Our research impact

The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy

Professor Paolo Madeddu and his team are working to delay the ageing of the heart. He tells Dr Leanne Grech how this research could allow older people to live a healthier life for longer.

The BPIFB4 gene has been associated with exceptional longevity

Each day, your heart beats around 100,000 times, pumping about eight pints of blood around your body. By the time you are 20, the heart’s function can begin to decline as part of normal ageing. As you get older, activities like running or playing tennis become more difficult. However, some 100-year-olds, like those living in Okinawa, a cluster of islands in southern Japan, appear to have unlocked the secret to a long and healthy life, with some of them seemingly having a heart younger than their age. “It’s a combination of a good lifestyle and good genes,” explains Professor Paolo Madeddu at the University of Bristol. “And we have discovered that one of these good genes can stop ageing.”

The gene that can stop ageing Professor Madeddu and his team have discovered that a naturally occurring variant of the BPIFB4 gene, which is more common in people who live to 100 or more, could help keep the heart young. A gene variant is a permanent change in the DNA sequence that makes up a gene. The team have already learned that mice treated with this variant have healthier hearts. In fact, transferring this gene variant to old mice seemed to help relax blood vessels in mice with high blood pressure and increase the amount of blood delivered to the muscles. In humans, ageing can affect many parts of the body, including weakening the heart and circulatory system. For example, heart failure, a serious and sometimes disabling condition for which there is no cure other than a heart transplant. Symptoms include breathlessness and feeling abnormally tired. Heart failure can occur at any age, but it is more common in older people, and in people who have had a heart attack and who have cardiomyopathy or high blood pressure.

Scientists are now beginning to understand how some natural variations in our genes might protect against heart diseases linked to ageing, such as heart failure. In this study, Professor Madeddu and his team in Bristol have been funded by the BHF with more than £172k to further investigate the role of the BPIFB4 gene variant. The BPIFB4 gene has been associated with exceptional longevity, helping protect against atherosclerosis (build-up of fatty material inside your arteries) and high blood pressure. The team now want to know if this gene variant can be given as a tablet and if it can reduce chronic inflammation (a damaging set of processes often seen in ageing hearts). Most genes contain the information needed to make functional molecules called proteins. Giving the corresponding protein as a pill instead of the gene variant could be an easier way to get the same result. Professor Madeddu and his team will test this idea in mice. If it succeeds, they hope to go on to a clinical trial in humans. “The study will provide proof of concept that our solution is valid. More studies are needed to show it is also safe – the fact that it is a human protein and not a [new] drug is encouraging. However, producing large quantities of protein is extremely expensive, and we will need investors or an industrial partner in the future. The BHF could help us to find the right partner,” explains Professor Madeddu.

I hope that the results of my work can make a difference in the lives of a lot of patients.

Helping older hearts Professor Madeddu is a cardiologist by background, and has been fascinated by the heart since he was a medical student. “Research requires a lot of determination and effort. I hope that the results of my work can make a difference in the lives of a lot of patients.” In 2021, around 12.5 million people in the UK were 65 or older. Life expectancy had been rising for decades, but the increases have slowed since 2010, and life expectancy for both men and women has fallen since the Covid-19 pandemic. Research like that of Professor Madeddu aims to help older adults stay healthy and independent for longer, which is among the UK Government priorities. “There is no current treatment to stop the heart’s ageing, and drugs used for heart disease can cause side effects in seniors,” explains Professor Madeddu. “We hope that giving older people a protein that is present in healthy centenarians, like those in Okinawa, helps their hearts work better for longer. Our approach proposes to increase health rather than simply combat disease. If we can find an effective treatment to delay ageing of the heart, we may be able to prevent serious disease in older people.”

