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  • Journal article
    Harbaum L, Klose H, Lund J, Sinn M, Lund GK, Francke P, Sinning CR, Tello K, Rothman AMK, Wilkins MRet al., 2025,

    Metabolomic signature of right ventricular-pulmonary arterial coupling differentiates hemodynamic response to imatinib therapy in pulmonary arterial hypertension.

    , J Heart Lung Transplant

    BACKGROUND: Right ventricular (RV) dysfunction is the leading cause of mortality in pulmonary arterial hypertension (PAH). Although RV metabolic remodeling in chronic pressure overload is recognized, the circulating metabolic signatures of RV-pulmonary arterial (PA) coupling and their clinical relevance remain poorly defined. METHODS: We first integrated pressure-volume-derived RV/PA metrics with untargeted plasma metabolomics in 33 PAH patients, using both network-based and single-metabolite analyses. Findings were replicated in 14 patients using echocardiographic surrogates. In 16 participants from the phase 2 PIPAH trial of imatinib, we examined longitudinal metabolite changes in relation to hemodynamic responses obtained from implanted devices. RESULTS: The end-systolic to arterial elastance ratio (Ees/Ea), a load-independent measure of RV contractility and RV-PA coupling, emerged as a central node in the metabolic network, while metrics related to afterload and RV stiffness were more peripherally located. In individual metabolite analyses, 9 metabolites were significantly associated with Ees/Ea and its echocardiographic surrogate, independent of potential confounders, including kidney and liver function. Pathway enrichment analysis confirmed a predominance of fatty acid metabolism, particularly acylcarnitines. In the PIPAH study cohort, individual-level analyses showed that reductions in acylcarnitine levels at 4 and 24 weeks of imatinib therapy discriminated patients with improved cardiac output (area under the curves 0.89 and 0.84). CONCLUSIONS: We identify a distinct circulating metabolomic signature, enriched in fatty acid metabolites, associated with RV-PA coupling in PAH. These metabolites may inform on the risk and trajectory of RV maladaptation during treatment and guide therapeutic decisions to optimize the benefit-harm ratio.
  • Journal article
    Al-Ansari D, Hu Y, Negrini NC, Jones D, Birdsey G, Celiz Aet al., 2025,

    Three-dimensional modelling of lymphangiogenesis in-vitro using bioorthogonal click-crosslinked gelatin hydrogels

    , Materials Today Bio, Vol: 35, ISSN: 2590-0064

    Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vessels, is crucial for maintaining tissue homeostasis and immune function. Despite recent advances in understanding the molecular mechanisms regulating lymphangiogenesis, most in vitro studies rely on traditional two-dimensional (2D) cell cultures, with limited replication of the complex microenvironment that governs lymphangiogenesis in vivo. Here, we present a three-dimensional (3D) lymphangiogenesis model using gelatin hydrogels modified with click-chemistry motifs (tetrazine and norbornene, GelTN), providing a biomimetic and mechanically tunable extracellular matrix (ECM) for lymphatic endothelial cells. By encapsulating human dermal lymphatic endothelial cells (HDLEC) spheroids in GelTN, we established a robust and reliable in vitro sprouting assay (<48 h duration) to investigate the effects of GelTN stiffness on lymphangiogenesis. HDLEC encapsulated in low GelTN concentrations exhibited enhanced sprouting in response to vascular endothelial growth factor (VEGF)-C stimulation, compared to HDLEC encapsulated in higher GelTN concentrations. We also provide evidence for the involvement of β3 integrin in lymphangiogenesis. The reduced sprout length upon β3 integrin inhibition further decreased with combined inhibition of α5β1, suggesting a synergistic interaction of the integrin subunits in controlling HDLEC-ECM mechanotransduction. GelTN hydrogels were also evaluated for their translational potential, demonstrating sustained release of VEGF-C in vitro and supporting cellular infiltration and neo-vessel formation following subcutaneous injection in an in vivo mouse model. Overall, these findings highlight the versatility of GelTN hydrogels as a platform for studying lymphangiogenesis and their potential use for therapeutic applications that require controlled growth factor delivery in tissue engineering and regenerative medicine.
  • Journal article
    Sajjad N, Zhang H, Ng F, Birdsey Get al., 2025,

    Improving medical students' research skills: a study on confidence and performance through in-course assessments [version 1; peer review: awaiting peer review]

