that the detection of T-Wave inversion in athletes should lead to a diagnostic search for underlying cardiomyopathies, with family screening and extensive imaging tests.

Former CRY Research Fellow Dr Aneil Malhotra followed with a talk on “Significance and evaluation of inferior T-Wave inversion”. Dr Malhotra shared some new research which aimed to investigate the prevalence and significance

Cardiac Risk in the Young

CRY International Medical Conference of inferior T-Wave inversions in large groups of healthy individuals and patients with cardiomyopathy.

As always, CRY Consultant Cardiologist Professor Sanjay Sharma attended to offer his support and expertise. With his talk, “Anterior T-Wave inversion in athletes”, Professor Sharma examined various matters, including the prevalence and determinants of anterior T-Wave inversion in athletes, how the prevalence of T-Wave inversion can vary depending on ethnicity, and which methods can be used to differentiate variants from those who might represent cardiac pathology.

To discuss our understanding of arrhythmogenic right ventricular cardiomyopathy (ARVC), CRY myheart cardiologist Dr Michael Papadakis gave a presentation entitled “Right ventricular remodelling in athletes: When enough is enough!”.

Dr Papadakis discussed the influential research completed by Dr Chris Miles. This study (“Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.” Miles C, et al. Circulation, 2019) revealed that ARVC is a biventricular disease and often affects the left ventricle.

Former CRY Research Fellow Dr Gherardo Finocchiaro presented research into using cardiac MRI in ARVC, and also discussed how we are continuing to discover that the left ventricle is often affected in this disease as well.

Professor Mary Sheppard from the CRY Centre for Cardiac Pathology (CRY CCP) followed. Professor Sheppard began her talk, “Arrhythmogenic right ventricular cardiomyopathy; A pathologist’s perspective”, by explaining how she got involved with CRY following the misdiagnosis of a case of arrhythmogenic cardiomyopathy. She went on to discuss ARVC and how the CRY CCP and new research has impacted the practice used to deal with this condition.

Cardiac Risk in the Young

The last presentation of the day, “Arrhythmogenic Right Ventricular Cardiomyopathy; Looking into the future”, came from Professor Domenico Corrado. Professor Corrado looked at current diagnostic criteria for ARVC from the 2010 International Task Force (ITF) and some of its significant limitations that need to be improved.

After the presentations were finished, the afternoon was made up of case study sessions. These were panelled by Professor Sharma, Professor Corrado, Professor Pelliccia, Professor Börjesson, Professor Behr and Dr Tome. The sessions focused on electrical disease, cardiomyopathies and structural disease, and served as a great way to spark discussions to see how different experts would approach various cases. Finally, Dr Joyee Basu hosted a quiz in the style of ‘Who Wants To Be A Millionaire’, which was an ideal end to the conference. The quiz was only light-hearted, but reinforced what was discussed through the day.

Many thanks must go to our sponsor Radcliffe Cardiology, and to our exhibitors GE Healthcare, Sanofi, Schiller, MediBioSense, and Abbott.

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 Research Highlights 2019

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Conferences

CRY’s first Family Research Day

On May 11 we hosted the first CRY Family Research Day, giving some of our supporters a chance to learn more about the massive impact of our research. CRY Chief Executive Dr Steven Cox began the day with a brief overview of how our research and team of specialists have developed over the years, CRY doctors and Research Fellows shared their insight on a variety of subjects.

will also examine a new health questionnaire to optimise our screening protocol, which will hopefully increase the number of people we can screen and reduce the cost.

Dr Sabiha Gati shared what her time as a CRY Research Fellow involved, from serving as a specialist at over 80 screenings throughout the UK to reviewing referrals in CRY clinics (primarily inherited cardiac diseases at University Hospital Lewisham). Dr Gati’s research focused on the structural changes within young, exercising individuals’ hearts. The study garnered worldwide interest and Dr Gati went on to receive a host of prizes.

Since completing her time as a CRY Research Fellow, Dr Gati has moved on to become a successful consultant cardiologist.

She has also started an educational training programme for GPs throughout the UK as a new initiative under CRY, which trains GPs how to better analyse abnormal ECGs for young individuals. With her impactful research and the work she has continued since, Dr Gati is a fantastic example of how valuable our Research Fellows are.

Dr Hamish MacLachlan talked about his next research project, which will provide the most comprehensive study on the incidence of sudden cardiac death yet. His research

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Professor Mary Sheppard spoke next about her role at the CRY Centre for Cardiac Pathology (CRY CCP). Professor Sheppard first shared a little information on how much work the heart has to do and exactly how it functions, before moving onto how her work as a pathologist involves looking at the abnormalities in the heart muscle. With Dr Tim Bowker, who is now one of CRY’s Trustees, Professor Sheppard produced one of the first surveys of sudden, unexpected cardiac death in the UK. “It was the first paper, really, to emphasize the entity of sudden adult death, or sudden arrhythmic death,” Professor Sheppard explained. “Because up until then [1994, when the survey was carried out] most people believed you died of coronary artery disease… We found that, no, in a significant number of sudden unexpected deaths, 7%, the pathologists found nothing…

“The Fellows and the clinicians and cardiologists have now begun to expand our knowledge of these causes. This paper was seminal in telling pathologists when you find a sudden death – a young person, heart is normal, toxicology is negative – you have to do further investigations. You cannot simply leave it unexplained or unascertained.”