Read the case report

Monica Cattaneo , Antonio P Beltrami , Anita C Thomas , Gaia Spinetti , Valeria Alvino , Elisa Avolio , Claudia Veneziano , Irene Giulia Rolle , Sandro Sponga , Elena Sangalli , Anna Maciag , Fabrizio Dal Piaz , Carmine Vecchione 4,5 , Aishah Alenezi , Stephen Paisey , Annibale A Puca , Paolo Madeddu The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy.  Cardiovasc Res. 2023 Jan 13;cvad008. PMID: 36635236 DOI: 10.1093/cvr/cvad008.

Stem cell plasters to stop children needing repeated heart surgeries

Researchers at the University of Bristol, funded by the British Heart Foundation (BHF), have developed ‘stem cell plasters’ to revolutionise the way surgeons treat children living with congenital heart disease, so they don’t need as many open-heart operations.

Heart defects are the most common type of anomaly that develop before a baby is born, with around 13 babies diagnosed with a congenital heart condition every day in the UK.  These include defects to the baby’s heart valves, the major blood vessels in and around the heart, and the development of holes in the heart.

Currently, for many of these children, surgeons can perform open-heart surgery to temporarily repair the problem, but the materials used for the patches or replacement heart valves are not completely biological and cannot grow with the baby. This means they can be rejected by the patient’s immune system which causes the surgical materials to gradually break down and fail in a few months or years.

A child might therefore have to go through the same heart operation multiple times throughout its childhood, which keeps them in hospital for weeks at a time, hugely impacts their quality of life and causes a lot of stress for the family.

Now, BHF Professor Massimo Caputo has developed the first type of stem cell patch to repair abnormalities to the valve in the large blood vessel that controls blood flow from the heart to the lungs, and to mend holes between the two main pumping chambers of the heart.

The stem cell plasters are designed to be sewn into the area of the child’s heart that needs repairing during surgery. The stem cells could then boost the repair of heart tissue without being rejected by the child’s body.

These patches have the potential to adapt and grow with the child’s heart as they get older, removing the need for repetitive heart surgeries and the many days at hospital recovering after each one.

There are around 200 repeat operations for people living with congenital heart disease every year in the UK. The technology could save the NHS an estimated £30,000 for every operation no longer needed, saving millions of pounds each year.

The BHF has awarded Professor Caputo nearly £750,000 with the aim to get these patches ready for testing in patients so clinical trials can start in the next two years, enabling more children and babies to benefit from the life-altering technology. The materials have already proven to work safely in animals.

The team is also in the early stages of developing other stem cell technologies using 3D bioprinting and gene therapy to one day be able to mend more complex congenital heart defects.

Massimo Caputo, BHF Professor of Congenital Heart Surgery at the Bristol Heart Institute, University of Bristol, said: “For years families have come to us asking why their child needs to have heart surgery time and time again. Although each operation can be lifesaving, the experience can put an unbelievable amount of stress on the child and their parents. We believe that our stem cell patches will be the answer to solve these problems.

“Our ultimate vision in the next decade is to create a paradigm shift in the way doctors treat congenital heart disease, by developing personalised stem cell and genetically-engineered treatments for the most complex of heart defects.”

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation, added: “If successful, this new stem cell therapy that acts like a healing plaster could revolutionise the results of heart surgery for children and adults living with congenital heart disease.

“It could offer a solution that means their heart is mended once and forever in a single operation, preventing people from facing a future of repeated surgeries and giving them the gift of a happier and healthier life.”

The work was partly funded by the National Institute of Health and Care (NIHR) Bristol Biomedical Research Centre (NIHR Bristol BRC), a partnership between University Hospitals Bristol and Weston NHS Foundation Trust (UBHW) and the University of Bristol.

Research aims to reduce strokes caused by tiny air bubbles entering the blood stream during heart surgery

Dr Ben Gibbison and his team from the Bristol Heart Institute and the Bristol Trials Centre are investigating how to reduce strokes and other brain problems following heart surgery, which can be caused by tiny air bubbles left in the bloodstream after opening the heart. These tiny air bubbles stop blood getting to part of the brain.

