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24th May 2024
A simple cheek swab test has shown promise in giving clinicians an understanding of a child’s risk of arrhythmogenic cardiomyopathy so sudden cardiac deaths can be prevented. Dr Angeliki Asimaki PhD and Professor Juan Pablo Kaski – the team behind the test – speak to Helen Quinn about the need for this innovation in clinical practice, the findings from their study and how patient care may be impacted going forwards.
Dr Angeliki Asimaki PhD, a cardiac pathology researcher and senior lecturer in cardiac morphology and sudden death at St George’s, University of London, is the driving force behind a cheap and simple cheek swab test that could change the clinical management of children with arrhythmogenic cardiomyopathies (ACM).
Working in partnership with Professor Juan Pablo Kaski, consultant paediatric cardiologist at Great Ormond Street Hospital (GOSH) and professor of paediatric inherited cardiovascular medicine at University College London (UCL), Dr Asimaki believes the test could be used to guide treatment nationwide, allowing doctors to diagnose early and provide timely intervention. For children who are at risk of sudden cardiac death, the test could be lifesaving.
ACM are estimated to affect up to one in 1,000 people and be responsible for up to 25% of sudden cardiac deaths in children. Monitoring children with ACM currently involves a combination of several heart scans and electrocardiographic tests, but these can leave an incomplete picture of the microscopic changes happening inside the heart.
Dr Asimaki and Professor Kasaki have shown that cells collected in cheek swabs can act as a ‘mirror’, reflecting what is happening in the heart muscles of children with ACM. The new test provides a quick and non-invasive method for monitoring the condition, potentially highlighting any abnormalities before clinical symptoms arise.
Before joining St George’s, Dr Asimaki worked in the US as a research associate at the Beth Israel Deaconess Medical Centre in Boston, Massachusetts, and a lecturer in cardiovascular pathology at Harvard Medical School. Her career and research interests have been driven by her own experiences of living with heart disease, which has included nine heart operations and having a pacemaker fitted at the age of 15.
She describes herself as ‘a heart disease warrior’ and explains: ‘I have grown up battling two different heart diseases, so I really would like to help other kids who, just like me, are facing such problems from a very young age.’
Her time in the US laid the foundations for her work today. Through studying the hearts of sudden cardiac death victims and the distribution of key proteins, Dr Asimaki was able to identify specific protein diagnostic markers that would enable a post-mortem diagnosis in cases where the cause of death was not apparent.
‘This was very helpful when we were trying to establish a post-mortem diagnosis in the sudden cardiac death victim. But it was not particularly helpful in living patients since it required a piece of the heart,’ Dr Asimaki says.
The migrating group of proteins acted as a molecular signature of the disease, and this finding was instrumental to her future research. After moving to the UK seven years ago, Dr Asimaki created a research group looking for diagnostic markers indicative of ACM progression and sudden death.
‘We were trying to find a surrogate tissue for the heart that would show equivalent protein movements and would help our diagnostic journey,’ Dr Asimaki explains.
Today, supported by the British Heart Foundation, which funded the three-year study starting in September 2023, Dr Asimaki and Professor Kaski are working with a cohort of 114 paediatric patients at the Centre for Inherited Cardiovascular Diseases at GOSH. The Centre has the largest paediatric cardiomyopathy service in Europe in terms of the number of patients, treating around 6,000 paediatric patients with inherited heart conditions every year.
Professor Kaski says: ‘Recruitment is never a problem. These patients are incredibly motivated to help because they often have a personal history in their families of individuals who’ve died suddenly.’
He adds: ‘These [diseases] are relatively rare in the paediatric population. But we know that there are a number of children at risk of dying suddenly as a result of these conditions, sometimes because they go undiagnosed. And other times, because we’re not able to pick up the earliest features of these conditions.’
Working with a team of research nurses, research assistants and a PhD student across GOSH, UCL and St George’s Hospital in London, children are seen routinely every six to 12 months and cheek swabs are monitored. Professor Kaski says: ‘I think there are fantastic, multidisciplinary collaborations covering the whole spectrum of research from fundamental basic science, through translation into the clinic.’
