Author: Rachel Skerry

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

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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.