̽��ֱ�� of Cambridge - heart

Anti-inflammatory drug could reduce future heart attack risk

Anonymous — Mon, 02 Sep 2024 10:52:31 +0000

A cancer drug that unlocks the anti-inflammatory power of the immune system could help to reduce the risk of future heart attacks, according to research part-funded by the British Heart Foundation. By repurposing an existing drug, researchers hope it could soon become part of routine treatment for patients after a heart attack.

̽��ֱ��findings will be presented at the European Society of Cardiology Congress in London by Dr Rouchelle Sriranjan, NIHR Clinical Lecturer in Cardiology at the ̽��ֱ�� of Cambridge.

High levels of inflammation in blood vessels are linked to an increased risk of heart disease and heart attacks. After a heart attack, the body’s immune response can aggravate existing inflammation, causing more harm and increasing risk even further. However, NICE guidelines don’t currently recommend the use of any anti-inflammatory drugs to reduce future risk.

Now, a team of researchers, led by Dr Joseph Cheriyan from Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, have found that low doses of an anti-inflammatory drug called aldesleukin, injected under the skin of patients after a heart attack, significantly reduces inflammation in arteries.

̽��ֱ��researchers are currently following up patients to investigate the longer-term impact of this fall in inflammation. To date, in the two and a half years after their treatment, there have been no major adverse cardiac events in the group that received aldesleukin, compared to seven in the group that received the placebo.

Professor Ziad Mallat, BHF Professor of Cardiovascular Medicine at the ̽��ֱ�� of Cambridge who developed the trial, said: “We associate inflammation with healing – an inbuilt response that protects us from infection and injury. But it’s now clear that inflammation is a culprit in many cardiovascular conditions.

“Early signs from our ongoing trial suggest that people treated with aldesleukin may have better long-term outcomes, including fewer heart attacks. If these findings are repeated in a larger trial, we’re hopeful that aldesleukin could become part of routine care after a heart attack within five to 10 years.”

Aldesleukin is already used to treat kidney cancer, as high doses stimulate the immune system to attack cancer cells. ̽��ֱ��Cambridge team previously found that doses one thousand times lower than those used in cancer treatment increased the number of regulatory T cells – a type of anti-inflammatory white blood cell – in patients’ blood compared to a placebo.

In the current trial at Addenbrooke's and Royal Papworth hospitals in Cambridge, 60 patients admitted to hospital with a heart attack or unstable angina received either low dose aldesleukin or placebo. Patients received an injection once a day for the first five days, then once per week over the next seven weeks. Neither the participants nor their doctors knew whether they had received the drug or placebo.

At the end of treatment, Positron Emission Tomography (PET) scans showed that inflammation in the artery involved in patients’ heart attack or angina was significantly lower in the group treated with aldesleukin, compared to those who received the placebo.

̽��ֱ��anti-inflammatory effect of aldesleukin appeared even more striking in the most inflamed arteries, leading to a larger reduction in inflammation levels in these vessels and a bigger difference between the two groups by the end of the study.

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation and consultant cardiologist said: “Thanks to research, we have an array of effective treatments to help people avoid heart attacks and strokes and save lives. But, even after successful heart attack treatment, unwanted inflammation in the coronary arteries can remain, which can lead to life-threatening complications.

“A treatment to reduce inflammation after a heart attack could be a game-changer. It would help doctors to interrupt the dangerous feedback loop that exacerbates inflammation and drives up risk. This research is an important step towards that treatment becoming a reality.”

̽��ֱ��study was predominantly funded by the Medical Research Council, with significant support from the BHF and National Institute for Health and Care Research Cambridge Biomedical Research Centre (NIHR-BRC).

Originally published by the British Heart Foundation.

Repurposed cancer drug helps to calm inflammation in arteries.

Sebastian Kaulitzki/Science Photo Library via Getty Images

Illustration of human heart

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

£16million gift to support Europe’s largest heart and lung research centre

cjb250 — Thu, 23 Mar 2023 14:00:31 +0000

̽��ֱ��Victor Phillip Dahdaleh Heart and Lung Research Institute (HLRI) is home to the largest concentration of scientists and clinicians in heart and lung medicine in Europe. It opened in July 2022 with the ambitious goal of identifying ten new potential treatments or diagnostic tests for heart and lung diseases within five years.