The study, which started in October 2021 and is currently recruiting, is called the CO2 Study. It is funded by the National Institute for Health Research (NIHR) and sponsored by University Hospitals Bristol and Weston NHS Foundation Trust (UHBW).


Diabetes breakthrough: gel-like sieve in blood vessels a new target for repairing damaged hearts

Drugs that repair damage to a gel-like layer in the tiny blood vessels of the heart could present a much-needed treatment for heart failure in people with diabetes, according to University of Bristol-led research funded by the British Heart Foundation and published today in Diabetologia.


SARS-CoV-2 Spike protein binds to heart’s vascular cells potentially contributing to severe microvascular damage

A new study has shown how SARS-CoV-2 may contribute to severe microvascular damage seen in severely-ill COVID-19 patients by transforming human heart vascular cells into inflammatory cells, without infecting them. The University of Bristol-led research, published in Clinical Science, indicates blocking antibodies could represent a new treatment to alleviate cardiovascular complications.


New multidisciplinary study could help doctors to predict heart failure

Nearly half of people diagnosed with advanced heart failure (HF) following a major heart attack die within five years. But research supported by GW4 Alliance funding could lead to earlier prediction and intervention – improving life expectancy.


Mixed Reality and AI to aid surgeons with keyhole heart valve surgery

Heart surgery
Cardiac surgeons could in the future be conducting procedures virtually before even stepping into an operating theatre. A research team from UWE Bristol’s Big Data lab and Faculty of Health and Applied Sciences (HAS) is developing technology that uses artificial intelligence (AI), augmented reality (AR) and virtual reality (VR) to assist cardiac surgeons in planning and preparing for complex keyhole heart valve surgery.

The team is initially collaborating with the Bristol Heart Institute (BHI), a Specialist Research Institute at the University of Bristol, whose surgeons will test the system when preparing for minimally invasive cardiac valve surgery (MICVS).

Compared to conventional open-heart surgery involving cutting through the breastbone to reach the heart, MICVS is less intrusive as the heart is accessed through smaller incisions using endoscopic instruments. And patient recovery time is generally quicker after this keyhole surgery.

However, MICVS is complex and requires hours of pre-operative planning and preparation.

Dr Hunaid Vohra, Consultant Cardiac Surgeon and Honorary Senior Lecturer and Researcher at the BHI, who is collaborating with UWE Bristol, said:

“In the operating room, despite pre-planning, it is currently very common to find unexpected challenges, as every patient’s height, weight and heart-lung anatomy is different. And patients’ frailty varies.

“Mixed Reality and AI will enhance our ability to prevent the conversion of a keyhole heart valve operation to an open heart surgery, avoiding two sets of scars, and delay in recovery.”

Surgeons will initially be able to use the system’s AI to tap into the patient’s medical data to predict the risks associated with the procedure. The likelihood of adverse events is then presented to the surgeon on a HoloLens using AR.

Next, the surgeon will have access to AR technology to show a patient a 3D version of their heart and explain the procedure to them via headsets.

Dr Muhammad Bilal, Associate Professor of Big Data and Artificial Intelligence at UWE Bristol and leading the research team, said:

“Most terms surgeons use to describe heart surgery during consultation draw a blank from patients and this system makes the explanation task much clearer and easier.”

Incorporated in the system is also a pre-operative logistics element that optimises operation planning. This will assist medical teams in preparing the right instruments and materials, and booking the appropriate operating theatre and hospital beds, among other tasks.

Crucially, the software’s virtual planning feature will provide surgeons with access to a complete digital version of the patient, enabling them to perform the entire operation beforehand on a replica of the patient’s thoracic cavity. This will include ‘what-if’ scenarios to determine the most optimal and personalised surgical strategies.

