A new study has shown how SARS-CoV-2 may contribute to severe microvascular damage seen in severely-ill COVID-19 patients by transforming human heart vascular cells into inflammatory cells, without infecting them. The University of Bristol-led research, published in Clinical Science, indicates blocking antibodies could represent a new treatment to alleviate cardiovascular complications.
Bristol & Weston Hospitals Charity (formerly Above and Beyond) has been awarded £57,000 from NHS Charities Together to support its appeal to provide at-home monitoring service for BHI patients with pacemakers.
Thousands of BHI patients have a cardiac implantable electronic device (CIED) or pacemaker to help control or monitor irregular heartbeats. Having a CIED requires them to attend hospital as often as every six weeks to be checked.
However, COVID-19 restrictions have severely affected patients’ ability to attend their hospital appointments. The average age of a person with a CIED in the UK is 75 years old, which puts these patients in a high-risk group.
Over lockdown, the BHI identified technology that would allow CIED patients to be monitored remotely instead. By providing patients with home monitoring equipment that they place by their bed, staff could routinely assess patients and perform essential tests without the patient leaving their home.
Remote monitoring reduces mortality in these patients as it enables the CIED clinic to detect heart failure events at an early stage and intervene before the patient develops symptoms. This includes being able to detect Atrial Fibrillation, which is the leading cause of stroke in the UK.
Following a successful trial in a cohort of complex CIED patients, this year Bristol & Weston Hospitals Charity launched an appeal to provide remote monitoring technology for all CIED patients at the BHI. This will reduce both waiting times in the clinic and the number of hospital visits overall, while providing an even more effective level of service and care.
The NHS Charities Together award, announced in September, comes as part of a package of support for 10 different health projects that will benefit more than 100,000 people in Bristol and beyond, not only those with heart conditions. Find out more
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
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