̽��ֱ��HLRI is located on Cambridge’s rapidly expanding Biomedical Campus, immediately adjacent to Royal Papworth Hospital. ̽��ֱ��institute brings together population health, laboratory and clinical scientists, with NHS clinicians and patients, with the aim of improving outcomes for people with cardiovascular and lung diseases such as heart attacks, pulmonary hypertension, lung cancers, cystic fibrosis and acute respiratory distress syndrome.

Dr Dahdaleh said: “Cambridge is one of the greatest Universities in the history of civilisation and, 800 years on, it is at the cutting edge of scientific progress. Over the years in which I have been supporting education and medical research around the world, I have realised the UK is a global leader in the prevention, identification and treatment of heart and lung diseases.

“I’m supporting this new Institute because, through collaboration with Royal Papworth Hospital and other leading institutions, it will enable a concentration of expertise that will make medical advances in these fields that are of international importance.”

Dr Dahdaleh has previously supported research at the ̽��ֱ�� of Cambridge looking into COVID-19 and national research on mesothelioma, a type of lung cancer linked to asbestos exposure. Cardiovascular and lung diseases kill more than 26 million people a year and have a major impact on the quality of life of many more. Alongside the immense human cost, the economic burden of these diseases – an estimated annual global cost of £840 billion – is already overwhelming and unsustainable. Yet declining air quality and increasing rates of obesity are set to compound the scale of the challenge faced worldwide.

Dr Anthony Freeling, Acting Vice-Chancellor of the ̽��ֱ�� of Cambridge, said: “We are truly grateful to Victor for his generous donation. There has never been a more pressing need to develop new approaches and treatments to help us tackle the heart and lung diseases that affect many millions of people worldwide. ̽��ֱ��Victor Phillip Dahdaleh Heart and Lung Research Institute is in a strong position to make a major difference to people’s lives.”

Professor John Wallwork, Chair of Royal Papworth Hospital NHS Foundation Trust, said: “When we moved our hospital to the Cambridge Biomedical Campus in 2019, one of our ambitions was to collaborate with partners to create a research and education institute on this scale. Victor’s kind donation will support all the teams working in HLRI to develop new treatments in cardiovascular and respiratory diseases, improving the lives of people in the UK and around the globe.”

̽��ֱ��HLRI includes state-of-the-art research facilities, space for collaboration between academia, healthcare providers and industry, conference and education facilities. It also includes a special 10-bed clinical research facility where the first-in-patient studies of new treatments are being conducted.

Professor Charlotte Summers, Interim Director of the HLRI, said: “We have set ourselves ambitious goals because of the urgent need to improve cardiovascular and lung health across the world. Victor’s generous gift will help us realise our ambitions. Collaboration is at the heart of our approach, with our researchers and clinicians working with patient, academic, charity and industry partners within the Cambridge Cluster, nationally and internationally.”

Dr Dahdaleh is also a significant supporter of the Duke of Edinburgh awards, York and McGill universities in his homeland of Canada, and the British Lung Foundation. Dr Dahdaleh and his wife Mona, via the Victor Dahdaleh Foundation, have a commitment to supporting scholarships for disadvantaged students pursuing higher education in addition to their extensive philanthropic support for research into cancer, lung and heart disease.

̽��ֱ��HLRI has already raised £30 million from the UK Research Partnership Investment Fund and £10 million from the British Heart Foundation, with additional funding from the Wolfson Foundation, Royal Papworth Hospital Charity and the ̽��ֱ�� of Cambridge. Additional support has been provided by the Cystic Fibrosis Trust for a Cystic Fibrosis Trust Innovation Hub within the institute.

Maintaining heart function in donors declared ‘dead by circulatory criteria’ could improve access to heart transplantation

cjb250 — Thu, 16 Mar 2023 00:55:17 +0000

̽��ֱ��organs are kept functioning by restarting local circulation to the heart, lungs and abdominal organs – but, crucially, not to the brain – of patients whose hearts have stopped beating for five minutes or longer and have been declared dead by circulatory criteria (donation after circulatory death, or DCD).

