Key Funding Successes

CADERA: Coronary Artery Disease Evaluation in Rheumatoid Arthritis
National Institute for Health Research (NIHR) EME award

This study bolts on to the VEDERA trial, a prospective longitudinal intervention study of patients with early RA, randomized to either first-line anti-TNF therapy or conventional DMARD therapy. It is proposed that VEDERA patients undergo cardiovascular MRI at baseline, 1 and 2 years. Baseline MRI results from the first 30 recruited patients will be compared with 30 matched controls. Changes in MRI findings between baseline and 1 year will be compared between VEDERA treatment groups. 

Evaluation of 3T Magnetic Resonance imaging for the management of patients with Coronary heart disease: the CE-MARC 2 study.
British Heart Foundation
Currently ~50% of invasive coronary angiograms performed in the UK do not lead on to a revascularisation procedure. The new NICE guidelines for the management of chest pain of recent onset (CG95; 2010) if implemented could increase this proportion even further. This is inefficient for patients and also of resources.

More widespread use of non-invasive functional imaging could reduce the rates of unnecessary angiography. We have shown that CMR at 1.5Tesla has a higher diagnostic accuracy for the detection of CHD than SPECT.

CE-MARC 2 will test the strategy in a randomised controlled trial of 1200 patients with known or suspected CHD, of using state-of-the-art 3Tesla CMR to guide management decisions compared to current best practice (NICE, AHA guidelines).

Read more about this project

Studies of the mechanisms of fibrin structure in thrombosis.
British Heart Foundation 5-year programme grant

One in three people in the developed world have heart disease. Ultimately it is the generation of a blood clot that results in death or severe damage to health. The structure of the blood clot that is formed will determine the risk of having a bad or good health outcome. Our research aims to discover the mechanisms that change the structure of the blood clot.  Fibrinogen is the molecule in blood that forms the scaffold of a blood clot. We will investigate how altered fibrinogens affect the development and structures of blood clots as well their ability to be broken down. We will also identify how they influence clot elasticity and the incorporation of cells involved in the blood clot. This will inform us about how various sites on fibrinogen change the structure of the blood clot and enhance its ability to be broken down. In the longer term, we will use the knowledge obtained from this research to develop and produce new drugs that will form a more favourable clot structure.
(Robert Ariens, Helen Philippou, Ramzi Ajjan, Victoria Ridger (Sheffield) and Simon Connell (Physics Leeds))

Characterisation of mechanism(s) for the unprecedented anticoagulant effects of small molecules.
British Heart Foundation Special Project 2 years
All current drug therapies to stop the blood from forming clots cause a high incidence of bleeding events. We have generated a new series of drug that has the ability to stop the blood from clotting without causing any bleeding consequences. Currently, we do not understand how these drugs work. This proposal aims to understand the processes by which this new class of drug is able to function so that we will be better placed to optimise these drugs to be used in man.
(Helen Philippou)

Does cellular insulin signalling modulate endogenous vascular repair and endothelial progenitor cell function via interaction with VEGF signalling?
This project will assess how the important processes which stimulate blood vessel healing and regeneration are altered by early diabetes (a disorder of blood sugar regulation) using a series of experiments which mimic the formation of new blood vessels in patients with early diabetes. We aim to find new means of stimulating repair and regeneration of blood vessels in patients with diabetes, possibly with drugs or stem-cells.
(Richard Cubbon)

Novel signalling pathways regulating nociception.
Medical Research Council 2013-2016
Although effective treatments for some types of pain are available, they are non-ideal. We will explore alternative targets within peripheral nociceptive pathways by focussing on a novel paradigm  concerning regulation of two specific ion channels expressed in sensory neurons, the M-type K+ channel and the T-type Ca2+ channel. Our current research indicates that both these channels are physiologically modulated by endogenous reactive oxygen species and gasotransmitters, particularly carbon monoxide (CO). We will build upon substantial pilot studies to characterise the intracellular signalling network through which M- and T-type channels are regulated by gasotransmitters and ROS, and to identify physiological triggers through which such pathways can control channel activity. Our results will provide a novel approach to pain management.

