Prospective drug found by testing in human heart muscle grown from stem cells.
Coronary heart disease is the major cause of heart attacks and it kills 180 people in the UK each day. Finding a drug that could limit the death of heart muscle during and after a heart attack, and stop the decline towards heart failure, has been a target of research for decades.
There are no existing therapies that directly address the problem of muscle cell death.
So, scientists from Imperial College and Domainex, a Cambridge medicinal chemistry firm have found a potential new drug candidate for treating the heart damage caused during a heart attack by targeting the way the heart reacts to stress, according to new research published in Cell Stem Cell.
The research team, led by BHF Professor Michael Schneider at the National Heart and Lung Institute, Imperial College London, was the first to discover that a protein called MAP4K4 plays a central role in how heart muscle cells die off after a heart attack.
They have developed a potential drug that targets MAP4K4, and which in mouse studies can minimise the damage after a heart attack by 60 per cent.
A heart attack happens when a blood clot blocks one of the main coronary arteries, the blood vessels supplying the heart muscle. The heart is starved of oxygen and nutrients and the muscle produces stress signals that ultimately cause heart cells to die. These dead cells are not replaced very well, and this means that the damaged heart cannot pump effectively, leading to heart failure. Heart failure is a debilitating condition that makes everyday tasks like climbing stairs, or getting dressed, exhausting.
More people than ever are surviving their heart attacks after receiving treatments such as stents and clot-busting drugs, but this means that the number of people living with heart failure has risen considerably. In the UK, there are an estimated 900,000 people living with heart failure.
The new drug could be given in the first few hours following a heart attack to minimise heart muscle death caused by the stress signals. These stress signals actually increase dramatically when the blood supply is restored, so although it is vital to resupply the heart with oxygen and nutrients by reopening the blocked coronary artery, additional treatments to counteract any ‘reperfusion injury’ have been sought for decades.
The researchers made their discovery by studying heart samples from people with heart failure and found out that MAP4K4 is activated in these patients.
They showed this was also the case in mice after a heart attack, and in human and rodent heart cells and heart tissue subjected to stress signals in the laboratory.
They found that if you raise the levels of MAP4K4, heart cells are made more sensitive to stress signals. If you block MAP4K4, the cells are protected, and is what the designed drug can achieve.
It is hoped that this work will be developed into a treatment that could be given as an injection whilst someone is being prepared to receive balloon angioplasty to open up the blocked coronary artery that caused their heart attack.
The treatment is also possibly important in regions and countries where there is limited access to rapid angioplasty, when it could be given whilst the patient is waiting for hospitalisation.
The team believes testing their results in human heart tissue grown from stem cells before moving to trials in heart attack patients can improve progress in this treatment area.
This research was funded by the British Heart Foundation and Wellcome Trust. Domainex partnered for the design, testing and manufacture of the drug candidates tested. [APBN]