It is hoped that this technique could increase the number of usable donated hearts by as much as 30% in the future, helping address the shortage of transplant organs. In 2021, 8,409 heart transplants were reported to the Global Observatory on Donation and Transplantation (GODT) by 54 countries. This activity is in contrast with the 21,935 patients who were on a heart waiting list during the year 2021, of whom 1,511 died while waiting and many others became too sick to receive a transplant.

John Louca, a final year medical student at Gonville & Caius College, ̽��ֱ�� of Cambridge, and the study’s first author, said: “Heart transplants are the last bastion for patients with end-stage heart failure. They are successful – patients who receive a transplant live on average a further 13 to 16 years. ̽��ֱ��biggest problem they face is actually getting access to a donated heart: many patients will die before an organ becomes available. That’s why we urgently need to find ways to increase the suitability of donor organs.”

Though the first heart transplant performed at the Groote Schuur Hospital in Cape Town (South Africa) in 1967 was obtained from a DCD donor, this technique was abandoned and replaced by heart transplants obtained from donors confirmed dead using neurological criteria (donation after brain death, or DBD) – in other words, their brain has stopped functioning entirely.

Until recently, heart transplants worldwide were still performed only with organs obtained from DBD donors. However, in recent years, heart transplants from DCD donors have become a clinical reality worldwide thanks to years of research carried out in Cambridge.

DCD is the donation of organs by patients who tragically have a non-survivable illness. These patients are typically unconscious in intensive care in hospital and dependent on ventilation. Detailed discussions between doctors, specialist nurses and the patient’s family take place and if the family agree to organ donation, the process starts.

After treatment is withdrawn, the heart stops beating and it begins to sustain damage to its tissues. After 30 minutes, it is thought that this damage becomes irreversible and the heart unusable. To prevent this damage, at the time of death these non-beating hearts are transferred to a portable machine known as the Organ Care System (OCS) where the organ is perfused with oxygenated blood and assessed to see whether it is suitable for transplantation.

This technique was pioneered by Royal Papworth Hospital NHS Foundation Trust in Cambridge, whose transplant team carried out the first DCD heart transplant in Europe in 2015. Royal Papworth has since become the largest and most experienced DCD heart transplant centre in the world.

DCD heart transplantation started simultaneously in Australia, followed by Belgium, ̽��ֱ��Netherlands, Spain and USA. According to the GODT, 295 DCD heart transplants were performed in these six countries in 2021.

Organ Care Systems are expensive, costing around US$400,000 per machine plus an additional $75,000 for consumables for each perfused organ. An alternative, and much more cost-effective approach, is known as thoraco-abdominal normothermic reperfusion (taNRP). This involves perfusing the organ in situ in the donor’s body and is estimated to cost around $3,000. Its use was first reported in 2016 by a team at Royal Papworth Hospital.

In a study published in eClinical Medicine, an international team of clinical scientists and heart specialists from 15 major transplant centres worldwide, including the UK, Spain, the USA and Belgium, looked at clinical outcomes of 157 DCD donor hearts recovered and transplanted from donors undergoing taNRP. They compared these with the outcomes from 673 DBD heart transplants, which represents the ‘gold-standard’.

̽��ֱ��team found that overall, the use of taNRP increased the donor pool significantly, increasing the number of heart transplantations performed by 23%.

Mr Stephen Large, Consultant Cardiothoracic Surgeon at Royal Papworth Hospital and chief investigator, said: “Withdrawing life support from a patient is a difficult decision for both the families and medical staff involved and we have a duty to honour the wishes of the donor as best we can. At present, one in ten retrieved hearts is turned down, but restoring function of the heart in situ could help us ensure more donor hearts find a recipient.”

Survival rates were comparable between DCD and DBD heart transplantation, with 97% of patients surviving for more than 30 days following taNRP DCD heart transplant, 93% for more than a year and 84% of patients still alive after five years.