Finally, in collaboration with UWE Bristol’s Centre for Print Research, surgeons performing very complex cases will be allowed to order a bespoke 3D printed model of the patient’s thoracic cavity mimicking organs, veins, and blood flow to simulate the procedure on a synthetic body.

Dr Vohra said:

“This will enable us to practise before the actual operation and minimise the potential for things to go wrong on the day. Overall, we are excited to be involved in this technology, which could spell the future for highly successful minimally invasive procedures of this type in adults and babies.”

Dr Bilal added:

“Currently, the practice of MICVS is limited to a small group of surgeons in the world. This technology-enabled guidance promises to increase the number of doctors able to perform these operations, providing wider access to the general population.

“There are significant engineering challenges to be resolved before this technology can be rolled out into the NHS but our collaboration with the BHI provides a perfect testing ground.”

TV watching linked with potentially fatal blood clots

Take breaks when binge-watching TV to avoid blood clots, say scientists. The warning comes as a study reports that watching TV for four hours a day or more is associated with a 35 per cent higher risk of blood clots compared with less than 2.5 hours. The University of Bristol research is published today in the European Journal of Preventive Cardiology, a journal of the ESC.

The study examined the association between TV viewing and venous thromboembolism (VTE). VTE includes pulmonary embolism (blood clot in the lungs) and deep vein thrombosis (blood clot in a deep vein, usually the legs, which can travel to the lungs and cause pulmonary embolism).

To conduct the study, the University of Bristol researchers conducted a systematic review to collect the available published evidence on the topic and then combined the results using a process called meta-analysis.

Lead author, Dr Setor Kunutsor from the University’s Bristol Medical School explained:

“Combining multiple studies in a meta-analysis provides a larger sample and makes the results more precise and reliable than the findings of an individual study.”

The analysis included three studies with a total of 131,421 participants aged 40 years and older without pre-existing VTE. The amount of time spent watching TV was assessed by questionnaire and participants were categorised as prolonged viewers (watching TV at least four hours per day) and never/seldom viewers (watching TV less than 2.5 hours per day).

The average duration of follow-up in the three studies ranged from 5.1 to 19.8 years. During this period, 964 participants developed VTE. The researchers analysed the relative risk of developing VTE in prolonged versus never/seldom TV watchers. They found that prolonged viewers were 1.35 times more likely to develop VTE compared to never/seldom viewers.

The association was independent of age, sex, body mass index (BMI) and physical activity. Dr Kunutsor said:

“All three studies adjusted for these factors since they are strongly related to the risk of VTE; for instance, older age, higher BMI and physical inactivity are linked with an increased risk of VTE.

“The findings indicate that regardless of physical activity, your BMI, how old you are and your gender, watching many hours of television is a risky activity with regards to developing blood clots.

“Our study findings also suggested that being physically active does not eliminate the increased risk of blood clots associated with prolonged TV watching,” said lead author Dr Kunutsor. “If you are going to binge on TV you need to take breaks. You can stand and stretch every 30 minutes or use a stationary bike. And avoid combining television with unhealthy snacking.”

Dr Kunutsor noted that the findings are based on observational studies and do not prove that extended TV watching causes blood clots.

Regarding the possible reasons for the observed relationship, he said:

“Prolonged TV viewing involves immobilisation which is a risk factor for VTE. This is why people are encouraged to move around after surgery or during a long-haul flight. In addition, when you sit in a cramped position for long periods, blood pools in your extremities rather than circulating and this can cause blood clots. Finally, binge-watchers tend to eat unhealthy snacks which may lead to obesity and high blood pressure which both raise the likelihood of blood clots.”

Dr Kunutsor concluded:

“Our results suggest that we should limit the time we spend in front of the television. Long periods of TV watching should be interspersed with movement to keep the circulation going. Generally speaking, if you sit a lot in your daily life – for example your work involves sitting for hours at a computer – be sure to get up and move around from time to time.”

