Our research impact

New research lifts the lid on cardiac microvascular dysfunction

Posted on by Rachel Skerry

New research has shown abnormalities in the tiny blood vessels of human hearts in regions well beyond the large arteries with atherosclerotic blockages that trigger the need for stents or bypass surgery. The findings could lead to the development of new treatments for patients with angina-like symptoms without blockages or those recovering from a heart attack or unexplained heart failure.

Normal intrinsic constriction of these micro-arteries in response to changing blood pressure is called myogenic (automatic) tone. Myogenic tone controls blood flow distribution within the heart muscle, and in other parts of the human body.

Current heart scans can identify blockages in large coronary arteries, but they are unable to show these tiny, hair size micro-arteries in patients, making it impossible to diagnose poor myogenic tone, which is thought to develop independent of disease in the larger arteries. This study used tissue biopsies to study the function, structure and alterations in pathways in the micro-arteries that link to abnormalities in myogenic tone.

The study, led by Professor Raimondo Ascione (Clinical Lead) at the University of Bristol and Professor Kim Dora (Basic Science Lead) at the University of Oxford, and funded by the BHF, is published in Cardiovascular Research.

The research team took small heart samples, that are otherwise discarded, from 88 patients with no large coronary artery blockages and undergoing valvular cardiac surgery at the Bristol Heart Institute. In addition, cardiac samples were obtained from three human organ donors from the Newcastle Institute of Transplantation Tissue Biobank and 45 pigs treated at the University of Bristol Translational Biomedical Research Centre (TBRC).

The research team found that 44 per cent of the micro-arteries from patients had abnormal myogenic tone despite retaining their cell viability. This abnormality was associated with an excessive presence of a molecule called caldesmon within the muscle cells in the wall of the abnormal micro-arteries and with poor alignment of these contracting cells compared to micro-arteries with normal myogenic tone from the other 66 per cent of patients, and all the organ donors and pigs.

Abnormalities in the micro-arteries affects the blood supply within the beating heart, and other organs in the body, affecting people’s quality of life and life expectancy.

The findings offer new insights on coronary microvascular dysfunction that could predate the development of clinically known heart disease such as heart failure.

Professor Raimondo Ascione, NHS Consultant Cardiac Surgeon and Head of the TBRC at the University of Bristol, said:

“It has been a pleasure to work with Professor Dora on this landmark study over the last seven years. No study had focused on ex vivo poor myogenic tone of the cardiac microcirculation before. These tiny arteries are sited deep within the cardiac wall, well beyond the blocked arteries we treat in the NHS with stents or bypass surgery and cannot be seen with a naked eye.

“Our study lifts the lid on cardiac microvascular dysfunction. It could help to develop new treatments to help patients with angina-like symptoms without coronary blockages, or those recovering from a heart attack or unexplained heart failure.”

Kim Dora, Professor of Microvascular Pharmacology at the University of Oxford, explained:

“I am so excited with the results of this study and the excellent teamwork with Professor Ascione in Bristol.  Not only will our findings enhance the development of new medical treatments and possibly new patient imaging modalities, but they represent a new ex-vivo research model for thousands of scientists globally working on microvascular dysfunction in the heart and other organs.”

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, added:

“This study is the first to develop techniques to understand the links between the structure of micro-arteries and impaired myogenic tone, representing the outcome of years of painstaking work to develop the methods and apply them to micro-arteries from human hearts. The findings provide new information that will help to develop treatments for the many patients whose angina occurs without significant narrowing of their coronary arteries.”

There is now a new area of research that confirms thousands of patients, mostly postmenopausal women, have angina-like symptoms despite their coronary angiogram showing no obvious blockages of the large epicardial arteries in the heart that are usually treated with stent or bypass. Other patients seem to develop heart failure associated with either the contraction or the relaxation of their heart for no obvious reasons.