Professor Filip Rega, Head of Clinic at the Department of Cardiac Surgery, UZ Leuven, Belgium, said: “This promising new approach will allow us to offer heart transplantation, a last resort treatment, to many more patients in need of a new heart.”

̽��ֱ��researchers say that some of the benefits from taNRP are likely thanks to the reduced amount of time the heart was not receiving oxygenated blood, known as its warm ischaemic time, when compared to direct procurement (that is, when the heart is removed immediately for transplant, and perfused outside the body). ̽��ֱ��median average time was 16.7 minutes, significantly less than the 30 minutes associated with permanent damage to the heart cells.

An added benefit to this approach is that it allows medical teams to simultaneously preserve several organs, such as the liver, pancreas and kidneys, without the need of several organ-specific external machine perfusion devices. This decreases complexity and costs.

Professor Ashish Shah, Head of the Department of Cardiac Surgery at Vanderbilt ̽��ֱ�� Hospitals, Nashville, USA, said: “Heart transplantation has been and always will be a uniquely international effort. ̽��ֱ��current study is another example of effective international collaboration and opens a new frontier, not just in transplantation, but in our basic understanding of how all hearts can be rescued.”

Dr Beatriz Domínguez-Gil, Director General of the National Organisation of Transplantation in Spain, said: “ ̽��ֱ��results of this collaborative study bring hope to thousands of patients in need for a heart transplant every year throughout the world. Its findings reveal that DCD heart transplantation based on taNRP can lead to results at least similar to the gold standard and increase hearts available for transplantation in a manner that contributes to the sustainability of health-care systems.”

Reference
Louca, J et al. ̽��ֱ��international experience of in-situ recovery of the DCD heart: A multicentre retrospective observational study. eClin Med; published online 2 March 2023; DOI: 10.1016/j.eclinm.2023.101887

More donated hearts could be suitable for transplantation if they are kept functioning within the body for a short time following the death of the donor, new research has concluded.

Patients who receive a transplant live on average a further 13 to 16 years. ̽��ֱ��biggest problem they face is actually getting access to a donated heart

John Louca

Sewcream (Getty Images)

Hands holding an image of a heart

Yes

New Heart and Lung Research Institute opens

cjb250 — Mon, 11 Jul 2022 06:31:58 +0000

A major new institute opens today, bringing together the largest concentration of scientists and clinicians in heart and lung medicine in Europe.

Heart surgery delays will cost lives, warns research

sc604 — Fri, 17 Jun 2022 09:19:34 +0000

Urgent action is needed to clear the backlog of people with a common heart condition who are waiting for lifesaving treatment, according to research published in the journal BMJ Open. ̽��ֱ��researchers have warned that a lack of action could result in thousands of people dying while waiting for treatment.

̽��ֱ��COVID-19 pandemic has led to thousands of heart procedures being postponed and record waiting lists. Previous work has estimated that 4,989 people in England with severe aortic stenosis missed out on life-saving treatment between March and November 2020.

Aortic stenosis develops when the heart’s aortic valve becomes narrowed, restricting blood flow out of the heart. Prompt treatment is vital for people diagnosed with severe aortic stenosis, as around 50 percent will die within two years of symptoms beginning.

Now, an international team of researchers, including from the ̽��ֱ�� of Cambridge, has modelled the impact that increasing treatment capacity and using a quicker, less invasive treatment option would have on waiting lists. Even in the best-case scenario, they found that the waiting list would take nearly a year to clear and over 700 people would die while waiting for treatment. ̽��ֱ��research was funded by the British Heart Foundation and the EPSRC Cambridge Centre for Mathematics of Information in Healthcare.

̽��ֱ��traditional treatment for aortic stenosis involves replacing the narrowed valve, most commonly through open-heart surgery (a surgical aortic valve replacement, SAVR). However, a newer keyhole procedure called a transcatheter aortic valve implantation (TAVI) is increasingly being used and is now recommended for patients aged 75 and over.

̽��ֱ��researchers investigated the impact that increasing treatment capacity and converting a proportion of operations to the quicker TAVI procedure would have on the backlog. They looked at how long it would take to clear the backlog and the number of people who would die while waiting for treatment.

