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The Bulletinof

The British Society for Cardiovascular ResearchRegistered Charity Number: 1011141

Vol. 29 No. 1Spring 2016

www.bscr.org

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The BulletinThe Publication of The British Society for Cardiovascular Research

Editors Dr Michael Dodd

Cardiac Metabolism Research GroupDepartment of Physiology, Anatomy and Genetics,

Sherrington Building Parks Road, Oxford, OX1 3PTTel: 01865 272560

E-mail: michael.dodd@dpag.ox.ac.uk

Dr Sarah WithersCardiovascular Research Group

Division of Cardiovascular and Endocrine SciencesCore Technology Facility, 46 Grafton Street

The University of Manchester, M13 9NTTel: 0161 275 1229

E-mail: sarah.withers@manchester.ac.uk

ChairProfessor Colin Berry

Institute of Cardiovascular and Medical Sciences126 University Place, University of Glasgow,

Glasgow G12 8TATel: 0141 330 5056

E-mail: colin.berry@glasgow.ac.uk

SecretaryDr David Grieve

Centre for Vision and Vascular Science Queen’s University Belfast

Institute of Clinical Science Block A Grosvenor Road, Belfast BT12 6BA

Tel: 028 9063 5013 E-mail: d.grieve@qub.ac.uk

TreasurerDr Melanie Madhani

School of Clinical and Experimental MedicineThe Medical School, Vincent Drive

The University of Birmingham, Birmingham B15 2TTTel: 0121 4144042

E-mail: m.madhani@bham.ac.uk

Membership SecretaryMrs Gayle Halford

Institute of Cardiovascular SciencesCollege of Medical and Dental Sciences

1st Floor IBRUniversity of Birmingham

Edgbston, Birmingham B15 2TT

CommitteeDr Samuel Boateng

Institute of Cardiovascular and Metabolic Research,Hopkins Building, Whiteknights campusUniversity of Reading Reading RG66UB

Tel: 01183787041 E-mail: s.boateng@reading.ac.uk

Dr Andrew BondUniversity of Edinburgh, Queens Medical Research Institute,

47 Little France Crescent, Edinburgh, EH16 4TJTel: 0131 242 6734

Email: Andrew.bond@ed.ac.uk

Dr Carolyn CarrCardiac Metabolism Research Group

Department of Physiology, Anatomy and Genetics, Sherrington Building, Parks Road, Oxford OX1 3PT

Tel: 01865 282247 E-mail: carolyn.carr@dpag.ox.ac.uk

Dr Sean DavidsonThe Hatter Cardiovascular Institute, University College London

67 Chenies Mews, London WC1E 6HXTel: 0207 380 9376 Fax: 0207 380 9505

Email: s.davidson@ucl.ac.uk

Dr Alicia D’SouzaInstitute of Cardiovascular Sciences, 3rd Floor Core Technology

Facility, University of Manchester, 46 Grafton St, Manchester, M13 9NT

Tel: 0161 27551207E-mail: alicia.dsouza@manchester.ac.uk

Professor Paul C. Evans, The Medical School, Beech Hill Road,

University of Sheffield, Sheffield S10 2RX, UK. Tel: 0114-2712591

E-mail: paul.evans@sheffield.ac.uk

Professor Derek HausenloyThe Hatter Cardiovascular Institute, University College London

67 Chenies Mews, London WC1E 6HX Tel: 0207 380 9894

E-mail: d.hausenloy@ucl.ac.uk

Dr Margaux A HornSchool of Medicine

David Weatherall BuildingKeele University, ST5 5BG

Tel - 01782 734672Email: m.horn@keele.ac.ukscr

Dr Pasquale MaffiaCentre for Immunobiology

Institute of Infection, Immunity and InflammationCollege of Medical, Veterinary and Life Sciences

University of Glasgow, Sir Graeme Davies Building120 University Place, Glasgow G12 8TA

Tel: +44 (0)141 330 7142Email: Pasquale.Maffia@glasgow.ac.uk

Dr Karen E PorterDivision of Cardiovascular & Diabetes Research,

Leeds Institute of Genetics, Health and Therapeutics,University of Leeds, Worsley Building,

Leeds LS2 9JTTel: 0113 3434806

E-mail: k.e.porter@leeds.ac.uk

Dr Sanjay SinhaAnne McLaren Laboratory for Regenerative Medicine

West Forvie Building, University of CambridgeRobinson Way, Cambridge CB2 0SZ

Tel. 01223 747479 E-mail: ss661@hermes.cam.ac.uk

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Editorial 3

Review: Immune mechanism of hypertension and vascular dysfunction 4

Secretary's Column 12

Review: Dissecting transforming growth factor-beta signalling pathways in acute vascular injury 14

Forthcoming cardiovascular meetings 19

Report: Scottish Cardiovascular Forum 2016, Queen's University, Belfast, Meeting Report 22

British Society of Cardiovascular Research at Three Major Public Engagement Events in Scotland 25

BSCR:BAS Spring meeting: Programme 27

BSCR Meeting Advert - Leeds 2016 31

British Heart Foundation Grants 33

Editorial

Michael Dodd and Sarah Withers

Cover artwork copyright Anthony Wright, 1997Cover design copyright Siân Rees and Anthony Wright, 1997

Contents

Spring is finally in the air, well at least the April showers certainly are which should allow you some time to browse the Bulletin's spring edition. Hopefully you all had a restful Easter ready for a busy spring/summer season ahead.

First of all, we would like to thank Nicola Smart for her years of service to the Bulletin. She has handed the baton on and we hope that we can continue to keep up her high standards. We would also like to thank Tony Cavalheiro, who has been working behind the scenes for many years to help keep everything going smoothly, including membership and sending out the Bulletin emails. Tony has handed over the role of membership secretary to Gayle Halford. Many thanks to both of them!

We have a busy edition this quarter, with several reports from colleagues in the University of Glasgow. Firstly we are pleased to include The Bernard and Joan Marshall Research Excellence prize review from Tomasz Guzik, from the University of Glasgow. He has

produced an excellent review on "Immune mechanism of hypertension and vascular dysfunction".

Next we have a review by Emma Low, a BHF 4 year PhD programme student from the University of Glasgow. Emma won the poster prize at the Autumn meeting and has produced us an excellent report on her research based on dissecting transforming growth factor-beta signalling pathways in acute vascular injury.

Next we have a meeting report by Heather Small, on the Scottish Cardiovascular Forum 2016, Queen's University, Belfast.

Our final contribution from Glasgow is a report on Suleman Sabir & Gianluca Grassia, on the excellent engagement work. British Society of Cardiovascular Research at Three Major Public Engagement Events in Scotland

We hope you enjoy this latest edition, we apologise that it's a little late, relearning the hard way; always back up your computer!

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Immune mechanism of hypertension and vascular dysfunction

Tomasz J GuzikBHF Centre for Excellence

Institute of Cardiovascular and Medical Sciences, University of Glasgow

Hypertension is a common disease with severe socioeconomic consequences. Despite number of therapies available for the treatment of hypertension, disease remains uncontrolled in up to 40% of treated subjects and cardiovascular risk remains significantly increased. This indicates the need for better understanding of pathogenesis of hypertension and associated cardiovascular risk. Inflammatory mechanisms are an important component of the disease with activation of T cells, monocytes, B cells and NK cells, their tissue infiltration leading to overproduction of cytokines including IL-17 and IFN-γ. These cytokines impair vascular endothelial function and interfere with the pressure natriuresis, linking immune mechanisms to classical pathogenetic pathways of hypertension.

Introduction: Hypertension is a common disease with severe socioeconomic consequences. In spite of many years of research, the cause of primary hypertension remains unknown, which makes effective treatment difficult. Some cases of hypertension are due to single gene mutations, or underlying correctable causes such as renal artery stenosis, pheochromocytoma or adrenal adenoma, but these are uncommon and most cases of adult hypertension have no clear etiology. Systemic vascular resistance is generally elevated either at rest or during exercise in humans with hypertension, and potent vasodilators effectively lower blood pressure in many patients (1). These observations would suggest that hypertension is a vascular disease. In contrast, the monogenic disorders causing hypertension uniformly affect

sodium transport in the distal nephron (2). Diuretics are effective anti-hypertensive agents and transplant of kidneys lacking the angiotensin II AT1a receptor into wild-type mice causes resistance to angiotensin II-induced hypertension (3). These observations suggest that the kidney is a major cause of high blood pressure. Finally, there is ample evidence that the central nervous system, and in particular the circumventricular organs surrounding the third ventricle, play a critical role in hypertension. These regions of the brain contain a poorly developed blood-brain barrier that allows access to hormones such as angiotensin II. Indeed administration of a small amount of angiotensin II in the subfornical organ raises blood pressure (4), and lesions of these regions prevent most causes of experimental hypertension (5). These seemingly disparate roles of the vasculature, the kidney and the CNS make the etiology of hypertension difficult to comprehend.

In addition to the kidney, the vasculature and the central nervous system, accumulating evidence indicates that the immune system contributes to hypertension and could be in fact responsible for the regulation of dysfunction observed within these target organs. While consensus has been reached that target-organ damage involves innate and acquired immunity, the pathogenetic role of the immune system in hypertension and regulation of increased blood pressure has recently been gaining its understanding.