The human coronary micro-arteries the Bristol and Oxford team has studied in the laboratory represent the microvascular area in human organs (lung, heart, brain and elsewhere) where COVID-19 has caused most of the problems during the ongoing pandemic.

Paper

‘Human coronary microvascular contractile dysfunction associates with viable 2 synthetic smooth muscle cells‘ by Kim A Dora, Raimondo Ascione et al in Cardiovascular Research [open access]

Early adulthood education and employment experiences play independent role in later life cardiovascular health

Posted on by Rachel Skerry

New research has found that education and employment experiences in early adulthood contribute to cardiovascular health inequalities in later life, independent of occupation and family income in mid-adulthood. The findings, published today in the Journal of Epidemiology and Community Health, involve researchers from the University of Cambridge, University of Bristol and UCL Social Research Institute.

There are important differences in health between different sectors of our society, with those who are less educated and in lower status jobs shown to be less healthy and have shorter life expectancy on average than the more privileged. While early adulthood is an important time for both the development of adult socioeconomic position and for development of behaviours related to cardiovascular health, until now the degree to which early adulthood socioeconomic trajectories contribute directly to health differences observed in later life has not been clear.

Researchers from the University of Cambridge, University of Bristol and UCL Social Research Institute analysed health and socioeconomic data collected over several decades from over 12,000 members of the 1970 British Birth Cohort, to determine the contribution of early adulthood to differences in cardiovascular health in mid-adulthood. The scientists used a data-driven method to divide the population into different socioeconomic trajectory groups based on their participation in education, different job types, unemployment or economic inactivity across early adulthood (ages 16-24). They studied the association of these groups with cardiovascular risk factors at age 46, including blood pressure, cholesterol levels, waist circumference. To determine if the association of early adulthood socioeconomic trajectories with cardiovascular health was mediated by socioeconomic status later in life, they examined how correcting for occupation or family income at age 46 affected the link.

Professor Kate Tilling from the MRC Integrative Epidemiology Unit at the University of Bristol, and senior author on the paper, said:

“Measuring socioeconomic position in early adulthood has always been difficult as this is a period of transition when most people’s occupations change over time. The method we’ve developed provides a flexible way to identify early adulthood socioeconomic position, and we hope that it will be used in future to answer other research questions related to this period of life.”

The researchers found that those who spent a longer time in education, going on to employment in professional or managerial roles during early adulthood, had better cardiovascular health more than 20 years later (at age 46) than other groups. Importantly this association wasn’t entirely because of a higher income or higher level job at age 46, suggesting an independent and long-term association of early adulthood influences with health.

The findings indicate that that material factors in mid-adulthood do not contribute to the pathway through which early adulthood socioeconomic trajectory affects mid-life health, and the authors suggest that the development of health behaviours or psychosocial factors such as stress, depression, and job control in early adulthood may play an important role.

Dr Eleanor Winpenny from the MRC Epidemiology Unit at the University of Cambridge, and first author on the paper, said:

“We found that an individual’s education and employment experiences in early adulthood had a far larger impact on measures of cardiovascular health more than twenty years later than their occupation or income at that time did.

“These results suggest that we need to provide more support for young adults to allow healthy development into middle age and prevent disease in later life. Given the added disadvantage to young adults as a result the current coronavirus pandemic, there is an urgent need to understand and mitigate the effect these circumstances may be having on their future health.”

The research was funded by the Medical Research Council and the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence. Funding from the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and Wellcome, under the auspices of the UK Clinical Research Collaboration.

Paper

‘Early adulthood socioeconomic trajectories contribute to inequalities in adult cardiovascular health, independently of childhood and adulthood socioeconomic position‘ by Winpenny, E. et al in the Journal of Epidemiology and Community Health

The beating heart of Royal Fort Garden

Posted on by Rachel Skerry

Bristol Heart Institute interpretation sign

The new interpretation sign for the University of Bristol brings a whole new meaning to the phrase ‘living statue’.

