Yorkshire Heart Center

Leeds, United Kingdom

Yorkshire Heart Center

Leeds, United Kingdom
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Li J.,University of Leeds | McKeown L.,University of Leeds | Ojelabi O.,University of Leeds | Stacey M.,University of Leeds | And 4 more authors.
British Journal of Pharmacology | Year: 2011

BACKGROUND AND PURPOSE The aim was to advance the understanding of Orai proteins and identify a specific inhibitor of the associated calcium entry mechanism in vascular smooth muscle cells (VSMCs). EXPERIMENTAL APPROACH Proliferating VSMCs were cultured from human saphenous veins. Intracellular calcium was measured using fura-2, whole-cell current was recorded using patch-clamp and cell migration quantified in modified Boyden chambers. Subcellular protein localization was determined by microscopy. Isometric tension was recorded from mouse aortic rings. KEY RESULTS Molecular disruption and rescue experiments indicated the importance of Orai1 in calcium entry caused by store depletion evoked passively or by platelet-derived growth factor (PDGF), suggesting the presence of Ca 2+ release-activated Ca 2+ (CRAC) channels like those of the immune system. The CRAC channel blocker, S66, was a potent inhibitor of the VSMC signals, IC 50 26 nM, which was almost two orders of magnitude greater than with leucocytes. S66 had no effect on PDGF- and ATP-evoked calcium release, overexpressed transient receptor potential canonical (TRPC)5 channels, native TRPC1/5-containing channels, stromal interaction molecule 1 clustering, non-selective cationic current evoked by store depletion and phenylephrine-evoked aortic contraction. S66 reduced PDGF-evoked VSMC migration while having only modest effects on cell proliferation and no effect on cell viability. CONCLUSIONS AND IMPLICATIONS The data suggest that Orai1 has a role in human VSMC migration, and that a CRAC channel inhibitor has high potency and selectivity for the associated calcium entry, suggesting a distinct characteristic of vascular CRAC channels and the potential for selective chemical suppression of vascular remodelling. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Several prognostic markers have been identified for patients admitted with acute cardiogenic pulmonary edema. Most of the markers are based on clinical risk scores. Unlike hypercapnic respiratory failure, acidosis is not an adverse predictor in these patients. Hemodynamic variables that assess pathophysiological mechanisms may be more helpful to guide appropriate management. © 2010 BioMed Central Ltd.

Turner N.A.,University of Leeds | Das A.,University of Leeds | O'Regan D.J.,University of Leeds | O'Regan D.J.,Yorkshire Heart Center | And 2 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2011

Neutrophil attraction and adhesion to endothelial cells occurs via well defined mechanisms, yet the ability of other cell types to express neutrophil-binding adhesion molecules is not well studied. Cardiac fibroblasts (CF) are a key cell type involved in repair of the infarcted myocardium, a scenario in which neutrophil recruitment is perceived to be detrimental. Here we determined the effects of proinflammatory cytokines on expression of neutrophil-binding adhesion molecules and neutrophil-attracting chemokines in CF cultured from multiple patients, and explored the underlying regulatory mechanisms. An adhesion molecule focused RT-PCR array identified 5 transcripts that were increased markedly in human CF treated with the proinflammatory cytokine interleukin-1 (IL-1, 10 ng/ml, 6 h); including intercellular cell adhesion molecule (ICAM-1) and E-selectin. Real-time RT-PCR verified the array data and immunoblotting confirmed cytokine-induced ICAM-1 and E-selectin protein expression. Treatment with a panel of pharmacological inhibitors identified the NF-κB pathway as mediating IL-1-induced ICAM-1 and E-selectin mRNA and protein expression. Additionally, E-selectin expression in human CF was markedly potentiated by the JNK inhibitor SP600125, but this was not observed when a more selective inhibitor ((L)-JNKI-1) was used, or in human vascular endothelial cells. IL-1 also stimulated CF to secrete the neutrophil chemoattractant CXCL8 via a p38- and NF-κB-dependent mechanism, as well as inducing CXCL1, CXCL2 and CXCL5 mRNA expression. In conclusion, human CF express neutrophil-binding adhesion molecules and neutrophil chemoattractants in response to proinflammatory cytokines suggesting that, in addition to EC, CF may play an important role in regulating neutrophil recruitment into the infarcted myocardium. © 2011 Elsevier Ltd. All rights reserved.

