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Journal articleRothman AMK, Villar S, Middleton J, et al., 2025,
Positioning imatinib for pulmonary arterial hypertension: a dose finding phase 2 study
, American Journal of Respiratory and Critical Care Medicine, Vol: 211, Pages: 1018-1027, ISSN: 1073-449XRationale: Imatinib, 400 mg daily, reduces pulmonary vascular resistance and improves exercise capacity in patients with pulmonary arterial hypertension. Concerns about safety and tolerability limit its use.Objectives: We sought to identify a safe and tolerated dose of oral imatinib between 100 mg and 400 mg daily and evaluate its efficacy.Methods: Oral imatinib was added to the background therapy of 17 patients with pulmonary arterial hypertension, including 13 who were implanted with devices that provide daily measurements of cardiopulmonary hemodynamics and physical activity. The first patient was started on 100 mg daily. The next 12 patients, recruited serially, were started on 200 mg, 300 mg, or 400 mg daily, following a continuous reassessment dose-finding model. An extension cohort (Patients 14–17) received 100 mg or 200 mg daily.Measurements and Main Results: The continuous reassessment model recommended starting dose was 200 mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (−6.5 mm Hg; 95% confidence interval [CI] = −2.4 to −10.6; P < 0.01) and total pulmonary resistance (−2.8 Wood units; 95% CI = −1.5 to −4.2; P < 0.001), with no significant change in cardiac output. The reduction in total pulmonary resistance was dose and exposure dependent; the reduction from baseline with imatinib, at 200 mg daily, was −20.3% (95% CI = −14.3 to −26.3%). Total pulmonary resistance and night heart rate declined steadily over the first 28 days of treatment and remained below baseline up to 40 days after imatinib withdrawal.Conclusions: Oral imatinib, 200 mg daily, is well tolerated as an add-on treatment for pulmonary arterial hypertension. A delay in the return of cardiopulmonary hemodynamics to baseline was observed after imatinib was stopped.
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Journal articleCheng L-H, Sun X, Elliot C, et al., 2025,
Mean pulmonary artery pressure prediction with explainable multi-view cardiovascular magnetic resonance cine series deep learning model
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundPulmonary hypertension (PH) is a heterogeneous condition and regardless of etiology impacts negatively on survival. Diagnosis of PH is based on hemodynamic parameters measured invasively at right heart catheterization (RHC); however, a non-invasive alternative would be clinically valuable. Our aim was to estimate RHC parameters non-invasively from cardiac magnetic resonance (MR) data using deep learning models and to identify key contributing imaging features.MethodsWe constructed an explainable convolutional neural network (CNN) taking cardiac MR cine series from four different views as input to predict mean pulmonary artery pressure (mPAP). The model was trained and evaluated on 1646 examinations. The model’s attention weight and predictive performance associated with each frame, view, or phase were used to judge its importance. Additionally, the importance of each cardiac chamber was inferred by perturbing part of the input pixels.ResultsThe model achieved a Pearson correlation coefficient of 0.80 and R2 of 0.64 in predicting mPAP and identified the right ventricle region on short-axis view to be especially informative.ConclusionHemodynamic parameters can be estimated non-invasively with a CNN, using MR cine series from four views, revealing key contributing features at the same time.