Inflammation and hypertensionLinks between inflammation and hypertension have

The Bernard and Joan Marshall Research Excellence Prize Review

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been defined by number of clinical observations and basic research studies(6-14). Hypertension is prevalent in a number of autoimmune or inflammatory conditions in humans and its risk in the general population is linked to C reactive protein (CRP) levels.Plasma levels of high sensitivity C-reactive protein increase with the quartile of blood pressure (15). The incidence of HTN is increased markedly in individuals with severe psoriasis(16) and rheumatoid arthritis(17). Pre-eclampsia is associated with lymphocyte and NK cell activation and cytokine imbalance in animal models and in humans(18, 19). An analysis of almost 6,000 people with HIV before the introduction of highly active retroviral therapy, showed that the incidence of hypertension was significantly lower than in a population of matched non-infected individuals. Treatment with highly active anti-retroviral therapy for 2 years restored the incidence of hypertension to that of the control population(20). It is also of interest that aging is associated with an increase in the frequency of hypertension, in parallel to changes in the immune system. Senescent T cells become more prevalent, T cell receptor diversity declines, natural killer cells increase, and the cytokine profiles are altered(21, 22). Interestingly a recent

study in humans, has indicated that hypertension is associated with increased numbers of senescent CD8+T cells (CD28null) in peripheral blood and target organs(23). Genetics of hypertension also contributes to better understanding of the role of immune mechanisms in human hypertension. GWAS studies have identified a negative regulator of T cell activation (SH2B3/LNK locus) as well as pro-inflammatory uromodulin (UMOD) genes as important in hypertension.

However, while clinical observations allow for identification of an important role of this mechanism and put the inflammatory pathways in hypertension in a clinical context, the determination of mechanistic link is often difficult in human studies. Number of key findings, in animal models, have supported the causal role of inflammation in hypertension and cardiac and vascular dysfunction associated with it. Our laboratory has contributed significantly to the understanding of a pivotal role of T cells in this process(6). These findings were then confirmed by independent groups. Mice(6) and rats(24) lacking lymphocytes (RAG-1-/-) are protected from severe hypertension and vascular dysfunction in response to angiotensin II, norepinephrine and

Figure 1. Perivascular T cell infiltration in hypertension

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DOCA-salt. Adoptive transfer of T cells, but not B cells, restores hypertension in these animals(6). More recently, Crowley et al confirmed that T cells are essential for full development of angiotensin II-induced hypertension using mice that have severe combine immunodeficiency(25). Moreover rats, similarly to mice, are also protected from development of severe salt sensitive hypertension in the absence of mature T and B cells (24). In addition, mice following transfer of anti-inflammatory T regulatory cells(26) are protected from experimental hypertension(27),(24). Hypertension is blunted in mice lacking the T cell effector cytokines IL-17A(28) and IFN-γ(29).

Central role of T cells in the pathogenesis of hypertensionThus, T cells play a central role in the immune mechanism of hypertension(30). Chronic angiotensin II infusion increases the expression of activation markers CD69, CCR5 and CD44 in peripheral blood T cells. The mechanisms of this activation are not clear and partially depend on initial blood pressure increase, although direct effects of pro-hypertensive substances such as angiotensin II or salt is also important. Activated effector T lymphocytes responding to the pro-hypertensive factors are able to infiltrate the adventitia and periadventital fat of the vessels, and possibly also renal cortex and medulla or even certain regions within central nervous system(6). Interestingly, angiotensin II infusion markedly increases the percentage of CCR5 positive cells in perivascular adipose tissue and in other target organs. Also the level of vascular RANTES chemokine (Regulated on Activation Normal T Cells Expressed and Secreted) is elevated at the same conditions(6). Recently, Roson et al showed that the level of chemokine ligand 5 is increased in the kidney after acute infusion of sodium (31). This interaction of RANTES and its receptor CCR5 facilitates T cell migration and accumulation in the perivascular adipose tissue and in the kidney. In these sites, activated T cells release pro-inflammatory cytokines such as IL-17, TNF-α and IFN-γ (6).

Cytokines and hypertensionTNF-α may be particularly involved in regulation of chronic immune activation in hypertension,

although T cells might be a target of TNF-α dependent dysregulation rather than the source of this chemokine in hypertension. Administration of soluble TNF-α receptor, Etanerecept, which is a useful biologic used in the treatment of rheumathoid arthritis and other autoimmune disease, prevented hypertension and reduced renal damage in rats and mice (6, 32). Also, the agent that interrupt CCR5/RANTES axis might become a novel therapeutic strategy to effective treatment of hypertension and cardiovascular disease. Antagonist of CCR1/CCR5, met-RANTES has been used to inhibit atherosclerosis (33). Other CCR5 receptor antagonists are clinically available and include Maraviroc or TAK-779 (34, 35), could be of interest in prevention at least of vascular disease in hypertension if not in the prevention of the disease. Recently, we reported that IL-17 is required for sustained hypertension (28). In this study angiotensin II infusion increased IL-17 production from T cells and mice lacking IL-17 displayed preserved vascular function, decreased superoxide production and reduced T cell infiltration in comparison to normotensive animals (28). Analysis of IL-17 in diabetes humans revealed that serum levels of this cytokine were markedly increased in those with hypertension compared with normotensive subjects (28). Recently, we obverted the increased percentage of IFN-γ and IL-17 producing T cell in patients with uncontrolled hypertension (unpublished data). Humanized anti-interleukin-17 monoclonal antibody, ixekizumab, has recently been introduced for the treatment of psoriasis and further studies are required to demonstrate whether IL-17 antagonists may be effectively used for the treatment of severe hypertension (36).

Chronic angiotensin II infusion stimulates also IL-6 production and an increase of arterial pressure and this effect may be blocked in IL-6 knockout mice (37). It has been suggested that angiotensin II induces IL-6 production through a mineralocorticoid receptor-dependent mechanism in humans (38). It can’t be excluded that using of IL-6 antagonists such as toclizumab, used primarily in the treatment of rheumatoid arthritis may play a vital role in management of recalcitrant

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hypertension (39).

Complex network of immune cell interactions in hypertension The bulk of mechanistic model studies clearly indicate that a complex network of interactions between T cells, dendritic cells, monocytes and B cells may be involved in hypertension and our research efforts focus to characterize these complex processes. Hypertension is partially prevented in the absence of cells that are important sources of these cytokines such as functional monocytes(40) or NK cells(29), and B cells (41) although interdependence of these mechanisms with T cell dependent regulation remain not entirely clear. Unquestionably T cell- antigen presenting cell interactions play an important role in the process. Molecules such as CD80 and CD86 involved in co-stimulation are elevated primarily in the secondary lymphoid organs and inhibition of T cell co-

stimulation prevents hypertension. Activation of naïve T cell requires the concomitant signalling provided by T cell (TCR) and the co-stimulatory receptors(42). In this process CD28 molecule interact with co-stimulatory receptors such as CD80 and CD86 (B7-1 and B7-2, respectively) on antigen-presenting cells (APC) e.g. dendritic cells (42). We have previously reported that CTLA4-Ig (cytotoxic T lymphocyte antigen-Ig), known as abatacept, a fusion protein blocker of CD80/CD86 prevented Ang II or DOCA-salt induced hypertension (30). Similarly to ethanercept, Abatacept is used for the treatment of rheumatoid arthritis. Stimuli that induce and regulate this activation are not yet clearly identified. They include potential neoantigens such as isoketal-modified proteins(43) or hsp70(44). Importantly, a broad range of other inflammatory signals could induce Ag-nonspecific bystander activation of T cells. The latter possibility is emphasized by alleviation of hypertension in a number of models

Figure 2. Central role of the T cell in mechanisms of hypertension

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associated with impaired general inflammatory responses, including mice lacking cytokines such as TNF-α(45, 46) or IL-6(37). Importantly hypertensive T cell activation and release of IFN-γ is blunted in these models. Cellular sources of these cytokines, that are key for regulating T cell function in hypertension are unclear. While T cells themselves can be a source of these cytokines, adoptive transfer of TNF-α -/- T cells in RAG1-/- mice does not support the key role of T cell as a source of TNF-α regulating hypertension. Importantly, hypertension is partially prevented in the absence of other cells that can be an important source of these cytokines such as functional monocytes(40), NK cells(29). This suggests that the immune mechanisms in hypertension are a result of a complex network of dysregulated inflammatory interactions that lead to T cell activation, which renders them pro-hypertensive.

Links between immune mechanisms and vascular and renal mechanisms of hypertensionT cells abundantly infiltrate the vascular wall (Figure 1) and the kidneys and are activated to release the effector cytokines. They stimulate vascular collagen deposition, making T cells critical in vascular remodeling(47). There are several mechanisms, that may link immune activation to functional regulators of increased blood pressure. In particular effects of pro-inflammatory cytokines on vascular cells and renal tubule cells is evident. Some studies also show links between monocyte subpopulations and their activation with endothelial function, which may be important in hypertension. In particular IFN-γ acting on endothelial and smooth muscle cells leads to endothelial dysfunction (10), as mice lacking IFN-γ are protected from this condition(29). IL-17 and IFN-γ impair vascular endothelial function(10) and interfere with the pressure natriuresis(48).

