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The cheek swab test with potential for preventing sudden cardiac death in children

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.

Identifying diagnostic markers in ACM

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.

A multidisciplinary approach to ACM

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.’

Monitoring protein changes via a cheek swab

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’.

Increasingly personalised care

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.’

National and international potential for the cheek swab test

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.