    , MedEdPublish, Vol: 15, ISSN: 2312-7996

    IntroductionResearch skills account for a core part of competent medical practice to improve patient outcome. Studies have highlighted the significance of supporting students learning experience during a research skills course by stimulating a research-oriented mindset and offering timely feedback. In this study, we aimed to evaluate the effectiveness of our research skills curriculum consisting of three in-course assessments (ICA), workshops and formative tutorials, on enhancing students’ confidence and performance in clinical research tasks.MethodStudents (n=26) completed an anonymised end-of-module survey on their self-perceived confidence rating before and after interventions. We aimed to quantify the relationship between the effectiveness of our in-course interventions, comprising workshops and tutorials, and students’ confidence rating (CR) and research proficiency (formative and summative assessment scores) using Likert scales. Within each teaching block, we compared students’ CR before and after each intervention, as well as the formative and summative assessment scores in each ICA using difference tests. We also performed univariate correlation tests between CR or student engagement and formative or summative ICA scores.ResultsStatistically significant increases in self-perceived CR after each intervention were observed in all ICAs. For each ICA, students obtained a significant score increase between formative and summative assessment. There was a gradual increase in students’ CR during the three ICAs. Post-workshop and post-tutorial CR levels were always higher compared to before the sessions. In ICA1, the formative score was positively correlated with pre-tutorial CR. Performance in the ICA 2 formative assessment was positively linked with pre-workshop CR. In ICA 3, the pre-abstract workshop CR was positively associated with formative lay summary and scientific abstract scores.ConclusionHere we demonstrate the effectiveness of educ
  • Journal article
    Keles M, Lawrie A, 2025,

    Revisiting prostaglandin biology in pulmonary arterial hypertension: targeting the EP4/ANXA2 axis

    , EUROPEAN HEART JOURNAL, ISSN: 0195-668X
  • Journal article
    Dunmore BJ, Moore S, Jones RJ, Hodgson J, Auckland K, Southwood M, Figg N, Kikuchi N, Bennett M, Lawrie A, Rhodes CJ, Toshner MR, Gräf S, Li W, Morrell NW, Upton PDet al., 2025,

    BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity

    , Angiogenesis, Vol: 29, ISSN: 0969-6970

    Deleterious mutations in the GDF2 gene, encoding BMP9, are causative of pulmonary arterial hypertension and hereditary haemorrhagic telangiectasia. Paradoxically, BMP9 germ-line knockout (Gdf2−/−; Bmp9 KO) and double Bmp9 KO/conditional Bmp10 cKO (dKO) mice exhibit an attenuated response to PAH-inducing stimuli. We asked whether this contradiction is due to the pathological, physiological, or genetic consequences of BMP9 knockout. In Bmp9 KO mice we observed reduced pulmonary vascular smooth muscle cell (SMC) coverage and using RNA-seq analysis of Bmp9 KO mouse lungs identified two novel genes, COLQ and ITGA6, which were differentially regulated in a human PAH RNA-seq dataset. In order to study BMP10 loss, postnatal tamoxifen treatment was required to induce Bmp10 cKO. As previously reported, in dKO mice we observed cardiomegaly and splenomegaly, as well as hyperplasia and hemosiderosis in the pulmonary vasculature. Surprisingly, tamoxifen treated Bmp9 KO control mice phenocopied these pathological changes in dKO mice and downregulated SMC marker gene transcription. Loss of BMP10 is not critical for severe tissue remodelling in the lung, heart, and spleen, rather Bmp9 KO mice appear sensitive to tamoxifen and BMP9 loss is the primary cause of mild vessel remodelling due to a basal reduction of smooth muscle cell coverage. This study suggests that interaction of the BMP pathway with tamoxifen needs to be carefully considered when studying Bmp9 KO mice and urges caution in the context of tamoxifen use when studying cardiovascular and pulmonary disease models.
  • Journal article
    Taniguchi Y, Khamis R, Joner M, 2025,

    Clinical needs and translational prospects of cardiovascular nanomedicine: Focus on intravascular and molecular imaging of atherosclerosis

    , BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 788, ISSN: 0006-291X
  • Journal article
    Hartley A, Williams MC, Kaura A, Verhemel S, Caga-anan M, Dey D, Dweck MR, Haskard DO, Joner M, Mayr M, Newby DE, Khamis RYet al., 2025,

    Anti-Malondialdehyde Low-Density Lipoprotein Antibodies and Valvular Calcification: A Substudy of the SCOT-HEART Trial

    , JOURNAL OF THE AMERICAN HEART ASSOCIATION, Vol: 14
  • Conference paper
    Foley M, Mohsin M, Ahmed-Jushuf F, Rajkumar C, Chotai S, Simader F, Wang D, Davies J, Keeble T, Okane P, Kotecha T, Nijjer S, Petraco R, Khamis R, De Silva R, Jonathan H, Cosgrove C, Spratt J, Mikhail G, Cole G, Harrell F, Howard J, Francis D, Kellman P, Shun-Shin M, Al-Lamee Ret al., 2025,

