NIHR Leicester Cardiovascular Biomedical Research Unit

NIHR Leicester Cardiovascular Biomedical Research Unit

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News Article | February 24, 2017

An approved international test to check whether people need open heart surgery could be sending twice as many people under the knife unnecessarily, at a cost of nearly £75m, research by the University of Leicester has suggested. Since 2012 doctors have been using exercise testing on people with a condition called aortic stenosis (AS) to determine whether they need an operation to save their life. However, a study, led by Gerry McCann, Professor of Cardiac Imaging and Honorary Consultant Cardiologist from the University of Leicester Department of Cardiovascular Sciences, who conducted the research as part of a NIHR Fellowship, has shown the current approach is "highly inaccurate" and if followed may send thousands of patients to surgery before it is needed. The exercise test, which involves cycling on a stationary bike, is used to determine whether surgery is needed for people with the condition - but it only has a 60 per cent accuracy rate, the study found. AS, which is the narrowing of the aortic heart valve, affects predominantly older people and affects up to three per cent of people over 75 years of age. Symptoms, such as chest pain, breathlessness and feeling faint, can take years to develop. However, when they do it means the person is seriously ill and could die from heart failure or sudden death. If exercise test participants become breathless, they are recommended to have valve replacement therapy. About 10,000 aortic valve replacements are performed every year at a cost of up to £15,000. Hospital recuperation then takes between seven and 10 days. Professor McCann, who is also a consultant cardiologist from the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU), said: "There is no doubt that valve replacement therapy is highly effective for patients with symptoms, however there are risks involved. It's a major operation and there's a one per cent chance of people dying or having a stroke during or after. There's also the chance they could develop an infection. "It can often take six months to recover, but if they survive they tend to do very well afterwards. However, if we know a patient has AS and no symptoms and we do nothing there's also a one per cent chance they will die so there's a fine line between whether we should intervene or not. "Our findings showed that this exercise test, which has been approved by the American Heart Association/American College of Cardiology and the European Society of Cardiology, was highly inaccurate as almost twice the number of people who became breathless during the test did not develop symptoms within a year." The findings have been published in the world-leading European Heart Journal1, which showcases work often considered in future guidelines. Professor McCann now wants to conduct further research to find a more accurate way to determine whether doctors should wait for symptoms to develop or to intervene beforehand. Ultimately a clinical study comparing early surgery versus waiting for symptoms to develop is needed. The study was funded by the NIHR and most of the research was carried out at the NIHR Leicester Cardiovascular BRU. The NIHR BRUs are focused on translational clinical research, taking new ideas from the laboratory bench to the patient's bedside to improve health. The NIHR Leicester Cardiovascular BRU at Glenfield Hospital harnesses the power of experimental science to explore and develop ways to help prevent and treat cardiovascular conditions. The BRU is one of 20 units around England funded by the NIHR, the research arm of the NHS.

