Our research impact

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

First use of ROB2 in Cochrane Review of Exercise Interventions for CHD

Posted on by Rachel Skerry

Graham Stuart and Guido Pieles collaborated with Craig Williams at the University of Exeter to publish a Cochrane Review, which gathered evidence for the effectiveness of physical activity interventions for people with congenital heart disease.

The Review compared three types of interventions from 15 trials, including programmes designed to increase physical activity, aerobic fitness and health-related quality of life. It found some evidence for increased physical fitness and physical activity, although there are no data yet to suggest this results in fewer hospital visits.

Read the Review in the Cochrane Library

Graham says:

Exercise used to be discouraged in patients with CHD. This was poor advice and led to an increase in cardiovascular and psychosocial morbidity.

Our Cochrane Review has shown that there is a need for further research to demonstrate why  exercise benefits disordered cardiovascular  physiology and to establish whether the  multiple theoretical benefits of exercise training  can translate into improved clinical outcomes.

All authors of Cochrane systematic reviews are now expected to use the Cochrane Risk of Bias tool (ROB2) to assess the risk of bias in any  randomized controlled trials they identify, to help people understand the trustworthiness of the findings. This was the first Cochrane Review to use ROB2 methodology.

Read the Cochrane editorial on ROB2

This post first appeared in the March 2021 BHI Newsletter

Mechanisms of cardiovascular complications in COVID-19

Posted on by Rachel Skerry

Paolo Madeddu discusses the progress of a timely research project.

Q: Why is this research significant?    

The coronavirus that causes COVID-19 enters the body through the epithelial-endothelial barrier of the lung and then spreads systemically. Its most severe manifestation is severe acute respiratory syndrome, where the epithelial-endothelial barrier is damaged to a level that fluid escapes into the alveoli. This makes it difficult for the lung to expand and allow the physiological exchanges of gases, resulting in severe hypoxia, shock and systemic organ damage. Organ damage is also caused by the virus’ ability to bring about a systemic inflammatory response and evade the immune system’s defences.

Pericytes – cells surrounding the vasculature – are essential to maintain vascular stability. We think that they can be damaged by the virus, which contributes to pulmonary and systemic damage.  We also think that the damage starts very early, when the viral S protein engages with the entry receptors expressed on cells. This is sufficient to activate detrimental signals in the pericytes and eventually prepare the ground for the virus to spread.

Q: What do you aim to do?

Our research aims to determine which receptors are expressed by human cardiac pericytes (ACE2 and also CD147, which is a more controversial receptor); determine if the S protein alone can induce signalling in exposed pericytes in culture; understand the functional consequences; and verify whether we can shield pericytes by blocking the interaction between S protein and receptors.

Q: How are you progressing?

The data we have gathered confirm the entry  receptor CD147 is expressed in pericytes. However, the expression of ACE2 receptors was low.

The S protein induces the phosphorylation of ERK1/2. This is a kinase enzyme involved in various cellular functions, but also used by the virus to activate RNA polymerase (the enzyme that makes copies of RNA and is used by the virus to make copies of itself). This reaction makes the pericytes less able to support the vascular network and also induces them to secrete inflammatory molecules typical of the cytokine storm. The instability is more evident in adult cells compared with young cells.

We can inhibit these reactions with an antibody  directed to the CD147 receptor, which suggests this is a viable method to shield human pericytes.

Our pre-prints in BioRXiv and the Lancet have received a lot of attention to date.

Q: What’s next?

Because cardiovascular patients are more  susceptible to complications from COVID-19, we  want to integrate the shielding approach of vascular cells within a more general strategy to protect the human body at the early stages of the disease.

A BHF grant is funding our work for one year. This work is carried out by Dr Elisa Avolio on cardiac pericytes provided by Professor Massimo Caputo, both acting as co-PIs.

As part of Bristol’s collective research effort into  COVID-19, we are seeking an additional  contribution from other charities and funding  agencies to work with fellow Bristol researchers  to generate an aerosol containing blockers of  entrance and attachment receptors.

This post first appeared in the March 2021 BHI Newsletter

BHF PhD programme funding renewed

Posted on by Rachel Skerry

BHI Deputy Director Alastair Poole explains the impact for our PhD in Integrative Cardiovascular Sciences.

In December 2020, the British Heart Foundation (BHF) announced new funding for its flagship four-year PhD programmes at 12 universities, aimed at nurturing the next generation of cardiovascular research leaders.

At the University of Bristol, we have been running the popular PhD programme in Integrative Cardiovascular Sciences since 2017, with tuition fees and research costs fully-funded by the BHF.

Understanding the biology and medicine of the cardiovascular system now requires approaches that cross-bridge disciplines, with our current cohort of students working across fundamental bioscience, clinical science and population health.

In this renewal, we aim to build on this successful strategy, introducing new disciplinary strands, supervisors and training in digital health, data analytics, coding and bioengineering. This aligns to the BHF strategy in aiming to prevent disease, identify and manage risk factors, through large scale genomics, data science, AI and multiparameter monitoring of environmental and medical measurements using novel personal and environmental devices. Bioengineering is now seen as an important component of regenerative medicine, and capitalizing on our broad base of expertise in Bristol, we have incorporated several new supervisors into this element. These will provide additional depth and breadth to the training for our students and further opportunities for innovative cardiovascular discovery.

When the funding was announced, Professor Metin Avkiran, the BHF’s Associate Medical Director, said:

“Today’s PhD students are tomorrow’s leaders in cardiovascular research. At this difficult time, it is more important than ever to maintain that pipeline of scientific talent and discovery towards future advances in the prevention, detection and treatment of heart and circulatory diseases.”

We look forward to welcoming our newest BHF PhD students in 2021.

PhD student Ffion Jones talks about what she enjoys about the programme:

This post first appeared in the March 2021 BHI Newsletter

The future may be on hold, but it has not been cancelled

Posted on by Rachel Skerry

BHI Director Gianni Angelini reflects on a turbulent year.

The COVID-19 pandemic made 2020 a year like no other.

It caused major disruption to our  cardiovascular research and teaching, which is continuing into 2021. Clinical translation research has virtually stopped, and basic science work has been significantly curtailed by the limited access to laboratories.

Charities, which are the backbone funders of our work, are experiencing unprecedented difficulties and this translates to reduced grant awards.  However, the renewal award of our BHF-funded PhD programme in Integrative Cardiovasular Science is excellent news.

And, at the same time, the use of  virtual platforms has transformed our work and opened avenues which were unthinkable a year ago. So, despite the gloom and doom, the pandemic is giving us a unique opportunity to regroup and reflect on what we did in the past, and what we can do better in the future.

These are the things that have not changed:

  • Our determination to continue to stand out as the leading academic cardiovascular centre in the UK, and amongst the foremost worldwide.
  • Our ability to turn innovations into benefit for adult and paediatric patients, and the health system.
  • Our creation of an environment where  clinicians, basic scientists and clinical research  methodologists can thrive, attract the most talented individuals and produce world-leading research.
  • Our resolve to facilitate a smooth and timely transition to the next generation of  cardiovascular clinicians and researchers.

This last point is possibly the most relevant for somebody heading towards the twilight of his career! We have an obligation to nurture and mentor our future research leaders by encouraging them to build the confidence to lead. We must pay more attention to our early- and mid-career  researchers and encourage them to play a  major role at the heart of our activities. They are the next generation who will guarantee our  continued success.

The future is still there for you to grab: it has not been cancelled.

This post first appeared in the March 2021 BHI Newsletter

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