After discussing some of her earlier work, Professor Sheppard went on to explain how the CRY CCP has excelled even more since moving to St George’s Hospital in 2014, becoming the largest pathology unit dealing with sudden cardiac death in the world. The CRY CCP has changed the way we understand

Cardiac Risk in the Young

CRY’s first Family Research Day specialists, and the cost.

“This was never going to take off if it wasn’t for someone with Alison’s energy [CRY Founder],” Professor Sharma said. He also credited the vital work of CRY’s Research Fellows. “We had a battery of Research Fellows that have been through us, and all of these people [referring to seven Fellows shown in his presentation] are now consultants… and all contributed so much to the way that we interpret a young person’s ECG.

and prevent young sudden cardiac death.

CRY myheart cardiologist Dr Michael Papadakis followed, looking at how CRY’s research has changed the way we investigate families after a young sudden cardiac death.

Dr Papadakis explained everything that goes into this kind of assessment, why there is a high prevalence of Brugada Syndrome, and the characteristics of various conditions like hypertrophic cardiomyopathy (HCM) and idiopathic left ventricular hypertrophy.

“Probably one of the proudest things that’s ever happened to me was that this 10 to 12 years of intensive research funded by all of [CRY’s supporters] culminated, for the first time in the history of sports cardiology, in something called the International Recommendations… i.e., if you used these criteria [to interpret ECG results] anywhere in the world, you were doing a good job.”

To finish, Dr Papadakis emphasised how important teamwork is in all areas to research these conditions and complete the necessary testing for people all around the UK. “It’s multi discipline teamwork,” Dr Papadakis said.

“A cardiologist cannot do it alone. We also need, apart from the geneticist and the pathologist, our nurses, our genetic counsellors, the GPs – very important, those are the individuals who’ve been dealing with the family for many years and will continue dealing with that family, so they need to keep very well informed. And obviously the psychologist and our patient groups, like Cardiac Risk in the Young, who support the families and also support our research.”

CRY research has also reduced false positive rates from 22% to just 3% in the white population. “So, [when] your family or your children have an ECG screening done by CRY, there’s only a 3% chance that we may say we need to do more tests,” Professor Sharma added. “And there’s a 1 in 300 chance that we’ll say to you there’s something wrong with your kid, and we can actually do something about it and prevent a sudden death in most people.”

Professor Sharma finished the event’s research presentations with a thank you to supporters, who truly make our research possible with their tireless fundraising efforts.

“I’d like to thank you all for raising so much money to support a charity whose mission it is to reduce young sudden cardiac death. Your money has gone a long way into improving the way that we diagnose people, improving what we know about causes of sudden death, improving methods of risk stratification – i.e. when someone is diagnosed, how do you predict someone is going to die or not.

Finally, there was no one better to discuss how CRY’s research has transformed the way we screen young people than CRY Consultant Cardiologist Professor Sanjay Sharma. CRY began by facing opposition to the pursuit of cardiac screening across the UK. Professor Sharma listed some of the concerns and opinions others had, questioning the use for screening due to the supposed low incidence of sudden cardiac death, a high number of false positives, whether we have the necessary

Cardiac Risk in the Young

“Clearly there’s a long way to go. We want to minimize the risk of sudden death and there’s a lot to learn, and I hope for your continued support.”

To watch all the presentations from the CRY Family Research Day you can also go to www.c-r-y.org.uk/crysfirst-family-research-day

Research Highlights 2019

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ESC Congress This year, the European Society of Cardiology conference was held in Paris, France. It was an excellent opportunity for the CRY doctors and researchers to address new evidence and studies in the field of sports cardiology and in the prevention of sudden cardiac death.

Professor Sanjay Sharma focussed on the use of imaging and its role with a talk entitled: “Should imaging be part of the cardiovascular evaluation of middle-aged individuals?”. He also spoke on “Cardiac magnetic resonance for identification of athletes at risk”.

Keteepe-Arachi (left) presented her poster and abstract on “Hypertension or hypertrophic cardiomyopathy? Using cardiovascular magnetic resonance imaging to unmask the great imitator”.

The conference was highly informative and continues to demonstrate the importance of CRY’s research.

EuroPrevent The EuroPrevent 2019 conference was held in Lisbon, Portugal in April, and CRY was well-represented by many current and former Research Fellows.

Those giving presentations included Dr Harshil Dhutia (“Syncope in an athlete; Listen to the story!”), Dr Aneil Malhotra (“Choose the right pacemaker for the right athlete”), Dr Gherardo Finocchiaro (“Interpret diastolic function in an athlete”) and Dr Sabiha Gati (“Sports after myocarditis”).

CRY doctors also gave a range of poster presentations, including Dr Bashar Ibrahim (“Aortic root remodeling in life long veteran endurance athletes”), Dr Malhotra (“Efficacy of the international recommendations in adolescent athletes”), Dr Hamish MacLachlan (“Additional yield and challenges of transthoracic echocardiography as a first-line screening tool; experience from a national cardiac screening programme in elite cricketers”), and Dr Gemma Parry-Williams (“The short PR interval in young athletes”).

Continuing with the imaging theme, CRY Fellow Dr Tracey

Professor Sanjay Sharma also attended and gave a talk on how to plan medical services for mass participation events.

Interview with Dr Sabiha Gati In this interview Dr Sabiha Gati discusses her research on aortic root dilatation in young athletes and how the condition can be managed (“Prevalence and progression of aortic root dilatation in highly trained young athletes.” Gati S, Malhotra A, Sedgwick C et al.

Heart, June 2019).

How did you conduct your study?

