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Journal articlePruktanakul T, Lynham S, Chen H, et al., 2026, , J Proteome Res, Vol: 25, Pages: 5734-5749
Mass spectrometry-based proteomics requires advanced data processing tools, yet most comparative studies have relied on noncardiovascular data sets or standard protein mixtures, limiting their relevance to cardiovascular research. We systematically compared three label-free data-dependent acquisition (DDA) tools (FragPipe, MaxQuant, and Proteome Discoverer) and five data-independent acquisition (DIA) tools (DIA-NN, DIA-Umpire, MSFragger-DIA, MaxDIA, and Spectronaut) using real-world cardiovascular tissue and blood-derived proteomics data sets. FragPipe and Spectronaut generally achieved the greatest quantitative proteome coverage among the evaluated DDA and DIA tools, respectively, particularly in cardiovascular tissue data sets, although tool rankings varied across sample types and proteome subsets. Despite differences in identification and quantification performance, peptide physicochemical characteristics were broadly similar across tools. Integration of complementary differential expression outputs increased differentially expressed protein detection in several data sets while maintaining agreement with the main results. These findings provide practical guidance for selecting data processing tools in cardiovascular proteomics and support the use of integrative approaches to maximize biological information from proteomics data sets.
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Journal articleFinney LJ, Lodge KM, 2026, , European Respiratory Journal, Vol: 68, Pages: 2601496-2601496, ISSN: 0903-1936
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Journal articleZhao L, Hopley S, Chen C-N, et al., 2026, , Sci Transl Med, Vol: 18
ZIP12, a membrane-bound zinc importer, is up-regulated in the remodeled pulmonary arterioles of patients with pulmonary arterial hypertension (PAH). Genetic deletion of its encoding gene, Slc39a12, ameliorates the disease in rodent models. Here, we show that ZIP12 overexpression in human pulmonary artery smooth muscle cells (PASMCs) increased intracellular labile Zn2+ and promoted proliferation. ZIP12 siRNA knockdown attenuated pulmonary hypertension in rodent models. We developed a humanized anti-ZIP12 monoclonal antibody, APL-9796, that normalized intracellular Zn2+ concentration, suppressed proliferation in fibroblasts derived from patients with PAH and PDGF-stimulated PASMCs, and reduced PDGF-induced cytoskeletal remodeling in PASMCs and contractility in PASMCs and engineered pulmonary artery tissues. APL-9796 showed dose-dependent efficacy in humanized Slc39a12 rats, improving cardiopulmonary parameters after induction of pulmonary hypertension and was well tolerated in phase 1 clinical studies. Transcriptomic profiling revealed modulation of several molecular pathways, including those involving AMPK, PPAR, and PI3K-Akt. ZIP12-driven labile Zn2+ signaling underpins the pathogenesis of PAH. Targeting ZIP12 with APL-9796 offers a promising therapeutic strategy.
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Journal articleNaghavi N, Barbaro L, Griffiths M, et al., 2026, , Scientific Reports, Vol: 16, ISSN: 2045-2322
Hemolysis, the rupture of red blood cells, releases hemoglobin, haem, and redox-active iron into the bloodstream. When the body’s scavenging capacity is overwhelmed, these species can exert deleterious effects, as seen in hemolytic disorders. Hemolysis can also occur in extracorporeal circuits due to mechanical forces acting on blood during circulation. To mitigate these effects, we developed a filter designed for integration into extracorporeal circuits that is designed to capture hemolysis-associated byproducts using immobilised ligands. The filter prototype comprises glyoxal-functionalized agarose beads covalently immobilized with three binding agents: haptoglobin (Hp, binds cell-free hemoglobin [cfHb]), human serum albumin (HSA, binds haem), and desferrioxamine (DFO, binds free iron). Ligand immobilization was optimized to achieve strong covalent attachment to the agarose matrix. Optimized immobilization produced high ligand loading per milliliter of beads (mean ± SD): Hp 74.4 ± 11.7 mg/mL, HSA 84.6 ± 8.2 mg/mL, and DFO 43.3 ± 4.8 mg/mL. In vitro studies showed removal capacities of 12.7 ± 0.2 mg/mL for cfHb, 2708.5 ± 18.5 µg/mL for haem, and 309.7 ± 13.7 µg/mL for iron. The system retained binding activity in plasma and hemolyzed whole blood, and no increase in TAT or D-dimer was detected under the tested ex vivo conditions. These findings demonstrate the potential of this affinity-based filtration system to reduce hemolysis-associated complications in extracorporeal circulation.
