Watch: Research to prevent amputation

It’s not just the arteries that supply your heart that can become blocked. The same processes in the body can cause blockages in leg arteries, which can lead to severe pain and even amputation. Bijan Modarai tells Sarah Brealey how he’s trying to find a cure for this problem.

What is critical limb ischaemia?

Just as the arteries supplying your heart can become blocked, so can the blood vessels in your legs and feet. This is called peripheral arterial disease. Peripheral arterial disease is quite common, affecting around one in five people over the age of 60,  though it is relatively rare in the under-50s. The most severe form is called critical limb ischaemia, which causes severe pain and can lead to limb amputation.

Critical limb ischaemia occurs in around 1 per cent of all people with peripheral arterial disease. This is estimated to mean between 500 and 1000 new cases each year per million people in the population  – so up to 60,000 new cases a year in the UK. 

How big is the problem?

Bijan Modarai, a consultant vascular surgeon and BHF Research Fellow, is based at King’s College London and Guy's and St Thomas' NHS Foundation Trust, which has the biggest vascular unit in the UK. He says: “We see close to 1,000 patients a year with critical limb ischaemia, which essentially is a severe restriction of blood flow to the leg. Initially it causes severe pain at rest, which gets worse at night. As the poor blood flow gets worse, they can develop gangrene and tissue loss. Many of them – up to a third – will eventually require limb amputation, which can be of the foot, below the knee or above the knee. 

“The majority of these patients are older and many of them have diabetes. There is good evidence that the quality of life of these patients is essentially the same as those with terminal cancer.”

His programme of research is aimed at finding new diagnostic and treatment strategies for these patients. 

 Atherosclerosis and normal artery

Peripheral arterial disease - atherosclerosis and blood clot

Developing more sensitive measurement

Being able to diagnose the problem more accurately could mean that patients get treated earlier. Mr Modarai says: “We need more sensitive measurement of blood flow to the muscle, so we are looking at fluid dynamics in a new way and also using MRI scans to assess blood flow. That might help us to treat the disease earlier on than we usually would.”

He adds: “We published a paper in the Journal of the American College of Cardiology in 2016. We showed that using MRI you can quite sensitively assess blood flow to muscle of patients with critical limb ischaemia.”

Having more sensitive measurement will also be helpful when running clinical trials of treatments for critical limb ischaemia. At the moment, the main measure of success is how many patients go on to have a limb amputation. This is the most important measure but a rather blunt tool, which is less helpful at recording small improvements.

Growing new blood vessels

Mr Modarai and his team are looking at cells with angiogenic properties – that is, that they help new blood vessels to grow. They are looking at stem cells which are derived from the patient’s own fatty tissue, as well as specific types of white blood cells called monocytes and macrophages. 

My aim is to produce a clinically effective treatment for these patients who would otherwise have no option other than amputation

“Recently we are looking particularly at monocytes and macrophages, because there is evidence that these cells are particularly powerful at promoting the growth of new blood vessels to re-route the blood flow,” says Mr Modarai. “Five or six years ago we found these cells circulating in higher numbers in the blood of patients with critical limb ischaemia. We found these cells have angiogenic value.

“We have isolated these cells in patients with critical limb ischaemia and injected them into the leg. We have done a first-in-man trial that showed it is possible to do this and there are no safety concerns. The research has been quite a success.”

However, there are still challenges. The introduced cells may die, move away from the injured area, or be rejected by the immune system as “foreign”. Mr Modarai has been investigating ways to put the cells into tiny capsules to see if that makes them more likely to stay in the affected area. This work is ongoing. He says: “We are looking at ways of making sure the cells remain healthy and viable.” 

“My aim is to produce a clinically effective treatment for these patients who would otherwise have no option other than amputation.”

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