Aortic root enlargement is reported in young people and athletes; however, it is unclear whether these changes are due to intensive physical activity or represent a potentially serious condition that may cause sudden cardiac death. Between 2003 and 2015, we conducted an observational study collecting echocardiography data (ultrasound of the heart) on athletes aged 14-35 years old to identify individuals with an enlarged aorta which is the main vessel that leaves the heart called the aorta (figure 1). We had screened 3,781 young athletes who trained for an average of 17 hours per week and compared

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them with 806 young sedentary volunteers who were recruited from a population screening programme offered by CRY. These individuals were subsequently followed up for approximately 7 years.

What were the main findings of this study?

Athletic individuals revealed a larger aortic diameter compared with sedentary controls. The 99th percentile value for aortic diameter in athletes was defined as the upper limit and was 40mm in males and 38mm in females. The aortic diameter measured >40mm in 5 males (0.17%); (range of 40-43mm) and >38mm in 6 females (0.4%); (range 39-41mm). None of the athletes with an enlarged aortic root diameter fulfilled the clinical features of Marfan syndrome, a condition known to cause aortic enlargement and sudden death.

The main determinants of an enlarged aorta were body surface area and the size of the main pumping chamber called the left ventricular cavity, suggesting that large athletes who trained intensively were more likely to have an enlarged aortic diameter compared with smaller athletes who trained less intensively.

Whether you were of black or white ethnicity had no significant influence on the size of the aorta. Our study also showed that males and females competing in predominantly endurance

Cardiac Risk in the Young

Interview with Dr Sabiha Gati sports such as running and cycling showed a trend towards a larger aortic diameter compared with athletes performing mixed sports such as football. During the follow-up period of just under 7 years, none of the athletes with an enlarged aorta showed progressive aortic enlargement compared with their first evaluation despite ongoing participation in exercise or competitive sport.

What impact does an aortic root dilatation have on an athlete?

This study provides upper limits for an aortic root diameter derived form a large cohort of young athletes. A small minority (0.3%) of athletes reveal an enlarged aortic size. Over a modest follow-up, athletes did not reveal progressive enlargement of their aorta to indicate pathology of the tissue lining the wall of the aorta. The precise mechanism for aortic root enlargement is unknown. A combination of size, sporting discipline, duration and intensity of training may be contributing factors, but blood pressure responses to exercise and genetic factors are also likely important. Athletes with an enlarged aortic root should remain under surveillance and have an annual echocardiography (ultrasound scan of their heart) whilst participating in intensive Figure 1: Aortic root enlargement with intensive exercise. Aortic root exercise or >40mm in males and >38mm competitive in females requires annual sort. Progressive surveillance with echocardiography. enlargement of the aorta >2mm over a 5 year period may be abnormal and consistent with pathology. Longer surveillance studies are required to establish the precise significance of an enlarged aortic diameter in athletes.

What can be done to treat and manage aortic root dilatation?

The majority of people with aortic enlargement simply require close monitoring with echocardiography (ultrasound scan of their heart) on a 6-12 monthly basis. Occasionally your doctor may send you for more advanced imaging test such as CT or MRI scan of the aorta for a detailed evaluation. The treatment of aortic enlargement depends on how big it is. If it’s less than 5cm or 2 inches, individuals might receive treatment with medications initially from their clinicians. The medications help lessen the chance of an enlarged aorta rupturing and causing sudden death. Your doctor may also give you advice on avoiding heavy lifting which could potentially put pressure on the aorta. If your enlarged aorta continues to grow and if you report symptoms of chest pain, jaw pain or back pain, your doctor may request you undergo surgery to replace the section of the aorta which is deformed and enlarged with a fabric tube called a graft.

Cardiac Risk in the Young

Dr Gati presenting some of her research into aortic assessment in athletes at CRY’s 2016 International Medical Conference.

How has this research changed the way clinicians would treat a person with an aortic root dilation?

The current guidelines recommend that male athletes with an aortic root of 40 mm (41 mm in tall males) and female athletes with an aortic root of 36 mm (36–38 mm in tall females) should only participate in low-intensity competitive sport. Our study suggests that male athletes with an aortic diameter up to 43 mm and female athletes with an aortic diameter up to 41 mm do not show progressive aortic enlargement over 5 years despite participation in sporting disciplines of a more dynamic nature. Therefore, there is scope for being more liberal in athletes with a slightly enlarged aortic diameter in the future, although annual assessments are recommended.

This study provides a guide for clinicians on the upper limits of aortic diameters in individuals who exercise to help differentiate physiological changes from exercise versus pathology which requires close monitoring and potential future treatment/surgery.

What kind of studies should be carried out next to further the findings of this research?

In this study, we did not do genetic testing to exclude for serious cardiac conditions such as Marfan syndrome and this is something we can think about for future studies involving individuals who exercise intensively with an enlarged aorta.

Furthermore, we need to collect data over a long term such as 15-20 years to decide how much the aorta grows with exercise.

We know that the aorta size is affected by age, exercise and blood pressure. In fact, the elasticity (i.e. stretchiness of the tissue lining the aorta wall) becomes stiff with age and perhaps we need to evaluate our mature/veteran athletes over the age of 40 years compare to our younger population and whether there any predictors as to which individuals may enlarge their aorta rapidly placing them at risk of sudden death and therefore, allowing the clinician to instigate treatment early.

Abbreviation: *Aortic root; LA: left atrium; LV: left ventricle; RA: right atrium; RV right ventricle.

You can read this study by going to https://bit.ly/2HNhC1D Research Highlights 2019

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Interviews

February 2019.)

