Cardiovascular

Cardiomyocytes developed in culture from neonatal mouse heart, stained with anti-sarcomeric myosin (green). Von Willebrand factor (stained in red, orange in the merged image) shows the expression of an endothelial marker. Nuclei are stained in blue with DAPI. Image Courtesy of G. Cossu.

Cardiovascular

Manchester supports a substantial body of academic, clinical-academic and clinical researchers who focus on Cardiovascular medicine. Our research into Regenerative Cardiovascular Medicine ranges from direct reprogramming for cardiac fibroblasts to cadriomyocytes and the use of cardiomyocyte iPS models to understanding the role developmental pathways play in hypertrophy and the role specific proteins involved in chanelopathies.

Academic

Dr Delvac Oceandy

Senior Lecturer
Faculty of Biology, Medicine and Health
delvac.oceandy@manchester.ac.uk
Dr Oceandy’s University Profile

Molecular Biology of Cardiac Remodelling and Cardiomyocyte Regeneration

Dr Oceandy’s research is focused on the basic molecular understanding of cardiac remodelling and regeneration. Projects in Dr Oceandy’s lab include:

1) Cardiomyocyte regeneration and cell reprogramming. Dr Oceandy is investigating the role of specific signalling pathway (Hippo pathway) that is important in cardiomyocyte replication and repair. His lab also focuses on studying Hippo signalling in induced pluripotent cells differentiation to cardiomyocytes. It is hoped that modulation of this signalling pathway may be useful to induce cardiac muscle cell regeneration.

2) The regulatory role of tumour suppressor molecules during cardiac hypertrophy, remodelling and failure: Dr Oceandy’s lab also focuses on the investigation of the close relationship between the regulation of cardiac hypertrophy and cancer growth, particularly the role of tumour suppressors during cardiac growth. Currently, he is focusing on the tumour suppressor Ras-association domain family protein (RASSF1) and the downstream Hippo signalling pathway in regulating cardiac hypertrophy and remodelling following pathological insults. (see Oceandy et al. Circulation 2009;120(7):607-16, and Oceandy et al. Trends Cardiovasc Med. 2009;19(8):262-7).

3 )Local calcium signalling in the heart regulated by sarcolemmal calcium pump: Dr. Oceandy’s group is studying how calcium microdomain governs the molecular signaling pathway. We use local calcium sensor attached to the plasma membrane to unravel the role of local calcium in mediating downstream signaling pathway. (see Mohamed et al. J Mol Cell Cardiol. 2013 Jul 21. (Epub ahead of print) and Oceandy et al. Circulation 2007;115(4):483-92).

4) Genetic and epigenetics determinants of valve diseases In collaboration with Prof Simon Ray (South Manchester University Hospital, Wythenshawe), his group analysed genetic determinants of adverse cardiac remodelling in patients with mitral valve prolapse (MVP). They are also interested in studying epigenetic modification in patients with aortic stenosis (see Oceandy et al. Eur J Heart Fail 2007;9(10):1010-7)

Dr Tamer Mohamed

Honorary Lecturer (Research)
Faculty of Biology, Medicine and Health
tamer.mohamed@manchester.ac.uk
Dr Mohamed’s University Profile

Small Molecules for Heart Failure Treatment and Novel Cardiac Regeneration Approaches

To pursue his long-term goal of translating findings in mouse models into human drug therapy for heart failure (at least with regard to the initial steps), Dr Mohamed research have taken three main directions:

1) Small molecule treatment for cardiac hypertrophy: Dr Mohamed’s research has identified the plasma membrane calcium ATPase isoform 4  (PMCA4) as a novel target for treatment of cardiac hypertrophy. Therefore, he developed a medium throughput screening assay for PMCA4 activity to screen for specific inhibitors (Mohamed et al., Methods Mol Biol, 2010 and Mohamed et al., JMCC, 2013) and in collaboration with the Fraunhofer IME Screening Port (Hamburg) he has established a novel fluorescent-based high throughput screening assay for PMCA4 activity to screen for more specific inhibitors (Mohamed et al., J Pharmacy & Pharmaceutical Sciences, 2013). 

2) Generation of human induced pluripotent stem cell-derived cardiomyocytes (iPS-CM). In order to be able to model human heart disease for drug screening approaches and due to the scarcity of human tissue, Dr Mohamed has initiated the use of iPS-CM models, which is the first human relevant cardiac cell model with the additional potential to derive patient-specific cardiac cells.

3) Direct cardiac reprogramming technologies:  With Professor Deepak Srivastava laboratory at the J David Gladstone Research institutes, Dr Mohamed has developed a novel small molecule screening platform for direct cardiac reprogramming and ran a high-throughput small molecule screening to improve the efficiency of direct cardiac reprogramming as a novel therapy for heart failure. He has identified small molecules (mainly TGF-β and WNT inhibitors) which are able to enhance the efficiency of cardiac reprogramming 7 fold.  The ultimate aim is to investigate the molecular mechanisms by which TGF-β and WNT signalling control the direct reprogramming process and perform the first translational attempt to use the small molecules to enhance in vivo cardiac reprogramming.

