Research into bone marrow

Pain may not always be a bad thing, at least when it comes to a heart attack. That’s the theory Professor Paolo Madeddu is investigating, as he looks at the role of bone marrow in communicating pain and promoting healing. He tells Sarah Brealey more.

Professor Paolo Madeddu

Pain is a common symptom of a heart attack. Heart attack patients are usually given pain relief, often in the ambulance before they even get to hospital. But what if that pain is useful? “The theory we are adopting is that when you have heart attack, you feel pain, which is like your body’s alarm system,” says Professor Madeddu. “So the pain could be playing a useful role.”

Some people experience ‘silent’ or undiagnosed heart attacks, which may have few symptoms, if any. It’s estimated that as many as 60 per cent of all heart attacks are silent. In some cases these people may simply have a higher pain threshold, but it can also be connected with diabetes.  Professor Madeddu has spent more than 30 years researching ways to help people with heart and circulatory conditions, including the last 17 years studying ways to help the heart heal itself. He’s been at the University of Bristol since 2005 and is now Professor of Experimental Cardiovascular Medicine there.

If someone with diabetes has a heart attack they may not feel the pain

“The symptoms that were described in medical textbooks 30 years ago as stressful and painful may actually have a useful function,” he says. Diabetes is a common cause of neuropathy (damage to the nerves). This can mean that pain is experienced differently – it may be stronger or it may not be felt at all. In the UK, 3.6 million adults have been diagnosed with diabetes, and it’s estimated that around one million people may be living with undiagnosed type 2 diabetes. Numbers are rising fast, mostly because of rising levels of obesity. Having diabetes can double the risk of heart and circulatory disease, so people with diabetes are already at higher risk of heart attacks.

“Sometimes people with neuropathy don’t realise they are getting injured because they don’t have pain,” Professor Madeddu explains. “If someone with diabetes has a heart attack they may not feel the pain. We know that patients who have a ‘silent’ heart attack have a worse prognosis on average than other heart attack patients. There is also higher mortality in heart attack patients who are given morphine for pain relief. I am not saying patients shouldn’t be given morphine, but I am saying that the pain may be serving a purpose.”

Self-repair system

So what is this purpose? Your bone marrow is where many new cells in the body are made, including stem cells, which have the ability to restore damaged tissue. “Normally bone marrow releases healing substances during a heart attack,” says Professor Madeddu. “We think that the pain itself is the signal to guide healing cells from the bone marrow to the heart. If pain is blocked – by diabetes or by painkillers – there’s no signal to stem cells to travel to the heart, which will result in more damage to the heart and worse recovery.” 

Diabetes damages blood vessels all around the body, meaning tissues, including bone marrow, don’t receive the oxygen they need

He’s looking at whether producing pain in heart attack patients could help them recover better, or whether there are other ways to stimulate the bone marrow to produce healing stem cells. Professor Madeddu’s research suggests that if you have diabetes, your body’s ability to deal with a heart attack is doubly limited. Firstly, if you have neuropathy, you may not feel the pain of a heart attack, so the body’s ‘alarm’ doesn’t go off and the bone marrow doesn’t release healing cells. To make matters worse, the bone marrow itself is less able to act as the body’s repair system, even if it does hear the ‘alarm’. This is because diabetes damages blood vessels all around the body, meaning tissues, including bone marrow, don’t receive the oxygen they need. High glucose levels in the blood – a sign of diabetes – also damages stem cells.

“Normally the bone marrow contains stem cells and the network of blood vessels that supply them,” says Professor Madeddu. “But in patients with diabetes there is a lot of fatty tissue in the bone marrow. So you have less healthy bone marrow left to produce the cells; there are fewer blood vessels and fewer nerves.”

Cells in the fatty bone marrow are also more likely to be inflamed. Inflammation is one of the key processes in the development of heart and circulatory disease.

Micrograph of healthy bone marrow

Healthy bone marrow

Future treatments 

Professor Madeddu is researching ways to ensure bone marrow stays healthy so it can produce new cells, especially in people with diabetes.

His team is looking at protein kinase C beta (PKCB), a protein involved in several cellular processes in the body. Scientists know how to inhibit or turn off this protein, using drugs that are already available to treat diabetes. It looks like this could help protect bone marrow. Professor Madeddu says: “We have shown that using a PKCB inhibitor can control the processes that lead to fatty tissue.”

What is good for the bone marrow can be good for the other organs and can also protect the heart

This would help other parts of the body as well. “What is good for the bone marrow can be good for the other organs – preventing obesity and other complications of diabetes – and can also protect the heart,” he says. “We are helped by the fact that PKCB inhibitors are already commercially available, though not for this purpose. So clinical trials could start quite soon, in a year or two, if we can prove that this can prevent inflammation and formation of fatty tissue.

“For drugs that aren’t already commercially available, we would need to test them much more rigorously for safety, so that would take number of years longer." Professor Madeddu believes large numbers of patients could ultimately benefit – not just those with heart attacks, but also people with other complications of diabetes, such as peripheral arterial disease, which can sometimes lead to amputation.

Professor Madeddu trained in medicine, specifically cardiology, and he says his research is based on problems that he has seen in patients. “This is not research of an abstract hypothesis, it is research to solve patients’ needs,” he says. “We hope that we will be able to bring real benefits for patients.”

BHF support

We’ve awarded Professor Madeddu and his colleagues, including BHF Professor Costanza Emanueli, more than £700,000 over five years to build on this knowledge. They are in the third year of this work, studying the circulatory system of the bone marrow in people and mice with diabetes. They’re using powerful microscopes and scanners to look at the behaviour of cells in the bone marrow and how blood flows around the bone marrow. 

They’ve recently been awarded a further £190,000 grant from the BHF to look at using PKCB to improve the outlook for people with heart attack or diabetic cardiomyopathy (changes in the structure of the heart in people with diabetes, which can lead to heart failure).

Professor Madeddu is grateful for BHF support. “The BHF is one of the biggest research funding organisations in the UK,” he says. “Many countries do not have a cardiovascular research charity like this. We are very lucky. Thank you to the BHF and all its supporters.”

 

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