They found that the best and most achievable option involved a combination of increasing capacity by 20 percent and converting 40 percent of procedures from SAVR to TAVI. This would clear the backlog within 343 days with 784 deaths while people wait for treatment.

“This simple yet relevant model tackles the critical question of how to clear waiting lists and is easy to interpret in practice,” said study co-author Professor Houyuan Jiang from Cambridge Judge Business School.

̽��ֱ��team say they want to see greater collaboration at local and national levels to agree the changes needed that can ensure that people with severe aortic stenosis receive life-saving treatment as quickly as possible.

Before the pandemic around 13,500 SAVR and TAVI procedures were performed each year across the UK. Increasing capacity by 20 percent would represent one or two additional TAVI procedures each week per centre.

“We think that with local and national collaboration this increase is achievable,” said study co-author Professor Mamas Mamas from Keele ̽��ֱ��. “Furthermore, we have created an algorithm that NHS Trusts can use to work out the best approach locally.

“Since November 2020 the UK has been hit with further waves of COVID-19 which have led to extreme pressure on the NHS and additional delays to treatment. We expect that number of people waiting for treatment in recent months will be even higher than the figure we used in our study. Doing nothing is simply not an option. If we continue as we are currently thousands of people will die from untreated aortic stenosis.”

“Our approach does not put the onus on only management or doctors, but creates a joint solution that is easier to implement in practice,” said co-author Professor Feryal Erhun, from Cambridge Judge Business School.

“As this modelling study shows, even increased use of this quicker and less invasive procedure won’t be enough to overcome the impact of COVID-19 related delays and stop people with aortic stenosis dying while waiting for treatment,” said Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation and consultant cardiologist. “Cardiac care can’t wait. ̽��ֱ��NHS desperately needs additional resources to help it tackle the backlog of care and ensure that heart patients receive the treatment and care they need.”

Reference:
Christian Philip Stickels et al. 'Aortic stenosis post-COVID-19: a mathematical model on waiting lists and mortality.' BMJ Open (2022). DOI: 10.1136/bmjopen-2021-059309

Adapted from a BHF press release.

Pandemic has delayed lifesaving treatment for thousands of people with severe aortic stenosis.

Our approach does not put the onus on only management or doctors, but creates a joint solution that is easier to implement in practice

Feryal Erhun

Thierry Dosogne via Getty Images

Surgeons performing heart surgery

Yes

Lab-grown beating heart cells identify potential drug to prevent COVID-19-related heart damage

cjb250 — Thu, 05 Aug 2021 08:35:20 +0000

̽��ֱ��heart is one the major organs damaged by infection with SARS-CoV-2, particularly the heart cells, or ‘cardiomyocytes’, which contract and circulate blood. It is also thought that damage to heart cells may contribute to the symptoms of long COVID.

Patients with underlying heart problems are more than four times as likely to die from COVID-19, the disease caused by SARS-CoV-2 infection. ̽��ֱ��case fatality rate in patients with COVID-19 rises from 2.3% to 10.5% in these individuals.

To gain entry into our cells, SARS-CoV-2 hijacks a protein on the surface of the cells, a receptor known as ACE2. Spike proteins on the surface of SARS-CoV-2 – which give it its characteristic ‘corona’-like appearance – bind to ACE2. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. ̽��ֱ��virus manipulates the host cell’s machinery to allow itself to replicate and spread.

A team of scientists at the ̽��ֱ�� of Cambridge has used human embryonic stem cells to grow clusters of heart cells in the lab and shown that these cells mimic the behaviour of the cells in the body, beating as if to pump blood. Crucially, these model heart cells also contained the key components necessary for SARS-CoV-2 infection – in particular, the ACE2 receptor.

Working in special biosafety laboratories and using a safer, modified synthetic (‘pseudotyped’) virus decorated with the SARS-CoV-2 spike protein, the team mimicked how the virus infects the heart cells. They then used this model to screen for potential drugs to block infection.

Dr Sanjay Sinha from the Wellcome-MRC Cambridge Stem Cell Institute said: “Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart.”