Is the immune system a reasonable target for treatment of hypertension? The notion that hypertension and other vascular diseases are inflammatory processes always prompts the question of why we don’t use anti-inflammatory or immune suppressant drugs to treat this disease. In this regard, it is hard to reconcile the fact that some anti-inflammatory agents, such as the non-steroidal anti-inflammatory drugs (NSAIDS),

and the T cell suppressing agent cyclosporine paradoxically cause hypertension. It should be noted that NSAIDS have untoward effects on renal function that could predispose to hypertension and cyclosporine increases sympathetic nerve activity and renal endothelin expression, both of which could promote hypertension. Various other immunomodulating agents, however, might have a favorable effect on hypertension. As mentioned above, the TNF-α antagonist Etanercept prevents hypertension and reduces renal injury in some experimental models. T cell modulating agents such as Abatacept or mycophenylate mofetil might also be useful. Animal studies provide the proof-of-concept that such interventions might be effective as an adjuvant for short-term therapy of malignant hypertension (42, 49).

Persistent T cell suppression can however increase neoplasia and increase susceptibility to exogenous pathogens, making long-term treatment of hypertension with immune-modulating drugs undesirable. It is possible however that immunomodulatory drugs could help bring blood pressure under control in newly diagnosed cases of severe hypertension, perhaps obviating the need for multiple anti-hypertensive agents. A particularly attractive target for immunomodulatory therapy is malignant hypertension because many of its consequences, including glomerular injury, a vasculitis-like state and diffuse myocardial damage have similarities to immune-mediated processes. Short-term treatment with immune-modulating agents might therefore prove useful in this emergency situation.

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recruitment and mutual activation of monocytes and NK-cells. Arterioscler Thromb Vasc Biol 33, 1313-131930. Vinh, A., Chen, W., Blinder, Y., Weiss, D., Taylor, W. R., Goronzy, J. J., Weyand, C. M., Harrison, D. G., and Guzik, T. J. (2010) Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension. Circulation 122, 2529-253731. Roson, M. I., Della Penna, S. L., Cao, G., Gorzalczany, S., Pandolfo, M., Toblli, J. E., and Fernandez, B. E. (2010) Different protective actions of losartan and tempol on the renal inflammatory response to acute sodium overload. Journal of cellular physiology 224, 41-4832. Muller, D. N., Shagdarsuren, E., Park, J. K., Dechend, R., Mervaala, E., Hampich, F., Fiebeler, A., Ju, X., Finckenberg, P., Theuer, J., Viedt, C., Kreuzer, J., Heidecke, H., Haller, H., Zenke, M., and Luft, F. C. (2002) Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol 161, 1679-169333. Veillard, N. R., Kwak, B., Pelli, G., Mulhaupt, F., James, R. W., Proudfoot, A. E., and Mach, F. (2004) Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. Circulation research 94, 253-26134. Meanwell, N. A., and Kadow, J. F. (2007) Maraviroc, a chemokine CCR5 receptor antagonist for the treatment of HIV infection and AIDS. Current opinion in investigational drugs (London, England : 2000) 8, 669-68135. van Wanrooij, E. J., Happe, H., Hauer, A. D., de Vos, P., Imanishi, T., Fujiwara, H., van Berkel, T. J., and Kuiper, J. (2005) HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 25, 2642-264736. Leonardi, C., Matheson, R., Zachariae, C., Cameron, G., Li, L., Edson-Heredia, E., Braun, D., and Banerjee, S. (2012) Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. The New England journal of medicine 366, 1190-119937. Brands, M. W., Banes-Berceli, A. K., Inscho, E. W., Al-Azawi, H., Allen, A. J., and Labazi, H. (2010) Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation. Hypertension 56, 879-88438. Luther, J. M., Gainer, J. V., Murphey, L. J., Yu, C., Vaughan, D. E., Morrow, J. D., and Brown, N. J. (2006) Angiotensin II induces interleukin-6 in humans through a mineralocorticoid receptor-dependent mechanism. Hypertension 48, 1050-105739. Kapoor, S. (2007) Interleukin-6 antagonists for the management of hypertension. Hypertension 49, e18; author reply e1940. Wenzel, P., Knorr, M., Kossmann, S., Stratmann, J., Hausding, M., Schuhmacher, S., Karbach, S. H., Schwenk, M., Yogev, N., Schulz, E., Oelze, M., Grabbe, S., Jonuleit, H., Becker, C., Daiber, A., Waisman, A.,

and Munzel, T. (2011) Lysozyme M-positive monocytes mediate angiotensin II-induced arterial hypertension and vascular dysfunction. Circulation 124, 1370-138141. Chan, C. T., Sobey, C. G., Lieu, M., Ferens, D., Kett, M. M., Diep, H., Kim, H. A., Krishnan, S. M., Lewis, C. V., Salimova, E., Tipping, P., Vinh, A., Samuel, C. S., Peter, K., Guzik, T. J., Kyaw, T. S., Toh, B. H., Bobik, A., and Drummond, G. R. (2015) Obligatory Role for B Cells in the Development of Angiotensin II-Dependent Hypertension. Hypertension 66, 1023-103342. Bu, D. X., and Lichtman, A. H. (2010) T cells and blood vessels: costimulation turns up the pressure. Circulation 122, 2495-249843. Kirabo, A., Fontana, V., de Faria, A. P., Loperena, R., Galindo, C. L., Wu, J., Bikineyeva, A. T., Dikalov, S., Xiao, L., Chen, W., Saleh, M. A., Trott, D. W., Itani, H. A., Vinh, A., Amarnath, V., Amarnath, K., Guzik, T. J., Bernstein, K. E., Shen, X. Z., Shyr, Y., Chen, S. C., Mernaugh, R. L., Laffer, C. L., Elijovich, F., Davies, S. S., Moreno, H., Madhur, M. S., Roberts, J., 2nd, and Harrison, D. G. (2014) DC isoketal-modified proteins activate T cells and promote hypertension. The Journal of clinical investigation 124, 4642-465644. Pons, H., Ferrebuz, A., Quiroz, Y., Romero-Vasquez, F., Parra, G., Johnson, R. J., and Rodriguez-Iturbe, B. (2013) Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension. American journal of physiology. Renal physiology 304, F289-29945. Zhang, J., Patel, M. B., Griffiths, R., Mao, A., Song, Y. S., Karlovich, N. S., Sparks, M. A., Jin, H., Wu, M., Lin, E. E., and Crowley, S. D. (2014) Tumor necrosis factor-alpha produced in the kidney contributes to angiotensin II-dependent hypertension. Hypertension 64, 1275-128146. Sriramula, S., Haque, M., Majid, D. S., and Francis, J. (2008) Involvement of tumor necrosis factor-alpha in angiotensin II-mediated effects on salt appetite, hypertension, and cardiac hypertrophy. Hypertension 51, 1345-135147. Wu, J., Thabet, S. R., Kirabo, A., Trott, D. W., Saleh, M. A., Xiao, L., Madhur, M. S., Chen, W., and Harrison, D. G. (2014) Inflammation and mechanical stretch promote aortic stiffening in hypertension through activation of p38 mitogen-activated protein kinase. Circulation research 114, 616-62548. Kamat, N. V., Thabet, S. R., Xiao, L., Saleh, M. A., Kirabo, A., Madhur, M. S., Delpire, E., Harrison, D. G., and McDonough, A. A. (2015) Renal transporter activation during angiotensin-II hypertension is blunted in interferon-gamma-/- and interleukin-17A-/- mice. Hypertension 65, 569-57649. Schiff, M. (2011) Abatacept treatment for rheumatoid arthritis. Rheumatology (Oxford, England) 50, 437-449

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THE BRITISH SOCIETY FOR CARDIOVASCULAR RESEARCHTHE BRITISH SOCIETY FOR CARDIOVASCULAR RESEARCH

The 2016 Marshall Awards

Young Investigator Award£2,500

• You must be in training for a higher degree, or have been awarded it after May 31st 2013

Research Excellence Award£4,000

• You must have been awarded your higher degree after May 31st 2001

To apply, send the following to the Secretary of the BSCR (d.grieve@qub.ac.uk):

1. CV2. Covering letter3. Recent manuscript4. Supporting letter

Full details at www.bscr.org

12

Secretary's Column

David Grieve

Easter always signals the start of a busy period for the BSCR.

Our joint annual meeting with the British Atherosclerosis Society (BAS) and British Cardiovascular Society (BCS) will take place in Manchester on 6-7 June and follows our usual “Frontiers-style” which has proved popular in recent years. This meeting has been organised by Pasquale Maffia and Paul Evans on behalf of the BSCR, who together with the BAS have put together another excellent programme in-cluding focussed sessions on inflammation, exosomes, embryonic programming and non-coding RNAs. This year, to promote increased interaction between basic and clinical scientists, the three societies will come together for a joint translational lunchtime symposium around PCSK9 targeting and also a com-bined Young Investigator Competition, both of which promise to be high quality and exciting sessions. As usual, there will also be a large number of poster communications from our members which I hope you will support. If you have not done so already, I would encourage you to register for the Spring meet-ing and our traditional Monday evening dinner via the BCS website. Remember that student members who are presenting abstracts are eligible to apply for a travel bursary, the deadline for which is 2nd May.

