Finding a drug to protect the heart from damage by COVID-19

COVID-19 can be fatal for patients with heart disease. Even patients without heart disease can suffer damage to their heart. Bioengineer Professor James Hudson has found a drug which could protect our hearts from this damage.

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First signs that COVID-19 damages hearts

When the COVID-19 pandemic hit in 2020, doctors discovered some patients with no pre-existing heart disease suffered heart damage. This occurred in 20-30% of patients who were hospitalised with COVID-19.

Bioengineer Professor James Hudson decided to find out why this damage occurs. ‘Two weeks into the pandemic we knew it was an important area to look at and we had a perfect model to do that,’ James says.

Miniature ‘beating hearts’ for researching heart disease

Before the pandemic, James had engineered miniature ‘beating hearts’ in the laboratory using stem cells. He calls these living human heart tissues organoids. James was using the organoids to research new therapies and heart regeneration.

During the pandemic, James used the organoid models to find out why COVID-19 damages the heart and how to prevent this.

No one knew how COVID-19 damaged the heart

No one knew how COVID-19 damaged the heart when James started the project. ‘We were going into the dark,’ James says. ‘We went through very rapid learning about what was happening.’ Fifty researchers worked with James on this project.

They started by investigating how the SARS-COV-2 virus affects human heart cells. They discovered that the virus could infect heart cells in the laboratory. ‘But there’s not much evidence that the virus infects the heart inside a human patient,’ James says. ‘People are not sure why.’

The immune system causes the heart damage

James’s team discovered the patient’s own immune system causes the heart damage.  ‘The virus can shut down the immune system initially. That creates a really heightened immune response later on,’ James explains. ‘This heightened immune response causes severe inflammation which can damage the heart.’

Inflammation has well-known associations with other kinds of heart disease. It happens in patients with sepsis and after heart attacks and other forms of heart failure. But the inflammatory factors that cause heart damage were unknown.

Finding which inflammatory factors cause heart damage

‘Thousands of things change in the body during a heightened immune response,’ James says. ‘We used the organoids to screen these changes and find out which inflammatory factors cause the heart damage. Importantly that meant we could precisely pinpoint how to stop it as well.’

During a heightened immune system response to COVID-19, the immune system triggers a cytokine-storm. Cytokines are a diverse family of molecules that defend the body against pathogens like the virus. They act like messengers by signalling to cells to change their functions.

James screened cytokines and other molecules that are elevated in COVID-19 patients. He found 2 cytokines and a molecule associated with viral infection cause the heart damage observed in COVID-19 patients. He termed this a cardiac cytokine storm.

Finding the drug target

James’s team then searched in heart cells for the sites that the cardiac cytokine storm induces to change. They did this using phosphoproteomics. This method finds sites of phosphorylation, a key biochemical signature of signalling.

‘Phosphorylation is one of the most used processes in a cell for signalling,’ James notes. ‘It indicates which signalling pathway is activated.' The team found phosphorylation sites on bromodomain-containing proteins (BRDs).

James decided to target the BRDs with drugs because drug inhibitors for BRDs already existed. These drugs are called bromodomain extraterminal inhibitor (BETi) drugs.

The team hoped to prevent the cardiac cytokine storm from damaging the heart by using BETi drugs to stop BRDs changing their functions.

Screening existing drugs

The team screened all the BETi drugs that have been tested in clinical trials for cancer and chronic diseases. They found that the drug INCB054329 reversed common COVID-19 heart damage in organoids and mouse hearts. But this drug has significant side effects.

The BETi drug apabetalone also prevented COVID-19 heart damage. It has a more selective binding to the BRDs which limits side effects. The team concluded apabetalone is a lead candidate to prevent COVID-19 damage to the heart.

The pharmaceutical company that owns apabetalone had supplied the drug to James’s team for the tests. Based on the positive results, the company began phase II clinical trials to test the drug in hospitalised COVID-19 patients. They aim to gain regulatory approval to use apabetalone to protect COVID-19 patients and their hearts.

Next generation drugs

‘Even though we discovered this treatment pathway as part of a COVID 19 project, it has broad implications for heart failure in general and that's what we're exploring now,’ James tells us. ‘This pathway could be really important.’

‘In heart failure, heart cells have suboptimal performance. The heart might have lost some cells after a heart attack, or you might have high blood pressure or diabetes. These insults cause pathological signalling which can be detrimental to heart function.’

James’s COVID-19 research showed that blocking that signalling process allows the heart cells to perform optimally while the insults are still there. He aims to develop next generation drugs to block other pathological signals to the heart cells. This could be a new way of treating heart failure.

‘We want the next generation drugs in this class to be developed by us here in Queensland,’ James says.

The greatest moment of James’s career

‘This project is probably the greatest moment of my career because we discovered something really important,’ James continues.  ‘We had no idea that was going to happen. Traditionally, it takes years to get from basic research to a clinical trial. Seeing that translation in such a rapid time frame proves our approach using the organoids works.’

The MRFF gave a grant of $390,000 to James’s project Preventing Cardiac Injury in Patients with COVID-19.

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