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Journal articleHajhosseiny R, Hartley A, Cole G, et al., 2025,
Free-breathing, non-contrast, 3D whole-heart coronary MRI for the identification of culprit and vulnerable atherosclerotic plaque
, Journal of Cardiovascular Magnetic Resonance, Vol: 27, ISSN: 1097-6647BackgroundDetection of vulnerable coronary plaque can predict future myocardial infarctions. We have developed a novel, non-contrast cardiovascular magnetic resonance sequence (iT2prep-BOOST), enabling simultaneous, co-registered coronary angiography and plaque detection.ObjectivesTo validate iT2prep-BOOST in patients with non-ST-segment elevation myocardial infarction (NSTEMI).Methods41 patients with suspected NSTEMI were recruited. Invasive coronary angiography ± intravascular imaging was used to classify coronary segments into the following categories: normal, non-culprit and culprit segments; stenosed segments as well as segments with vulnerable plaque features (lipid, calcium, fibroatheroma, thin cap fibroatheroma (TCFA), plaque-rupture and thrombus). The plaque/myocardial signal intensity ratio (PMR) in each coronary segment was analyzed on iT2prep-BOOST.ResultsThe mean ± standard deviation PMR of culprit segments was significantly higher than non-culprit segments and normal segments (1.01 ± 0.14 vs. 0.67 ± 0.18 vs. 0.35 ± 0.24, P<0.001 respectively). Coronary segments with lipid, calcium and fibroatheroma had a significantly higher PMR compared to normal coronary segments (P<0.001), but significantly lower than segments with plaque-rupture and intraluminal thrombus (P<0.05). There was a progressive increase in PMR with increasing coronary segment stenosis (P<0.001). There was a significant association on multivariable analysis between HbA1c as well as family history of coronary artery disease and mean PMR (P=0.05 and P=0.04 respectively).ConclusionsiT2prep-BOOST has the potential to simultaneously visualize coronary artery lumen and plaque and differentiate normal segments from non-culprit and culprit plaque segments non-invasively and without contrast. The prognostic value of PMR needs to be investigated in a prospective multicenter study.
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Conference paperPisacano N, Dhutia A, Rothery S, et al., 2025,
ANCA IGG PROMOTION OF NEUTROPHIL RECRUITMENT, MIGRATION AND VASCULAR DAMAGE IN ANCA ASSOCIATED VASCULITIS MAY BE ENHANCED BY HYPOXIA
, European Congress of Rheumatology, Publisher: ELSEVIER, ISSN: 0003-4967 -
Journal articleMacLeod MA, Knott KD, Allinson JP, et al., 2025,
Prevalence and Clinical Correlates of Radiologically Detected Coronary Artery Disease in Chronic Obstructive Pulmonary Disease A Cross-Sectional Observational Study
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 211, Pages: 946-956, ISSN: 1073-449X- Cite
- Citations: 3
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Journal articleAhmed-Jushuf F, Foley MJ, Rajkumar CA, et al., 2025,
Ischemia on Dobutamine Stress Echocardiography Predicts Efficacy of PCI Results From the ORBITA-2 Trial
, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 85, Pages: 1740-1753, ISSN: 0735-1097- Cite
- Citations: 2
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Journal articleFoote K, Rienks M, Schmidt L, et al., 2025,
Oxidative DNA damage promotes vascular ageing associated with changes in extracellular matrix-regulating proteins.
, Cardiovasc Res, Vol: 121, Pages: 614-628AIMS: Vascular ageing is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular ageing, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular ageing. METHODS AND RESULTS: We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of ageing, and ECM proteomics in mice from 22 to 72 w. Vascular ageing was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1+ (Ogg1) or an inactive mutation (Ogg1KR). Ogg1-/- and Ogg1KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalized all parameters to 72 w. ECM proteomics identified major changes in collagens with ageing, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness. CONCLUSION: Vascular ageing is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory prote
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Journal articleFrancois AA, Yin X, Oka S, et al., 2025,
On the utility of immobilized phenylarsine oxide in the study of redox sensitive cardiac proteins
, SCIENTIFIC REPORTS, Vol: 15, ISSN: 2045-2322 -
Journal articleGorog DA, de Silva R, Boden WE, 2025,
The year in cardiovascular medicine 2024: the top 10 papers in ischaemic heart disease
, EUROPEAN HEART JOURNAL, Vol: 46, Pages: 1579-1581, ISSN: 0195-668X- Cite
- Citations: 1
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Journal articleMourikis P, Benkhoff M, Wildeis L, et al., 2025,
Icosapent ethyl reduces arterial thrombosis by inhibition of cyclooxygenase-1 induced platelet reactivity
, Science Translational Medicine, Vol: 17, ISSN: 1946-6234Large, randomized trials testing omega-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation to reduce cardiovascular events have reported contradictory results. Interpretation of these trials is challenging, because different dosages and formulations of ω-3 PUFA were tested. Furthermore, the exact mechanisms for the reduction in cardiovascular events are unclear. In this study, we investigated the effects of ω-3 PUFA on platelet adhesion, degranulation, and aggregation in vitro and in patients with cardiovascular disease using different formulations of ω-3 PUFA. We also investigated the effects of ω-3 PUFA in rodent models of arterial thrombosis and in tail bleeding assays, including in cyclooxygenase-1 (COX-1)–deficient animals. The ω-3 PUFA eicosapentaenoic acid (EPA) dose-dependently reduced platelet adhesion, degranulation, and aggregation in vitro. Moreover, arterial thrombus formation in wild-type mice was inhibited by oral EPA administration before thrombus formation. Photoaffinity labeling and in silico docking analyses suggested a direct, competitive interaction of EPA and arachidonic acid at the level of COX-1. The COX-1 dependency of EPA’s inhibitory effects was confirmed by platelet-specific COX-1–deficient animals that had no reduction of thrombus burden by EPA. In patients with cardiovascular disease, switching from 2 grams of EPA twice daily to 1 gram of docosahexaenoic acid (DHA) (460 milligrams of EPA and 380 milligrams of DHA) once daily completely blunted the platelet inhibition achieved by EPA. Our results may partially explain contradictory results with different ω-3 PUFA formulations in clinical trials.