Interview with Dr Gherardo Finocchiaro

In this interview, former CRY Research Fellow Dr Gherardo Finocchiaro discusses his research into hypertrophic cardiomyopathy, entitled “Sudden Death Can Be the First Manifestation of Hypertrophic Cardiomyopathy: Data From a United Kingdom Pathology Registry.” (Finocchiaro G, Papadakis M, Tanzarella G, et al. Journal of the American College of Cardiology. Clinical Electrophysiology,

How did you conduct your study?

The study was conducted analysing a database of 5,100 consecutive cases of sudden cardiac death referred to our Cardiac Risk in the Young specialist cardiac pathology centre between January 1994 and March 2017.

The aim was to identify cases of hypertrophic cardiomyopathy (HCM).

How can early identification of HCM in asymptomatic individuals be improved?

This study demonstrates that often sudden death is the first manifestation of the disease in individuals that did not report significant cardiac symptoms.

The take home message is that we, as a society, have to do

better in order to identify HCM (and other cardiomyopathies) in asymptomatic and apparently healthy individuals.

Basic tests like the ECG have been shown to be abnormal in > 90% of patients with HCM. Population screening with the ECG may raise the suspicion of the disease in individuals with specific ECG abnormalities; this process would lead to a final diagnosis establishing appropriate therapy and lifestyle management that can reduce significantly the risk of sudden death.

What research could be completed next to further the findings of this study?

Further studies should be focused on understanding the molecular mechanisms underlying the susceptibility for fatal arrhythmias in sudden death victims diagnosed with HCM.

Key findings of this study:

What is the key take home message for clinicians who treat patients with HCM?

• We identified 196 (4%) cases with HCM. Sudden death was the first manifestation of HCM in the majority (78%) of cases, and only 50 (26%) decedents had reported cardiac symptoms prior to death.

HCM is a multifaceted disease and risk stratification is still challenging. We have to focus on early identification of the disease in the community as diagnosis is the first step in managing risk in these patients.

• Death during exercise or during emotional stress occurred in 46 individuals (23%) who were predominantly male (89%) and young.

• The diagnosis of HCM was often made only after death (78% of cases).

• Sudden death from HCM mostly occurred during rest or usual life activities (77% of cases) other than strenuous exercise, suggesting that exercise may be a risk factor for fatal arrhythmias only in young male subjects.

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Dr Finocchiaro presenting some of his research on arrhythmogenic right ventricular cardiomyopathy at the 2019 CRY Conference.

Research Highlights 2019

What are the implications of this research for people living with HCM? Most sudden deaths occurred during daily activities and at rest. Labelling a patient with HCM often means restriction from intense physical activity. There is no hard evidence to support that exercise is a risk factor for potentially fatal arrhythmias in patients with HCM. Our study encourages a discussion regarding sport participation in patients with HCM. It is possible that, for unknown reasons, only young males with HCM are at risk of dying suddenly during sport.

You can read more of this study by going to https://bit.ly/34h3llA

Cardiac Risk in the Young

In the following interview, Dr Finocchiaro shares some of the key findings and implications of his research into anomalous coronary artery, entitled “Anomalous Coronary Artery Origin and Sudden Cardiac Death: Clinical and Pathological Insights From a National Pathology Registry.” (Finocchiaro G, Behr ER, Tanzarella G et al. Journal of the American College of Cardiology. Clinical Electrophysiology, April 2019).

How did you conduct your study?

The Cardiac Risk in the Young Centre for Cardiac Pathology (CRY CCP) at St George’s University of London is led by an expert cardiac pathologist (Professor Mary Sheppard) and receives over 500 whole hearts of cases of sudden cardiac death (SCD) across the United Kingdom each year. Coronary artery anomalies have been reported as the second-most frequent cause of SCD in young athletes in the United States, accounting for 12% of deaths. Most coronary anomalies are thought to be benign anatomical variants and discovered incidentally during diagnostic imaging or at autopsy. The most feared coronary anomalies are those arising from the pulmonary artery (ALCAPA) or the wrong sinus (AOCA) with an interarterial course between the pulmonary artery and aorta.

The aim of the study was to describe the clinical and pathological features of a cohort of SCD victims with anomalous origin of a coronary artery diagnosed at expert autopsy. We reviewed a total of 5,100 cases of SCD referred to the CRY CCP from 1994 to 2017.

How common is AOCA as a cause of sudden cardiac death?

AOCAs are rarely identified during life, especially in asymptomatic individuals, and the prevalence of inter-arterial ALCA and ARCA is rare (0.03% and 0.23%, respectively), as is ALCAPA (1 in every 300,000 live births). In our study based on

Key findings of this study: • 30 cases (0.6%) with AOCA were identified.

Anomalous left or right coronary artery arising from the wrong sinus of Valsalva with inter-arterial course was the most common anatomical variant followed by anomalous coronary artery arising from the pulmonary artery.

• Specifically, most frequently observed were the anomalous right coronary artery arising from the left coronary cusp (ARCA), followed by anomalous left coronary artery arising from the right coronary cusp (ALCA).

• In ALCA, death occurred commonly during exercise.

• In ARCA, death occurred usually during rest or sleep.

Dr Finocchiaro presenting his research on left ventricular hypertrophy at the 2018 CRY Conference.

post-mortem examination of SCD victims, the prevalence of AOCA was 0.6%.

What impact does this research have on clinical practice relating to people with Anomalous Coronary Arteries?