But the collaboration doesn’t end there as Professor Kaski adds: ‘We do a lot of patient involvement exercises with our families, to understand what they think our research priorities should be. Preventing sudden cardiac death and identifying disease early, are two things that always come up and so it’s an honour to be able to work towards something that is really important to the families that we see.’
He adds: ‘One of the lovely things is that we get to see families as they grow, I transition them to adult care when they’re 18, but actually, I then end up seeing their children in my clinic. And so, we tend to develop a really lovely relationship with the families that we look after.’
The new test measures the movement of proteins in cheek cells, which occurs simultaneously with heart cell changes. This shift in the distribution of proteins can cause heart inflammation, leading to abnormal rhythms, but by the time children show clinical evidence of disease, the proteins have already moved.
Dr Asimaki explains: ‘We ended up showing that the cheek is, in fact, a mirror for the heart. So, the same protein movements in the heart are shown in the cheek, which allows us to establish a diagnosis using a very risk-free, non-invasive and economical way.’
Once the proteins start moving, the researchers say this is a good indication that something in the heart is starting to change, too. At this point, they will increase the frequency of the appointments and put management plans in place early enough to minimise the risk of potential sudden cardiac disease.
‘We believe that it is a window of a few months, where we can see the protein shift first before we start seeing changes in the clinical modalities,’ Dr Asimaki adds.
The new test can also detect periods of higher disease activity, known as ‘hot phases’, when children are potentially at the highest risk of sudden death. If a separate protein involved in the inflammation pathway is detected, patients can visit hospitals for check-ups and treatment more regularly.
‘We know that even if somebody inherits a gene variant for these conditions, those variants usually don’t express themselves at the very beginning, they develop over time,’ says Professor Kaski. ‘So, the beauty of the cheek swab is that if it really does predict clinical changes, this could be a game changer in terms of screening children.’
For children whose cheek swabs come back normal, he says the test could mean clinicians could ‘perhaps reduce how often we need to see them’.
In addition, the researchers are simultaneously investigating whether the diagnostic markers can be found in blood samples taken from children with ACM, offering another way to undertake non-invasive tests for high-risk children.
Results from cheek swabs or blood testing could lead to a level of personalised care that would see children tested a few times a year – or more regularly during hot phases of the disease – and treated only when necessary. This would remove the need for precautionary lifelong medication, which can have side effects. The findings would also help identify the children who really need an implantable cardioverter defibrillator (ICD) fitted, which would have a considerable clinical impact because of the complications that can be associated with implanting ICDs in children.
‘This is what we envision to happen in the future,’ Dr Asimaki says. ‘We do not intend to replace any of the clinical modalities. But during the early years when these kids keep being brought back to the hospital for numerous clinical investigations, which are quite a burden both for the families and for the NHS, we could be looking at a new era.’
The team has optimised the cheek swab test so that it can be left at room temperature for a few weeks. This will allow them to explore the use of home testing kits, which can be sent to patients when needed and simply posted back for analysis.
Feedback from the families involved in the study highlights how the ease of testing and the fast turnaround of results can offer reassurance and ease the burden of living with the fear of sudden cardiac death. Dr Asimaki adds: ‘Every additional labour you can offer these families to help safeguard their children can alleviate some of the anxiety.’
The test is currently being used for research in other locations in the UK and the Netherlands, and the researchers would like to see this type of biomarker testing adopted into the NHS and further afield. They are currently working in partnership with NHS commercial services to hopefully see this to fruition.
‘It has already been applied in another couple of laboratories in the world with similar results. So, this is quite promising because it means that once this launches, it’s not only going to be for those privileged to live in the UK but can be used by any country in the world,’ Dr Asimaki says.
She adds that she’s very proud and happy to be able to support the development and rollout of this life-saving test, concluding: ‘A bad experience ended up shaping me to be in the position today to help a much larger group of children. In my eyes, even if this cheek smear test ends up saving one life, it’s like it has fulfilled my purpose in life.’