Just three months later on 5-6 September, the BSCR Autumn 2016 meeting will be held in Leeds with a focussed theme of “Cardiovascular disease and diabetes”. This has been organised by Karen Porter, Neil Turner, Stephen Wheatcroft and Sandra Jones. Abstract submission and registration for this meet-ing will open soon – details to be announced. One of the highlights of the Autumn meeting will be the Bernard and Joan Marshall Research Prizes, the application deadline for which is 31st May. The Young Investigator Prize competition (£2500) is open to students and post-docs who are within 3 years of the award of their PhD, MPhil or MD, whilst established researchers who are within 15 years of receiving their higher degree are eligible to apply for the Research Excellence Prize (£4000). Three shortlisted Young Investigators will compete for the prize in Leeds in a dedicated Marshall session together with lectures from the Research Excellence Prize winner (which will be decided by the BSCR committee) and the Distinguished Investigator, who this year is Domenico Accili from New York. Further details of these prestigious awards and the application process are available on the BSCR website and I would be grateful if you could all advertise these as widely as possible within your departments and would strongly encourage eligible members to apply.

In the current issue of the Bulletin, you will find a nomination form for new committee members. At the end of 2016, Samuel Boateng, Margaux Horn, and Karen Porter will complete their current terms on the committee. As such, we are seeking nominations for up to 3 new committee members and I would urge you to consider putting yourself forward for election (deadline 27th May). I would particularly encour-age clinically-qualified members and those from large UK cardiovascular centres who do not currently have committee representation to apply. It is important that we maintain a committed and enthusiastic committee which is strongly representative of UK cardiovascular research.

I look forward to seeing many of you in Manchester.

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14

Dissecting transforming growth factor-beta signalling pathways in acute vascular injury

Emma L LowInstitute of Cardiovascular and Medical Sciences, Glasgow Cardiovascular Research

Centre, University of Glasgow, UK

Revascularisation surgeries such as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) are frequently prescribed for advanced or acute presentations of coronary heart disease (CHD), aiming to widen occluded coronary arteries. However, the long-term patency of such procedures is hampered by the development of intimal hyperplasia (IH) within the vessel, resulting in re-occlusion and the need for repeat intervention1-3. The development of intimal hyperplasia IH is initiated following activation of the vessel endothelium by injury caused from stent deployment or increased arterial sheer stress2,4. In response, circulating platelets and macrophages adhere to the endothelium and release growth factors and cytokines5. This pro-inflammatory microenvironment drives a phase of medial smooth muscle cell (SMC) proliferation and migration into the intima, which is subsequently followed by hypo-cellularity and fibrosis6-8. The resulting hyperplastic neointima can act as a substrate for atherosclerotic plaque formation, which further contributes to the occlusion of the vessel9. Therefore, early IH is a key target for therapeutics aimed at improving clinical outcome following PCI or CABG surgery.

TGFbeta signalling in intimal hyperplasiaThe involvement of TGFbeta in the development of IH was established in the early 1990’s whereby TGFbeta expression was shown to be increased in restenotic tissues from patients undergoing revascularisation surgery10. Subsequently,

numerous in vivo studies have convincingly shown that TGFbeta promotes IH in vein grafts and models of PCI11-15; however the underlying signalling mechanisms remain to be fully elucidated.

The TGFbeta signalling pathwayTGFbeta signals via binding to specific transmembrane type I (TbetaRI) and type II (TbetaRII) serine/threonine kinase receptor complexes16. Ligand binding stimulates the transphosphorylation and activation of TbetaRI by TbetaRII and subsequent activation of the canonical Smad signalling pathway, as well as other non-canonical signalling pathways such as the Erk, JNK and the p38MAPK pathways17. Receptor-regulated Smads (R-Smads: Smads 1, 2, 3, 5 and 8) become phosphorylated by the activated TbetaRI, form a heteromeric complex with Smad4 and translocate to the nucleus to regulate the

Figure 1: The Smad TGFβ signalling pathway

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transcriptional activation or repression of specific target genes18,19.

Two TbetaRI’s that are of particular interest in the context of IH are activin receptor-like kinase 5 (ALK5) and activin receptor-like kinase 1 (ALK1). TGFbeta via ALK1 induces Smad1/5/8 phosphorylation, whereas ALK5 induces Smad2/3 phosphorylation (Figure 1). Thus, ALK1 and ALK5 contribute to the signalling specificity of the TGFbeta receptor complex and help dictate the cellular response to TGFbeta in the vasculature.

Understanding the mechanism of TGFbeta-induced intimal hyperplasiaThe majority of studies investigating the role of TGFbeta in IH have focused on the canonical ALK5/Smad2/3 signalling pathway, which has been shown to mediate the pro-fibrotic responses to TGFbeta20,21. However, recent work has indicated that ALK1-mediated signalling may play an important role in TGFbeta-induced IH22,23. We aimed to perform mechanistic characterisation of the ALK5 and ALK1 TGFbeta signalling pathways in the context of acute vascular injury.

Functional analysis in human saphenous vein SMCs (HSVSMCs) following exposure to ALK5 and ALK1 inhibitorsSince vascular SMC proliferation and migration are fundamental processes during the development of neointima formation1,5, we performed proliferation and migration assays in SMCs derived from surplus saphenous vein from Scottish CABG patients. In order to dissect the ALK1 and ALK5 signalling pathways, we utilised small molecule inhibitors of ALK1 (K02288) or ALK5 (SB525334) in the presence of TGFbeta1.

Although no effect on proliferation was observed, HSVSMC migration was significantly increased in the presence of SB525334, whereas K02288 treatment significantly reduced migration (p<0.05 and p<0.001, respectively, n=4) (Figure 2). Gene expression analysis revealed that SB525334 treatment enhanced the expression of matrix metalloproteinase-9 (MMP-9), whereas treatment with K02288 reduced MMP-9 expression (data not shown).

Figure 2: TGFβ signalling via ALK5 and ALK1 differentially regulates HSVSMC migration but not proliferation. HSVSMCs were stimulated with rTGFβ1 ± ALK5 (SB525334) or ALK1 (K02288) inhibitors. Proliferation was assessed at 48h by EdU incorporation (A). Migration 20h after scratch was compared to 0h timepoint (B). Example migration images are shown in (C). *** = p<0.001 compared to 0.2% FBS. # = p<0.05 and ### = p<0.001 compared to TGFβ1 (one-way ANOVA; n=4).

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Histological assessment of ALK5 and ALK1 signalling in animal models of vascular injuryTo investigate how the ALK5 and ALK1 signalling pathways regulate neointima formation in vivo, we performed immunohistochemistry for pSmad2/3 and pSmad1/5/8 (the ALK5 and ALK1 signalling mediators, respectively) in sections from three animal injury models (a murine carotid artery ligation and vein graft model and a porcine vein graft model) prior to and following vascular injury. Interestingly, we observed pSmad2/3 expression within alpha SMA+ SMCs in both uninjured and injured vessels, whereas pSmad1/5/8 expression was only detected within SMCs following vascular injury (Figure 3A-D). The percentage of alpha SMA+ intimal and medial SMCs showing nuclear localisation of pSmad2/3 and pSmad1/5/8 in pig vein grafts was quantified (Figure 3E&F).

Taken together, these data suggest that the ALK5 pathway is active in both uninjured and injured vessels, whereas the ALK1 pathway is only activated following vascular injury in small and large animal models.

Histological assessment of ALK5 and ALK1 signalling in failed human vein graftsTo identify how the ALK5 and ALK1 signalling pathways regulate neointima formation in vivo in CHD patients, we performed immunohistochemistry for pSmad2/3 and pSmad1/5/8 in sections from failed human saphenous vein grafts as well as in pre-implantation graft sections. We identified that in both pre-implantation and failed vein graft sections, pSmad2/3 and pSmad1/5/8 were localised to the nucleus of alpha SMA+ SMCs, suggesting activation of both the ALK5 and ALK1 pathways (Figure 4A-D). A H&E stain of pre-implantation saphenous vein graft sections from two Scottish CHD patients

Figure 3: ALK1 signalling is activated in a 28 day pig vein graft model. Expression of pSmad2/3 (A,C) and pSmad1/5/8 (B,D) was determined by IHC before grafting (‘Uninjured’) and 28 days following graft-ing ('injured') (n=3). The % of αSMA+ cells showing nuclear localisation of pSmad2/3 or pSmad1/5/8 was quantified in uninjured (E) and injured (F) vessels.

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Figure 4: ALK5 and ALK1 are activated in pre-implantation and failed human saphenous vein grafts from CABG patients. Expression of pSmad2/3 (A,C) and pSmad1/5/8 (B,D) was determined by IHC in pre-implantation and failed saphenous vein grafts. Inset images show nuclear localisation of pSmads in αSMA+ SMCs (n=6 for pre-implantation and n=3 for failed vein grafts). H&E staining of pre-implantation human saphenous vein sections showed a pre-existing intimal layer (E, black arrows).

illustrated areas of pre-existing neointima (Figure 4E).

Overall, our data suggests that the ALK1/Smad1/5/8 TGFbeta signalling pathway is activated following

vascular injury and induces specific transcriptional changes to promote vascular SMC migration. Further mechanistic characterisation is required in order to effectively target TGFbeta-mediated IH therapeutically.

