Research into pulmonary hypertension
Pulmonary arterial hypertension is a rare but serious condition, which damages the arteries in the lungs, and can be fatal. Professor Martin Wilkins tells Sarah Brealey about his ground-breaking research to find new treatments.
What is pulmonary arterial hypertension?
Pulmonary arterial hypertension (PAH) is a condition caused by high blood pressure in the arteries of the lungs. People with the condition feel breathless and tired. It can occur alone or with other illnesses. As a disease on its own it is rare – affecting between 10 and 57 people per million – but it leads to heart damage. Some patients will need a lung transplant, or heart-lung transplant, and it can even be fatal.
The BHF is funding at least a dozen pieces of research into this disease. We’ve funded Professor Martin Wilkins and his team at Imperial College London with successive awards over 20 years to pursue underlying disease mechanisms and new treatment ideas.
Normal healthy artery (left) compared to diseased artery affected by pulmonary hypertension
Professor Wilkins says: “Survival with the disease is still unacceptably poor. Around 35 per cent of patients die within five years of diagnosis. We don't have treatments which arrest, let alone reverse, the disease. The disease tends to present in a well advanced state, ie patients are severely ill when they come to us.
“Our overall ambition is to identify treatments which arrest and reverse the disease. This treatment will be different for different individuals. We do know of some individuals where genes are involved, but we still don’t know the best way to treat them and there are many patients where the cause is unknown.”
Iron deficiency and pulmonary arterial hypertension
Professor Wilkins and his team have found out that some people with PAH have low levels of iron – not only that, but there is a relationship between how long people with PAH live.
“We found that a low iron level is common in patients with PAH. Other studies have found the same. We then related iron levels to how long patients lived. There was a clear relationship between the two. Patients weren’t particularly anaemic – in other words, they still had normal levels of red blood cells - but could be iron-deficient and if they were, they lived less long than those who had no iron deficiency.
“It raises the question of whether low iron levels are a cause of low survival, or whether there are other factors determining the course of the disease and the iron levels are just a by-product of whatever is causing the more rapid deterioration.”
Now they are running a BHF-funded trial to see whether giving these patients a large dose of iron (as a single dose via a drip) helps them.
It raises the question of whether low iron levels are a cause of low survival
Professor Wilkins says: “We are replacing iron in patients who are iron-deficient and then measuring how well they do – to see whether iron makes any difference to how they feel, function and survive. We don’t have results yet but we have found that it is safe to do this.”
The trial will conclude over the coming year. Its main aim is to check that the technique of replacing iron is safe and doesn’t cause major side effects, although it will look at any benefits too. “If we get results that suggest the patients are walking further, able to exercise more and feeling better, maybe an international study would be called for to more accurately study the role of iron replacement in patients with PAH,” says Professor Wilkins.
Partly as a result of Professor Wilkins’ previous research, European guidelines for treating PAH now highlight the fact that 43 per cent of PAH patients are iron deficient and suggest that iron replacement should be considered.
CT scan showing the chest of a patient with pulmonary arterial hypertension (PAH). The pulmonary artery (centre right) is dilated, putting pressure on the right side of the heart.
Zinc and pulmonary arterial hypertension
After more than 20 years of research into the genetics of PAH, Professor Wilkins and his colleague, Professor Lan Zhao, have also discovered a gene that is involved in the condition. The gene produces a protein that regulates zinc levels in cells.
The starting point was the knowledge that people (and other mammals) that live at high altitudes, where there is low oxygen, are at risk of pulmonary hypertension. In a low oxygen atmosphere, the blood vessels constrict and then become stiffer and narrower. This puts increased pressure on the right side of the heart, and then leads to PAH. In some people and animals this doesn’t seem to happen, so Professor Wilkins and Professor Zhao decided to look for which genes that were involved.
They found this by studying rats that were naturally resistant to developing PAH in a low oxygen atmosphere.
No one has ever associated zinc transport with PAH before
“We thought that finding a protective gene would help identify a pathway that we might then be able to target with drugs to reproduce the effect,” says Professor Wilkins. “We took a rat strain that was protected against hypoxia-induced pulmonary hypertension and bred it with a strain that was more susceptible. And we followed the DNA sequences that tracked with offering protection.
“We found that a mutation in a gene that regulates zinc transportation across cell membranes was associated with resistance to the effects of low oxygen on the pulmonary circulation. This was entirely surprising as little has previously been done on zinc and cardiovascular disease. This is giving us new insights into how the circulation in the lungs works.
“It turns out that gene regulates zinc transportation across cell membranes. No one has ever associated zinc transport with PAH before, although there is already a lot of literature on zinc and cardiovascular disease. This is giving us new insights into how the circulation in the lungs works.
“We think when you are exposed to a low oxygen atmosphere, such as up a mountain, the pulmonary circulation becomes zinc-hungry. It makes the cells grow and the blood vessels become stiffer as a result.”
This discovery opens the way for new medications to treat it by targeting the specific process of zinc transport in the pulmonary circulation.
Professor Wilkins says: “Our intention is to find drugs that mimic the effects of the gene mutation. That would give us an entirely new way of treating this condition. We would want to regulate zinc levels in specific cells in the pulmonary vasculature. You can't do that through dietary alteration, because your cells need zinc.
“Currently no drugs exist that specifically regulate zinc transport in cells. We have received funding from a venture company to help us in new drug discovery. We hope to make progress over the next year in terms of finding a possible new drug. It then takes some refinement and several years to work those up as drugs to a stage where we can do clinical trials.”
Both Professor Wilkins’ findings – about low iron levels and zinc transport in cells – are potentially significant, and are likely to benefit different groups of PAH patients.
The professor says: “Our overall approach is to try and identify therapies which benefit individuals in a personalised medicine approach. Although PAH is a rare disease, it is a diverse disease."
Professor Wilkins says: “The zinc finding is a real case of benefiting from consecutive BHF project grants which led to the final discovery after years of work. To get that continuous funding from the BHF has been really important.”
“BHF funding has been absolutely essential to my work. Research into PAH has received a tremendous amount of funding from the BHF: it is one of the most active research areas of vascular disease in the country. There are other excellent examples of research going on around the UK – in Cambridge, Sheffield, Newcastle and Glasgow, for example.”
He also highlights the role that patients have played. “We are really grateful to the patients who participate in our research, for example through giving blood samples, making special visits and taking the time to take part in a study. Without them volunteering their time, we would not be able to make the progress we have.”