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Conference paperGomez-Arroyo J, Houweling A, Bogaard HJ, et al., 2025,
Association of FOXF1 Genomic Variants With Children and Adults With Pulmonary Arterial Hypertension
, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Conference paperYogeswaran A, Annis J, Meike F, et al., 2025,
Male Survival Disadvantage in Pulmonary Hypertension in the PVRI Godeep Meta-registry
, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Conference paperKlinger JR, Vasilaki E, Walters R, et al., 2025,
Small Molecule Compound BX-912 Reverses Increased Susceptibility to Pulmonary Hypertension in SOX17 Enhancer Knockout Mice
, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X -
Journal articleLeroy A, Teh AL, Dondelinger F, et al., 2025,
Longitudinal prediction of DNA methylation to forecast epigenetic outcomes
, EBioMedicine, Vol: 115, ISSN: 2352-3964Background:Epigenetic changes in early life play an important role in the development of health conditions in children. Longitudinally measuring and forecasting changes in DNA methylation can reveal patterns of ageing and disease progression, but biosamples may not always be available.Methods:We introduce a probabilistic machine learning framework based on multi-mean Gaussian processes, accounting for individual and gene correlations across time to forecast the methylation status of an individual into the future. Predicted methylation values were used to compute future epigenetic age and compared to chronological age.Findings:We show that this method can simultaneously predict methylation status at multiple genomic sites in children (age 5–7) using methylation data from earlier ages (0–4). Less than 10% difference between observed and predicted methylation values is found in approximately 95% of methylation sites. We show that predicted methylation profiles can be used to estimate other molecular phenotypes, such as epigenetic age, at any timepoint and enable association tests with health outcomes measured at the same timepoint.Interpretation:Limited longitudinal profiling of DNA methylation coupled with machine learning enables forecasting of epigenetic ageing and future health outcomes.Funding:Wellcome Trust, Singapore National Research Foundation (NRF), Singapore National Medical Research Council (NMRC), Agency for Science, Technology and Research (A∗STAR), UK Academy of Medical Sciences and the UK Engineering and Physical Sciences Research Council (EPSRC).