Dr Halina Dobrzynski

Senior Lecturer
Faculty of Biology, Medicine and Health
Halina.Dobrzynski@manchester.ac.uk
Dr Dobrzynski University Profile

Cellular and Molecular Compisition of the Sinus and Atrioventricular Nodes

Dr Dobrzynsk’s research focuses on the functional properties, as well as the  cellular and molecular make-up of the sinus and atrioventricular nodes of the heart.  Her work utilises  a variety of techniques including electrophysiology, histology, immunohistochemistry, Western blotting, in situ hybridization and real-time PCR. The current focus of her research is the molecular make-up of the human sinus and atrioventricular nodes, as well as functional and structural changes in the cardiac conduction system in health, ageing and disease. Her research is sponsored mainly by the British Heart Foundation and she works in collaboration with Professors Mark Boyett and Hengui Zhang.

Professor Ann Canfield

Professor of Vascular Cell Biology
Faculty of Biology, Medicine and Health
ann.canfield@manchester.ac.uk
Professor Canfield’s University Profile

Molecular and Cellular Mechanisms of Vascular Calcification

The primary focus of Professor Canfield’s research is to elucidate the molecular and cellular mechanisms regulating pathological vascular calcification, which is highly correlated with increased morbidity and mortality in patents with atherosclerosis, diabetes and end-stage renal disease. Her group was the first to demonstrate that vascular pericytes may be involved in this process as she demonstrated that these cells can differentiate along several lineages including osteogenic, chondrogenic and adipogenic in response to specific stimuli. She has now confirmed that vascular smooth muscle cells (VSMC) can also undergo osteogenic differentiation and deposit a mineralised matrix. Using both pericytes and vascular smooth muscle cells, she has demonstrated that the Wnt- and TGFbeta-signalling pathways are master controllers of differentiation and that they also contribute to the pathogenesis of vascular calcification. In addition, she has discovered other novel inhibitors of vascular calcification including TSG-6, CaR, Axl and its ligand, Gas6 and HtrA1 (a serine protease with the ability to regulate TGFbeta signalling). Therefore, current research aims to determine the mechanisms by which these signalling pathways regulate pericyte and VSMC differentiation and vascular calcification. Ultimately, these studies should enable her to develop approaches to (a) prevent pathological calcification, and (b) manipulate cells along VSMC lineages for therapeutic tissue regeneration.

Dr Cathy Holt

Senior Lecturer
Faculty of Biology, Medicine and Health
cathy.holt@manchester.ac.uk
Dr Holt’s University Profile

Encapsulated MSCs as a Protein Delivery System to Enhance Cardiac Repair

Stem cell therapy is an exciting and emerging treatment option to promote post-myocardial infarction (post-MI) healing; however, cell retention and efficacy in the heart remain problematic. Therefore, Dr Holt’s group are attempting to circumvent this difficulty through encapsulating hMSC’s within alginate beads. They have demonstrated that encapsulation of hMSCs engineered to produce a Glucagon-like peptide-1 (GLP-1), an incretin hormone with cardio-protective properties but a short half-life in vivo, improves cardiac recovers post-infarct. Post-MI delivery of GLP-1 encapsulated genetically modified MSCs provided a prolonged supply of GLP-1 and paracrine stem cell factors, which improved LV function and reduced epicardial infarct size. This was associated with increased angiogenesis and an altered remodelling response. Combined benefits of paracrine stem cell factors and GLP-1 were superior to those of stem cells alone. These results suggest that encapsulated genetically modified MSCs would be beneficial for recovery following Myocardial Infarction.

Dr Tao Wang

Senior Lecturer in Medical Genetics
Faculty of Biology, Medicine and Health
tao.wang@manchester.ac.uk
Dr Wang’s University Profile

Understanding the Cellular Basis of Vascular Dementia: Role of Notch Signalling in Vascular Development and Pathologies; Improving Coronary Stents

Notch signalling in cardiovascular function, disease and signalling in VSMC differentiation form stem cells: Notch proteins are transmembrane receptors that transduce signals from neighbouring cells. Notch signalling determines cell fate during embryonic development and is equally important in the homeostasis in the adult tissues; dysregulation of Notch signalling leads to diverse human diseases from cancer to cardiovascular disorders. Dr Wang’s current research focuses on the role of Notch signalling in the cardiovascular system, using patient-specific induced pluripotent stem cells (iPSCs) to study genetic vascular conditions such as vascular dementia, also known as CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), which is the most common type of genetic stroke syndrome, and caused by mutations in the NOTCH3 gene. Additionally, Notch signalling is required for several distinct steps during vascular development. Dr Wang’s group are interested in elucidating the precise function of Notch signalling during VSMC differentiation and explore the translational applications of laboratory findings.

Improve the biocompatibility of coronary stents: Coronary artery disease (CAD) causes over 100,000 deaths in the UK every year. Coronary stents are widely used for the treatment of this condition; however, overcoming complications associated with coronary stenting such as restenosis and thrombosis, remains a big challenge. Through multidisciplinary collaborations with expertise in engineering and material sciences, we aim to improve the biocompatability of coronary stents by changing their surface properties using advanced bioengineering technologies.