    Endocardial to epicardial blood flow ratio predicts the placebo-controlled efficacy of the coronary sinus reducer

    , American-Heart-Association Scientific Sessions / American-Heart-Association Resuscitation Science Symposium, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322
  • Journal article
    Ficany A, Del Alamo M, Bernabeu C, Shovlin CL, Rossi Eet al., 2025,

    Epistaxis Prevention, Treatment, and Future Perspectives for Hereditary Hemorrhagic Telangiectasia

    , JOURNAL OF CLINICAL MEDICINE, Vol: 14
  • Journal article
    Tsai T, Keulards D, Corradetti S, De Silva R, Tobe A, Miyashita K, Oshima A, Onuma Y, Serruys Pet al., 2025,

    Comparative Analysis of Angiography-Derived Indexes of Microvascular Resistance (IMR) Versus Absolute Resistance in an Core

    , JACC-JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 86, ISSN: 0735-1097
  • Conference paper
    Buschmann E, Van de Hoef T, De Silva R, Patterson T, Banai S, Luyapan J, West N, Verheye Set al., 2025,

    Sex Specific Outcomes of Treating Patients with Refractory Angina with the Coronary Sinus Reducer: One-year outcomes from the REDUCER-I Registry

    , 37th Annual Symposium on Transcatheter Cardiovascular Therapeutics (TCT), Publisher: ELSEVIER SCIENCE INC, ISSN: 0735-1097
  • Journal article
    Wilkins MR, Villar SS, Wason J, Toshner M, Rothman AMKet al., 2025,

    Drug Development for Pulmonary Arterial Hypertension: Unleashing the Potential of Single-Patient Studies Using Continuous Monitoring

    , PULMONARY CIRCULATION, Vol: 15, ISSN: 2045-8932
  • Journal article
    Singh B, Tzoulaki I, Mayr M, 2025,

    Precision medicine requires precision proteomics: discordance between proteomic and clinical assays in UK Biobank

    , CARDIOVASCULAR RESEARCH, ISSN: 0008-6363
  • Journal article
    Haskard D, Cao J, Boyle J, Chatterton-Bartley Cet al., 2025,

    Impact of an Alu insertion on the cellular localisation of tissue factor protein

    , Scientific Reports, ISSN: 2045-2322
  • Journal article
    de Silva R, Cheng K, Henry TD, Perera D, Taqueti VR, Abreu A, Vervaat F, Gulati M, Shimokawa H, Andreotti F, Kaski J-Cet al., 2025,

    Refractory angina: mechanisms and stratified treatment in obstructive and non-obstructive chronic myocardial ischaemic syndromes

    , European Heart Journal, Vol: 46, Pages: 3738-3757, ISSN: 0195-668X

    The diagnosis of refractory angina has conventionally been limited to patients with angina and ischaemia secondary to obstructive atherosclerotic epicardial coronary disease who experience persistent symptoms despite optimal pharmacological and revascularization therapies. It is now well-established that angina may also be caused by ischaemia resulting from coronary microcirculatory disorders, coronary vasospasm, and bridging in the absence of obstructive epicardial coronary disease or after “successful” revascularization. This increasingly prevalent and symptomatic group of patients, with both angina and demonstrable ischaemia, have been excluded from the conventional definition of refractory angina. In patients with obstructive epicardial coronary disease, disturbed microcirculatory and vasomotor function, amongst other ischaemic mechanisms, may account for continuing symptoms despite revascularization. Under-recognition of these mechanisms results in inadequate treatment and symptom persistence. In this review, a redefinition of refractory angina is proposed to include the full spectrum of patients experiencing persistent angina despite current maximal guideline-directed medical and revascularization therapies. Systematic approaches for comprehensive investigation are suggested to identify underlying mechanisms of ischaemia and stratify treatments accordingly. The complex needs of patients with refractory angina are likely best addressed by an inter-disciplinary Angina Heart Team with the aim of improving patient symptoms, quality of life, and clinical outcomes.
  • Journal article
    Yogeswaran A, Hassoun PM, Saleh K, Funderich M, Balasubramanian A, Konswa Z, Kiely DG, Lawrie A, Thenappan T, Eichstaedt CA, Grunig E, Wilkins MR, Howard L, Olschewski H, Kovacs G, Cajigas HR, Frantz R, Sabbour H, Sweatt AJ, Zamanian RT, Arvanitaki A, Giannakoulas G, Elwing J, Jose A, Beckmann S, Olsson KM, Stadler S, Held M, Halank M, Ewert R, Behr J, Milger-Kneidinger K, Pausch C, Pittrow D, Majeed RW, Wilhelm J, Ghofrani HA, Grimminger F, Tello K, Hoeper MM, Seeger W, PVRI GCet al., 2025,

