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Fumarate greatly reduces heart attack damage in mice

7 March 2012

Boosting levels of the simple compound fumarate in mice significantly reduces damage from a heart attack, an Oxford University-led study has shown.

The researchers say that there should now be clinical trials in humans to see if fumarate, which comes in the form of simple pills to swallow, can reduce injury to the heart in a range of conditions. Fumarate is already known to be safe and well-tolerated from clinical trials in multiple sclerosis and psoriasis.

The team is now beginning planning for a trial of fumarate in patients undergoing heart surgery.

The Oxford University researchers – along with colleagues from the University of Birmingham, the MRC Mitochondrial Biology Unit in Cambridge, the National Hospital of Neurology in London, Aarhus University Hospital in Denmark and the National Institutes of Health in the USA – investigated whether increasing levels of fumarate in mice was protective for the heart.

They showed that fumarate greatly reduces the amount of heart tissue damage occurring in a mouse model of a heart attack.

The amount of dead heart tissue after the heart attack as a proportion of the whole heart volume was 9.3% in mice given fumarate compared with 36.9% in untreated mice.

‘We have shown that heart attack size in mice can be reduced substantially by boosting their fumarate levels,’ says Dr Houman Ashrafian of Oxford University, who led the study.

The findings of the study are published in the journal Cell Metabolism. The research was funded predominantly by the British Heart Foundation.

Coronary heart disease is still the biggest killer in the UK. It occurs when blocked arteries reduce the blood flow to the heart. The lack of oxygen reaching the heart muscle results in tissue damage.

A heart attack is caused by a sudden block in the blood flow and rapid treatment is needed to remove the blood clot and re-open the artery. Despite modern treatments contributing to a reduction in death rates, there are still many patients that sustain significant heart damage.

There is a need for additional treatments that can help protect the heart – not just in heart attacks but also in patients with a range of conditions whose hearts may be exposed to other causes of injury. This could include patients undergoing high-risk surgery and also some cancer patients undergoing chemotherapy that may be at increased risk.

Fumarate is a simple chemical compound or metabolite that forms part of the normal metabolic pathway the body uses to break down food and release energy – the process known as the citric acid or Krebs cycle.

But metabolites can also have roles in biological pathways that control the responses of cells to stress, such as low oxygen.

For example, increased levels of fumarate have been implicated in allowing some cancer cells to thrive in the low oxygen levels that surround them.

Some seals that can dive to great depths under the Antarctic where there is little oxygen appear to activate similar biological pathways that employ fumarate.

These lines of evidence led the Oxford University researchers to become interested in whether there was any role of fumarate in heart cells’ response to stress, and whether fumarate could be protective against low oxygen levels.

As well as showing the reduction in heart attack size in mice, the researchers also identified the biological pathways triggered by increased levels of fumarate which appeared to result in the extra protection for the heart.

‘The advantages of fumarate are that it would present a relatively safe, cheap drug that wouldn’t need to be given for very long,’ says Dr Ashrafian. ‘It could be used upfront to protect the heart ahead of surgery or other predictable insults. Potentially it may also be beneficial in heart attacks in addition to standard treatments.

‘But let’s be clear: it’s great to show we can reduce heart attack damage in mice. It’s another thing altogether to show that fumarate is protective in humans. But it is now ready to test in clinical trials.’

Dr Ashrafian has applied for patents on the use of fumarate in heart surgery and coronary heart disease through Isis Innovation, the University of Oxford-owned technology transfer company.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation (BHF), which was the major funder of the study, said: ‘This very promising study shows that fumarate, already safely trialled in patients for other conditions, including multiple sclerosis, might be repurposed for the benefit of heart patients. It provides strong foundations to build on in the future, and we look forward to seeing the results of the first clinical trials.’

For more information please contact Dr Houman Ashrafian on +44 (0)7789 778075 or houman.ashrafian@cardiov.ox.ac.uk

Or the University of Oxford press office on +44 (0)1865 280530 orpress.office@admin.ox.ac.uk

Notes for Editors:

  • The paper ‘Fumarate is cardioprotective via activation of the Nrf2 antioxidant pathway’ by Houman Ashrafian and colleagues is to be published in the journal Cell Metabolism on Tuesday 6 March 2012.
  • The study was funded predominantly by the British Heart Foundation.
  • The British Heart Foundation (BHF) is the nation’s heart charity, dedicated to saving lives through pioneering research, patient care, campaigning for change and by providing vital information. But we urgently need help. We rely on donations of time and money to continue our life-saving work. Because together we can beat heart disease.
    For more information visit bhf.org.uk/pressoffice.
  • Isis Innovation is the research and technology commercialisation company of the University of Oxford. The Technology Transfer and Oxford University Consulting divisions provide access to technological developments and expertise from University of Oxford researchers, through intellectual property licensing, spin-out company formation, material sales and consulting.

    Isis is the highest University patent filer in the UK, has attracted investment into over 65 spin-out companies since 2000, and in the last financial year provided expertise to over 150 clients in 22 countries. Through the Isis Enterprise division, Isis offers innovation management to university, government and industrial clients around the world.For updates on innovations from Oxford, follow Isis on LinkedIn and Twitter or subscribe at www.isis-innovation.com
  • Oxford University’s Medical Sciences Division is one of the largest biomedical research centres in Europe, with over 2,500 people involved in research and more than 2,800 students. The University is rated the best in the world for medicine, and it is home to the UK’s top-ranked medical school.

    From the genetic and molecular basis of disease to the latest advances in neuroscience, Oxford is at the forefront of medical research. It has one of the largest clinical trial portfolios in the UK and great expertise in taking discoveries from the lab into the clinic. Partnerships with the local NHS Trusts enable patients to benefit from close links between medical research and healthcare delivery.

    A great strength of Oxford medicine is its long-standing network of clinical research units in Asia and Africa, enabling world-leading research on the most pressing global health challenges such as malaria, TB, HIV/AIDS and flu. Oxford is also renowned for its large-scale studies which examine the role of factors such as smoking, alcohol and diet on cancer, heart disease and other conditions.