Novel computer system can help inform future therapies for patients with inherited heart disease

Wellcome Sanger InstituteJun 14 2021

An integrated, genomic computer system for precision cardiology has been created using clinical data that can help inform medical and surgical decisions to support future therapies for patients with inherited heart disease.

This global study, by researchers from the Wellcome Sanger Institute, University of Cambridge, Massachusetts Institute of Technology and Lund University, shows how some genetic mutations can cause different cardiovascular diseases with varying outcomes, depending on where they occur in a gene, and the possible mechanisms behind this.

The research, published today (14^th June 2021) in npj Genomic Medicine, verifies which genetic variations and potential ‘hot spots’ are linked to different types of inherited heart diseases where the functioning of the heart muscle is impacted. These may have different outcomes and treatments, including invasive surgical procedures such as fitting defibrillators and heart transplantation.

Overall, researchers developed an integrated computerized system from genomic data combined with biological and chemical information, which was then validated with global data from over 980 patients with inherited heart muscle disease. This model can help inform future patient care, by enabling cardiologists and clinical geneticists to work in unison with patients to better assess the potential risk of developing disease, meaning that more effective and personalized treatment plans can be created.

The cardiomyopathies are a group of diseases where the heart muscle is affected and can cause the heart to be a different shape, size or structure, and can impact the functioning of the muscle.

About 0.2 per cent of the global population, roughly 1 in 500 people, have inherited cardiomyopathies, making it the most common form of genetic heart disease. Within these inherited genes, genetic variations are commonly found in the regions that code for sarcomeric proteins, which are the building blocks of heart muscle and include proteins called troponins.

Different variations at specific locations within the genes that code for troponins are linked to different types of cardiomyopathies and also differing prognosis. For example, some cause the heart muscle to become scarred, increasing the risk of sudden cardiac death, while others may cause the heart to become enlarged and so lead to heart failure.

These variations within the cardiomyopathies have been shown to have different treatments ranging from tablets, needing a cardiac defibrillator, or even being listed for a heart transplant. However, it has been difficult to understand how and why some genetic variations can have such different outcomes and how much certain variations impact a person’s risk. Understanding this in more detail can help inform which treatments could be best and when they should be started, allowing for earlier, more personalized treatment plans to be created depending on which variants the individual carries.

In this new study, researchers from the Wellcome Sanger Institute, University of Cambridge, Massachusetts Institute of Technology and Lund University, built a novel computer-based model to predict how genetic variations may contribute to changes in troponins, which are important proteins involved in these inherited heart diseases. They then analysed freely available, global data from around 100 previous studies pertaining to over 980 patients globally to investigate the impact of genetic variations on the interactions between proteins in the heart muscle. As a result, the team created an approach that shows the different genetic ‘hot spots’ and their clinical outcomes.

While further research is now required to see if new drugs could be developed to target some of these genetic hotspots, the researchers hope that this method will be used to help inform medical decisions and encourage future global studies into this area.

Dr Lorenzo Monserrat, co-senior author and previously CEO of Health in Code, said: “We have combined advanced structural and functional evaluation of genetic variants with novel knowledge management strategies that integrate all of the information previously available in international literature about pathophysiology and the clinical manifestations of patients with those genetic variants. These kind of studies are essential for the development of a really personalized medicine in inherited cardiovascular diseases, addressing not only diagnostic and preventive challenges, such as the decision to implant a defibrillator or not, but also for the development and appropriate selection of novel treatments.”

This new tool is a significant advancement in precision cardiology, with real potential to benefit patients with inherited heart disease and influence genomic healthcare. The study demonstrates the importance of collaboration and knowledge sharing in driving innovation with real world outcomes.”

Professor Sir Mark Caulfield, Chief Scientist, Genomics England

Dr Rameen Shakur, lead author and clinical scientist in cardiology at Massachusetts Institute of Technology, previously a Wellcome fellow at the University of Cambridge and Wellcome Sanger Institute, said: “To better assimilate genomic data into real world clinical options for the millions of patients with inherited cardiovascular diseases and their families, we require a more integrated appreciation of genetic, physical, bio-chemical and clinical data, as shown in this study. This study is the next step in integrating precision cardiology into clinical care, and working more closely with clinical genetics colleagues and patients with their families, bridging the gap between research and day to day treatment decisions. This research has allowed us to also open the door to potential new therapies, which we hope to introduce soon.”