    Hemodynamics and Phosphodiesterase-5 Inhibitor Treatment Associated with Survival in Pulmonary Hypertension in Interstitial Lung Disease A PVRI GoDeep Meta-Registry Analysis

    , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 211, Pages: 1855-1866, ISSN: 1073-449X
  • Journal article
    Mahomed AS, Burke-Gaffney A, Moledina S, Toe QK, Dongmin S, Quinlan GJ, Rhodes CJ, Pease JE, Wort Set al., 2025,

    SOX17-silenced HPAECs upregulate NF-κB-induced CXCL10 and CXCL11: implications for lymphocyte chemotaxis in SOX17-PAH

    , Scientific Reports, Vol: 15, ISSN: 2045-2322

    Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasculopathy characterized by extensive pre-capillary arterial remodeling, instigating increased pulmonary vascular resistance and eventual right heart failure. Rare mutations in the SOX17 gene and common variants in the enhancer region are thought to predispose to PAH. Central to the PAH pathobiology is lung immune cell recruitment, orchestrated by the overproduction of chemokines (e.g. CXCL10) via the induction of NF-κB. Emerging evidence from murine models of SOX17 impairment suggests perivascular leukocyte accumulation in the lung, likely due to disordered inflammatory mediator expression. Therefore, in the current study we assessed the role of SOX17 deficiency in human pulmonary artery endothelial cells (HPAECs) on selected inflammatory mediator release. Following a semi-quantitative array of 100 cytokines and chemokines, we identified markedly elevated CXCL10 and CXCL11 mRNA and soluble protein release in SOX17-silenced HPAECs (versus control siRNA-treated cells), driven by excessive NF-κB p65 activity. Further, we show that plasma CXCL10 levels are raised in a small cohort (n = 3) of carriers of pathogenic SOX17 rare variants versus healthy controls. Finally, SOX17 knockdown HPAEC supernatants mediated the in vitro migration of transfectants expressing CXCR3. Therefore, enhanced lymphocyte migration may be a pathomechanism of PAH due to SOX17 loss, driven by a CXCL10/CXCL11/CXCR3 axis.
  • Journal article
    Das H, Ironton H, Coote N, Cabuntug JA, Ranger JE, Alsafi A, Shovlin Cet al., 2025,

    Adolescent exercise capacity predicts higher exercise tolerance later in life when compounded by anaemia in patients with pulmonary arteriovenous malformations

    , Thorax, Vol: 80, Pages: 756-760, ISSN: 0040-6376

    Exercise tolerance predicts survival and mental health. To test benefits during adolescence for patients with pulmonary arteriovenous malformations (PAVMs) that cause hypoxaemia, we examined current and retrospective exercise tolerance aged 12y and 19y, linking to clinical records. In the 85 patients (65 female, mean age 56y), current metabolic equivalents ranged from 1.75 to 14.8(mean 7.85) kcal.kg-1.min-1. Oxygen saturation explained only 2.2% of the variability. There were stronger associations between current exercise tolerance and anaemia indices, particularly the need for blood transfusions. In univariate and multivariate analyses, thestrongest anaemia-independent predictor was exercise tolerance aged 19y. In this cohort, the benefit associated with modestly increased activity by 19y (2.9 METs) was greater than the decrements from severe anaemia (~2.54 METs) or 3 decades of life (2.13 METs). The data support enhanced exercise for people with PAVMs, as for the general population, in preparation for later-life health challenges.
  • Journal article
    Carulli E, McGarvey M, Chabok M, Panoulas V, Rosser G, Akhtar M, Smith R, Chandra N, Al-Hussaini A, Kabir T, Barker L, Bruno F, Konstantinou K, de Silva R, Hill J, Xu Y, Lane R, Bucciarelli-Ducci C, Luescher T, Dalby Met al., 2025,

    Transcoronary cooling and dilution for cardioprotection during revascularisation for ST-segment elevation myocardial infarction: design and rationale of the STEMI-Cool study (vol 282, pg 40, 2025)

    , AMERICAN HEART JOURNAL, Vol: 288, ISSN: 0002-8703
  • Journal article
    Zoodsma M, Beuchel C, Yasmeen S, Kohleick L, Nepal A, Koprulu M, Kronenberg F, Mayr M, Williamson A, Pietzner M, Langenberg Cet al., 2025,

    A genetic map of human metabolism across the allele frequency spectrum

    , NATURE GENETICS, Vol: 57, ISSN: 1061-4036

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