News Article | November 29, 2016

"Early detection is key to this condition which, if left untreated, can become a ticking time bomb for patients" -- Professor Matt Bown, University of Leicester Thousands of lives could be saved every year after it was discovered a fatal cardiovascular condition could be linked to four genes, research has found. A 10-year project, led by a Leicester surgeon, looked at 10,000 people worldwide and found those who had suffered an abdominal aortic aneurysm (AAA) had four genes in common. It is hoped that the findings could help doctors understand more about the condition, which can lead to fatal internal bleeding if left untreated. Professor Matt Bown, a vascular surgeon from the University of Leicester and the NIHR Leicester Cardiovascular Biomedical Research Unit (BRU) and Honorary Consultant Vascular Surgeon, University Hospitals of Leicester NHS Trust, said: "Abdominal aortic aneurysm commonly affects the older population and can only be treated by surgery. "Early detection is key to this condition which, if left untreated, can become a ticking time bomb for patients. Thousands of people die from burst AAAs each year yet about one in five men do not attend their free screening appointments so we can't detect if there may be a problem. "The discovery of the four genes, which is the culmination of more than a decade of a global research effort, could help us determine those at risk much earlier. If we are able to do this, then we could potentially save thousands of lives." The research, which has been published in the journal Circulation Research, was funded by the Wellcome Trust and the British Heart Foundation (BHF) and supported by the NIHR Leicester Cardiovascular BRU. It also involved institutions from New Zealand, South Africa, Poland, Belgium, The Netherlands, Iceland, Australia, Denmark, Italy, Saudi Arabia, Estonia, Germany, Sweden and the USA. As part of the study, researchers compared the genes of people with AAAs to those without. A new research programme, funded by the British Heart Foundation, will now investigate whether the four common genes affect the speed at which the AAAs grow. In order to continue with their work, they are asking for men who have been found to have an AAA by screening to provide blood samples. In the UK men aged 65 or over are invited to attend a free aneurysm screening appointment. Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which part-funded the genetic study and is funding Professor Bown's current research programme, said: "The only available treatment for abdominal aortic aneurysms is surgery, which is expensive and can be risky. We desperately need to find new ways of treating aneurysms, but can only do so by learning more about how and why they grow. "The discovery of four new genes associated with these aneurysms will enable us to explore their function, and could provide a potential target for treatments. "Professor Bown will harness this discovery in his BHF-funded research aimed at improving the detection of people whose aneurysms are at greatest risk of a deadly rupture." The paper 'Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm 1 Identifies Four New Disease-Specific Risk Loci' published in the journal Circulation Research is available on request. An image of Professor Matt Bown is available here: https:/ To arrange an interview with a patient who has been diagnosed with abdominal aortic aneurysm contact Fiona Bailey on or call 01604 882342

Miller C.A.,University of Manchester | Borg A.,University of Manchester | Clark D.,Wythenshawe CMR Unit | Steadman C.D.,NIHR Leicester Cardiovascular Biomedical Research Unit | And 7 more authors.
Journal of Magnetic Resonance Imaging | Year: 2013

Purpose To compare local sine-wave modeling (SinMod) with harmonic phase analysis (HARP), for assessment of left ventricular (LV) circumferential strain (εcc) from tagged cardiovascular magnetic resonance images. Materials and Methods Mid-ventricular spatial modulation of magnetization was performed in 60 participants (15 each with hypertrophic, dilated or ischemic cardiomyopathy and 15 healthy controls) at 1.5 Tesla. Global and segmental peak transmural εcc were measured using HARP and SinMod. Repeated measurements were performed on 25% of examinations to assess observer variability. Effect of contrast was assessed in 10 additional patients. Results SinMod showed a high level of agreement with HARP for global εcc (mean difference -0.02, 95% limits of agreement -6.46 to 6.43%). Agreement was much lower for segmental εcc. Both methods showed excellent observer agreement for global εcc (intraclass correlation coefficient >0.75). Observer agreement for segmental εcc was also excellent with SinMod, but was significantly lower with HARP. Analysis time was significantly shorter using SinMod. Pre- and postcontrast εcc measurements were not significantly different using either technique, although postcontrast measurements showed greater variability with HARP. Conclusion SinMod and HARP-based measurements of global εcc have a high level of agreement, but segmental agreement is substantially lower. SinMod has generally lower observer variability, is faster and is less affected by contrast, but requires further validation. © 2012 Wiley Periodicals, Inc. Copyright © 2012 Wiley Periodicals, Inc.

Winter J.,University of Leicester | Brack K.E.,University of Leicester | Coote J.H.,University of Birmingham | Ng G.A.,University of Leicester | Ng G.A.,NIHR Leicester Cardiovascular Biomedical Research Unit
International Journal of Cardiology | Year: 2014

Background/objectives Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility. Methods Experiments were conducted in isolated New Zealand white rabbit hearts (2.0-2.5 kg, n = 25). The effects of CCM (± 20 mA, 10 ms phase duration) on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS. Results CCM significantly shortened MAPD close to the stimulation site (Basal: 102 ± 5 [CCM] vs. 131 ± 6 [Control] ms, P < 0.001). VFT was reduced during CCM (2.6 ± 0.6 [CCM] vs. 6.1 ± 0.8 [Control] mA, P < 0.01) and was correlated (r2 = 0.40, P < 0.01) with increased MAPD dispersion (26 ± 4 [CCM] vs. 5 ± 1 [Control] ms, P < 0.01) (n = 8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation. Conclusions CCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart. © 2014 The Authors.