The solid oak monolith is the third instalment in a series of iconic totems dedicated to the University’s research institutes. This sign embodies the work of the Bristol Heart Institute and has been designed to reflect the relationship between human life and nature. Joining many other works of art in the Royal Fort Garden this piece stands proud at three metres high, and if you get close enough you can hear the low thud of a heartbeat coming from deep within the structure day and night.

Previous designs highlighted the work of the Bristol Population Health and the Bristol Bio Design Institutes.

The new monolith is built from four solid oak panels which have been laser cut and hand painted to represent a human cardiovascular system. Following a couple of years of pandemic enforced hiatus, it’s great to add to the collection and celebrate the work of the Bristol Heart Institute in such a creative way.  

(Photo by Green Hat. Words adapted from text supplied by Green Hat)

Study shows aspirin can reduce the risk of heart attacks and strokes in patients with pneumonia

Posted on by Rachel Skerry

Aspirin can reduce the risk of serious cardiovascular events such as ischemic stroke and heart attack in patients with pneumonia, according to new research.

Serious cardiovascular complications are common in cases of pneumonia and are strongly associated with long-term mortality. A study by Dr Fergus Hamilton and colleagues at the University of Bristol looked at whether aspirin could reduce the risk of ischemic stroke (stroke caused by blockage of blood vessels, representing some 80 per cent of strokes) and heart attack, and if the drug could have a preventative role to play in primary care settings. 

The team analysed the details of all patients aged over 50 with pneumonia from the Clinical Practice Research Datalink (CPRD), a large UK primary care database of more than 61 million patients. The primary outcome was defined as the occurrence of both ischemic stroke and myocardial infarction (MI – heart attack), while either of those events happening individually was defined as the secondary outcome. 

Of the 48,743 patients identified as being eligible for inclusion in the study, the researchers found 8,099 aspirin users who were matched to 8,099 non-users also selected from the sample group. 

The authors found that the risk of the primary outcome (stroke and MI) was 36 per cent lower in aspirin users compared to non-users. The drug was also associated with a reduced risk of both secondary outcomes with ischemic stroke and MI rates being 30 per cent and 54 per cent lower, respectively, in aspirin users. 

The researchers conclude: “This study provides supporting evidence that aspirin use is associated with reduced ischaemic events after pneumonia in a primary care setting. This drug may have a future clinical role in preventing this important complication.”

Dr Fergus Hamilton, Wellcome Doctoral Fellow at the University of Bristol and an NIHR Academic Clinical Fellow at North Bristol NHS Trust, said: “This research really paves the foundation for a clinical trial of aspirin in pneumonia, which remains the most common reason for admission to hospital in many countries.”

Paper

‘Aspirin reduces cardiovascular events in patients with pneumonia: a prior event rate ratio analysis in a large primary care database’ by F. Hamilton, D. Arnold, W. Henley and R. Payne in the European Respiratory Journal

Cardiovascular researchers visit Bristol primary school

Posted on by Rachel Skerry
Giovanni Biglino shows Year 6 students a 3D printed heart model
Giovanni Biglino shows Year 6 students a 3D printed heart model

Drs Lucy Culliford, Andrew Shearn and Giovanni Biglino took part in an outreach activity at Parson Street Primary School in Bedminster, south Bristol. in May 2021.

The visit was organised by Lucy on behalf of the Bristol Trials Unit. The group explained some of their research to the Year 6 students (aged 10 and 11) and, as the visit happened in the same week as Clinical Trials Day, it was also an opportunity for Lucy to ask the students to think about clinical studies, the idea of randomisation and ‘what is a clinical trial?’. The group showed the THERMIC 3 animation video, which was developed as part of the TRECA study exploring children’s and young people’s engagement with clinical trials.

Giovanni gave an overview of the technology involved in 3D printing and Andrew brought a series of heart models, both adult and paediatric, including examples of babies’ hearts with congenital heart disease, which sparked some stimulating conversations with the 53 students who attended.