But it’s not just children that the test has the potential to help. Dr Asimaki and her colleagues will soon start a study using the test to monitor women with ACM throughout their pregnancies in several London hospitals.
They are also looking into developing a cheek swab test for diagnosing ACM, which would simplify the diagnostic process for clinicians, provide answers more quickly and support even more individuals through their patient journey.
Update: Since this publication of this article, Dr Asimaki and Professor Kaski’s paper has been published in the journal Circulation: Genomics and Precision Medicine.
14th February 2024
Dr Matthew Webber, a clinical training fellow at University College London’s Institute of Cardiovascular Science, is co-developer of a reusable heart vest that can map the electrical activity of the heart in fine detail. He speaks to Katherine Price about how this innovation could potentially be used to better identify people at high risk of sudden cardiac death.
Around two million people experience heart rhythm disorders in the UK, according to the NHS, and 500 people die every year from sudden cardiac arrest.
‘Often, there was no particular warning,’ says Dr Matthew Webber, who works at Barts Heart Centre in London – a centre of excellence for cardiovascular care and the largest cardiac centre in the UK. ‘Usually, these patients will either have genetic rhythm problems, which they’re born with, or heart muscle disorders that they’re either born with or develop.’
Genetic heart rhythm disorders and cardiomyopathy can be difficult to detect, and it is similarly hard to predict risk of sudden cardiac death, as it is not known how structural features or abnormalities of a heart can influence risk.
Although medication or implantable cardioverter-defibrillators can prevent sudden cardiac events, it is challenging for cardiologists to assess who is at risk and who is not.
Cardiac magnetic resonance (CMR) imaging can show the health of the heart tissue, but not its electrical activity, and so Dr Webber says that ‘to complete that picture, you need to overlay the electrical information onto the heart scan to help better establish that risk’.
A 12-lead electrocardiogram (ECG) can help, as it’s a quick and cheap procedure, but it hasn’t really advanced over the last 50 years. It also involves applying electrodes with gel, which can irritate the skin and be uncomfortable, and the image resolution also isn’t high enough to provide more detail than the general location of where in the heart a problem is coming from.
Until recently, detailed mapping of the heart’s electrical activity was rare, requiring either a catheter to be inserted inside the heart cavity or the use of expensive, single-use devices that were time consuming to set up and involved radiation.
But that has all changed thanks to some innovative thinking from Dr Webber and colleagues at the UCL Institute of Cardiovascular Science, who are pictured above.
It was Dr Gaby Captur (pictured sitting, centre), consultant cardiologist in inherited heart muscle conditions at the Royal Free London NHS Foundation Trust and senior lecturer at University College London’s (UCL) Institute of Cardiovascular Science, who had the initial idea: developing an electrocardiographic imaging (ECGI) vest that could be used alongside MRI, and she brought Dr Webber on board as co-developer.
‘We needed to invent a vest that could be used with cardiac MRI, was reusable, cheap, quick, safe and effective, could be used on large numbers of patients for research, and then hopefully for clinical use as well,’ explains Dr Webber. ‘We could [then] complete this picture of heart disease by incorporating the electrical map of the heart with the cardiac MRI.’
The team received a grant from the British Heart Foundation (BHF) and the Society for Cardiovascular Magnetic Resonance to develop the concept, working with UCL BHF clinical research training fellows Dr George Joy and Dr Fiona Chan.
The design of the vest was based on the layout of the only commercially available ECGI vest – Medtronic’s CardioInsight single-use vest, which is compatible with computed tomography.
Conventional single-use ECG electrodes are made from silver-silver chloride and used with electrolyte gel. For the vest, the team developed bespoke dry electrodes from silver-coated polyamide yarn and the vest is fitted with 256 of these on the front and back.
The team tested the electrodes in-house for electrical characterisation, ECG signal quality, surface resistivity and washability. The textile-based sensors use conductive polymers that don’t require gel and can be washed and therefore re-used – the first time such electrodes have been used for ECGI.
