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Journal articleMeena D, Huang J, Smith A, et al., 2026,
Blood pressure, plasma proteins and cardiovascular diseases: a network Mendelian randomisation and observational study
, European Heart Journal, Vol: 47, Pages: 331-342, ISSN: 0195-668XBackground and AimsThe biological pathways leading to elevated blood pressure (BP) and subsequent cardiovascular diseases (CVDs) remain incompletely understood. Investigating the proteomic landscape of BP and its overlap with CVD could provide critical insights into the molecular determinants and pathways involved in BP regulation and its subsequent effect on CVD.MethodsA proteome-wide Mendelian randomization (MR) study was conducted by leveraging genetic instruments from 2007 plasma proteins to assess their causal effects on BP (systolic and diastolic BP). Proteins showing strong associations with BP were further analyzed for potential causal effects on coronary artery disease (CAD) and stroke subtypes. Network MR was performed to estimate the proportion of CVD risk mediated through BP. Bayesian colocalization was applied to determine whether identified associations share common causal variants. Observational associations were examined in UK Biobank participants to assess associations between proteins, BP, and incident CVD events using linear regression and Cox proportional hazard models.ResultsProteome-wide MR identified 242 proteins associated with BP, of which 48 were also linked to CAD or stroke, with four (ACOX1, FGF5, FURIN, MST1) also supported by genetic colocalization analyses (FDR 5% and PP ≥70%). Genetically predicted FURIN and FGF5 were strongly associated with BP and stroke risk, while ACOX1, FGF5, and MST1 exhibited potential causal effects on CAD. Network MR suggested that a substantial proportion of their effect on CAD and stroke (30.5%–77.2%) was mediated through BP regulation. Observational analyses further supported these findings.ConclusionsThis study identifies key plasma proteins with potential causal roles in BP regulation and CVD risk, highlighting BP as a major mediator of their effects on CAD and stroke. These findings provide novel insights into the molecular mechanisms underlying hypertension-related CVD and identify promising p
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Journal articleDe Bie E, Correa-Jaque P, Jones R, et al., 2026,
Inflammation and obesity correlate in pulmonary hypertension but associate with diverging outcomes
, American Journal of Respiratory and Critical Care Medicine, Vol: 212, Pages: 117-128, ISSN: 1073-449XRationale & Objectives: Inflammation is associated with all types of Pulmonary Hypertension (PH) both as a known cause and/or a putative confounder. The most common marker of inflammation, C-reactive protein (CRP), has not been widely studied in PH. This study set out to clarify if CRP informed clinical endotyping and outcomes. Methods & Measurements: Time-series clustering of longitudinal CRP levels was employed. Clinical differences between clusters were validated in three independent UK/international cohorts using clinical cut off values (n=10,301; UK-cohort, ASPIRE and FDA cohort). Associations were analysed with functional and mortality outcomes by linear and Cox regression models including all-causes of PH (groups 1-5). To add mechanistic insight, multi-omics were interrogated from associated previously published arrays. Main Results: Patients segregated into two stable CRP clusters (median CRP 2 versus 6.5 mg/l), with the high cluster exhibiting significantly higher BMI (difference between medians DBM=5.4 kg/m2), higher RAP (DBM=2mmHg) and reduced 6-minute walk distance (6MWD (DBM=55m)). Inflammation was associated with worse survival, comorbidities, higher pulmonary vascular resistance (PVR), and smoking status. CRP and BMI were associated with differing inflammatory profiles in proteomic and transcriptomic analyses. Despite the relationship with CRP, higher BMI associated with improved survival, lower PVR and did not negatively affect 6MWD treatment-related functional responses. Conclusions: We establish a relationship between CRP and BMI across all-cause PH, though CRP and BMI associate with diverging clinical outcomes. Inflammation and obesity are relevant phenotypes for consideration in clinical trial design. Understanding their impacts on outcomes is important for clinical practice.
