Discovering the causes of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is an inherited disease that causes the muscle wall of the heart to get thicker, which over time can affect how well the heart can pump blood around the body. It’s passed down through families. In some cases, it can cause sudden death due to a fatal abnormal heart rhythm triggered by the thickening of the heart muscle, before someone even realises that they have a heart problem.

First discoveries

In the 1960s, the BHF funded Professors John Goodwin and Celia Mary Oakley at the Royal Brompton Hospital in London. They were early pioneers in improving our understanding of HCM. In 1960, they proposed the term ‘hypertrophic obstructive cardiomyopathy’ to name a disease about which little was known at that time.

In the 1970s and 1980s, BHF Professor Michael Davies at St George’s University of London was one of the first scientists to carry out detailed studies of the hearts of people who had died of HCM. His work found specific features - in particular, disturbances in the way that heart muscle cells are arranged - which helped explain why they had died suddenly from a fatal heart rhythm problem. His work with Professor Bill McKenna, also at St George’s University of London, led to the discovery that HCM was caused by faults in the genes, and Professor Davies suggested there had to be more than one genetic cause. 

Finding genes that cause a potentially deadly condition

BHF-funded researchers Professor Bill McKenna and Professor Hugh Watkins started looking for possible genetic causes of HCM in the 1980s. After a decade of painstaking research, they were among the first to find that HCM is linked to faults in genes which encode molecules needed for heart muscle cells to contract. The contraction of your heart muscle is the force that pumps blood around your body, so having one or more of these faulty genes can make it harder for the heart to work properly.

Professor Watkins and his team used these findings to set up the UK’s first genetic testing service for HCM. The service, based in Oxford, helps relatives of someone known to have a faulty gene to find out if they also have it - allowing those who do to get treatment to prevent a sudden death, and helping to reassure those who don’t. In 2016, the Oxford centre reached a landmark milestone by welcoming its 10,000th family. But at that time, access to this type of testing was often more difficult for people living in other areas of the UK.

Making genetic testing available

The Miles Frost fund, launched by the BHF in 2016, raised £1.5 million to help make genetic testing available to more families affected by HCM. The fund was set up in memory of Miles Frost, the eldest son of Sir David Frost, who died suddenly of HCM in July 2015. Thanks to the generosity of our supporters, we have been able to support 13 Inherited Cardiac Condition Services across all four nations of the UK.  The funding has enabled us to support existing services and help develop new services that can identify people with HCM and importantly, test relatives of people with the condition. 

More than 500 people affected by HCM have been identified and supported by specialist cardiac genetic nurses and genetic counsellors. These genetic testing services will now be sustained by the NHS - a fitting legacy for Miles created by his family.

Targeting care to those at the highest risk

We have now known for over 25 years that HCM is caused by ‘rare’ genetic faults in the machinery responsible for helping the heart muscle to contract and pump blood around the body. However, up until recently researchers and cardiologists were unable to explain why the condition is so varied amongst family members who have the same rare mutation and why some people without these mutations still go on to develop HCM. In 2021, BHF Professor Hugh Watkins and his team discovered that the inheritance of a different type of genetic fault – called ‘common variants’ - not involved in the contractile machinery, form a missing piece to this long-awaited puzzle.

By comparing the DNA of people with and without HCM, the team found that the number of these common variants, in combination with the rare mutations, determine whether a person is protected or more susceptible to the disease. Another important finding is that people who have HCM due to the common variants alone are unlikely to pass the disease onto their children, which could help to reduce the need for genetic testing and regular follow-ups for family members. This research also revealed that lowering blood pressure in people with HCM caused by these 'common' genetic faults could help to prevent the disease from developing - an important finding as blood pressure is something that can be controlled through lifestyle changes and medication.

Professor Watkins said: "It's now time we think differently about the way this hidden heart condition is detected and treated. We now have a new genetic tool that we believe will better predict which members of affected families will have a bad form of the disease, identifying those who need early intervention. It will also take away the worry and need for ongoing testing for many families as it enables us to identify those who are unlikely to pass faulty genes onto their children."

First published 1st June 2021