The author, Emma Low, is a 4-year BHF programme PhD student at the University of Glasgow, supervised by Dr. Angela Bradshaw and Prof. Andrew Baker. Emma was the recipient of the 2015 British Society for Cardiovascular Research Best Poster Prize, awarded at the Autumn meeting held in Glasgow on 7-8th September.

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1. Motwani, J. G. & Topol, E. J. Aortocoronary saphenous vein graft disease: pathogenesis, predis-position, and prevention. Circulation 97, 916-931 (1998).

2. Mitra, A. K. & Agrawal, D. K. In stent restenosis: bane of the stent era. J Clin Pathol 59, 232-239 (2006).

3. Fitzgibbon, G. M. et al. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 28, 616-626 (1996).

4. Wong, A. P. et al. Expansive remodeling in venous bypass grafts: novel implications for vein graft disease. Atherosclerosis 196, 580-589 (2008).

5. Ferns, G. A. & Avades, T. Y. The mecha-nisms of coronary restenosis: insights from experi-mental models. Int J Exp Pathol 81, 63-88 (2000).

6. Jiang, Z. et al. Established neointimal hyperplasia in vein grafts expands via TGF-beta-mediated progressive fibrosis. Am J Physiol Heart Circ Physiol 297, H1200-1207(2009).

7. Khan, R., Agrotis, A. & Bobik, A. Under-standing the role of transforming growth factor-beta1 in intimal thickening after vascular injury. Cardiovasc Res 74, 223-234 (2007).

8. Zhang, W. D. et al. Association of smooth muscle cell phenotypic modulation with extracel-lular matrix alterations during neointima formation in rabbit vein grafts. J Vasc Surg 30, 169-183 (1999).

9. Schwartz, S. M., deBlois, D. & O'Brien, E. R. The intima. Soil for atherosclerosis and resteno-sis. Circ Res 77, 445-465 (1995).

10. Nikol, S. et al. Expression of transforming growth factor-beta 1 is increased in human vascu-lar restenosis lesions. J Clin Invest 90, 1582-1592 (1992).

11. Nabel, E. G. et al. Direct transfer of trans-forming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci U S A 90, 10759-10763 (1993).

12. Schulick, A. H. et al. Overexpression of transforming growth factor beta1 in arterial en-dothelium causes hyperplasia, apoptosis, and carti-laginous metaplasia. Proc Natl Acad Sci U S A 95, 6983-6988 (1998).

13. Wolff, R. A., Malinowski, R. L., Heaton, N. S., Hullett, D. A. & Hoch, J. R. Transforming growth factor-beta1 antisense treatment of rat vein grafts reduces the accumulation of collagen and increases the accumulation of h-caldesmon. J Vasc Surg 43, 1028-1036 (2006).

14. Smith, J. D. et al. Soluble transforming growth factor-beta type II receptor inhibits nega-tive remodeling, fibroblast transdifferentiation, and intimal lesion formation but not endothelial growth. Circ Res 84, 1212-1222 (1999).

15. Yamamoto, K. et al. Ribozyme oligonu-cleotides against transforming growth factor-beta inhibited neointimal formation after vascular injury in rat model: potential application of ribozyme strategy to treat cardiovascular disease. Circulation 102, 1308-1314 (2000)

16. Massague, J. TGF-beta signal transduction. Annu Rev Biochem 67, 753-791 (1998).

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17. Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-beta fam-ily signalling. Nature 425, 577-584 (2003).

18. van Meeteren, L. A. & ten Dijke, P. Regulation of endothelial cell plasticity by TGF-beta. Cell Tissue Res 347, 177-186 (2012).

19. Massague, J., Seoane, J. & Wotton, D. Smad transcription factors. Genes & development 19, 2783-2810 (2005).

20. Pardali, E., Goumans, M. J. & ten Dijke, P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol 20, 556-567 (2010).

21. Bobik, A. et al. Distinct patterns of transforming growth factor-beta isoform and receptor expression in human atherosclerotic lesions. Colocalization implicates TGF-beta in fibrofatty lesion development. Circulation 99, 2883-2891 (1999).

22. Yao, Y., Zebboudj, A. F., Torres, A., Shao, E. & Bostrom, K. Activin-like kinase receptor 1 (ALK1) in atherosclerotic lesions and vascular mesenchymal cells. Cardiovasc Res 74, 279-289 (2007).

23. Cooley, B. C. et al. TGF-beta signaling mediates endothelial-to-mesenchymal transition (EndMT) during vein graft remodeling. Science translational medicine 6, 227ra234 (2014).

Forthcoming Cardiovascular MeetingsBiennial International Congress on Thrombosis 2015 will take place in Istanbul, Turkey from 4th - 7th May 2016. The Scientific Programme of the upcoming Congress will cover topics ranging from various fields of clinical and laboratory issues on thrombosis and related scientific issues. Full details are available through http://www.thrombosis2016.org/index.php?go=inicio

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery - Barcelona - Spain - May 12th - May 13th 2016 . Full details: http://www.aulavhebron.net/aula/index.php?go=info_cursos&curso=30&idioma=en

Society for Heart and Vascular Metabolism's 14th Annual Meeting - Beijing, China - 9-12th Oct 2016 - Meeting topic - Cardiac Adaptations to Obesity, Diabetes and Insulin Resistance: Novel Targets and Therapies. Further Information: http://shvm2016.azuleon.org/

American Heart Association’s Scientific Sessions 2016 - New Orleans, LA - Nov 12-16th - https://professional.heart.org/professional/EducationMeetings/Meetings/ScientificSessions/UCM_316900_Scientific-Sessions.jsp

British Society for Heart Failure 19th Annual Autumn Meeting - London - UK - 24-25 Nov 2016 Venue: Queen Elizabeth II Centre, London. Further details: http://www.bsh.org.uk/meetings/bsh-future-meetings/

20

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Simulate the low oxygen environmentof the stem cell niche

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Options include:· A removable front (fitted with patented oval ports) to facilitate the transfer of large items of equipment for use inside the chamber· The Whitley Automatic Humidification System – sterile, on-demand moisture control· The Whitley Internal HEPA Filtration System with Enhanced Biological Containment· Ethernet connection for remote access· Data downloading

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22

Scottish Cardiovascular Forum 2016 Queen's University, Belfast

Meeting Report6th February 2016

Heather Yvonne Small University of Glasgow

The annual meeting of the Scottish Cardio-vascular Forum (SCF) was held on the 6th February 2016; a short trip across the Irish Sea in Belfast. The venue was the recently opened Wellcome-Wolfson Institute for Experimental Medicine on Queen’s University Belfast’s Health Sciences Campus. The main aims of the SCF meeting are to be an encouraging place for young researchers to present their science as well as promoting collaborations between scientists at all levels of training. The diverse programme included work from clinical medicine, public health and basic science allowing all of the participants to appreciate the true breadth of cardiovascular research currently being under-taken in two relatively small countries. The meeting included oral presentations and a busy poster ses-sion. These were capped at the beginning and end of the meeting with fantastic keynote lectures. The day was so thoroughly enjoyed by all that the day met its conclusion to a standing ovation… More on this to follow! The first presentation of the day was a key-note address from Dr. David Grieve of Queen’s

University. His group focusses on elucidating the molecular mechanisms of increased cardiovascular risk in patients with diabetes. Dr Grieve presented research concerned with Glucagon-like Peptide 1 (GLP-1); a molecule with a defined role in glucose metabolism but with a novel protective function in the cardiovascular system. Dr. Grieve presented recent, exciting findings from his group that showed that a GLP-1 mimetic significantly improves ex-tracellular matrix remodelling and heart function through the modulation of infiltrating macrophage populations post-myocardial infarction in a mouse model of diabetes. Selective targeting of GLP-1 was proposed as a novel therapeutic for people with diabetes who had also suffered a cardiovascular event. The formidable task of following the key-note fell to the final year PhD students who were competing for the Roger Wadsworth Prize, which

Venue for the day: Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University, Belfast.

Dr David Grieve's Keynote address on the therepeutic potential of GLP-1

2322

included myself. This prize was introduced in 2014 in memory of Prof. Wadsworth who was a researcher dedicated to cardiovascular science and a founding member of the SCF. The presentations from all of the competitors were of a very high standard… as were the questions from the audi-ence! The speakers’ topics were varied, touching upon atherosclerosis, obesity, endothelial dysfunc-tion and hypertension. This made for an excellent session and, I am sure, a very difficult deliberation for the judges. My own presentation focussed on the causative role of the pro-inflammatory cytokine TNFα in deficient pregnancy-induced vascular remodelling in a hypertensive rat model. We have shown that treatment with a TNFα antagonist, etanercept, improved pregnancy-induced vascular remodelling in the hypertensive rats and improved pregnancy outcome. Utilising the example of the athlete Jessica Ennis-Hill, I spoke about how preg-nancy induces more adaptation in the cardiovascular system than years of intensive training as an elite athlete. This makes pregnancy a neat system to look at changes in the heart and vessels over a relatively short period of time. We had a break for lunch, although there wasn't much time to eat if you wanted to get round all of the 42 posters in the beautiful, open-plan atrium of the Wellcome-Wolfson Institute! The poster session was moderated and presenters gave turbo-talks about their research and answered ques-tions. In-keeping with the oral presentations, the topics were varied and included a full complement of methodology for assessing the cardiovascular system from cells to humans as well as cutting-edge

technology utilising omics and stem cell biology. The afternoon session of oral presentations followed lunch where, among others, there were two excellent presentations from the University of Edinburgh focussing on the molecular mechanisms of angiogenesis in two different disease settings. Robert Ogley showed data regarding the novel role of Wt1 in promoting angiogenesis and covered a number of different models: the hind limb isch-emia model, sponge implantation and endometrial decidualisation model. Callam Davidson discussed his data relating to glucocorticoid inhibition and its role in promoting angiogenesis in cancer. His findings showed that indeed glucocorticoid inhibi-tion promoted tumour growth but did not alter the vascularisation of these tumours. Therefore, further investigation is required as to how glucocorticoid inhibition promotes tumour growth.