The management and therapeutic approach of asymptomatic patients diagnosed incidentally with AOCA is also problematic and subject to debate, especially in individuals without documented ischemia. All cases of suspected inter-arterial ALCA or ARCA should be considered for coronary computed tomography or cardiac magnetic resonance imaging to visualize anatomic features. Although considerable debate remains regarding the optimal therapeutic management of these patients, surgical repair and coronary deroofing is generally preferred in patients with an early intramural course.

Exercise appears to be the trigger of fatal arrhythmias mainly in young individuals with inter-arterial ALCA, whereas in ARCA most SCD occur during rest or sleep. Although in ARCA sudden death occurred less frequently during exercise, our study does not provide any information on the actual risk of exercise-induced fatal arrhythmias in individuals with ARCA and therefore does not affect the recommendation to avoid competitive sport in patients diagnosed with this condition.

However, the results of our study raise speculations about the possibility of exercise-related risk in specific anatomical variants of the coronary anomaly.

What are the implications of this research for people who are diagnosed with an Anomalous Coronary Artery?

Cardiac symptoms were present in 11 individuals (37%) and syncope was the most common, followed by chest pain, palpitations and breathlessness. It is important to remember that these symptoms may be a sign of a cardiac condition, such as coronary anomaly, and therefore an individual suffering these symptoms should seek a clinical evaluation.

What would you like to focus on in your research next?

I will continue to study epidemiology and causes of sudden death in young individuals and athletes.

You can read this study by going to https://bit.ly/2Sg8CnQ

Cardiac Risk in the Young

Research Highlights 2019

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Marking CRY’s 25th year

The launch of the CRY Centre for Inherited Cardiovascular Conditions and Sports Cardiology

Here are two articles from the “Looking Back at 25” series which has been running on CRY’s website to mark our 25th year anniversary, remembering key developments and events from the charity’s history.

In 2009, CRY was chosen as one of the charities to benefit from the ICAP Charity Day. ICAP is a large finance company dealing in electrical markets, and on their charity days, the commission earned on any deals brokered during the day is split between selected charities. CRY was fortunate enough to be chosen thanks to the efforts of one of our supporters, Kent Representative James Brown. James’ wife, Katrina, died suddenly in 2006 when she was just 31 years old.

Charity Patrons are able to attend on the day, with the opportunity to speak to clients on the phone to help close deals. We were thrilled to have CRY Patron Pat Jennings OBE represent us, who attended with CRY’s Founder Alison Cox. He closed two deals in New York and another in Athens, and signed countless autographs, took photos, and shook hundreds of hands along the way as he travelled around the dealing floors at ICAP. “It was a brilliant day,” Pat said when reflecting on the occasion, “and just so nice that people went to so much trouble for all the chosen charities.”

There was even an auction for ICAP clients and employees to help fundraising even more. We had received a tennis racket from Bjorn Borg 16 years earlier that we were able to enter into the auction, and raised over £1,000. One of our other Patrons, Jeremy Bates, was a big help in making this possible, too. A certificate to authenticate the racket was needed, so Jeremy contacted his friend and former Wimbledon champion Pat Cash, who was playing a tournament in China with Bjorn at the time, to get a certificate signed and returned within two days.

“It was an extraordinary day,” Alison said at the time, “with brokers and ICAP staff all investing considerable time, energy and personal funds in selecting personal themes for dressingup and creating a colourful uplifting and festive atmosphere – with all profits made going to the selected charities. I was so privileged to be escorting truly one of the most courteous, congenial and accommodating of the UK’s historic sporting heroes.”

All of the funds raised on the day went towards a massive new initiative for CRY in 2010: we were able to offer free screenings to all young people in the South East born in 1995, the year CRY was founded.

This new injection of funds also helped spark a major development in our history: the launch of the CRY Centre for Inherited Cardiovascular Conditions and Sports Cardiology at St

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George’s Hospital in London on April 28th, 2010.

We used the new CRY centre as the venue for our South East initiative, and it has gone on to become the home of regular screenings over the last 10 years as our national screening centre, overseen by CRY Consultant Cardiologist Professor Sanjay Sharma.

After the funding from the ICAP Charity Day helped get screening at our St George’s centre off the ground, we’ve received tremendous support over the years to develop its operation as our national centre. For instance, we have received funds from numerous trusts (such as the Carval Foundation and The Leathersellers’ Company Charitable Fund), and, of course, from CRY families in memory of those they have lost to a sudden cardiac death.

This includes over £150,000 raised in memory of Tom Clabburn and Claire Prosser, which has made a huge difference to our screening programme. These funds have been put to great use at St George’s as well, covering 11 screening days there (including six in 2016 alone) to test 1,000 young people, and paying for a new echocardiogram machine.

We received a whole year of funding in 2017 in memory of Jack Thompson, which was raised from the BGC Charity Day. This allowed us to hold 25 screenings at St George’s with these funds, and screened a total of 2,399 young people with 127 being referred for further tests. We have also received valuable support to fund screenings at St George’s in memory of Gary Pope, Sara Pilkington and Amy Osborne.

Since 2010, we have held a total of 177 screening days at St George’s, testing 14,251 young people.

Unfortunately, due to the COVID-19 pandemic, we have needed to put all screening events on hold until at least the end of August. However, as soon as it is safe to do so, we will be getting back on the road and heading around the UK to provide our usual cardiac screening service, which has still seen phenomenal growth in recent years. We screened over 30,000 young people in a year for the first time in 2019, and we now have a new fleet of screening vans to make sure everything is running as effectively as possible when we’re back.