Academic-Clinical

Dr Chris Miller

University Hospital of South Manchester
NIHR Clinical Lecturer in Cardiology
christopher.miller-2@manchester.ac.uk
Dr Miller’s University Profile

MRI Imaging of Myocardial Injury and Adaptation

Dr Miller’s research centres on the use of MRI to find patho/physlogical process indicators of cardiac injury and repair, to act as novel biomarkers .  This includes the development of techniques such as determining Cardiac Extracellular Volume and collagen deposition post-infarct, in addition to tracking cells labelled Fe/Fe2+.

Dr Paul Kingston

Senior Lecturer in Cardiology & Honorary Consultant Cardiologist
Faculty of Biology, Medicine and Health
Salford Royal NHS Foundation Trust
paul.a.kingston@manchester.ac.uk
Dr Kingston’s University Profile

Vascular Gene Transfer and Vector Development

Dr Kingston’s research interest lies in the field of therapeutic vascular gene transfer.
He is using recombinant adenoviruses to investigate the potential for a variety of anti-fibrotic transgene products to inhibit the vascular responses to injury, with the intention of preventing the forms of accelerated atherosclerosis that occur after percutaneous coronary intervention and in aorto-coronary bypass conduits. He is developing the same anti-fibrotic transgenes for therapeutic application in the setting of cardiac fibrosis, which is a major cause of morbidity and mortality in patients with cardiovascular disease and for which no satisfactory treatments exist. Additionally, Dr Kingston is working with Professor Mark Boyett on the application of biopacemaking, by gene transfer of ion channels to pacemaking and conducting tissues.

Dr Kingston is also investigating means of maximizing gene expression from non-viral gene transfer vectors; through the development of chimeric promoter/enhancer constructs and by manipulation of other cis-acting elements within plasmid expression vectors, he is developing plasmids that will confer maximal transgene expression after vascular gene transfer. Importantly, he is also collaborating with colleagues to develop clinically applicable non-viral mechanisms of gene deliver.

His external collaborations are aimed at the exploitation of non-viral gene transfer of angiogenic growth factors in the setting of critical limb ischaemia.

Clinical

Professor Simon Ray

University Hospital of South Manchester
simon.ray@uhsm.nhs.uk
Mr Ray’s MAHSC Profile

Clinical Cardiology; Echocardiography, Heart Valve Disease, Assessment and Device Closure of Patent Foramen Ovale and Atrial Septal Defects

Professor Simon Ray has been a consultant cardiologist at University Hospital of South Manchester since 1995 and Director of the Research and Development directorate since October 2011. His own clinical and research interests are focused on heart valve disease and he believes strongly that clinical research is core business for the NHS and in particular, for organisations that are part of academic health science centres. Well conducted clinical research has wide benefits across a health care community and has a positive impact on staff, as well as on the quality of patient care. Research will only continue to flourish within the Trust if it becomes embedded within the culture of the organisation, so that the involvement of our staff and of our patients in clinical trials becomes the norm rather than the exception.

Dr Matthias Schmitt

University Hospital of South Manchester
Consultant Cardiologist: Nuclear cardiology, echocardiography, CT/MRI; Clinical sub-speciality: Cardiac Imaging
matthias.schmitt@uhsm.nhs.uk
Mr Schmitt’s UHSM Profile

Service Lead for Cardiac MRI and Cardiovascular Research Theme Lead

Mr Schmitt is the head of the cardiac MRI Department at UHSM and interested in studying cardiac pathologies through novel MRI imaging techniques.  These pathologies include primary and acquired heart muscle disorders (Cardiomyopathies), chronic stable ischemic heart disease, (Angina management) and valvular heart diseases.

Dr Mamta Buch

Consultant Interventional Cardiologist
University Hospital of South Manchester
Mamta.Buch@UHSM.NHS.UK
Ms Buch’s UHSM Profile

Cardiac Surgery and Myocardial Stem Cell Delivery

Dr Buch is a consultant cardiac surgeon with doctoral and post-doctoral research experience.  She undertook her post doctoral work work with Eduardo Marban and Raj Makkar at Cedars Sinai Heart Institute in Los Angeles, focusing on myocardial stem cell delivery in experimental models.  Her current research interest is to translate these findings to pre clinical and clinical models.

Dr Jaydeep Sarma

University Hospital of South Manchester
Consultant Interventional Cardiologist
Honorary Senior Lecturer University of Manchester
Jaydeep.Sarma@UHSM.NHS.UK
Mr Sarma’s UHSM Profile

Consultant Cardiologist with a Special Interest in Percutaneous Cardiac Intervention

Dr Sarma’s specialties include: general cardiology, interventional cardiology, acute coronary syndromes, primary PCI for myocardial infarction, rotational atherectomy, pressure wire assessment, intravascular ultrasound and structural intervention in adult patients.