Read the paper

Television viewing and venous thrombo-embolism: a systematic review and meta-analysis in the European Journal of Preventive Cardiology by Setor Kunutsor, Richard Dey and Jari Laukkanen.

Further information

Authors’ note:

The findings are based on observational studies, so they do not prove cause and effect.

These findings are based on the results of only three studies. More studies are needed to confirm or refute the findings.

Pioneering stem cell therapy at Bristol Royal Hospital for Children

Dr Filippo Rapetto discusses an innovative case using donor stem cells which offers hope for babies born with heart problems.

FinleyFilippo, can you tell us what happened?

Finley was four days old when he was diagnosed at Bristol Royal Hospital for Children with transposition of the great arteries, which affects about one in 3,000 newborns. The treatment, which is very well established, is an operation called arterial switch procedure, which includes a complex surgical step called coronary artery translocation. Unfortunately, in this case, one of the coronary arteries had an anomalous course and the translocation was not successful. This caused a significant deterioration in Finley’s cardiac function.

We struggled for a couple of months with various treatments, such as extra corporeal membrane oxygenation (ECMO). After we managed to wean him off that, he was still in intensive care for many weeks, dependent on inotrope drugs to increase his heart function, which was very poor.

Because there was no conventional way to treat his condition, Professor Massimo Caputo with the Paediatric Cardiac Surgery team, the Paediatric Cardiology team and the Paediatric Intensive Care team, suggested we source donor mesenchymal stromal cells (stem cells) to inject directly into Finley’s heart with a second surgical procedure. We have a collaboration with the Centre for Cell, Gene and Tissue Therapeutics (Royal Free Hospital, UCL) which provided us with the cells within a few days. Professor Caputo managed to get compassionate funding from the Trust, and he got the process going quickly.

Following the procedure, we noticed a slow but consistent improvement in the patient’s clinical conditions. We then did multiple echocardiograms to monitor the cardiac function, and it got gradually and consistently better. He was able to go home about three months after the stem cell injection.

Has he made a full recovery?

He started from what we call a severe dysfunction and now his heart function is close to normal, comparable with someone who had a heart operation as a newborn.

What evidence do you have that the procedure worked?

From a scientific point of view, the only way to know whether this procedure helped would be to take some of the patient’s myocardium (muscular tissue of the heart) and analyse it, which clearly we cannot do, but the clinical change after the injection was impressive. This stem cell injection technique is not something that we invented, but this case is the first in the world that we know of, for this condition, at this age, in a patient with established cardiac dysfunction (rather than as a preventive measure), and with donor stem cells rather than previously collected cells from the patient.

How difficult is it to find a match from donor stem cells?

One of the criticisms made about this approach in the past is that there is a potential risk of triggering an immune response, but this has been shown not to be the case. No complex immunological matching is needed to utilise the cells, as they don’t necessarily have to survive in the patient for a long time. The hypothesis is that they promote the recovery of the patient’s own tissues by acting as modulators of the patient’s healing processes.

Once we took the decision to try this procedure, then everything happened pretty quickly, and that’s the beauty of it. Because he was getting worse, we didn’t have the possibility of isolating their own cells and making them grow to obtain a sufficient dose – he was too unwell.

Was there an alternative?

In desperate cases like this one, you could go to urgent transplantation, but it’s very difficult to find a heart for a newborn because there are very few donors. Also, this happened in the middle of the first lockdown, when the transplantation service had pretty much stopped all over the country, for nearly all patients, so this wasn’t an option.

Stem cell treatment is not the codified, recognised treatment, whereas transplantation is, so we had a discussion with several transplant centres. But I think the chances of finding a heart in time, and ultimately the chances of a good outcome, would have been minimal if we had waited longer.

What’s the next step in the research?

This case is important because it demonstrates that cells that are not autologous (that come from different individuals) are safe to use. There are a lot of patients with other congenital heart conditions that could potentially benefit from this concept, so this is extra evidence that stem cell therapy has potential.