Cardiac Risk in the Young

The development of the CRY Centre for Cardiac Pathology Before CRY began in 1995, young sudden cardiac death (YSCD) was never considered to be a significant health issue. It was quite the opposite. The common belief was that there was just one young sudden cardiac death a week. Families were not being given a clear cause of death after losing someone suddenly, coroners didn’t always have the funding to complete additional post-mortem investigations, expert pathologists could take up to two years to complete their investigations, and most people didn’t realise the importance of specialist testing for family members.

In 1994, Professor Mary Sheppard joined Dr Tim Bowker (now one of CRY’s Trustees) to produce one of the first surveys of sudden, unexpected cardiac death in the UK. At the CRY Family Research Day in May 2019, Professor Sheppard explained how important this was in revealing that the incidence of YSCD was higher than people thought.

including Hannah Turberville and over £700,000 in memory of Sebastian and Howard.

The CRY CCP examines hundreds of hearts every year to determine the causes of death when a young person dies suddenly, and returns their report to the coroner within two weeks of the referral. This provides affected families with much-needed clarity over what has happened, and exactly what kind of specialist testing they may need to undergo. Previously some families would endure a wait of anything from three to 18 months for answers following their tragedy.

“It was the first paper, really, to emphasize the entity of sudden adult death, or sudden arrhythmic death,” Professor Sheppard said. “Because up until then [1994, when the survey was carried out] most people believed you died of coronary artery disease… We found that, no, in a significant number of sudden unexpected deaths, 7%, the pathologists found nothing…

“The Fellows and the clinicians and cardiologists have now begun to expand our knowledge of these causes. This paper was seminal in telling pathologists when you find a sudden death – a young person, heart is normal, toxicology is negative – you have to do further investigations. You cannot simply leave it unexplained or unascertained.”

Professor Sheppard at the CRY Centre for Cardiac Pathology in 2014.

The CRY CCP continued to develop even more in 2014 when it moved to St George’s Hospital, the location of our national cardiac screening centre, which allowed Professor Sheppard and her team to work with some of CRY’s doctors and the hospital’s cardiologists.

The centre is now the largest pathology unit dealing with sudden cardiac death in the world, with more than 80% of UK coroners now routinely referring to the centre. Professor Sheppard and her team have conducted more than 2,500 expert cardiac post-mortems on young people, making the CRY CCP the world’s largest database of expert cardiac investigations. Meanwhile, Professor Sheppard has also contributed to over 100 journal articles on cardiac pathology, she contributes to research projects both in the UK and around the world, and discusses difficult cases with other pathologists around the country on a regular basis.

In 2008, we launched the CRY Centre for Cardiac Pathology (CRY CCP, shown above), an international cardiac referral centre, led by Professor Sheppard with a team of staff funded

by CRY. We were able to launch the centre with the help of £175,000 that had been donated in memory of Sebastian and Howard English. This donation provided a three-year grant for Professor Sheppard to carry out research at the Royal Brompton Hospital, and also funded a research scientist, a PhD student to work on the centre’s database, a part-time medical secretary to help with documentation, and a specialist microscope and laboratory facilities.

Over the last 12 years, we have continued to receive significant donations for the centre in memory of many young people,

Cardiac Risk in the Young

In 2018, the World Health Organization released new ICD codes (International Classifications of Disease), including codes to identify SADS and ARVC as important causes of death.

Without the research completed at the CRY CCP to show the significance of these conditions and the importance of cardiac pathology in general, this development might not have been possible.

We would not have been able to continue developing the CRY CCP without Professor Sheppard’s expertise and the tireless work of her and her team, and the phenomenal support we’ve received from CRY families. The centre has completely changed our understanding of YSCD and how to carry out specialist testing for relatives after a tragedy, all while supporting families with the information they need.

Research Highlights 2019

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Research

Papers/Articles • “Impact of geographical origin upon the electrical and structural manifestations of the black athlete’s heart.” Riding NR, Sharma S, McClean G, et al.

European Heart Journal, January 2019.

“The collective term ‘black’ should not imply that the hearts of all black athletes are universally comparable. There is considerable variability in the cardiac electrical and structural remodelling response to exercise that appears to be dependent on geographic origin.”

•

“Diagnostic accuracy and Bayesian analysis of new international ECG recommendations in paediatric athletes.” McClean G, Riding NR, Pieles G, et al. Heart, January 2019.

“In Arab and black male paediatric athletes, new international recommendations outperform both the Seattle criteria and 2010 ESC recommendations, reducing false positive rates, while yielding a ‘fair’ diagnostic accuracy for cardiac pathology that may predispose to SCA/D.” •

“Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC).”

Pelliccia A, Solberg EE, Papadakis M, et al. European Heart Journal, January 2019.

“The present document, therefore, aims to offer a comprehensive overview of the most updated recommendations for practicing cardiologists and sport physicians managing athletes with cardiomyopathies and myo-pericarditis and provides pragmatic advice for safe participation in competitive sport at professional and amateur level, as well as in a variety of recreational physical activities.”

•

“Canadian Cardiovascular Society/Canadian Heart Rhythm Society Joint Position Statement on the Cardiovascular Screening of Competitive Athletes.” Johri AM, Poirier P, Dorian P, et al. The Canadian Journal of Cardiology, January 2019.

“The recommendations presented in this position statement comprise a tiered framework that allows institutions some choice as to program creation. The creation of a network of such regions of excellence, with the goal of further implementation, research, and standardization will enhance the safety of our athletes.”