The final talk of the day was a keynote lec-ture from Dr. Mark Tully from the Centre for Public Health, Queen’s University Belfast. Dr. Tully’s research focus is on improving levels of physical inactivity in the population. He spoke very pas-sionately about how improving physical activity can be an effective preventative measure and treatment for cardiovascular disease as well as cancer, dia-betes and mental health. Dr. Tully put his research into practice and had the audience standing whilst we had to brainstorm in groups how to improve physical activity in traditionally difficult to reach populations. Dr. Tully’s presentation forced us all to address our level of activity and think about how

Undergraduate students Philip Doyle and Anna Ke-arney discuss their posters

Callam Davidson and Robert Ogley receive the joint prize from Moira Wadsworth for their oral

presentations.

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we could do more… I have certainly been standing doing my lab work rather than sitting but I think I will pass on the treadmill desk for the moment!

The meeting was closed with the prize giv-ing where all of the judges reiterated what a fan-tastic quality of science had been presented at the meeting. I was very pleased to be presented with the Roger Wadsworth prize. This was particularly lovely for me as I gave my first oral presentation as a PhD student at SCF 2015. I remember watching the Roger Wadsworth prize presentations wondering if I would ever be able to do that! Congratulations to the University of Edinburgh who had an excel-lent day winning the oral presentation prize, jointly awarded to Robert and Callam, and the poster prize awarded to Mark MacAskill.

In conclusion, this was a really fantastic day

Dr. Mark Tully educates the audience about the many benefits of being physically active.

The Bulletin editors look forward to publishing travel reports written by BSCR members. These can be on any conference, course or laboratory visit of interest to other members and we encourage you to include your best photographs. If you are planning to travel to a relevant cardiovascular meeting and would like to write a report for The Bulletin, please contact the editors beforehand. A limited number of bursaries are available towards the cost of your visit, which will be provided upon receipt of the report. For a UK meeting, we can pay £100 and, for international meetings, we pay £200 (within Europe) or £300 (rest of the world).

Bon voyage!

Travel Reports for The Bulletin

with a broad spectrum of great science which was presented very well by all involved. Thanks to Dr. David Bell, Dr. Chris Johnson and all of the organ-isers of the SCF 2016 for a great meeting. We are looking forward to hosting the SCF meeting 2017 here in Glasgow – see you there!

Mark MacAskill is awarded the poster prize from Dr. Susan Currie

Heather Small receives the Roger Wadsworth Prize from Moira Wadsworth.

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British Society of Cardiovascular Research at Three Major Public Engagement Events in Scotland

A report by Suleman Sabir & Gianluca Grassia, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

A group of British Society of Cardiovascular Research members lead by Dr Gianluca Grassia and Suleman Sabir portrayed the importance of studying cardiovascular disease running a ‘science stall’ with hands-on activities at three recent large public engagement events in Scotland. The team aim to investigate how nanoparticles could be used to improve the diagnosis and treatment of atherosclerosis as part of joint Glasgow/Strathclyde University projects supported by the EPSRC and European Commission.

On Friday 25th September 2015, the group contributed to the ‘Explorathon’ night at the

Glasgow Science Centre, an extravaganza of discovery and entertainment to celebrate European Researchers’ Night. Over 3000 members of the public attended the event. The BSCR station engaged with approximately 300 children and 120 adults.

On Wednesday 14th October 2015, the group contributed to the Midlothian Science Festival (MSF) at Newtongrange Library, Dalkeith. MSF is designed to provide an entry point for hard to reach rural audiences to engage with science. We engaged with approximately 67 children and 40 adults, including some individuals with severe attention

Photo Legend 1: From L to R: Robert Benson, Jonathan Noonan, Neil MacRitchie, Shafqat Jaigirdar, Suleman Sabir, Gianluca Grassia and Catherine Hughes at the ‘Explorathon’ night. The British Society of Cardiovascular Research supported the event, and stickers with the Society logo were distributed to the public.

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deficit hyperactivity disorder (ADHD), receiving excellent feedback from the local organiser “…the local audience included several with ADHD…they were very enthusiastic with NO antisocial behaviours – this is a real success and testament to the high quality of the science staff/volunteers”.

Finally on Wednesday 9th December 2015, the group met children from across Glasgow attending the Barras Art and Design Venue for performances of “Panto Science: The Periodic Fable”, a unique show that blends pantomime with fun, interactive science. The show had its debut at 2015 Edinburgh Festival Fringe; the Barras shows were the first to be staged in Glasgow. Organised by the Glasgow Science Festival this was an excellent opportunity

for children to meet real life scientists.

Dr Pasquale Maffia, member of the BHF Centre of Excellence in Vascular Science and Medicine in Glasgow, said: “We will use nanoparticles that can be tagged onto antibodies, which possess the ability to recognise inflammatory markers. The nanoparticles can then be detected by a technique called Surface Enhanced Raman Scattering, whereby a light source is shone on the nanoparticles, transferring energy and causing them to vibrate. The vibrations could be exploited to develop a highly-sensitive means of measuring inflammation in atherosclerotic vessels”.

Both children and adults were invited to select either a plastic or magnetic nanoparticle that was inserted into a hyper-realistic artery. Magnetic nanoparticles were attracted to magnets embedded in the large plaque, while plastic nanoparticles passed by. Researchers reinforced the notion that the magnetic nanoparticles were specific for “bad” aspects of the plaque, thus allowing scientists to identify and treat the lesions. Children were also invited to play a specifically-designed computer game, and to create their own “good” or “bad” cell from clay, paint it and take it home as a souvenir.

Overall three successful and extremely engaging days of science.

Photo Legend 2: Feedback from the ‘Explorathon’ night.

Photo Legend 3: The ‘Panto Science: The Periodic Fable’ show at the Barras Art and Design Venue.

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Programme  

 Monday  6th  June  (Day  1)    Posters  go  up  at  the  start  of  the  day    08.00  to  10.00   BSCR  committee  meeting              

 10.45  to  12.15   What  is  the  best  way  to  target  inflammation  in  cardiovascular  disease?  Charter  2/3  Chairs:  Pasquale  Maffia  and  Tomasz  Guzik    Targeting  inflammation  to  reduce  CVD  risk:  a  realistic  clinical  prospect?  Paul  Welsh,  University  of  Glasgow,  UK    T  cell  plasticity  in  atherosclerosis  Elena  Galkina,  Eastern  Virginia  Medical  School,  USA    Interleukin-­‐1  in  cardiovascular  diseases  Sheila  Francis,  University  of  Sheffield,  UK    Role  of  lymphocytes  in  myocardial  injury,  healing,  and  remodelling  after  myocardial  infarction  Stefan  Frantz,  Universitätsklinik  und  Poliklinik  für  Innere  Medizin  III,  Halle,  Germany  

   12.15  to  13.45    12.15  to  13.45  

   Lunch,  exhibition    Hot  Topic  sessions  Education  Hall  

   13.45  to  15.15  

   Exosomes  and  cardiovascular  disease  Charter  2/3  Chairs:  Sarah  George  and  Sean  Davidson    Cardiac  fibroblast  -­‐  derived  microRNA  passenger  strand-­‐enriched  exosomes  mediate  cardiomyocyte  hypertrophy  Thomas  Thum,  Hannover  Medical  School,  Germany    Exosomal  miRNAs  as  potential  biomarkers  of  cardiovascular  risk  in  children  Abdelnaby  Khalyfa,  University  of  Chicago,  USA    Exosomes:  a  potential  key  target  in  cardio-­‐renal  syndrome  Gloria  Alvarez-­‐Llamas,  Fundación  Jiménez  Díaz,  Madrid    Exosomes:  nanoparticles  involved  in  cardioprotection?  Sean  Davidson,  University  College  London,  UK  

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 Monday  6th  June  (continued)      15.15  to  16.00   Tea,  exhibition  

   

16.00  to  17.00   BSCR/BAS  Poster  Session  1  Education  Hall      Poster  Judges:  TBC      

17.00  to  18.00   Sir  Thomas  Lewis  Keynote  Lecture  Auditorium  Prediciton  and  prevention  of  sudden  cardiac  death  in  the  young  Michael  Ackerman,  Mayo  Clinic,  USA      

18.00  to  19.00   The  BAS  John  French  Lecture  Charter  2/3  From  insulin  resistance  to  vascular  repair  –  protective  effects  of  IGF-­‐binding  proteins  in  cardio-­‐metabolic  disease  Stephen  Wheatcroft,  University  of  Leeds,  UK      