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Journal articleDucker CB, Preece MV, Schofield J, et al., 2026, , Br J Haematol
Inflammation contributes to primary antiphospholipid syndrome (PAPS) pathogenesis, but cytokine profiles and associated thrombotic phenotypes remain incompletely defined. A panel of 20 cytokines, chemokines and endothelial activation markers was analysed in 37 PAPS patients on stable anticoagulation and 12 healthy controls (HC). We compared concentrations between groups and performed unsupervised hierarchical clustering and principal component analysis (PCA) to identify inflammatory subgroups. Compared with HC, patients with PAPS exhibited significantly elevated levels of 14/20 analytes: granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, interleukin (IL)-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-13, IL-17a, tumour necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), P-selectin and macrophage inflammatory protein-1β (MIP1β) (all p < 0.05). Unsupervised clustering identified three inflammatory antiphospholipid syndrome (APS) subgroups distinct from HC. A core cytokine signature comprising GM-CSF, IL-6, IL-10, IL-12p70, IL-13 and TNF-α was elevated across all APS clusters. One cluster, enriched for arterial thrombosis, demonstrated a more pronounced inflammatory phenotype, with increased IFN-α. Comparison of phenotypes showed significantly higher concentrations of GM-CSF, IFN-α, IL-1α, IL-4, IL-6, IL-10, IL-17a and TNF-α in arterial versus venous thrombosis. Our findings demonstrate widespread cytokine dysregulation and distinct inflammatory subgroups in PAPS, with arterial thrombosis showing stronger inflammation than venous thrombosis, supporting divergent thrombo-inflammatory mechanisms and potential precision immunomodulatory therapeutic targets.
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Journal articleKeles M, West LE, Arnold ND, et al., 2026, , Cardiovasc Res
AIM: Pulmonary arterial hypertension (PAH) is driven by sustained vasoconstriction and structural remodelling of distal pulmonary arteries. We have previously demonstrated that osteoprotegerin (OPG, tnfrsf11b) is upregulated in PAH animal models and patient tissues, with circulating levels being prognostic. OPG knockout mice exhibit an attenuated PAH phenotype, and therapeutic inhibition using a human monoclonal anti-OPG antibody reduces disease severity in multiple rodent models. However, the key cellular source of pathogenic OPG and the mechanism underlying therapeutic blockade remain unknown. METHODS AND RESULTS: To define the main cellular source of OPG, conditional Tnfrsf11b deletion was generated by crossing OPGfl/fl mice with PGKcretg/+ (global), LysMcretg/+ (myeloid), Myl2cretg/+ (cardiac myocytes), Cdh5cretg/+ (endothelial cells, ECs), smMHCcretg/+ (VSMCs), Col1a2cretg/+ (fibroblasts, FBs). Knockouts were induced by tamoxifen injection, and PAH established using Sugen5416/hypoxia (SuHx) model. Cardiopulmonary phenotyping included echocardiography, cardiac catheterisation, and histological analysis. Mechanistic studies were performed in VSMCs using peptide-based kinase activity profiling (PamStation).PGKcretg/+/OPGfl/fl mice phenocopied the previous results obtained with global OPG knockout (OPG-/-). Only VSMC-specific deletion (smMHCcretg/0/OPGfl/fl) resulted in significantly improved haemodynamic parameters, evidenced by reduced RVSP and pulmonary vascular resistance (PVR), and reduced pulmonary vascular remodelling demonstrating that VSMC-derived OPG is the primary driver of PAH pathogenesis.Kinome profiling of control and IPAH-PASMCs treated with OPG +/- anti-OPG antibody revealed IPAH specific regulation of PI3K-Akt and enrichment of pathways involving autophagy, and longevity regulation linked to cellular stress resistance and growth. Anti-OPG antibody treatment reduced AKT phosphorylation in IPAH PASMCs. Knock-down of AKT1 by siRNA reduced OPG-induced
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Journal articleMasood M, Pan H, Delgado-SanMartin J, et al., 2026, , BMC Pulmonary Medicine, ISSN: 1471-2466
BackgroundPulmonary hypertension (PH) is a life-threatening condition often diagnosed late due to non-specific symptoms and overlapping comorbidities with other cardiovascular and respiratory diseases. Although there have been advances in treatment, diagnostic delays are common, and patients are treated late in their disease course. Investigating the temporal ordering of recorded comorbidities may provide insight into diagnostic patterns associated with delayed PH recognition and adverse outcomes.MethodsWe identified 2,727 PH patients from the UK Biobank cohort of 440,014 participants with diseases diagnoses, and sampled two demographics-matched cohorts of chronic obstructive pulmonary disease (COPD) and heart failure (HF) with the same number of patients as the PH cohort but were not diagnosed with PH. Employing process mining, a methodology originating from business process analysis to extract temporal patterns from event logs, the temporal diagnostic sequences of comorbidity combinations preceding PH diagnosis were compared to those sequences in patients who received a final diagnosis COPD or HF. We also assessed the relative risk of mortality given different combinations of comorbidities and the genetic correlation between comorbidities.ResultsPatients diagnosed with PH had prior diagnoses of hypertension (58.1%), atrial fibrillation (31.2%), and heart failure (43.2%). Process mining revealed that the temporal order of cardiometabolic comorbidities influences the timing to diagnosis of PH, COPD and HF. Patients in which type 2 diabetes was diagnosed before systemic hypertension had received PH diagnosis 2 years and 9 months faster than the reverse sequence, where hypertension preceded diabetes. For patients with a final diagnosis of PH, HF and COPD, diagnostic sequences in which hypercholesterolemia was recorded before systemic hypertension and type 2 diabetes were associated with shorter median intervals to PH diagnosis. A sequence involving diabetes, hypertens
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Journal articleSaid MM, de Mooij RB, Jiao D, et al., 2026, , Br J Clin Pharmacol
AIMS: Imatinib improves hemodynamics in pulmonary arterial hypertension (PAH), but dose-dependent toxicity has limited its clinical development. We aimed to quantify the dose-efficacy-toxicity relationship and evaluate alternative dosing strategies using data from the PIPAH trial. METHODS: We analysed data from the Phase II PIPAH trial (17 enrolled; 15 contributed pharmacokinetic and safety data, 11 daily hemodynamic data). Total pulmonary resistance (TPR) was described using a turnover model and recurrent adverse events (AEs) using a repeated time-to-event model. RESULTS: Simulations showed that TPR reduction was dose-dependent ( E max 50%; E D 50 247 mg), whereas AE risk increased nonlinearly with dose ( E D 50 307 mg). Although a cumulative dose of 2400 mg produced similar TPR reductions, 300 mg once daily achieved a 20% reduction earlier than 200 mg (8 vs. 12 weeks) with only a modest increase in AE burden. CONCLUSIONS: Simulations support initiating treatment at 200 mg once daily with escalation to 300 mg after 8-12 weeks in patients who tolerate treatment.
