Understanding why some families are prone to ‘big hearts’

The Institute's research into the causes and potential treatments for hypertrophic cardiomyopathy (HCM)

19 January 2024

Professor Livia Hool has been working for over 15 years to try to answer one question: what causes some people to develop big hearts – otherwise known as hypertrophic cardiomyopathy (HCM).

This research focus has paid off, with Professor Hool and her team at the Institute’s lab at The University of Western Australia not only advancing our understanding of the genetic causes of HCM, but also developing the first therapy that could prevent and reverse this inherited condition.

What is hypertrophic cardiomyopathy (HCM)?

Hypertrophic cardiomyopathy (HCM) is a genetic condition that causes the heart muscle to become enlarged. This usually occurs in the posterior wall of the left ventricle and in the interventricular septum. In HCM, this thickening of the heart muscle occurs in the absence of other contributing factors, such as hypertension.

It is currently estimated that between one in 200 and one in 500 people carry a genetic mutation for HCM. Researchers believe that number could be higher, as some people may carry the genetic mutation without ever developing thickening of the heart muscle.

HCM is the leading cause of sudden cardiac death in five- to 15-year-olds. Sadly, as symptoms may not yet be apparent in this age group, this can sometimes be the first sign of the disease.

Professor Hool on uncovering the role of calcium channels in HCM

An area of focus for Professor Hool’s research is to better understand the role of calcium channels in the development of HCM. Calcium channel blockers are prescribed to treat the symptoms of HCM, but it has previously been unclear whether the channel contributes to the disease.  

Professor Hool and her collaborators have found that the communication between these calcium channels and mitochondria, which generates the energy needed to power our cells, is abnormally early in the disease process. This means that calcium channels are a viable target for preventative therapy.

The team has identified that when there is a mutation in contractile proteins (sarcomere) or the proteins that regulate the heart muscle contraction process, as is seen in people with HCM, the communication between the calcium channels and mitochondria is altered and this leads to an enlarged heart. 

It is now understood that approximately 40 percent of patients with HCM have a mutation in the gene that expresses a protein that allows heart muscles to contract – known as myosin heavy chain or MYH7 gene. 

Mutations in genes that encode proteins that regulate the muscle contraction process, such as myosin binding protein C, troponin or tropomyosin, have also been identified as a cause of HCM.

“This is a big area of research - all up there's at least a dozen genes and probably more than 1500 mutations that we now can identify as being linked to HCM,” says Professor Hool.

Professor Hool and her team are also studying variants of uncertain significance (VUSs) which are increasingly being identified as a result of availability of genetic testing in people with HCM.

“VUSs refer to a particular mutation that hasn’t been found in anyone else in the family, but that person still has a diagnosis of HCM. The reason we call the variants of uncertain significance, is because we can’t be sure if this mutation is the cause of the HCM unless a certain number of people have it,” says Professor Hool.

“We are finding more and more of these VUSs listed on clinical databases that researchers like myself and Professor Diane Fatkin work on, particularly using our animal models of disease, to confirm whether or not that mutation is causing the disease. Identifying these gene mutations is important because it aids with clinical diagnosis and provides certainty for the patients so they know exactly what has caused their big heart.”

Developing the first potential therapy to prevent and treat HCM

A potential new drug therapy developed by Professor Hool and her team is offering hope to people currently affected by HCM, along with those at risk due to an inherited genetic mutation.

In 2020, the team published their findings of a peptide that targets a calcium channel in the heart to prevent thickening of the heart muscle.

“What happens with these hearts is they get big, similar to when you go to the gym and you increase the size, or ‘hypertrophy’, your muscles, but with hypertrophic cardiomyopathy your heart gets big due to a mutation and consumes enormous amounts of oxygen - so it's working really hard,” says Professor Hool.

“We identified a novel pathway between the calcium channel and mitochondria. The mitochondria is known as the ‘powerhouse’, as it is the part of the cell that produces the heart’s energy. We modified the calcium channel's communication with the mitochondria so that it decreased that oxygen consumption and that's how we've managed to prevent the hypertrophy.”

Aside from a drug therapy that can help improve blood flow in people with a form of HCM known as obstructive hypertrophic cardiomyopathy, treatment for HCM is currently focused on managing symptoms rather than treating the disease itself, making this new treatment a potential game-changer for those affected.

“I’m excited about this potential new treatment because it appears to be very effective in the animal models at preventing the development of the disease – so there’s a very good chance this will become the first preventative therapy for those with HCM,” says Professor Hool.

In April 2021, Professor Hool and her team received a funding boost to advance clinical trials into the new treatment.

The team also published a paper in July 2023 examining how arrhythmias and sudden cardiac death occur in HCM mouse models. They found that the mouse model is highly susceptible to arrhythmia when stimulated with adrenaline. Since not all people with HCM develop arrhythmias, this suggests that some patients are protected from developing arrhythmias and discovering the mechanisms for this may help Professor Hool and her team design a therapy to protect those who are susceptible.

Giving hope to families with HCM

When Professor Hool first began studying HCM, the only options available for people with the condition was treatment of symptoms and genetic screening for family members but at that time screening was very expensive.

After many years of research, Professor Hool now sees hope on the horizon for families who are affected by this potentially life-threatening condition.

“We have spent over a decade working in this area and it is exciting to see the research evolve from fundamental discovery to designing therapy that will impact patients in the clinic,” says Professor Hool

“We are very excited that our therapy may make a difference in the lives of these people as a first-in-class therapy since there is currently no preventative therapy for HCM.”

During her time studying HCM, Professor Hool has also seen the impact of advancements in genetic testing for the disease.

“A decade ago when I began working with the Institute, it would have cost several thousand dollars to be tested for HCM - so understandably most people would say, “I'm not going to do it. It's too expensive. And what am I going to do if I find out I have a mutation anyway?” says Professor Hool.

“As a scientist it’s so rewarding to be a part of the advancement of genetics testing as we learn more about the gene mutations that cause HCM. We now have clinicians coming to us saying, “we've got a problem with a patient, can you work out in your cell models in the lab whether that's likely to be the cause of the disease for my patient?”. I can then go back to them and say yes this is the cause of the problem, or no it’s not so let's look at another option. It’s a great marriage of research and clinical work.”

Considering the future of HCM treatment, Professor Livia Hool is excited about the potential for gene therapies that could address gene mutations before they have a chance to cause disease.

“There are groups around the world working to see if they can directly modulate gene mutations – and while the field is not there yet with this type of gene therapy for HCM, it is encouraging to know this work is happening and where that could lead in the future,” says Professor Hool.

Key Collaborators and Funders of this research

Collaborators

• Professor Filip van Petegem, University of British Columbia, Canada
• Professor Tatiana Rostovsteva, National Institutes of Health, Baltimore, USA
• Professor Aleksandra Filipovska, Telethon Kids Institute Perth, WA
• Associate Professor Evan Ingley, Murdoch University, Perth, WA
• Professor Kricket Seidman, Harvard University, Boston, USA
• Professor Chris Semsarian, Centenary Institute, Sydney
• Associate Professor Adam Hill, Victor Chang Cardiac Research Institute, Sydney

Funding

• NHMRC Ideas Grant 2021-25
• CSL Research Acceleration Initiative Award
• Wesfarmers Ltd
• Woodside Energy