̽��ֱ��team showed that some drugs that targeted the proteins involved in SARS-CoV-2 viral entry signiﬁcantly reduced levels of infection. These included an ACE2 antibody that has been shown previously to neutralise pseudotyped SARS-CoV-2 virus, and DX600, an experimental drug.

DX600 is an ACE2 peptide antagonist – that is, a molecule that specifically targets ACE2 and inhibits the activity of peptides that play a role in allowing the virus to break into the cell.

DX600 was around seven times more effective at preventing infection compared to the antibody, though the researchers say this may be because it was used in higher concentrations. ̽��ֱ��drug did not affect the number of heart cells, implying that it would be unlikely to be toxic.

Professor Anthony Davenport from the Department of Medicine and a fellow at St Catharine’s College, Cambridge said: “ ̽��ֱ��spike protein is like a key that fits into the ‘lock’ on the surface of the cells – the ACE2 receptor – allowing it entry. DX600 acts like gum, jamming the lock’s mechanism, making it much more difficult for the key to turn and unlock the cell door.

“We need to do further research on this drug, but it could provide us with a new treatment to help reduce harm to the heart in patients recently infected with the virus, particularly those who already have underlying heart conditions or who have not been vaccinated. We believe it may also help reduce the symptoms of long COVID.”

̽��ֱ��research was largely supported by Wellcome, Addenbrooke’s Charitable Trust, Rosetrees Trust Charity and British Heart Foundation.

Reference
Williams, TL et al. Human embryonic stem cell-derived cardiomyocyte platform screens inhibitors of SARS-CoV-2 infection. Communications Biology; 29 Jul 2021; DOI: 10.1038/s42003-021-02453-y

Cambridge scientists have grown beating heart cells in the lab and shown how they are vulnerable to SARS-CoV-2 infection. In a study published in Communications Biology, they used this system to show that an experimental peptide drug called DX600 can prevent the virus entering the heart cells.

Using stem cells, we’ve managed to create a model which, in many ways, behaves just like a heart does, beating in rhythm. This has allowed us to look at how the coronavirus infects cells and, importantly, helps us screen possible drugs that might prevent damage to the heart

Sanjay Sinha

Beating heart cells infected with virus

sbtlneet

Heart

Yes

Licence type:

Public Domain

New artificial heart valve could transform open-heart surgery

sc604 — Mon, 29 Jun 2020 13:50:16 +0000

̽��ֱ��valve, called PoliValve, has been developed by scientists at the Universities of Cambridge and Bristol. ̽��ֱ��team’s latest in vitro results, published in the journal Biomaterials Science, suggest that the PoliValve can last for up to 25 years in patients, far longer than other types of replacement heart valves. In addition, a small pilot study in sheep showed that the valve is highly compatible with biological tissue. ̽��ֱ��researchers anticipate that the PoliValve can be tested in humans within five years.

More than 1.3 million patients with diseased heart valves need valve replacement globally each year. There are two types of artificial valves currently available, however both have limitations either in durability or in biocompatibility.

Biological valves are made from pig or cow tissue and have good biocompatibility, meaning patients do not need lifelong blood-thinning medication; however, they only last 10-12 years before failing. And mechanical valves, while they have good durability, have poor biocompatibility and patients must take daily blood-thinning drugs to prevent blood clots.

Professor Geoff Moggridge from the ̽��ֱ�� of Cambridge and Professor Raimondo Ascione from the ̽��ֱ�� of Bristol have spent three years conducting developmental work and testing on the PoliValve, supported by funding from the British Heart Foundation.

̽��ֱ��device is made from a special co-polymer and is designed to resemble a natural heart valve. It was created by Professor Moggridge, Dr Marta Serrani and Dr Joanna Stasiak at Cambridge and Professor Ascione in Bristol, and builds on earlier work by Professor Maria Laura Costantino’s group at the ̽��ֱ�� of Milan.

̽��ֱ��PoliValve combines excellent durability with biocompatibility, addressing the limitations of current biological and mechanical artificial valves. It is made through a simple moulding process, which also sharply reduces manufacturing and quality control costs.