Bentham J.,Yorkshire Heart Center | Qureshi S.,Evelina Childrens Hospital | Eicken A.,German Heart Center | Gibbs J.,Yorkshire Heart Center | And 2 more authors.
Catheterization and Cardiovascular Interventions | Year: 2013

Objective To describe the cases of percutaneous valve failure following implantation of the Medtronic Melody™ and the Edwards Sapien™ valve in the tricuspid position. Background: There have been recent reports of the use of percutaneously delivered valves to manage failing bioprosthetic tricuspid valves. Total patient numbers remain small and follow-up times are limited. Methods We describe four procedures in three patients from two centers where implantation of percutaneous valves within the scaffold of a bioprosthetic tricuspid valve was technically successful but there was early valve failure. Results In all cases, immediate results suggested excellent valve function; however, valve failure occurred early in three and later in one. Two patients elected for valve explantation and surgical placement of a further tricuspid valve. The third patient underwent a second percutaneous valve-in-valve procedure though this valve is also showing early signs of failure. Conclusions Transcatheter placement of percutaneous valves in the tricuspid position is technically a relatively straightforward procedure but early valve failure raises some concerns about the viability of the valve in this position, at least in some patients. © 2013 Wiley Periodicals, Inc.

Viswanathan K.,Yorkshire Heart Center | Hall A.S.,Yorkshire Heart Center | Barth J.H.,Clinical Biochemistry
Clinical Biochemist Reviews | Year: 2012

Cardiac troponins have been the biomarkers of choice for the diagnosis of acute coronary syndrome (ACS) for over a decade. There has, however, been considerable interest over the last two decades for newer biomarkers that would bring added value to the measurement of troponin such as the provision of prognosis and assistance in the choice of therapeutic interventions. In this manuscript, we review the development of heart-type fatty acid binding protein (H-FABP) in patients with ACS using the evidence-based laboratory medicine format. Phase I studies have established that H-FABP reference intervals and pre-analytical factors influencing H-FABP. Phase II studies have confirmed a) that H-FABP is elevated in patients with established myocardial infarction; b) that its serum concentration is related to the extent of infarction using survival as a surrogate; and c) that its use in chest pain patients can identify ACS patients and also provide prognostic information on survival. Furthermore, it is an independent prognostic marker for patients with suspected ACS who are troponin negative. Phase III studies involving randomised control trials for diagnosis and prognosis have not yet been performed and Phase IV studies await uptake of H-FABP in a routine service.

Bentham J.R.,Yorkshire Heart Center | Thomson J.D.R.,Yorkshire Heart Center
Archives of Disease in Childhood | Year: 2015

Congenital interventional cardiology seeks to provide alternative percutaneous solutions to congenital cardiac problems in preference to more traditional surgical approaches. Simpler procedures have been refined and are now achievable in smaller children and infants. More complex procedures are increasingly recognised as superior to surgical alternatives, though most patients with complex disease inevitably undergo combinations of interventional, surgical and joint or hybrid procedures. This review seeks to highlight recent advances in these techniques of most interest to the readership of this journal.

A 56-year-old man with sudden onset chest pain, absent right lower limb pulses and ECG changes suggestive of inferior ST elevation Ml underwent coronary angiogram through the right radial artery with a view to primary percutaneous coronary intervention (PCI). The left coronary angiogram demonstrated severe proximal stenotic disease in the left anterior descending and circumflex coronary arteries, but the right coronary artery could not be selectively cannulated. An ascending aortogram to visualise the right coronary artery not only failed to demonstrate it, but revealed, instead, a dissection flap in the ascending aorta, arch and descending thoracic aorta, with moderately severe aortic regurgitation. At operation, the patient was found to have an acute dissection of the ascending aorta, arch and descending aorta with an entry tear in the descending aorta below the left subclavian artery origin. Triple coronary artery bypass grafting with re-suspension of the aortic valve, supracoronary replacement of the ascending aorta and hemiarch and transaortic repair of the descending aortic tear was performed. The patient made an uncomplicated recovery, with the re-appearance of right limb pulses. A postoperative magnetic resonance (MR) scan revealed complete thrombosis of the false channel in the residual arch and a considerably shrunken false channel in the descending aorta and no aortic regurgitation. Retrograde dissection of the ascending aorta from the descending aorta has been reported infrequently in the past. We believe the scale of the problem has been underestimated because of the failure to adopt open distal anastomosis routinely in the past and, hence, failure to inspect the arch and the descending aorta routinely, particularly when the intimal tear was not identified in the ascending aorta. Retrograde dissection of the ascending aorta from an intimal tear in the descending aorta, when identified as such, has been managed, either on the principle of exclusion of the tear in the descending aorta by various elephant trunk procedures and their variants or, alternatively, on the principle of excision of the tear by extended one-stage aortic replacement, usually combined with an elephant trunk procedure. Neither of these procedures is widely adopted, owing to procedural, institutional and outcome considerations. We describe a transaortic repair of the intimal tear in the descending aorta with supracoronary interposition graft replacement of the ascending aorta and hemiarch with excellent clinical and radiological result. We also review the diagnostic and therapeutic approaches to this incompletely understood lethal disease. © The Author(s) 2011.