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“Response by Sheikh et al to Letter Regarding Article, ‘Diagnostic Yield of Genetic Testing in Young Athletes With T-Wave Inversion’.” Sheikh N, Papadakis M, Wilson M, et al.

Circulation, February 2019.

“Sudden Death Can Be the First Manifestation of Hypertrophic Cardiomyopathy: Data From a United Kingdom Pathology Registry.” Finocchiaro G, Papadakis M, Tanzarella G, et al. Journal of the American College of Cardiology. Clinical Electrophysiology, February 2019.

“Myocardial inflammation in Brugada syndrome.” Miles C, Asimaki A, Behr ER, et al. Journal of the American College of Cardiology, March 2019.

“Persistent left ventricular dysfunction after acute lymphocytic myocarditis: Frequency and predictors.” Merlo M, Ammirati E, Gentile P, et al. PLOS One, March 2019.

“Patients with acute lymphocytic myocarditis presenting with LV systolic dysfunction exhibit a persistent LV impairment at 1-year in more than 50% of the cases. Features suggestive of a poor inflammatory process associated with cardiac enlargement, and lack of early recovery, emerged as potential useful tools for predicting persistent LV systolic dysfunction during follow-up.”

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“Anomalous Coronary Artery Origin and Sudden Cardiac Death: Clinical and Pathological Insights From a National Pathology Registry.” Finocchiaro G, Behr ER, Tanzarella G, et al. Journal of the American College of Cardiology. Clinical Electrophysiology, April 2019.

Research Highlights 2019

“AOCA is a rare cause of SCD. ALCA and ARCA with interarterial course are the most common anatomical variants recognized at the postmortem of SCD victims. ALCA is more commonly associated with death during exercise. Cardiac arrhythmias causing sudden death seem most likely in the cases without overt myocardial damage.”

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“Comparison of Ajmaline and Procainamide Provocation Tests in the Diagnosis of Brugada Syndrome.” Cheung CC, Mellor G, Deyell MW, et al. Journal of the American College of Cardiology. Clinical Electrophysiology, April 2019.

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“Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.” Miles C, Finocchiaro G, Papadakis M, et al. Circulation, April 2019.

“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.”

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“The right heart of the elite senior rugby football league athlete.”

Forsythe L, Somauroo J, George K, et al. Echocardiography, May 2019.

“The primary aim of this study was to establish the normal right ventricular (RV) phenotype in elite RFL athletes using standard 2-D echocardiography and myocardial mechanics. The secondary aim was to describe right atrial (RA) structure and function using 2-D echocardiography.”

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“Inherited cardiomyopathies.” Miles C, Fanton Z, Tome M, et al.

British Medical Journal, May 2019.

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“Athletic Remodeling in Female College Athletes: The ‘Morganroth Hypothesis’ Revisited.” Kooreman Z, Giraldeau G, Finocchiaro G, et al. Clinical Journal of Sport Medicine, May 2019.

“Female collegiate athletes participating in higher intensity dynamic and resistive sports have higher indexed LV mass even when scaled to LBM. The remodeling process does however appear to be a balanced process not only at the intraventricular level but also at the interventricular and atrioventricular levels.”

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“Brief recommendations for participation in competitive sports of athletes with arterial hypertension: Summary of 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 Journal of Preventive Cardiology, May 2019.

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“Scaling to produce size-independent indices of echocardiographic derived aortic root dimensions in elite Rugby Football League players.” Oates SA, Forsythe L, Somauroo JD, et al. Ultrasound, May 2019.

“The study aims to define relationships between aortic root dimensions and body surface area/height. Two hundred and twenty elite Rugby Football League athletes were recruited. All participants completed anthropometric assessments, a 12-lead ECG and echocardiogram.”

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“A Lethal Blow to the Chest as an Underdiagnosed Cause of Sudden Death in United Kingdom Sports (Football, Cricket, Rugby).” Cooper S, Woodford NW, Maron BJ, et al. The American Journal of Cardiology, June 2019.

“This study is a retrospective analysis of a database of 6000 cases of sudden cardiac death examining commotio cordis in the setting of collapse and death shortly following a blow to the precordium where no structural heart disease was identified at autopsy.”

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“Prevalence and progression of aortic root dilatation in highly trained young athletes.” Gati S, Malhotra A, Sedgwick C, et al.

Heart, June 2019.

“Aortic root dilatation is reported in young athletes; however, it is unclear whether such remodelling is physiological or, whether it represents a potential aortopathy. This observational study investigated the prevalence and progression of aortic root dilatation in young athletes competing at regional or national level.”

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“Emergency response facilities including primary and secondary prevention strategies across 79 professional football clubs in England.” Malhotra A, Dhutia H, Gati S, et al. British Journal of

Cardiac Risk in the Young

Papers/Articles Sports Medicine, July 2019.

“Additional improvements such as increasing awareness of European guidelines for emergency planning, AED training and mentorship with financial support to lower division clubs are necessary to further enhance cardiovascular safety of athletes and spectators and close the gap between the highest and lower divisions.”

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“Accuracy of the 2017 international recommendations for clinicians who interpret adolescent athletes’ ECGs: a cohort study of 11,168 British white and black soccer players.” Malhotra A, Dhutia H, Yeo TJ, et al. British Journal of Sports Medicine, July 2019.

“These recommendations perform more effectively than previous ECG criteria in both white and black adolescent soccer players.”

