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Categories: Sanger Science18 June 20215.4 min read

Getting to the heart of the matter

Last week, footballer Christian Eriksen collapsed on the pitch following a cardiac arrest during a Euro 2020 match. He swiftly received CPR and was transferred to hospital, where he is reported to be doing well1.

Dr Rameen Shakur, based at Massachusetts Institute of Technology, USA, and previously at the University of Cambridge and Wellcome Sanger Institute, is an academic cardiologist.

He says “Eriksen was lucky - he received immediate treatment. It has put sudden cardiac arrests in the spotlight, and now as tests begin to understand why this happened to him, there are more calls for better research in this area of genomics and clinical outcomes.”

Rameen researches rare heart conditions called cardiomyopathies that can cause cardiac arrests in children and young people. He has recently published work that aims to help clinicians tailor treatments for inherited heart disease and enhance the field of precision cardiology.  

We spoke about his work, starting with discussing why he went into cardiology.

The person at the end of the bed

Dr Rameen Shakur

“My mother once said to me, well, if you're going to do biology, you might as well make it count. Why don't you do it on patients? And you know, you could look after your Mom as well!” Rameen told me.

Rameen studied at Cambridge and Oxford University for his medical training and undertook his PhD at Cambridge – following his Mum’s advice. “Looking at biological problems is so much more tangible when there's someone at the end of the bed or in a clinic, it makes it real,” he says.

“The reason I went to cardiology, I'll be very honest, is because I like the directness of it. It is medicine and surgery together. It is also a clinically robust speciality and is very evidenced based. It is acute. So if there is a blockage, unblock it – sort out the plumbing. If there is an electrical problem you go get the electricity, the defibrillator, and sort it. It is very algorithmic in that sense. But at the same time, the nuances of it are very interesting.”

The genetics of heart disease

“My aim was always to study genetics, in the long run. I’m interested in the simplest questions, the ‘so what?’ questions that genetics is able to answer,” says Rameen.

Rameen has been investigating some of the nuances of heart disease in his work on inherited cardiomyopathies. These are a group of diseases that affect the muscles of the heart, reducing its ability to pump blood around the body. About 0.2 per cent of the global population, roughly 1 in 500 people have inherited cardiomyopathies2.

For each of the cardiomyopathies, there are a range of outcomes for patients. Some people will be largely unaffected by the disease their whole lives. Others may have a high risk of sudden cardiac arrest and need medication, a pacemaker or a defibrillator. Some may need a heart transplant.

“Having seen adults and young children in clinic with inherited cardiomyopathy – it is never easy. Especially as a parent myself. And in terms of treatments, there is not always straightforward way to assess their future needs and determine which treatment will be best. Fitting a defibrillator, for example, is never risk-free , and we would not do that unless it was absolutely necessary. So we need a more accurate way to be able to identify those patients who will benefit from each different treatment and preferably earlier in the disease progression,” says Rameen.

Inherited cardiomyopathies are often caused by genetic variations in the regions of the genome that code for sarcomeric proteins, which are the building blocks of heart muscle. One type of protein in particular, the troponins, plays a key role.

Previous work into these conditions has shown that there are specific genetic mutations affecting the troponins that correlate with clinical outcomes for patients – but the picture is complex.

Building an unbiased model

World Heart Rhythm Week poster

Rameen set out to assess the effects of genetic variations “from the bottom up” with the troponins as an example. Global clinical patient outcomes were superimposed on top. Using systems biology, he built a model of the disease that takes into account the precise genetic changes in the genome, the genes involved, the position of the change and its surroundings, the protein structure, and protein interactions, the physio-chemical changes and how these are affected by calcium which allows for the heart to contract and produce a heartbeat3.

“The model showed that there are discrete individual regions within the thin filament complex where you see variations that are linked to some particular phenotypes and also clinical outcomes. Changes in one region are linked to a particular phenotype in hypertrophic cardiomyopathy. Variation in another region is related to dilated cardiomyopathy. When looking at survival curves from global data from 980 patients seems to be very defined. I was very surprised.”

Part of that wonder came from the fact that the team saw these regions right from the beginning - before any patient or clinical data had been added to the model to verify it. “Usually, models like this are made the other way around – we might see something in patients or in groups of patients and try and make a model that fits what we see, to work out why its happening.”

“It is unusual to have an unbiased view on this where you build the model, then you work up.”

Clinical practice

Rameen hopes his work will inform clinical practice, bringing together cardiologists and clinical geneticists with patients to decide the best course of treatment. He aims to  bridge the gap between research and day to day treatment decisions.

“We really need to get into prognostic and predictive medicine. We need to understand what that genomics background looks like for each patient. And we now know that if someone has a certain genomic variation, it does affect their risk of sudden cardiac arrest. That information can help.” “Protein interactions  in the heart are a system within a system. It's one of those things that people always say is too complex. But even if we just try and lift the lid on just one minutia of that complexity, there is value.”

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