Might this technique become a standard way of treating these kinds of conditions?

With Professor Caputo’s research group, we already use similar stem cells in our animal research projects, and we are trying to translate their use from animals to humans. There are several common congenital heart defects, which require some sort of surgical valve and/or vascular replacement with prosthetic materials, but these materials don’t grow or repopulate with the patient’s tissues. We want to reduce the rate of replacement, so we are trying to merge the currently available materials with stem cells to create a more biologically compatible tissue to be used in children.

We are delighted that Professor Caputo has been awarded a three-year BHF Translational Award to take this research to the next stage. If a subsequent clinical trial shows that the therapy is effective, this new treatment could potentially avoid repeated high risk and stressful heart operations, and significantly improve quality of life for many children living with congenital heart disease.

Read the case report

Allogeneic Mesenchymal Stromal Cell Injection to Alleviate Ischemic Heart Failure Following Arterial Switch Operation‘ by Filippo Rapetto, Demetris Taliotis, Qiang Chen, Iakovos Ttofi, Dominga Iacobazzi, Paolo Madeddu, Serban C. Stoica, Ben Weil, Mark W. Lowdell, and Massimo Caputo, in JACC: Case Reports

Research into new treatments for CHD boosted by funding awards

Two new grants will further BHI research into progeria and pulmonary hypertension:

MRC: Gene-inspired therapy to rescue cardiovascular disease in progeria: awarded to Professor Paolo Maddedu

Hutchinson-Gilford progeria syndrome (HGPS), characterised by a rapidly ageing appearance, is a rare disease caused by an abnormal gene and related protein. Because there is no effective cure, children with HGPS will, on average, die of cardiovascular disease at around 14 years old.

This project proposes a new treatment where a gene – found in people who live a long and healthy life – is transferred to rescue the premature cardiovascular senescence typical of HGPS patients.

Professor Paolo Madeddu’s team has discovered a beneficial variant of the BPIFB4 gene, and shown in animal models that transferring this gene reduces the suffering from a heart attack, diabetes and high blood pressure. Preliminary studies showed that the longevity BPIFB4 mutation can benefit some molecular mechanisms that are dysfunctional in children with HGPS.

Paolo says:

“We will determine the efficacy of BPIFB4 gene therapy in HGPS mice, looking at the treatment’s ability to preserve heart and blood vessel function. In addition, we will investigate the mechanisms underpinning this benefit, using human cells from HGPS patients. If results are positive, we will continue our research confirming the lack of toxicity, defining the best dose and timing of treatment for prolonged benefit and the advantage of adding BPIFB4 therapy to current drugs, in view of obtaining permission for a clinical study in patients.”

HRUK: Targeting
pericytes for halting pulmonary hypertension in infants with CHD: awarded to Professor Paolo Madeddu, Professor Massimo Caputo and Dr Elisa Avolio

 Some children are born with a ventricular septal defect: a hole in the wall between the two lower chambers of the heart, where blood can flow across the hole from the left side of the heart to the right. If the defect is not corrected in time, children are likely to develop pulmonary hypertension (high pressure in the blood circulation to the lung).

Surgical correction of the ventricular shunt usually allows the blood pressure in the lungs to return to normal levels. In some cases, however, the pressure may stay higher than normal after surgery.

At least five to 10 per cent of patients with congenital heart disease develop pulmonary arterial hypertension (PAH), which can lead to heart failure. The risk of developing pulmonary hypertension is higher for children living in poor countries and areas of social deprivation, because of the limited access to specialist centres where the cardiac defect can be recognised and corrected before complications arise.

Recent research indicates pericytes – multi-functional cells embedded within the walls of capillaries – could be targeted for the treatment of PAH. Paolo says:

“Our research will investigate why pericytes from children with CHD constrict and block the pulmonary circulation. It will also test a new treatment to reduce the contraction of pulmonary pericytes and prevent pulmonary hypertension occurring.”