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Book chapterSchmidt L, Suna G, Mayr M, 2026,
Proteomics
, Encyclopedia of Cardiovascular Research and Medicine, Pages: Vol1-V383Proteins perform most biological functions and constitute the main drug targets. Proteomics can reveal information that cannot be obtained at the genetic level. Recent advances in proteomics are linked to the rapid development of mass spectrometry technology, and novel methodologies have enabled the study of proteins at an unprecedented scale. This chapter outlines a typical proteomics workflow, followed by a comparison of mass spectrometry techniques for protein discovery and quantification. The application of proteomics in cardiovascular research is illustrated through specific examples.
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Journal articleHada M, Collet C, Storozhenko T, et al., 2026,
Rationale and design of European microcirculatory resistance and absolute flow team: The Euro-CRAFT registry
, AMERICAN HEART JOURNAL, Vol: 291, Pages: 136-143, ISSN: 0002-8703 -
Journal articleYogeswaran A, Annis JS, Funderich M, et al., 2026,
Male survival disadvantage in pulmonary hypertension: independent of aetiology, age, disease severity, comorbidities and treatment
, EBIOMEDICINE, Vol: 123, ISSN: 2352-3964 -
Journal articleHoward LS, Kiely DG, Lawrie A, et al., 2026,
Performance of Guideline-Recommended Approaches to Echocardiographic Investigation for Pulmonary Hypertension: Analysis of the CIPHER Study.
, Pulm Circ, Vol: 16, ISSN: 2045-8932Guidelines recommend different approaches to investigate for pulmonary hypertension (PH) by transthoracic echocardiography (TTE). We used data from the CIPHER study (NCT04193046) to prospectively evaluate TTE detection of PH. Participants newly referred to PH clinics who underwent right heart catheterization (RHC) within 6 weeks and TTE within 60 days of enrolment (blinded central TTE reading) were classified by TTE probability of PH applying (i) the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) TTE algorithm or (ii) right ventricular systolic pressure (RVSP) > 40 mmHg. For calculation of sensitivity and specificity, 'non-assessable' patients (peak tricuspid regurgitation velocity [TRV] missing or ≤ 2.8 m/s with missing data on other echocardiographic signs) and patients with missing RVSP were counted as PH-negative. Performance was measured against RHC-confirmed diagnosis of mean pulmonary artery pressure > 20 mmHg. Of 475 patients included, 345 (73%) had PH. Using the ESC/ERS algorithm, PH probability was high, intermediate, low and non-assessable for 198, 104, 22 and 151 patients and PH prevalence was 98%, 75%, 23%, and 44%, respectively. Seventy-three patients were missing RVSP and 292 had RVSP > 40 mmHg. The two TTE approaches achieved similar results: sensitivity was 79%-77%, specificity was 78%-79%. This prospective study of patients newly referred to PH centres for RHC found similar sensitivity and specificity when using either RVSP > 40 mmHg or the 2015 ESC/ERS TTE algorithm. Among patients who were low-probability or non-assessable by ESC/ERS algorithm, 42% had PH, highlighting the persistent need for additional non-invasive investigative tools.
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Journal articleVon Koch S, Sharma T, Khamis R, et al., 2026,
Long-acting nitrate use before and after revascularization to evaluate angina in chronic coronary syndrome: a case-crossover study from SCAAR
, LANCET REGIONAL HEALTH-EUROPE, Vol: 60, ISSN: 2666-7762 -
Journal articleSamaranayake CB, Chen Y-C, Fang M, et al., 2026,
GLP-1 agonist, semaglutide use in acute pulmonary embolism recovery: a four-week proof-of-concept study including proteomic profiling.
