The researchers now hope the chemicals will provide a starting point for developing new injectable drugs that could be used to prevent some of the long-term damage caused by heart attack and stroke.
The research, which was conducted in rodents, was part-funded by the British Heart Foundation (BHF) and Medical Research Council (MRC).
During a heart attack or stroke, a clot can starve the heart or brain of blood and oxygen, causing irreversible damage. Further damage is caused when the clot is dislodged and blood rushes back into the heart or brain. Until now, it was unclear how the return of blood flow starts this damage.
In research published in Nature, scientists led by teams at the MRC Mitochondrial Biology Unit, MRC Cancer Unit and the University of Cambridge and involving groups from the University of Glasgow, are the first to find that this damage is caused by a build-up of a chemical called succinate. Succinate occurs naturally in the body when sugar and fat is broken down to release the energy stored in food.
The research shows that succinate builds up to abnormally high levels inside an organ when blood flow is limited. When the blood flow returns, the excessive build-up of succinate interacts with oxygen as the blood rushes in to the oxygen-starved tissues. This causes the release of destructive molecules which react with muscle cells in the organ, damaging them.
In the months and years after a heart attack, this damage can ultimately lead to heart failure, a debilitating condition that leaves people unable to carry out everyday tasks like washing themselves or climbing stairs.
The researchers identified the increase in succinate by measuring a range of different chemicals in the vital organs before and after heart attack and stroke, in a technique called metabolomics.
Crucially, the researchers have discovered that they can reduce organ damage in mice and rats by administering simple chemicals, called malonate esters, when blood flow is restored. Malonate esters stop the build-up of succinate and the resulting release of destructive molecules.
Malonate esters are cheap, readily available and are found naturally in fruits like strawberries, apples and grapes, although not in high enough volumes to be beneficial.
The findings could also have implications in surgery where transplanted organs such as the kidney, liver and the heart all suffer damage after they are connected to the transplant patient’s blood flow.
Dr Michael Murphy from the MRC Mitochondrial Biology Unit, co-author on the research paper said: “This research explains how organ damage occurs during the first few minutes of restoring blood supply after a heart attack or stroke and, importantly, how to stop this damage.
“We have used simple chemicals found in everyday fruits like apples and grapes that had never been suspected as being therapeutically useful before. Amazingly, these chemicals worked very well.”
Dr Lorraine Work, from the Institute of Cardiovascular & Medical Sciences at the University of Glasgow and co-author of the paper, said: “We were very excited to contribute to this study and to confirm the findings seen after a heart attack in our stroke model.
“The long-lasting damage often seen after a stroke or heart attack can have a huge negative impact on quality of life. Through the findings of these studies we now understand more about the processes behind this damage and by delivering commonly occurring chemicals we were able to see marked improvements.
“This provides a new avenue for further research in the search to identify treatments for stroke and heart attack sufferers.”
Dr Richard Hartley, from the School of Chemistry at the University of Glasgow and also a co-author of the paper, said “It’s been believed for a while that reactive oxygen species (ROS) cause much of the damage to the heart, when a person has a heart attack. This work is game-changing because it shows for the first time that a single biochemical pathway is responsible for ROS production, and gives a way of preventing the damage. It was great that our molecular probe, MitoB, could show that malonate stops the damage by reducing mitochondrial ROS.”
Professor Jeremy Pearson, Associate Medical Director at the BHF, which part-funded the study, said: “This is an important breakthrough. By discovering a way to limit severe organ damage following a heart attack or stroke, the scientists have paved the way for translation of these results into treatments for the hundreds of thousands of people who suffer from heart attacks and stroke in the UK every year. Further research is now needed before trialling this treatment in patients.” The research team included scientists from the Medical Research Council (MRC), the University of Cambridge, King’s College London, University College London, the University of Rochester Medical Centre, the University of Glasgow and Addenbrooke’s Hospital in Cambridge and was funded by the British Heart Foundation, MRC, the Canadian Institutes of Health Research and the Gates Cambridge Trust.
Find out more about BHF-funded research at www.bhf.org.uk/research.
Notes to editors:
This research involved the use of rats and mice.
Researched published in Nature online 05/11/14. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS doi:10.1038/nature13909
Please contact the BHF press office for a copy of the paper.
MRC Technology filed a UK priority patent application around this work in 2014