The vest itself is made from cotton for its durability, comfort and ECG signal quality and was designed to fit a range of body habitus and size. It was also tested for its suitability for the CMR environment and to be machine washable up to 100 cycles.
The recording process takes approximately five minutes, requiring around 15 minutes of processing time in total per patient.
‘Anyone can do the recording, it doesn’t really require any special skill, just a bit of training on the software, and then patients go and have their cardiac MRI scan after that,’ says Dr Webber. ‘This can be done in one sitting in one centre and it doesn’t rely on the patient moving around or having an invasive test to complete that cardiac examination.’
Initially, Dr Webber had to manually combine the electrical data from the vest’s sensors with detailed images of the heart structure taken by MRI to generate 3D digital models of the heart and its electrical activity. The Barcelona Supercomputing Center then came on board to support the development of more efficient semi-automated techniques.
Before 2020, studies mapping the electrical activity of the heart had 20 or 30 patients at most. But, once up and running, Dr Webber and the team assessed the vest’s feasibility in 77 patients.
The results, published in the Journal of Cardiovascular Magnetic Resonance, found it to be reliable and durable, with good reproducibility in younger and older participants.
The vest has since been used on 800 patients, and a larger study mapping the hearts of people with diseases such as hypertrophic cardiomyopathy and dilated cardiomyopathy is due to be published in the journal Circulation.
‘We had pretty much 100% tolerability in terms of safety and comfort. Some patients couldn’t necessarily lie flat for five minutes if they had back problems, but that was fairly limited,’ says Dr Webber. ‘The patients commented that they felt it was comfortable and easy and quick.’
He adds: ‘Out of the 800 cases we did, we had around 10 or 15 that couldn’t be analysed, so a very small number that dropped out of the analysis for various reasons.’
By making high-throughput, non-invasive and radiation-free CMR-ECGI possible, the vest could open the door to making whole-heart panoramic electrophysiological mapping suitable for healthcare and large-scale population research studies.
It may also provide insights into arrythmia, potentially paving the way for more personalised risk stratification in patients with heart muscle disease.
‘We hope that the vest can be a cost-effective screening tool, and the rich electrical information that it provides can help us better understand patients’ risk of heart rhythm disorders and help with treatment of those,’ says Dr Webber. ‘It can also be used to assess the impact of drugs and lifestyle interventions on the heart. It completes that overall picture, it’s that missing link.’
It’s early days, and potential biomarkers obtained through CMR-ECGI that could predict risk of sudden cardiac death and heart rhythm disorders will need to be monitored over time to assess the relationship to outcomes.
For now, the vest has been patented and the FDA approval process is underway. The team hopes to sell it to research groups before rolling it out clinically within the next five years.
As wearable health technology and artificial intelligence become more prevalent and change the way results are taken and risk is identified, the vest’s potential is seemingly infinite.
‘Using smart wearable devices is going to be a big deal, allowing people to wear diagnostic devices at home like smart watches so they don’t have to go to hospital,’ concludes Dr Webber.
‘Smart wearable devices and using automated AI to help establish patients’ risk is going to be the way forward.’
Image courtesy of UCL Institute of Cardiovascular Science / James Tye.
8th December 2023
The first clinical trial to challenge the routine use of implantable cardioverter defibrillators (ICDs) in myocardial infarction survivors with heart failure has enrolled its first patient.
With modern drug treatments demonstrating the ability to lower the risk of sudden death in these patients, there is potentially less of a need for life-saving ICD shocks.
The PROFID EHRA trial will therefore test whether in post-myocardial infarction patients with symptomatic heart failure and reduced left ventricular ejection fraction (35% or less) drug treatment alone is not inferior to drug treatment plus an ICD for preventing sudden death.
Dr Nikolaos Dagres, chief investigator of the trial, said: ‘The PROFID EHRA trial is set to influence clinical practice around the world by closing a huge evidence gap that has existed for the past 20 years.
‘The trial is re-evaluating the role of ICD implantation in post-myocardial infarction patients in the context of contemporary medical treatment and will provide vital new information to optimally guide therapy and address this serious health issue.’