“These impressive results show the PoliValve is a promising alternative for valve replacement surgery,” said Moggridge, who leads the Structural Materials Group at Cambridge’s Department of Chemical Engineering and Biotechnology. “While further testing is needed, we think it could make a major difference to the hundreds of thousands of patients who get valve replacement surgery every year.”

According to ISO standards, a new artificial heart valve must withstand a minimum of 200 million repetitions of opening and closing during laboratory testing, equivalent to five years of life span, before it can be tested in humans. ̽��ֱ��new Cambridge-Bristol polymeric valve has comfortably surpassed this.

Initial testing in sheep has been undertaken at Bristol’s Translational Biomedical Research Centre (TBRC) facility as a first step to ensure safety. Long-term testing in sheep, also funded by the British Heart Foundation, will be carried out before bringing this new treatment to human patients.

“Patients requiring an artificial heart valve are often faced with the dilemma of choosing between a metallic or tissue valve replacement,” said Professor Sir Nilesh Samani, Medical Director at the British Heart Foundation. “A metallic valve is long-lasting but requires the patient to take lifelong blood-thinning drugs. Although this medication prevents clots forming on the valve, it also increases the risk of serious bleeding. Patients who have a tissue valve replacement usually don’t need to take this medication. However, the valve is less durable and means the patient may face further surgery.

“ ̽��ֱ��polymer valve combines the benefits of both – it is durable and would not require the need for blood-thinning drugs. While further testing is needed before this valve can be used in patients, this is a promising development, and the BHF is pleased to have supported this research.”

̽��ֱ��PoliValve has also exceeded the requirements of ISO standards for hydrodynamic testing, showing a functional performance comparable to the best-in-class biological valve currently available on the market. ̽��ֱ��small pilot study in sheep demonstrated the device is easy to stitch in, and showed no mechanical failure, no trans-valvular regurgitation, low trans-valvular gradients, and good biocompatibility with tissue.

“ ̽��ֱ��transformational PoliValve results from an advanced Bristol/Cambridge-based biomedical cross-fertilisation between experts in biomaterials, computational modelling, advanced preclinical development/testing and clinical academics understanding the patient needs. ̽��ֱ��new valve could help millions of people worldwide and we aim to test in patients within the next five years,” said Ascione.

̽��ֱ��British Heart Foundation-funded study also included Dr James Taylor from Cambridge’s Whittle Laboratory, a team at Newcastle ̽��ֱ�� headed by Professor Zaman, Professor Saadeh Sulaiman at ̽��ֱ�� of Bristol and Professor Costantino’s group at Politecnico di Milano.

Reference:
Joanna R. Stasiak et al. “Design, Development, Testing at ISO standards and in-vivo feasibility study of a novel Polymeric Heart Valve Prosthesis.” Biomaterials Science (2020). DOI: 10.1039/D0BM00412J

Adapted from a ̽��ֱ�� of Bristol press release.

A new type of artificial heart valve, made of long-lived polymers, could mean that millions of patients with diseased heart valves will no longer require lifelong blood-thinning medication after valve replacement surgery.

These impressive results show the PoliValve is a promising alternative for valve replacement surgery

Geoff Moggridge

Professor Raimondo Ascione, ̽��ֱ�� of Bristol

An advanced prototype of the PoliValve

Yes

Cause of hardening of the arteries – and potential treatment – identified

sc604 — Tue, 11 Jun 2019 15:00:00 +0000

̽��ֱ��team, led by the ̽��ֱ�� of Cambridge and King’s College London, found that a molecule once thought only to exist inside cells for the purpose of repairing DNA is also responsible for hardening of the arteries, which is associated with dementia, heart disease, high blood pressure and stroke.

There is no current treatment for hardening of the arteries, which is caused by build-up of bone-like calcium deposits, stiffening the arteries and restricting blood flow to organs and tissues.

Supported by funding from the British Heart Foundation, the researchers found that poly(ADP ribose), or PAR, a molecule normally associated with DNA repair, also drives the bone-like calcification of arteries.

Additionally, using rats with chronic kidney disease, the researchers found that minocycline – a widely-prescribed antibiotic often used to treat acne – could treat hardening of the arteries by preventing the build-up of calcium in the circulatory system. ̽��ֱ��study, the result of more than a decade of fundamental research, is published in the journal Cell Reports.