They explained that 3D printing technology can produce models of human organs using scans taken during routine visits to the hospital. Bristol Royal Hospital for Children use this technique to create heart models from patients with congenital heart disease. Being able to hold a life-size model of the patient’s heart can complement information the surgeon or cardiologist can get from medical imaging – for example, they can practice aspects of the surgery or decide the best route to access a specific part of the heart. The models are also used when explaining the details of the case to a patient or a parent.

The children asked lots of questions about ‘hole in the hearts’, as some had had siblings with this condition. They also asked how smoking can affect the heart, and if the researchers could show them a video of a beating heart.

Lucy said:

“This is the first time we’ve done a talk in a school as part of our outreach activities around Clinical Trials Day, and it was a real pleasure to talk to the children. They were very engaged and although they had only started learning about the heart the day before, they already knew lots about heart anatomy, and had more questions than we had time to answer!”

How to get involved in schools outreach

If you would like to run a schools outreach activity, contact your local school.

Schools often have science weeks, or may be doing a topic related to cardiovascular research. For example, Parson Street Primary School use the Cornerstones curriculum and the year 6s had just started the ‘blood heart’ topic – the following week they had a visitor demonstrating a heart dissection.

Smoking during pregnancy associated with child’s risk of having congenital heart disease

Posted on by Rachel Skerry

Children born to mothers who smoked during pregnancy were at increased risk of having congenital heart disease, a new study published today [27 May] in the Journal of the American Heart Association has found.

The study was led by the University of Bristol, in an international collaboration with researchers from seven institutions. It brings together data on more than 230,000 families from seven European birth cohorts from the UK, Ireland, the Netherlands, Denmark, Norway and Italy, including the world-renowned Children of the 90s study at the University of Bristol. The research was supported by the British Heart Foundation and the H2020 program of the European Commission.

Each day, around 13 babies in the UK are diagnosed with congenital heart disease. This means the heart or the large blood vessels surrounding the heart have not developed properly in the womb. Identifying causes of congenital heart disease could help prevent some of these cases and ultimately save lives.

Lead author, Kurt Taylor, a PhD student at the University of Bristol said:

“Birth cohorts are unique in that many possess a wealth of data not only in mothers and children, but also in fathers. Crucially, having access to data in the fathers as well as mothers and children allowed us to use a novel study design to investigate possible causes of congenital heart disease.”

The study analysed associations between body mass index, smoking, and alcohol consumption on offspring congenital heart disease. Data on these characteristics were obtained through measurements of weight and height and questionnaires administered during early pregnancy when most of the cohorts began recruitment. Measurements were harmonised across cohorts as part of the LifeCycle project; an initiative that aims to research the role of pregnancy and infancy factors on offspring health and wellbeing across childhood and into adulthood. The researchers were able to test the reliability of their findings by using an approach that compares the results from mothers and fathers to help discern whether the effects they see are “real” or are as a result of other factors.

Kurt continued:

“Here, we have shown that mothers who smoke during pregnancy are more likely to have a child with congenital heart disease. Our results also suggest that being overweight or obese at the start of pregnancy or consuming alcohol may not be causes of congenital heart disease, despite previous research suggesting otherwise. These results might help in supporting women of reproductive age not to start smoking. Meanwhile it continues to be appropriate to recommend that women, and men, maintain a healthy weight and limit alcohol consumption prior to and during pregnancy.”

Professor Deborah Lawlor, British Heart Foundation Chair in Cardiovascular Science and Clinical Epidemiology of the University of Bristol, who oversaw the study, added:

“Smoking rates are declining but remain high in more deprived groups in the UK and other high-income countries and are promoted in low- and middle-income countries. These findings further highlight the need to support smoking cessation globally. Also, if we can work out exactly how maternal smoking increases risk of congenital heart diseases this could identify new ways of preventing these diseases even in the absence of smoking.”