, Eur Heart J Open, Vol: 6AIMS: Vasorelaxant and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) agonists support their investigation in aiding the recovery of patients with acute pulmonary embolism (PE) at risk of worse outcomes. METHODS: We undertook a four week non-randomized, controlled open-label study examining proteomic changes, markers of vascular inflammation and exploratory imaging endpoints in response to GLP-1 agonist, semaglutide (0.25 mg weekly) added to standard of care anticoagulation in patients with intermediate high-risk PE. RESULTS: 44 plasma proteins were downregulated in response to semaglutide that were significantly enriched for glycoproteins (false discovery rate q < 0.01). Glycopeptide analysis of highly abundant glycoproteins between diagnosis and follow-up demonstrated a reduction in glycopeptide abundance suggesting protein deglycosylation as a possible mechanism of glycoprotein down-regulation. Down-regulated proteins included regulators of metabolic stress and complement pathway intermediates, which were at higher abundance in PE patients at diagnosis compared to age and sex-matched controls without PE (all P < 0.001). Exploratory evaluation of radiological markers of right ventricular dysfunction improved from baseline to follow-up only in patients who received semaglutide (P < 0.01). CONCLUSIONS: These findings suggest merit in wider investigation of immunometabolic changes in the plasma proteome during acute PE recovery and their potential relevance to modulation using GLP-1 agonists. REGISTRATION: The study was registered under clinicaltrials.org (NCT06118203).
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Journal articleZiotti SDV, Dourado LOC, Silva RD, et al., 2026,
Coronary Sinus Reduction for the Treatment of Refractory Angina: What Have We Learned after 70 Years of the Beck Surgery?
, Arq Bras Cardiol, Vol: 122With the increasing prevalence of chronic coronary syndromes, many patients with extensive atherosclerosis experience uncontrolled angina, even while receiving optimal medical therapy. This is especially true for patients who are not suitable candidates for surgical or percutaneous revascularization. Numerous treatments have been investigated for managing angina pectoris, and in this context, the coronary sinus reducer has emerged as a promising therapeutic option. Since the 1950s, beginning with Beck's surgery, the coronary venous sinus has been a focal point of research in anti-ischemic therapies. Significant scientific advances have been made in narrowing the venous sinus in the past two decades. Thanks to technological improvements in minimally invasive procedures and better methods for assessing myocardial blood flow, a new therapeutic option has become available for patients suffering from refractory angina and, possibly, for microvascular dysfunction. In this review, we aim to examine key concepts related to angina pectoris and myocardial ischemia, highlighting the historical background, pathophysiological rationale, and technical aspects of coronary sinus reduction as a therapy for refractory angina. Additionally, we will explore the scientific evidence from recent decades, as well as identify existing gaps and outline future research directions concerning this emerging treatment.
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Journal articleGuo J, Kostrzyńska K, Kamzolas I, et al., 2025,
Endoglin as a BMP9 co-receptor in vascular endothelial cells: prodomain displacement and TGFBRII recruitment.
, Nat Commun, Vol: 17Endoglin (ENG) is a single-pass transmembrane protein highly expressed in vascular endothelial cells (ECs), where it plays fundamental roles in EC functions. ENG is implicated in several cardiovascular disorders including hereditary haemorrhagic telangiectasia, pulmonary arterial hypertension (PAH) and preeclampsia. However, molecular mechanisms underlying ENG function are not fully understood. Initially identified as a co-receptor for TGF-β signalling, ENG's extracellular domain was later found to only bind BMP9 and BMP10 with high affinity. The relationship between these two observations is unclear. Here, we provide evidence for two primary functions of co-receptor ENG. First, ENG efficiently displaces prodomains from BMP9 and BMP10, enabling effective capturing of both ligands from the circulation. Second, ENG binds to and recruits TGFBRII into the BMP9 signalling complex, thereby explaining ENG's involvement in both TGF-β and BMP9 pathways. We identify BMP9 target genes NOG and ADAMTSL2 as preferentially dependent on ENG and show that their transcript levels have strong positive correlation with ENG in human lung tissues; the expression levels of all three genes are significantly reduced in PAH. Our findings address an important gap in our understanding on ENG biology and provide crucial insight for therapeutic targeting these pathways in vascular diseases.