“Artery hardening happens to everyone as they age, and is accelerated in patients on dialysis, where even children develop calcified arteries. But up until now we haven’t known what controls this process and therefore how to treat it,” said Professor Melinda Duer from Cambridge’s Department of Chemistry, who co-led the research as part of a long-term collaboration with Professor Cathy Shanahan from King’s College London.

“This hardening, or biomineralisation, is essential for the production of bone, but in arteries it underlies a lot of cardiovascular disease and other diseases associated with ageing like dementia,” said Shanahan. “We wanted to find out what triggers the formation of calcium phosphate crystals, and why it seems to be concentrated around the collagen and elastin which makes up much of the artery wall.”

In earlier research, Duer and Shanahan had shown that PAR – normally associated with the repair of DNA inside the cell – can in fact exist outside the cell and is the engine of bone production. This led the researchers to hypothesise that PAR may also play a role in biomineralisation. In addition, PARP1 and PARP2, the dominant PAR-producing enzymes, are expressed in response to DNA damage and oxidative stress, processes which are associated with both bone and vascular calcification.

“We could see signals from bone that we couldn’t explain, so we looked for molecules from first principles to figure it out,” said Duer.

“I’d been thinking for years that hardening of the arteries was linked to DNA damage, and that DNA damage is a pathway switched on by many agents including smoking and lipids,” said Shanahan. “When this pathway is switched on, it drives the pathologies associated with ageing. If enough damage is present, the arteries will eventually reflect it.”

Using NMR spectroscopy, the researchers found that when the cells become stressed and die, they release PAR, which binds very strongly to calcium ions. Once released, the PAR starts mopping up calcium into larger droplets which stick onto the components in artery walls that give the artery its elasticity, where they form ordered crystals and solidify, hardening the arteries.

“We never would have predicted that it was caused by PAR,” said Duer. “It was initially an accidental discovery, but we followed it up - and it’s led to a potential therapy.”

Having discovered the links between DNA damage, PAR, bone and artery calcification, the researchers then looked into a way of blocking this pathway through the use of a PARP inhibitor.

“We had to find an existing molecule that is cheap and safe, otherwise, it would be decades before we would get a treatment,” said Shanahan. “If something has already been shown to be safe in humans, the journey to the clinic can be much faster.”

Working together with Cycle Pharmaceuticals, a Cambridge-based company, the researchers identified six known molecules that they thought might inhibit the PARP enzymes. Detailed experiments with these showed that the antibiotic minocycline was highly effective in preventing hardening of the arteries.

“It’s been 12 years of basic research to get to this point,” said Duer. “We set out with absolutely no expectation of finding a potential treatment – there is no treatment currently and nobody would have believed us if we had said at that point we were going to cure hardening of the arteries.”

̽��ֱ��technology has been patented and has been licensed to Cycle Pharmaceuticals by Cambridge Enterprise, the ̽��ֱ��’s commercialisation arm. ̽��ֱ��researchers are hoping to carry out a proof of principle trial in patients in the next 12 to 18 months.

“Blood vessel calcification is a well-known risk factor for several heart and circulatory diseases, and can lead to high blood pressure and ultimately, a life-threatening heart attack,” said Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation. “Now, researchers have shown how calcification of the walls of blood vessels takes place, and how the process differs from normal bone formation. By doing so, they have been able to identify a potential treatment to reduce blood vessel calcification without any adverse effects on bone. This type of treatment would benefit many people, and we eagerly await the results of the anticipated clinical trials looking at whether this drug lives up to its early promise.”

Reference:
Karin H. Müller et al. ‘Poly(ADP ribose) links the DNA damage response and biomineralization.’ Cell Reports (2019). DOI: 10.1016/j.celrep.2019.05.038

A team of UK scientists have identified the mechanism behind hardening of the arteries, and shown in animal studies that a generic medication normally used to treat acne could be an effective treatment for the condition.

Artery hardening happens to everyone as they age...but up until now we haven’t known what controls this process and therefore how to treat it

Melinda Duer

False colour image of calcium phosphate deposits on bone

Yes