Dr Sonya Babu-Narayan, Associate Medical Director at the British Heart Foundation and cardiologist, said:

“Smoking is one of the biggest risk factors for developing heart and circulatory disease. It is also the greatest cause of health inequality across Europe, but supporting people to quit smoking is one of the most effective things we can do to reduce these inequalities. We need to make it easier for everyone to quit by offering them appropriate smoking cessation support and advice.”

Read the paper

‘Effect of maternal prepregnancy/early-pregnancy body mass index and pregnancy smoking and alcohol on congenital heart diseases: A parental negative control study‘ by Kurt Taylor et al in The Journal of the American Heart Association [open access]

Modelling inflammation after heart surgery

Posted on by Rachel Skerry

Ben Gibbison shares an update on an interdisciplinary project which is part-funded by the NIHR Bristol Biomedical Research Centre.

Up to five per cent of patients remain in intensive care for more than 48 hours after surgery. These patients, who require ventilators for prolonged periods of time, may be showing signs of uncontrolled inflammation – a poor response to the physiological stress of surgery.

We are investigating levels of the stress hormone cortisol in critically ill adults requiring prolonged ventilation after heart surgery, to determine whether cortisol levels correlate with inflammation.

From this work, we can determine if these patients need higher levels of cortisol, then administer it in a pattern tailored to the individual.

Watch the video

MINOCA study recruitment wraps up

Posted on by Rachel Skerry

Principal Investigator Matt Williams on the MINOCA study, which completed its recruitment phase at UHBW in March.

One in 10 patients who suffer a suspected heart attack do not have a blocked or narrowed heart artery. These patients are classified as having a myocardial infarction with non-obstructive coronary arteries (MINOCA).

Previously thought to be low risk, MINOCA patients were often discharged with no treatment or follow up. However, research shows that these patients have mortality of nearly five per cent at only 12 months.

MINOCA patients are more likely to have had a stressful event prior to admission and a history of anxiety or depression. Previous research has even suggested that people with a stress cardiomyopathy – a common cause of MINOCA – have structural and functional differences in their brain, which may lead to differences in emotional processing and increased sympathetic drive  compared to people who do not develop this condition in response to stress.

The MINOCA study is investigating for the first time this link between the heart and the brain in MINOCA patients.

Over the last two years, our team has conducted a functional brain MRI and a cardiac MRI, as well as blood tests, ECGs and questionnaires, on 100 participants within two weeks of being admitted to hospital, with follow up MRI scans at six weeks and six months.

We are looking to see if patients with MINOCA have specific functional and anatomical changes in their brain which might explain why they develop this condition. Ultimately, it may be possible to target increased stress related brain activity to reduce the risk of this condition and improve patient outcomes.

Our study has been funded by grants from Above and Beyond, the James Tudor Foundation and the Rosetrees Trust.

This post first appeared in the March 2021 BHI Newsletter

Restoring respiratory sinus arrhythmia in heart failure

Posted on by Rachel Skerry

A CiC award will enable Eva Sammut to test the safety and feasibility of a novel device to reinstate RSA in dyssynchronous heart failure.

Confidence in Concept (CiC) awards fund proof of concept studies, which provide robust evidence of the feasibility of a proposed solution to a clinical need.

Dr Eva Sammut, NIHR-funded academic clinical lecturer in Cardiology at the BHI, received a £100K Elizabeth Blackwell Institute MRC CiC award in January to look at the feasibility, safety and effectiveness of a novel device to restore respiratory sinus arrhythmia in patients with heart failure.

Q: Why is your research significant?

Heart failure is a global clinical pandemic with clear unmet clinical need. Despite some advancements in therapy, prognosis remains poor with a 50 per cent five-year mortality representing a significant societal and healthcare burden.