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“Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy.” Raju H, Ware JS, Skinner JR, et al. BMC Cardiovascular Disorders, July 2019.

“We aimed to determine the mutation yield and clinical applicability of “molecular autopsy” following sudden arrhythmic death syndrome (SADS) by validating and utilizing low-cost high-throughput technologies.”

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“Coronary Atherosclerosis in Athletes: Exploring the Role of Sporting Discipline.” Aengevaeren VL, Mosterd A, Sharma S, et al. Journal of the American College of Cardiology: Cardiovascular Imaging, August 2019.

“The electrocardiogram in the diagnosis and management of patients with hypertrophic cardiomyopathy.” Finocchiaro G, Sheikh N, Biagini E, et al. Heart Rhythm, August 2019.

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“Getting to the heart of the matter: investigating the idiopathic sudden cardiac death of a previous well soldier.” Eveson LJ, Cox AT, Dhutia H, et al. Journal of the Royal Army Medical Corps, October 2019.

“This case generates discussion on sudden cardiac death, family screening in SADS, BrS and the limitations of recruit screening with an ECG.” •

“Insights from examination of hearts from adults dying suddenly to the understanding of congenital cardiac malformations.”

Westaby J, Cooper S, Edwards KA, et al. Clinical Anatomy, November 2019.

“Here, we demonstrate the value of simple sequential segmental analysis in describing and categorizing the cases, with the concept of the ‘morphological method’ serving to identify the distinguishing features of the cardiac components.”

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“Histological Evidence for Impaired Myocardial Perfusion Reserve in Severe Aortic Stenosis.” Mahmod M, Chan K, Raman B, et al.

Journal of the American College of Cardiology: Cardiovascular Imaging, November 2019.

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“European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death.”

Fellmann F, van El CG, Charron P, et al. European Journal of Human Genetics, December 2019.

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“Reaping the rewards of exercise: it is never too late to start.”

Sharma S, Malhotra A. European Heart Journal, December 2019.

“To date, the ECG remains an irreplaceable first step when evaluating patients with hypertrophic cardiomyopathy (HCM) and an abnormal ECG may be the only manifestation of disease at an early stage.”

“The take-home message of this article could be delivered with the following key points: firstly, exercise is a life-long medicine that should be promoted in all age groups; secondly, one does not have to exceed current recommendations to benefit from exercise; and finally, it is never too late to take up exercise to reap the beneficial rewards on the cardiovascular system.”

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“Determinants of the athlete’s heart: a cardiovascular magnetic resonance imaging study.” Gati S, Sharma S. European Journal of Preventive Cardiology, August 2019.

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“Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis.”

Corrado D, van Tintelen PJ, McKenna WJ, et al. European Heart Journal, October 2019.

“New imaging techniques in combination with more contemporary tools such as genetic testing can contribute towards establishing a clinical diagnosis, predicting prognosis, guiding therapy and offering the opportunity for cascade family screening. Genetic evaluation for instance may one day better define a clinical phenotype.”

“Abnormal ECG Findings in Athletes: Clinical Evaluation and Considerations.” Abela M, Sharma S. Current Treatment Options in Cardiovascular Medicine, December 2019.

Presentations at EuroPrevent, ESC Congress and BCS • “Syncope in an athlete; Listen to the story!” Dhutia H, EuroPrevent, 2019.

• “Choose the right pacemaker for the right athlete.” Malhotra A, EuroPrevent, 2019.

• “Interpret diastolic function in an athlete.” Finocchiaro G, EuroPrevent, 2019.

• “Additional yield and challenges of transthoracic echocardiography as a first-line screening tool; experience from a national cardiac screening programme in elite cricketers.” MacLachlan H, (poster) EuroPrevent, 2019.

• “The short PR interval in young athletes.” Parry-Williams G, (poster) EuroPrevent, 2019.

• “Sports after myocarditis.” Gati S, EuroPrevent, 2019.

• “Should imaging be part of the cardiovascular evaluation of middle-aged individuals?” Sharma S, ESC Congress, 2019.

• “Medical services planning during mass endurance events.”

Sharma S, EuroPrevent, 2019.

• “Cardiac magnetic resonance for identification of athletes at risk.”

Sharma S, ESC Congress, 2019.

• “Aortic root remodeling in life long veteran endurance athletes.”

Ibrahim B, (poster) EuroPrevent, 2019.

• “Hypertension or hypertrophic cardiomyopathy? Using cardiovascular magnetic resonance imaging to unmask the great imitator.” Keteepe-Arachi T, ESC Congress, 2019.

• “Efficacy of the international recommendations in adolescent athletes.” Malhotra A, (poster) EuroPrevent, 2019.

• “Insights from the English Football Association cardiac screening program.” Malhotra A, BCS, 2019.

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 2019

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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 September 2020 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.

• 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)

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

Treatment

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

23.1% of CRY’s funding supports research Fundraising Awareness 14.3% 15.2% Governance 2.2% Support 8.2%

Screening 37%

Research 23.1%

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 2019 the following ringfenced funds made significant contributions to support CRY’s research team at St George’s Hospital: • The Lewis Barry Memorial Fund • The Joe Kellogg Memorial Fund • The Alan Lumley Memorial Fund

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Research Highlights 2019

• The Rosie Mitchell Memorial Fund • The Jason Nixon Memorial Fund • The Rebecca Phillips Memorial Fund

• The Suanu Saro-Wiwa Memorial Fund • The Sarah Simpson Memorial Fund • The Natalie Stewart Memorial Fund

Cardiac Risk in the Young