Salem M.K.,University of Leicester | Bown M.J.,University of Leicester | Bown M.J.,NIHR Leicester Cardiovascular Biomedical Research Unit | Sayers R.D.,University of Leicester | And 6 more authors.
European Journal of Vascular and Endovascular Surgery | Year: 2014

Objectives: In patients with carotid stenosis the risk of stroke is highest in the first few days after onset of symptoms and it is low in asymptomatic patients. The ability to identify patients with a high (or low) probability of having a histologically unstable plaque might become a complimentary method that can refine the indications for surgical intervention. Methods: Two histopathologists, using validated American Heart Association criteria, independently graded plaques harvested during carotid endarterectomy. Preoperative Duplex images were independently assessed for juxtaluminal black area, plaque type, plaque area, and grey-scale median (GSM) following image normalization. Logistic regression analysis was then performed to create a model for predicting predominantly histologically unstable or stable plaques. Results: A total of 126 patients were included in the study. Based on the presence and extent of histological features including haemorrhage, thrombus, fibrous tissue, lipid core, inflammation, neovascularity, foam cells, and cap rupture, 39 plaques were graded as predominantly stable, while 87 were predominantly unstable. Unstable plaques were associated with a plaque area >95 mm2 (OR 4.15; 95% CI 1.34-12.8 p =.009), a juxtaluminal black area >6 mm2 (OR 2.77; 95% CI 1.24 to 6.17 p =.01) and a GSM <25 (OR 3.76; 95% CI 1.14-12.39). Logistic regression indicated that patients with the first two features had a 90% probability of having a histologically unstable plaque. The model was used to calculate the probability of having an unstable plaque in each patient. The receiver operating characteristic curve using the p value was 0.68 (95% CI 0.59-0.78). Conclusions: Computerized plaque analysis has the potential to identify patients with histologically unstable carotid plaques. This model requires validation, but offers the potential to influence patient selection for emergency interventions and the monitoring of medical therapy. © 2014 European Society for Vascular Surgery.

Hussain S.T.,National Health Research Institute | Paul M.,National Health Research Institute | Plein S.,University of Leeds | McCann G.P.,NIHR Leicester Cardiovascular Biomedical Research Unit | And 12 more authors.
Journal of Cardiovascular Magnetic Resonance | Year: 2012

Background: In patients with stable coronary artery disease (CAD), decisions regarding revascularisation are primarily driven by the severity and extent of coronary luminal stenoses as determined by invasive coronary angiography. More recently, revascularisation decisions based on invasive fractional flow reserve (FFR) have shown improved event free survival. Cardiovascular magnetic resonance (CMR) perfusion imaging has been shown to be non-inferior to nuclear perfusion imaging in a multi-centre setting and superior in a single centre trial. In addition, it is similar to invasively determined FFR and therefore has the potential to become the non-invasive test of choice to determine need for revascularisation. Trial design. The MR-INFORM study is a prospective, multi-centre, randomised controlled non-inferiority, outcome trial. The objective is to compare the efficacy of two investigative strategies for the management of patients with suspected CAD. Patients presenting with stable angina are randomised into two groups: 1) The FFR-INFORMED group has subsequent management decisions guided by coronary angiography and fractional flow reserve measurements. 2) The MR-INFORMED group has decisions guided by stress perfusion CMR. The primary end-point will be the occurrence of major adverse cardiac events (death, myocardial infarction and repeat revascularisation) at one year. Clinical identifier NCT01236807. Conclusion: MR INFORM will assess whether an initial strategy of CMR perfusion is non-inferior to invasive angiography supplemented by FFR measurements to guide the management of patients with stable coronary artery disease. Non-inferiority of CMR perfusion imaging to the current invasive reference standard (FFR) would establish CMR perfusion imaging as an attractive non-invasive alternative to current diagnostic pathways. © 2012 Hussain et al.; licensee BioMed Central Ltd.