Respiratory sinus arrhythmia (RSA) is a physiological phenomenon of a subtle increase of heart rate during inspiration and the converse during expiration. RSA is a major component of physiological heart rate  variability, a sign of good cardiac health, and is known to be lost in patients with heart failure. Loss of RSA is associated with increased ventricular  arrhythmia and sudden cardiac death. Restoring RSA in heart failure patients could improve their life  expectancy and markedly reduce hospitalisation costs. Existing preclinical models are inadequate to validate the safety of new treatments in this priority area.

Q: What are you developing?

Our group have developed a novel device which is able to reinstate RSA. Our preliminary results are very promising and demonstrate feasibility. Further proof of concept data from an advanced preclinical model is now pivotal to ensure the safety, feasibility and applicability of the new device to  progress it toward bedside to benefit patients.

This project will test the safety and feasibility of this new technology in the setting of dyssynchronous HF. This is a complex form of heart failure that responds poorly to the best available current treatment –  a specialised pacemaker named cardiac  resynchronisation therapy.

This study will be performed at the University’s Translational Biomedical Research Centre facility. We will develop an advanced preclinical model of dyssynchronous heart failure with balloon catheter myocardial infarction and superimposed pacemaker-induced ventricular dyssynchrony. Next, we will use this model to test this novel pacemaker approach to reinstating respiratory sinus arrhythmia in addition to cardiac resynchronisation therapy.

Q: Who are you working with?

A unique multidisciplinary team has been assembled including Professors Julian Paton, Raimondo Ascione and Alain Nogaret, and Drs Tom Johnson, Ed Duncan and Vito Domenico Bruno, who are co-applicants supporting this project.

We are also working in collaboration with Ceryx Medical, a spin out company formed by the universities of Bristol, Bath and Auckland.

Q: What next?

We are delighted to receive this funding to be able to take this exciting new technology to the next  developmental stage. This project is critical to ensure safety, feasibility and applicability of the new device in this setting. If positive results are demonstrated this would pave the way for larger, efficacy translational studies, with a view to reach patients in the NHS  within the next five to six years.

This post first appeared in the March 2021 BHI Newsletter

Preventing vascular damage associated with protein in urine

Posted on by Rachel Skerry

Becky Foster and Simon Satchell received a three-year BHF grant to investigate endothelial glycocalyx restoration. Principal Investigator Becky explains:

Proteinuria (protein within the urine) is an independent risk factor for cardiovascular disease. This is not only relevant for patients with kidney disease, but also for five per cent of the general population who have low-level proteinuria. A twofold increase in proteinuria increases risk of  cardiovascular mortality by 30 per cent.

If we knew how proteinuria is linked to vascular damage, we would potentially be able to treat these patients to prevent vascular disease.

Proteinuria begins in the filtering microvessels that form the glomerulus in the kidney. The microvessel wall is a specialised filtration barrier made up of  endothelial cells, a glomerular basement  membrane and epithelial cells (podocytes). Podocyte damage is often key to major glomerular protein leakage. A proteoglycan-rich endothelial glycocalyx (eGlx) layer lines all blood vessels. Damage to eGlx leads to increased vascular  leakage around the body, which can progress to vascular disease.

We have also shown that, in conditions of  proteinuria, eGlx is also damaged in non-kidney blood vessels, and that this is associated with increased vascular leak. Heparanase is an enzyme that is upregulated in conditions of proteinuria by  podocytes and also induces eGlx damage.

Our study will address our novel research  question, that podocyte-induced heparanase  expression causes vascular eGlx damage in  proteinuric disease.

From this project, we will know whether  heparanase upregulation by podocytes induces vascular damage, whether podocyte damage in proteinuria causes eGlx vascular damage and whether this is dependent upon heparanase. We will also use a clinically relevant heparanase  inhibitor, which can be used to drive translatProteinuria diagramion  into the clinic for these patients.

 

 

 

 

 

 

 

This post first appeared in the March 2021 BHI Newsletter

Bristol Heart Institute (BHI) is a Specialist Research Institute at the University of Bristol.