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Journal articleHarvey C, Leedham-Green KE, Koppel C, et al., 2025,
Improving medical students’ learning strategies, management of workload and wellbeing: a mixed methods case study in undergraduate medical education
, BMC Medical Education, Vol: 25, ISSN: 1472-6920Background:The transition from secondary education to university challenges students’ learning strategies and academic performance, especially in self-directed, problem-based environments like medical school. Passive study methods often fail, while evidence-based strategies like retrieval practice, active learning, and growth mindset foster success. We evaluate a novel academic support programme (Academic Tutoring- (AT)) to enhance study skills, feedback use, and self-directed learning.Methods:We developed and implemented AT for 1st year medical students, informed by the psychology of learning and behaviour change, AT aimed to support the development of self-efficacy and effective learning strategies during the transition into university. The programme involved meeting an Academic Tutor one-to-one once per term, and also as a group once per term. Academic Tutors engaged students in learner-centred conversations on study skills and professional development plus their wellbeing and welfare. A Likert questionnaire was designed to measure students’ responses to the experiences and perceived outcomes of AT. We also measured self-efficacy and mindset. Qualitative data was gathered through open-ended response items. Demographic and socioeconomic data was also gathered.Results:AT positively impacted time-management and learning strategies. ‘Learning from successes and failures’ and ‘thinking how to achieve goals’ were associated with a growth mindset. All outcome measures were associated with self-efficacy. We noted that students from a widening participation (WP) background tended to show higher growth mindset relative to those from a non-WP background (r = -0.223, p = 0.08) and female students reported higher engagement with the programme (r-0.294, p < 0.001). Students reported changes in behaviours and attitudes, and improved wellbeing.Conclusions:Providing medical students with the tools to
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Journal articleHopkinson N, Polkey M, Price L, et al., 2025,
Dietary nitrate supplementation enhances exercise capacity in WHO Group 3 pulmonary hypertension: a double-blind, placebo-controlled, randomised crossover study (EDEN-OX2)
, Thorax, Vol: 80, Pages: 335-338, ISSN: 0040-6376Dietary nitrate supplementation, which improves skeletal muscle oxygen utilisation, vascular endothelial function and exercise capacity in people with chronic obstructive pulmonary disease, may benefit other lung conditions. In a double-blind, placebo-controlled, crossover study, in 19 adults with Group 3 pulmonary hypertension who desaturated during exercise, 140 mL of nitrate-rich beetroot juice improved endurance shuttle walk time compared with nitrate-depleted beetroot juice placebo (median (IQR) ESWT NR-BRJ 197 (140–273) s vs PL-BRJ 174 (107–229) s; median difference (MD) (95% CI) 30 (6.19 to 91.07) s, p=0.0281), endothelial function, flow-mediated dilatation (+3.40±5.47% vs −1.33±4.78; MD (95% CI) 4.73 (1.44 to 8.02), p=0.007) and lowered mean arterial blood pressure (−3.9 (−7.4 to −0.4) mm Hg, p=0.028).
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Journal articleWalther R, Singh B, Yin X, et al., 2025,
Proteomic Profiling of Age-Related Proteins Following Extracorporeal Apheresis
, HORMONE AND METABOLIC RESEARCH, ISSN: 0018-5043- Cite
- Citations: 1
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Journal articleSagawe JS, Loake V, Openshaw P, et al., 2025,
Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection
, GeroScience, Vol: 47, Pages: 1485-1500, ISSN: 2509-2723Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.
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Journal articleShort E, International Consortium for the Classification of Ageing-Related Paathologies, Gil J, et al., 2025,
Defining an ageing-related pathology, disease or syndrome: International Consensus Statement
, GeroScience, Vol: 47, Pages: 1713-1720, ISSN: 2509-2723Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.
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Journal articleBoichenko V, Noakes VM, Reilly-O'Donnell B, et al., 2025,
Circulating non-coding RNAS as indicators of fibrosis and heart failure severity
, Cells, Vol: 14, ISSN: 2073-4409Heart failure (HF) is a leading cause of morbidity and mortality worldwide, representing a complex clinical syndrome in which the heart’s ability to pump blood efficiently is impaired. HF can be subclassified into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), each with distinct pathophysiological mechanisms and varying levels of severity. The progression of HF is significantly driven by cardiac fibrosis, a pathological process in which the extracellular matrix undergoes abnormal and uncontrolled remodelling. Cardiac fibrosis is characterized by excessive matrix protein deposition and the activation of myofibroblasts, increasing the stiffness of the heart, thus disrupting its normal structure and function and promoting lethal arrythmia. MicroRNAs, long non-coding RNAs, and circular RNAs, collectively known as non-coding RNAs (ncRNAs), have recently gained significant attention due to a growing body of evidence suggesting their involvement in cardiac remodelling such as fibrosis. ncRNAs can be found in the peripheral blood, indicating their potential as biomarkers for assessing HF severity. In this review, we critically examine recent advancements and findings related to the use of ncRNAs as biomarkers of HF and discuss their implication in fibrosis development.
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