Romaine S.P.R.,University of Leicester | Tomaszewski M.,University of Leicester | Tomaszewski M.,NIHR Leicester Cardiovascular Biomedical Research Unit | Condorelli G.,University of Leicester | And 4 more authors.
Heart | Year: 2015

MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs. © 2015, BMJ Publishing Group. All rights reserved.

Harrison M.,NIHR Leicester Cardiovascular Biomedical Research Unit
Nursing standard (Royal College of Nursing (Great Britain) : 1987) | Year: 2014

University Hospitals of Leicester NHS Trust is one of the top ten trusts for recruiting patients to research studies. Although research nurses constitute the largest specialist nurse group in the trust, comprising three per cent of the nursing workforce, their roles and the benefits they bring are poorly understood.

Wouters O.J.,The London School of Economics and Political Science | Naci H.,The London School of Economics and Political Science | Samani N.J.,University of Leicester | Samani N.J.,NIHR Leicester Cardiovascular Biomedical Research Unit
Heart | Year: 2015

In recent years, cost-effectiveness data have strongly influenced clinical practice guidelines for several cardiovascular treatments. Economic considerations are increasingly common as health systems are under mounting pressure to maximise value for money. The quality-adjusted life year (QALY)â€"an outcome measure that expresses the duration and quality of lifeâ€"is the main pillar of cost-effectiveness analyses. It is widely used in assessments of the clinical and economic value of new cardiovascular treatments, but how the QALY is derived is often unclear to clinicians. In this article, we first explain how QALYs are defined and calculated. We then review a selected set of cost-effectiveness analyses of recently introduced cardiovascular treatments and outline how these studies derived their QALYs. Finally, we discuss the limitations of the QALY and how the presentation of the measure could be improved in cost-effectiveness studies.

PubMed | University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit
Type: Journal Article | Journal: European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery | Year: 2016

Microarray-based gene expression profiling studies may detect transcriptional signatures carrying prognostic value in abdominal aortic aneurysms (AAA). A gene expression profiling study was conducted to compare individuals with AAA with screened controls.The peripheral blood transcriptome was compared between 12 individuals with AAA and 12 age- and sex-matched controls using microarray. Validation by Taqman real-time quantitative (qPCR) was performed in an independent group as described. Peripheral blood RNA was hybridized to Illumina microarrays, each representing 37,846 genes, allowing comparison of gene expression between cases and controls. Eleven differentially expressed genes were re-quantified by qPCR in the independent group with AAA (n=95), controls (n=92), pre- and postendovascular AAA repair (EVAR, n=31); or open AAA repair (n=13), AAA wall biopsies (n=11), and in matched smooth muscle cultures (n=7).Microarray detected 47 significantly differentially expressed genes in AAA after correction for multiple testing (p<.05). These genes conferred roles in regulation of apoptosis, proteolysis, the electron transport chain, leukocyte migration, and the humoral immune response. Gene quantification in the independent group demonstrated three genes to be downregulated in AAA compared with controls: MSN, PSMB10, and STIM1; however, their expression remained unchanged post-AAA repair. PSMB10 was the only gene conferring a consistent direction of effect in both the discovery and validation analyses (downregulated). EIF3G, SIVA, PUF60, CYC1, FIBP, and CARD8 were downregulated post-EVAR. Expression of all 11 genes of interest was detected in aortic biopsies and matched smooth muscle cultures.This study demonstrates differential expression of transcripts in peripheral blood of individuals with AAA, with functional roles in proteolysis, inflammation, and apoptotic processes. These were modulated by aneurysm exclusion from the circulation and expressed in matched aortic biopsies and smooth muscle cultures. These observations further support the key roles for these pathways in the pathogenesis of AAA.

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