19.00  to  20.00   BHF  Reception  for  Basic  Scientists  Atrium  outside  Charter  1    

20.00   BSCR/BAS  Conference  Dinner:  

 Chaophraya  Manchester  19  Chapels  Walks  Off  Cross  Street  Manchester,  M2  1HN  http://chaophraya.co.uk/venues/chaophraya-­‐manchester/      

Tuesday  7th  June  (Day  2)    08.30  to  10.00  

 Embryonic  programming  of  cardiovascular  disease  Charter  2/3  Chairs:  Nicola  Smart  and  Carolyn  Carr    Developmental  origins  of  cardiovascular  health  and  disease  Mark  Hanson,  University  of  Southampton,  UK    

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Understanding  how  adult  cardiac  dysfunction  is  programmed  by  maternal  obesity  Susan  Ozanne,  University  of  Cambridge,  UK    Developmental  programming  of  cardiovascular  disease  by  prenatal  hypoxia  Dino  Giussani,  University  of  Cambridge,  UK    Influence  of  maternal  nutritional  status  on  vascular  function  in  the  offspring  Lucilla  Poston,  King's  College  London,  UK  

   10.00  to  10.45      10.45  to  12.15                                    12.15  to  13.45            13.45  to  15.15  

   Coffee,  exhibition      BCS/BSCR/BAS  Highlight  Session:  Novel  concepts  in  cholesterol  lowering  -­‐  How  to  target  PCSK9  to  improve  patient  outcomes  Charter  2/3  Chairs:  Jeremy  Pearson  and  John  Deanfield    Discovering  PCSK9  as  a  therapeutic  target  –  from  genes  to  biology  Steve  Humphries,  University  College  London,  UK    Developing  a  therapeutic  to  target  PCSK9  Ricardo  Dent,  Amgen  (Europe)  GmbH,  Zug,  Switzerland    Clinical  trials  of  antibodies  targeting  PCSK9  John  Chapman,  University  of  Pierre  and  Marie  Curie,  Paris,  France    Novel  approaches  to  targeting  PCSK9  -­‐  RNAi  and  others  Anthony  Wierzbicki,  St.  Thomas’  Hospital,  London,  UK      Young  Investigators  Prize  Competition  Charter  2/3    Judges:  TBC      BSCR/BAS  Poster  Session  2  Education  Hall    Poster  Judges:  TBC  

                                 

   15.15  to  16.00    16.00  

Tea,  exhibition          

   16.00  to  17.20          

   Non-­‐coding  RNAs  in  basic  and  translational  cardiovascular  science  Charter  2/3  Chairs:  Andrea  Caporali  and  Marco  Meloni    

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                               17.20  to  17.30        17.30  to  18.30  

Long  noncoding  RNA  in  cardiac  hypertrophy  Ching-­‐Pin  Chang,  Indiana  University,  USA      Gene  ontology  annotation  of  cardiovascular-­‐relevant  microRNAs  Ruth  Lovering,  University  College  London,  UK    MicroRNAs  and  cardiac  regeneration  Mauro  Giacca,  International  Centre  for  Genetic  Engineering  and  Biotechnology,  Trieste,  Italy    Cardiac  enhancer-­‐associated  noncoding  RNAs  in  heart  development  and  disease  Thierry  Pedrazzini,  University  of  Lausanne,  Switzerland      Closing  remarks  and  poster  prize  giving  Charter  2/3      The  BCS  Keynote  Lecture  Auditorium  Sir  Nilesh  Samani,  University  of  Leicester,  UK  

 

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BSCR Autumn Meeting 2016

Cardiovascular Disease and DiabetesUniversity of Leeds

Monday 5th and Tuesday 6th September 2016

‘Vascular Signalling in Diabetes’‘The Diabetic Heart’

‘Molecular Mechanisms Towards Novel Therapeutics’

Abstract submission opens May 2016

Organisers:Karen Porter (Leeds), Neil Turner (Leeds), Stephen Wheatcroft (Leeds), Sandra Jones (Hull)

Confirmed speakers: Domenico Accili (New York, USA) - Keynote,

Esther Lutgens (Amsterdam), Maria Gomez (Malmö), Jorge Ferrer (Imperial),Cathy Shanahan (KCL), Barbara Casadei (Oxford), Jaipaul Singh (Lancashire),Sven Plein (Leeds), Frans van Nieuwenhoven (Maastricht), Bart Staels (Lille),

Anna Zampetaki (KCL), David Bates (Nottingham), Peter Grant (Leeds)

Meeting Sponsors:

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British Heart Foundation GrantsBHF Chair of Cardiovascular ImmunologyCH/15/2/32064Professor Federica Marelli BergQueen Mary, University of London10 years £1,072,526

Project GrantsPG/15/53/31371 Dr Sebastian Oltean et al.Bristol, University of mRNA splicing control in diabetes: a novel therapeutic strategy for treatment of diabetic nephropathy 3 years £268,270

PG/15/54/31559 Professor Paolo Madeddu Bristol, University of Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease 3 years £219,503 PG/15/55/31568 Dr Andrew F James et al.Bristol, University of Selective late sodium current blockers as antiar-rhythmic drugs in atrial fibrillation 3 years £226,944 PG/15/56/31573 Dr Gregory Quinlan et al.Imperial College London The disrupted hepcidin/ferroportin axis and pro-liferative responses in pulmonary arterial hyper-tension 3 years £294,534 PG/15/57/31580 Professor Steven Ley et al.National Institute for Medical Research

Regulation of atherosclerosis by TPL-2 kinase 3 years £258,466

PG/15/58/31611 Dr Bill Chaudhry et al.Newcastle upon Tyne University of Zebrafish to dissect the role of jnk1 in cardiac development 3 years £252,850 PG/15/59/31621 Dr Emmanuel Dupont et al.Imperial College London An In silico model of action potential propaga-tion, biologically validated in the HL1-6 myocyte cell line: A framework for characterising myocar-dial re-entry and fibrillation in the human heart 3 years £296,235 PG/15/60/31629 Dr Ran Yan et al.King’s College London Development of novel 18F-PET tracers for direct detection of myocardial oxidative stress in cardio-vascular disease 3 years £262,527 PG/15/61/31634 Dr Martina E Daly et al.Sheffield, University of Identification and characterisation of FLI1 and RUNX1 regulated determinants of platelet gran-ule biogenesis and secretion 3 years £194,647 PG/15/62/31653 Dr Stephen Wheatcroft et al.Leeds, University ofIncreasing IGFBP1 levels as a strategy to pro-mote therapeutic angiogenesis in diabetes 3 years £222,000

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PG/15/63/31659 Professor Margaret MacLean et al.Glasgow, University of Investigating oestrogen metabolism in pulmonary artery smooth muscle cells 2 years £176,845 PG/15/64/31681 Dr Jacob George et al.Dundee, University ofVascular Effects of Smoking Usual cigarettes Versus electronIc cigaretteS(VESUVIUS) 2 years 9 months £199,368 PG/15/65/31707 Professor Nicholas Brindle et al.Leicester, University of An angiopoietin-2-specific ligand-trap with po-tential to treat cardiovascular disease 3 years £198,173 PG/15/66/31710 Professor M-Saadeh Suleiman et al.Bristol, University of Role of cyclic AMP/PKA/Epac signalling in car-dioprotection 2 years £169,119 PG/15/67/31715 Professor Houman Ashrafian et al.Oxford, University of Adenosine A2A receptors in myocardial fibrosis 2 years £207,329 PG/15/68/31717 Dr Maarten Koeners et al.Bristol, University of Carotid body-renal interactions in renovascular hypertension 3 years £265,526 PG/15/69/31719 Dr Beata J Wojciak Stothard et al.Imperial College London Role of endothelial clic4 in the regulation of

pulmonary vascular remodelling in pulmonary hypertension 2 years £173,452 PG/15/70/31724 Professor Andrew Trafford et al.Manchester, University of Investigating the role of Amphiphysin II (BIN1) in the control of cardiac t-tubule biogenesis and function 3 years £234,436 PG/15/71/31731 Dr Stefan Piechnik et al.Oxford, University ofAnalysis of diffuse fibrosis with T1 mapping in the CMR in Hypertrophic Cardiomyopathy (HCMR) Study 3 years £287,133 PG/15/72/31732 Dr Thomas Nightingale et al.Queen Mary, University of London An investigation into novel regulatory mecha-nisms for Von Willebrand factor secretion from endothelial cells 3 years £197,752

PG/15/73/31743 Dr Stephen Wheatcroft et al.Leeds, University of Examining the mechanisms underpinning protec-tion from atherosclerosis in mice with increased endothelial cell insulin-like growth factor-1 receptor expression 3 years £267,233

PG/15/74/31747 Dr Luca Biasiolli et al.Oxford, University of Clinical MRI of carotid atherosclerosis using T2 mapping: development and validation of novel methods for plaque lipid quantification 3 years £204,611