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Journal articleKhawaja AA, Whitlock G, Fidler S, et al., 2025,
Evaluation of the effect of 48 weeks of BIC/F/TAF and DRV/c/F/TAF on platelet function in the context of rapid ART start
, HIV Research & Clinical Practice, Vol: 26, ISSN: 2578-7470IntroductionThe BIC-T&T study aimed to determine the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF) at suppressing viral load in a two-arm, open-label, multi-centre, randomised trial under a UK test-and-treat setting. This sub-study aimed to evaluate potential off-target cardiovascular impact by examining ex vivo platelet function.MethodsPlatelets were isolated by centrifugation of citrated blood from participants attending Chelsea and Westminster Hospital or St Mary’s Hospital at Week 48 following enrolment. Platelet activation was assessed by real-time flow cytometry to examine integrin activation and granule release and platelet aggregation was evaluated by light transmission aggregometry. Statistical significance was determined by 2-way ANOVA with a Šidák’s multiple comparisons post-test.ResultsAn analysis of 21 participants was performed at Week 48 (96% male and 48% white; mean (range) age was 37 (23–78) years). No difference between arms was observed in ADP-, collagen- or thrombin receptor activator for peptide (TRAP)-6-evoked platelet αIIbβ3 integrin activation, granule release or platelet aggregation in response to any of the agonists tested. Despite differences in the demographics between treatment arms, the presence of an unboosted integrase inhibitor or boosted protease inhibitor in a test-and-treat setting did not impact platelet function.ConclusionsOur study provides no evidence of differences in downstream platelet responses between participants taking BIC/F/TAF compared to DRV/c/F/TAF following 48 wk of treatment. Further data are required to explore whether there are biologically significant off-target effects, including effects on platelets and other components of the cardiovascular system between these two test-and-treat regimens.
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Journal articleXiao S, Liu B, Argentieri MA, et al., 2025,
Proteomic signatures of smoking and their associations with risk of incident diseases and mortality in diverse populations.
, Nat Commun, Vol: 17Smoking is the most important behavioural determinant of morbidity and mortality. Using machine learning on plasma levels of 2,917 proteins in the UK Biobank (n = 43,914), we develop a proteomic Smoking Index (pSIN) comprising 51 proteins that accurately distinguish current from never smokers (AUC = 0.95; 95% CI 0.94-0.95). Validation in the China Kadoorie Biobank (n = 3,977) shows similar accuracy (AUC = 0.91; 95% CI 0.89-0.92). pSIN is significantly associated with the risk of all-cause mortality and 18 major chronic diseases, including cardiovascular, renal, pulmonary, neurodegenerative, and cancer outcomes. Among current and former smokers, pSIN predicts death and 11 diseases independently of self-reported smoking history and lifestyle factors. Genome-wide analysis identifies 125 genes (e.g., ALPP, CST5, IL12B) associated with pSIN, while exposome analysis highlights maternal smoking, diet, physical activity, and air pollution as key modifiers. Notably, pSIN tracks recovery among former smokers and identifies those whose disease risks remain comparable to current smokers. These findings demonstrate that plasma proteomics effectively capture the biological imprint of smoking and predict smoking-related morbidity and mortality, offering a more nuanced, molecularly grounded assessment of individual variation in biological response to smoking.