The Role of Coagulation Factor XIII-A in Myocardial Tissue Repair and Cardiac Function 
British Heart Foundation

Scar tissue in the heart occurs in a number of conditions including diabetes and following heart attacks and its presence has serious effects on the heart. We have identified that deficiency of a clotting factor leads to deposition of blood cells and excess scar tissue in the heart. Our studies aim to understand why deficiency of the clotting factor leads to these changes and to clarify the effects this has on heart function.
(Peter Grant Richard Pease Mark Kearney Christopher Jackson Michael Marber)

Key Publications

Pieters, M., Kotze, R.C., Jerling, J.C., Kruger, A., Ariëns, R.A.S.
Evidence that fibrinogen gamma’ regulates plasma clot structure and lysis, and relationship to cardiovascular risk factors in black Africans.
Blood. Published on-line.

Greenwood, J.P., Maredia, N., Younger, J.F., Brown, J.M., Nixon, J., Everett, C.C., Bijsterveld, P., Ridgway, J.P., Radjenovic, A., Dickinson, C.J., Ball, S.G., Plein, S. (2012).
Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial.

Lancet 379, 453-460.

Dallas, M.L., Yang, Z., Boyle, J.P., Boycott, H.E., Scragg, J.L., Milligan, C.J., Elies, J., Duke, A., Thireau, J., Reboul, C., Richard, S., Bernus, O., Steele, D.S., Peers, C. (2012).
Carbon Monoxide Induces Cardiac Arrhythmia via Induction of the Late Na Current.

Am J Respir Crit Care Med, 186(7), 648-56.

Sukumar, P., Sedo, A., Li, J., Wilson, L.A., O’Regan, D., Lippiat, J.D., Porter, K.E., Kearney, M.T., Ainscough, J.F.X., Beech, D.J. (2012).
Constitutively-active TRPC channels of adipocytes confer a mechanism for sensing dietary fatty acids and regulating adiponectin.
Circulation Research 111, 191-200.

Fairbairn, T.A., Meads, D.M., Mather, A.N., Motwani, M., Pavitt, S., Plein, S., Blackman, D.J., Greenwood, J.P. (2012)
Serial change in health related quality of life over one year following Transcatheter Aortic Valve Implantation: Predictors of health outcomes.
J Am Coll Cardiol 59, 1672-1680.

Imrie, H., Abbas, A., Viswambharan, H., Sukumar, P., Cubbon, R.M., Gage, M., Smith, J., Galloway, S., Yuldeshava, N.Y., Skromna, A., Kahn, M., Futers, S., Aziz, A., Gatenby, V.K., Grant, P.J., Channon, K.M., Beech, D.J., Wheatcroft, S.B., Kearney, M.T. (2012)
Novel Role of the IGF-1 receptor in endothelial cell function and repair: studies in endothelium-targeted IGF-1R transgenic mice.
Diabetes 61 (9), 2359-68.

Rajwani, A., Ezzat, V., Smith, J., Yuldasheva, N.Y., Duncan, E.R., Gage, M., Cubbon, R.M., Kahn, M.B., Imrie, H., Abbas, A., Viswambharan, H., Aziz, A., Sukumar, P., Vidal-Puig, A., Sethi, J.K., Xuan, S., Shah, A.M., Grant, P.J., Porter, K.E., Kearney, M.T., Wheatcroft, S.B. (2012).
Increasing circulating IGFBP1 levels improves insulin-sensitivity, promotes nitric oxide production, lowers blood pressure and protects against atherosclerosis.
Diabetes 61, 915-924.

Jogiya, R., Kozerke, S., Morton, G., De Silva, K., Redwood, S., Perera, D., Nagel, E., Plein, S. (2012).
Validation of dynamic 3-dimensional whole heart magnetic resonance myocardial perfusion imaging against fractional flow reserve for the detection of significant coronary artery disease.
J Am Coll Cardiol. 60, 756-765.

Uitte de Willige, S., Miedzak, M., Carter, A.M., Lisman, .T, Rosendaal, F.R., Grant, P.J., Philippou, H., Ariëns, R.A. (2011).
Proteolytic and genetic variation of the alpha-2-antiplasmin C-terminus in myocardial infarction.
Blood 117, 6694-6701.

Abbas, A., Imrie, H., Viswambharan, H., Sukumar, P., Rajwani, A., Cubbon, R., Gage, M., Smith, J., Galloway, S., Yuldeshava, N., Kahn, M., Xuan, S., Grant, P., Channon, K., Beech, D., Wheatcroft, S., Kearney, M. (2011).
The Insulin-like Growth Factor-1 receptor is a negative regulator of nitric oxide bioavailability and insulin sensitivity in the endothelium.
Diabetes 60, 2169-2178.