Kaul P.,Yorkshire Heart Center
Journal of Cardiothoracic Surgery | Year: 2013

A 56 year old Caucasian man presented with sudden loss of consciousness while driving and was found to have an 11 cm Haughton D type left cervical aortic arch aneurysm with normal brachiocephalic branching and normal descending thoracic laterality but with considerable tortuosity and redundancy of aortic arch. The aneurysm arose between the left common carotid artery and the left subclavian artery. It compressed and stretched the left common carotid artery, compressed the pulmonary trunk and the left pulmonary artery, stretched the vagus, left recurrent laryngeal and left phrenic nerves and caused extreme deviation of trachea, severely compromising the tracheal lumen. Patient underwent successful interposition graft replacement of distal aortic arch under total circulatory arrest and selective unihemispherical cerebral perfusion. © 2013 Kaul; licensee BioMed Central Ltd.

Objective: To evaluate the impact of increased age on outcome from a strategy of early invasive management and revascularisation in patients with acute coronary syndromes (ACS). Design: Retrospective analysis of a national Acute Coronary Syndrome registry (ACACIA). Setting: Multiple Australian (n=39) centres; 25% rural, 52% with onsite cardiac surgery. Patients: Unselected consecutive patients admitted with confirmed ACS, total n=2559, median 99 per centre. Interventions: Management was at the discretion of the treating physician. Analysis of outcome based on age >75 years was compared using Cox proportional hazard with a propensity model to adjust for baseline covariates. Main outcome measures: Primary outcome was allcause mortality. Secondary outcomes were bleeding and a composite of any vascular event or unplanned readmission. Results: Elderly patients were more likely to present with high-risk features yet were less likely to receive evidence-based medical therapies or receive diagnostic coronary angiography (75% vs 49%, p<0.0001) and early revascularisation (50% vs 30%, p<0.0001). Multivariate analysis found early revascularisation in the elderly cohort to be associated with lower 12-month mortality hazard (0.4 (0.2-0.7)) and composite outcome (0.6 (0.5-0.8)). Propensity model suggested a greater absolute benefit in elderly patients compared to others. Conclusions: Following presentation with ACS, elderly patients are less likely to receive evidence-based medical therapies, to be considered for an early invasive strategy and be revascularised. Increasing age is a significant barrier to physicians when considering early revascularisation. An early invasive strategy with revascularisation when performed was associated with substantial benefit and the absolute accrued benefit appears to be higher in elderly patients.

Cullington D.,Yorkshire Heart Center
Expert Review of Cardiovascular Therapy | Year: 2014

16th British Society for Heart Failure Annual Autumn Meeting Queen Elizabeth II Conference Centre, London, UK, 28-29 November 2013 The 16th Annual Meeting for the British Society for Heart Failure took place in the impressive surroundings of the Queen Elizabeth II Conference Centre in Westminster (London, UK). Over the two-day conference, more than 700 delegates attended-the largest number to date. Over 40 talks were delivered by some of the world's experts in heart failure. For 2013, the theme was making sense of acute heart failure-a clinical entity which is frequently encountered, poorly understood, and for which there exists virtually no evidence base for treatment. © 2014 Informa UK Ltd.

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