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Journal articleTänzer M, Scott AD, Khalique Z, et al., 2025,
Accelerating cDTI with deep learning-based tensor de-noising and breath hold reduction. a step towards improved efficiency and clinical feasibility
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundCardiac Diffusion Tensor Imaging (cDTI) non-invasively provides unique insights into cardiac microstructure. Current protocols require multiple breath-hold repetitions to achieve adequate signal-to-noise ratio, resulting in lengthy scan times. The aim of this study was to develop a cDTI de-noising method that would enable the reduction of repetitions while preserving image quality.MethodsWe present a novel de-noising framework for cDTI acceleration centred on three fundamental advances: (1) a paradigm shift from image-based to tensor-space de-noising that better preserves structural information, (2) an ensemble of Vision Transformer-based models specifically optimised for tensor processing through adversarial training, and (3) a sophisticated data augmentation strategy that maximises training data utilisation through dynamic repetition selection.ResultsOur approach reduces scan times by a factor of up to 4 while achieving a 20% reduction in cDTI maps errors over existing de-noising methods (Table 1) and preserving anatomical features such as infarct characterisation and transmural cardiomyocyte orientation patterns. Crucially, our proposed method succeeds in clinical cases where other algorithms previously failed.ConclusionsThis demonstrates substantial improvements in cDTI acquisition efficiency, achieving up to 4-fold scan time reduction (3-5 breath-holds) while maintaining diagnostic accuracy across diverse cardiac pathologies.
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Journal articleAlexander SPH, Fabbro D, Peach CJ, et al., 2025,
The Concise Guide to PHARMACOLOGY 2025/26: Catalytic receptors.
, Br J Pharmacol, Vol: 182 Suppl 1, Pages: S259-S306The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point-in-time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70233. The Concise Guides provide expert-curated recommendations of 'Gold Standard' selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid-2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. Catalytic receptors are
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Journal articleHao Z, Leitinger B, 2025,
Warburg-Cinotti disease variant p.Tyr740Cys enhances catalytic activity of DDR2 kinase
, PLoS ONE, Vol: 20, ISSN: 1932-6203The discoidin domain receptor DDR2 is a collagen-binding receptor tyrosine kinase whose dysregulation is associated with a wide range of diseases. Missense mutations in the DDR2 kinase domain cause Warburg-Cinotti syndrome in an autosomal dominant manner. Warburg-Cinotti syndrome is a severe connective tissue disorder, characterised by a range of manifestations including joint contractures of the hand, corneal vascularisation and pannus, skin fusion and infection, keloid plaques and acro-osteolysis. The Warburg-Cinotti variants, p.Leu610Pro and p.Tyr740Cys, were previously hypothesised to cause disease through a gain-of-function mechanism but mechanistic studies addressing this notion have been lacking. Here we show that both disease variants exhibit ligand-independent constitutive autophosphorylation when expressed as full-length proteins in mammalian cells. We also characterised the enzyme kinetics of soluble WT and DDR2-Y740C kinase constructs. WT DDR2 kinase was found to follow the same two-step activation mechanism previously characterised for DDR1 kinase but with enhanced autophosphorylation and substrate phosphorylation rates. Compared with WT DDR2, DDR2-Y740C displayed further enhanced autophosphorylation and substrate phosphorylation rates, but no effect on ATP binding affinity. The increased catalytic rates of unphosphorylated DDR2-Y740C kinase were similar to those of fully phosphorylated WT DDR2, indicating that the missense variant bypasses all autoinhibitory constraints and adopts the fully active kinase conformation. Tyrosine-740 is a residue in the A-loop of DDR2 kinase that forms autoinhibitory hydrogen bonds with key catalytic residues. These hydrogen bonds cannot form in the cysteine-substituted variant, providing a structural explanation for the release of the A-loop from its autoinhibitory conformation.
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Journal articleKeles M, Lawrie A, 2025,
Revisiting prostaglandin biology in pulmonary arterial hypertension: targeting the EP4/ANXA2 axis
, EUROPEAN HEART JOURNAL, ISSN: 0195-668X -
Journal articleDunmore BJ, Moore S, Jones RJ, et al., 2025,
BMP9 knockout impairs pulmonary vessel muscularisation and confers aberrant tamoxifen sensitivity
, Angiogenesis, Vol: 29, ISSN: 0969-6970Deleterious 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.
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Journal articleTaniguchi 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 articleHartley A, Williams MC, Kaura A, et 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 paperFoley M, Mohsin M, Ahmed-Jushuf F, et 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
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