Over the next 30 months, the trial will recruit some 3,595 patients from 180 hospitals in 13 countries: Austria, Belgium, Czechia, Denmark, France, Germany, Hungary, Israel, Poland, Spain, Sweden, the Netherlands and the UK.
The first patient was enrolled from the Heart Centre Segeberger Kliniken in Germany.
Participants will be randomly allocated to either optimal medical therapy alone or optimal medical therapy plus ICD implantation. Participants will be followed up for around 2.5 years for the primary outcome of all-cause death.
The investigators will also examine the impact of the two treatment strategies on death from cardiovascular causes, sudden cardiac death, hospital readmissions for cardiovascular causes, length of stay in hospital, quality of life and cost effectiveness.
The study is due to last for approximately 49 months, with results expected in early 2027.
Professor Gerhard Hindricks, chief investigator of the trial, said: ‘PROFID EHRA is a ground-breaking study that could change the prevention of sudden cardiac death in clinical practice.
‘Currently, many patients who receive an ICD never need one, while some who could benefit miss out.
‘This trial will provide novel, randomised evidence on which patients should receive a defibrillator, and which patients can be spared an unnecessary procedure, which typically requires an overnight stay in hospital and may lead to complications or unintended shocks from the device.’
The PROFID EHRA trial is part of the PROFID project, which aims to personalise the prevention of sudden cardiac death after myocardial infarction.
The project involves a consortium of 21 multidisciplinary partners, including the European Society of Cardiology, and has received funding from the European Union’s Horizon 2020 research and innovation programme.
23rd December 2021
Higher intakes of alcohol are generally considered to damage the cardiovascular system although light to moderate alcohol intake appears to be protective. The term ‘holiday heart syndrome‘ has been coined to describe any alcohol-induced atrial arrhythmias and/or conduction disturbance associated with heavy consumption in a person without other clinical evidence of heart disease. Whilst the relationship between atrial arrhythmias and alcohol has become well recognised, there is a paucity of data linking alcohol intake with ventricular arrhythmias (VA). In fact, the available evidence is inconsistent, with some data showing a non-significant association whereas other studies suggesting that heavy alcohol consumption is an important contributing factor. Moreover, the influence of the type of alcoholic drink on VA or even sudden cardiac death (SCD) is also uncertain.
For the present study, researchers used information held in the UK Biobank which provides data on approximately half a million community-dwelling individuals aged 40 to 69 years across the UK. For their analysis, the researchers focused on incident cases of VA but excluded those with a previous history of the condition and former drinkers. The amount of alcohol intake was reported in terms of a standard drink, defined as 8g of alcohol and the average number of standard drinks consumed per week. For alcohol intake, the team also considered the type of each beverage consumed and created regression models which adjusted for several covariates such as age, sex, race, education.
Findings
Data for a total of 408,712 individuals with an average age of 58.3 years (52.1% female) were included in the analysis and who were followed up for a median duration of 11.5 years. The median alcohol intake for the whole cohort was 8 drinks per week although 5.5% of the group reported having never consumed alcohol.
There were a total of 1733 incident VA events and 2044 SCDs which occurred during the follow-up period. Overall, there was no statistically significant association between total alcohol intake and the risk of VA. However, when considered by type of alcoholic beverage, only alcoholic spirit intake was linearly linked with an increased risk of VA among those consuming greater than 14 drinks per week (hazard ratio, HR = 1.15, 95% CI 0.98 – 1.34) and this became statistically significant with more than 28 drinks per week (HR = 1.33, 95% CI 1.03 – 1.73).
For SCD there was a U-shaped distribution of risk with the lowest risk at around 7 drinks per week.
The authors concluded that they were unable to find an association between total intake of beer, cider and wine and VA and that only increased alcoholic spirit intake was linked to a higher risk. In fact, wine intake was associated with a lower risk of SCD although the authors suggested that these findings require clarification from experimental studies.
Citation
Tu SJ et al. Alcohol consumption and risk of ventricular arrhythmias and sudden cardiac death: An observational study of 408,712 individuals Heart rhythm 2021
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