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PG/15/75/31748 Dr Ashraf William Khir et al.Brunel University London The determination of local arterial stiffness and left ventricular load: a new non-invasive tech-nique for calculating PWV and wave intensity 3 years £264,511 PG/15/76/31756 Professor Ziad MallatCambridge, University of Marginal zone B cells and the regulation of the pro-atherogenic T follicular helper response 2 years £201,386 PG/15/77/31761 Professor Andrea E MunsterbergEast Anglia, University of Signaling cross-talk regulating migration and fate choice in cardiac progenitor cells 3 years £182,012 PG/15/78/31771 Professor Gurtej K Dhoot et al.Royal Veterinary College, University of London Mechanism of Sulf1/Sulf2 functionin cardiovas-cular development and myocardial repair 3 years £213,324 PG/15/79/31777 Professor Timothy Warner et al.Queen Mary, University of London Control of thrombosis by endogenous pathways of platelet inhibition and relevance to anti-platelet therapy 3 years £233,827 PG/15/80/31781 Dr Krishnan Bhaskaran et al.London School of Hygiene and Tropical Medi-cineImpact of the media interest in side effects on the initiation and cessation of statins in the UK 1 year £55,099

FellowshipsNon-Clinical Fellowships Senior Basic Science Research Fellow-ship FS/15/56/31645 Professor Leanne Hodson University of OxfordHeterogeneity in hepatic synthesis pathways may influence the development of non-alcoholic fatty liver disease (NAFLD) and atherogenic dyslipi-daemia: studies in humans using in vivo and in vitro approaches 5 years £995,475

Intermediate Basic Science Research Fel-lowshipsFS/15/57/31557 Dr Andrew Sage University of CambridgeUnderstanding the pathogenic role of B cells in atherosclerosis 4 years £423,428

FS/15/58/31784 Dr Alexandra Mazharian University of BirminghamA novel mechanism controlling platelet pro-duction involving suppression of ERK1/2 by DUSP1/6 4 years £484,415

FS/15/59/31839 Dr Christopher Rhodes Imperial College LondonMolecular phenotyping of pulmonary hyperten-sion 4 years £395,949

Immediate Post doctoral Basic Science Research FellowshipsFS/15/60/31510 Dr Robert Menzies

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University of EdinburghDruggable target discovery in hypertensive renal injury: vascular purinergic receptor X7 3 years £229,524 FS/15/61/31626 Dr Loes Rutten Jacobs University of Cambridge Identification of novel pathophysiological mecha-nisms in cerebral small vessel disease: an epide-miologic and genetic approach 3 years £126,016

4 year PhD StudentshipsFS/15/62/32032 Professor Martin BennettUniversity of Cambridge Cambridge 3rd intake 2015 4 Year PhD Student-ship (3rd) Scheme: Ms Sarah Burgess; Ms Sophie McManus; Mr Joshua Hodgson; Ms Annabel Taylor £627,196 FS/15/63/32033 Dr Matthew BaileyUniversity of Edinburgh Edinburgh 3rd intake 2015 4 Year PhD Student-ship (3rd) Scheme: Ms Sarah Finnie; Ms Natalie Jones; Ms Charlott Repschlager; Ms Kathleen Scullion £596,156

FS/15/64/32035 Professor Rhian TouyzUniversity of Glasgow Glasgow 3rd intake 2015 4 Year PhD Student-ship (3rd) Scheme: Ms Aisling McFall; Ms Sarah McNeilly; Ms Alexandra Riddell; Ms Francesca Vidler £576,920

FS/15/65/32036 Professor Sian HardingImperial College London Imperial 3rd intake 2015 4 Year PhD Student-ship (3rd) Scheme: Ms Adela Constantinescu; Mr Jerome Fourre; Ms Alveera Hasan; Ms Viktoria

Kalna £642,196 FS/15/66/32037 Professor Metin AvkiranKing’s College LondonKCL 3rd intake 2015 4 Year PhD Studentship (3rd) Scheme: Ms Grace Anderson; Mr Sean Burnap; Ms Ailbhe O’Brien; Ms Ms Meredith Whitehead £630,136 FS/15/67/32038 Dr Elizabeth CartwrightUniversity of Manchester Manchester 3rd intake 2015 4 Year PhD Student-ship Scheme: Ms Lorenz Becker; Ms Elisavet Fo-tiou; Ms Miriam Lettieri; Ms Damilola Olubando £578,016 FS/15/68/32042 Professor David GreavesUniversity of Oxford Oxford 3rd intake 2015 4 Year PhD Studentship (3rd) Scheme: Ms Kathryn Acheson; Mr Matthew Kerr; Mr Hamish Lemmey; Ms Irina Lupu £626,180 FS/15/69/32043 Professor Timothy WarnerQueen Mary, University of London QMUL 3rd intake 2015 4 Year PhD Studentship (3rd) Scheme: Ms Lauren Callender; Ms Alice Hamilton; Ms Eithne Maguire; Mr Michael Pre-edy £619,312 FS/15/70/32044 Professor Peter Scambler University College LondonUCL 3rd intake 2015 4 Year PhD Studentship (3rd) Scheme: Mr Daniel Aggio; Ms Rebecca Bolton; Ms Kirsty Naylor; Ms Kaloyan Takov £627,244

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PhD Studentships FS/15/71/31677 Professor Stephen P Watson University of Birmingham (Mr. Alex Hardy) The regulation and role of Syk phosphorylation by platelet glycoprotein receptors 2 years £73,020

FS/15/72/31676 Professor Asif Ahmed Aston University (Miss Athina Georgiadou) An investigation of the impact of soluble Flt-1 and soluble endoglin-induced sensitisation of the endothelium to pro-inflammatory cytokines to promote preeclampsia 3 years £107,160

FS/15/73/31672 Professor Shamshad Cockcroft University College London(Mr. Nicholas Blunsom) Regulation of the rate-limiting enzyme, CDP-diacylglycerol synthase (CDS) in mitochondrial biogenesis in cardiomyocytes 3 years £123,214

FS/15/74/31669 Dr Lingfang Zeng King’s College London (Mr. Bijaya Shrestha) The role of the endothelial cell differentiation-related LAF4IR in vascular repair 3 years £116,384

FS/15/75/31688 Professor David Middleton Lancaster University (Miss Sophie Lau)The structure-function relationship of enhanced cardioprotective apolipoprotein A-I mutants in high density lipoprotein nanoparticles 3 years

£105,187 FS/15/76/31720 Professor Timothy Palmer University of Bradford(Ms Ellanor Whiteley)Prostanoid-mediated Inhibition of IL-6 Trans-Signalling in Pulmonary Arterial Hypertension; a Role for Epac1-Mediated Induction of “Suppres-sor of Cytokine Signalling 3” (SOCS3) 3 years £106,986

FS/15/77/31823 Professor Ioakim Spyridopoulos University of Newcastle (Mr. Emanuele Andreano)Lymphocyte Activation and Transmigration Through the CX3CL1/CX3CR1 Axis During Myocardial Ischemia/Reperfusion 3 years £122,928

Clinical Fellowships Clinical Research Training FellowshipsFS/15/78/31678Dr Divaka Perera King’s College London (Dr Bhavik Modi) Fractional flow reserve in serial and diffuse coro-nary artery disease 3 years £211,153 FS/15/79/31736 Mr. Prakash P Punjabi Imperial College London (Miss Amina Khalil) Characterisation of chamber-specific fibroblasts from adult human heart and investigation of their potential contribution to the function of engi-neered heart tissue 2 years £152,776

FS/15/80/31803 Dr Oliver Rider University of Oxford

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(Dr Mark Peterzan) The role of myocardial ATP delivery rates in myocardial hypertrophy 3 years £271,941

FS/15/81/31817 Professor Stuart Cook Imperial College London (Dr Catherine Francis) Genetic determinants of aortic morphology and function 2.5 years £159,463

FS/15/82/31824 Professor Robert Storey University of Sheffield(Dr Wael Sumaya) The fibrin network and clinical outcomes in patients with acute coronary syndrome: An addi-tional therapeutic target? 3 years £213,387

Programme GrantsRG/15/14/31880 Professor Peter ScamblerUniversity College London Morphogenetic Signalling Pathways Affected in DiGeorge and Charge Syndromes: Their Role in Cardiovascular Development (renewal) 5 years £1,415,379 RG/15/15/31742 Professor Andrew TinkerQueen Mary, University of London The role of the ATP-sensitive potassium chan-nels in cardiovascular physiology and disease (renewal) 5 years £1,091,688 RG/15/16/31758 Professor Alastair Poole et al.Bristol, University of Platelet secretion: Control mechanisms and role in thrombosis, cardiac damage and repair (re-newal) 5 years

£1,537,451 RG/15/17/31749 Professor Mark Hanson et al. Southampton, University of Epigenetic Biomarkers and Determinants of Car-diovascular Risk in Children 5 years £1,179,307

Clinical Study Grants CCS/15/7/31679

Dr Vijay Kunadian et al The OLDer Patients Randomised Interventional Trial in Acute Non-ST Elevation Myocardial Infarction:The OLD-RITA Trial 5 years £1,705,737 CS/15/8/32065 Professor Keith MuirGlasgow, University of Sixth Joint Stroke Association/BHF Clinical Study: Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis 5 years £750,000

Translational GrantsTG/15/3/31692 Professor Adrian Hobbs et al.Lead optimisation of novel small molecule natri-uretic peptide receptor (NPR)-C agonists for the treatment of myocardial infarction 2 years £396,422 TG/15/4/31891 Dr Geoffrey Moggridge et al.A Novel Transcatheter Valve for Younger Patients with Aortic Stenosis 1.5 years £248,018