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Journal articleSingh B, Mayr M, 2026, , JACC Basic Transl Sci, Vol: 11
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Journal articleKelly JA, Salih M, Patel A, et al., 2026, , Eur J Vasc Endovasc Surg, Vol: 72, Pages: 491-499
OBJECTIVE: Endovascular thoraco-abdominal aortic aneurysm (TAAA) repair can impair spinal cord perfusion, leading to paraplegia. The mechanisms driving this devastating complication are poorly understood. This study aimed to interrogate the cerebrospinal fluid (CSF) proteome in patients after TAAA repair to identify biomarkers that herald permanent paraplegia. It also aimed to investigate a potential therapeutic target identified by proteomics using an in vivo model of ischaemic spinal cord injury (iSCI). METHODS: CSF was collected for proteomic analysis from patients before and following TAAA repair. A differentially expressed protein identified in human paraplegic subjects was subsequently interrogated in a rodent model of iSCI. The protein composition of CSF was analysed using tandem mass tag proteomics. Neurological examinations were carried out by a blinded neurologist and T2 weighted magnetic resonance imaging (MRI) was used to measure spinal cord volume and oedema. A rodent model of iSCI was used to investigate a clinically relevant therapeutic target informed by proteomic findings. RESULTS: CSF analysis was taken from 37 patients, all of whom had aneurysm repair using a custom branched and or fenestrated device (median age 73.5 years, range 67 - 78 years; 27 men, ten women; Crawford classification: six type I, 11 type II, 15 type III, three type IV, and two type V). Five patients remained permanently paraplegic and seven recovered from transient paraplegia. The CSF of patients who remained paraplegic contained approximately fourfold more aquaporin-4 (AQP4) (41.8 ± 19.2 ng/mL, n = 5) than those who recovered from paraplegia (10.8 ± 1.3 ng/mL, n = 7; p = .005) or did not develop paraplegia (10.8 ± 1.2 ng/mL, n = 25; p = .004). Permanently paraplegic patients had CSF AQP4 levels > 15 ng/mL and this was associated with greater cord oedema on T2 weighted MRI (1.77 ± 0.19 vs. 1.03 ± 0.36; p = .032). In a rodent model of iSCI
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Journal articleYin S, Mayr U, Barallobre-Barreiro J, et al., 2026, , Arterioscler Thromb Vasc Biol, Vol: 46
BACKGROUND: Calcific aortic valve (AV) disease (CAVD) is recognized as an active pathological process involving extracellular matrix remodeling. This study investigates extracellular matrix remodeling through proteomic analysis and a novel mouse model of aortic stenosis. METHODS: Proteomic and glycoproteomic analyses were conducted on AV leaflets from heart transplant donors (n=29) and patients with CAVD (n=17). Each CAVD sample was subdivided into noncalcified and calcified regions. To investigate the functional impact of extracellular matrix remodeling on aortic stenosis, we crossed apolipoprotein E-deficient mice (ApoE-/-) with mice lacking the catalytic domain of ADAMTS5 (Adamts5Δcat) to generate a mouse model combining hyalectan accumulation with hypercholesterolemia. RESULTS: Proteomic and glycoproteomic analyses revealed hyalectan accumulation in CAVD compared with control valves. Versican predominated in noncalcified regions, while aggrecan was enriched in calcified regions. The shift in hyalectan composition correlated with changes in AV pressure gradient, elevated osteoblast-like cell markers, and inflammatory proteins, most notably pentraxin 3. Both versican and aggrecan are characterized by their ability to bind hyaluronan and serve as substrates of ADAMTS5. In Adamts5Δcat/ApoE-/- mice, hyalectan accumulation was associated with narrowed aortic cusp separation and increased post-AV velocity. Proteomic analysis of AVs from Adamts5Δcat/ApoE-/- mice revealed elevated versican, aggrecan, and pentraxin 3, recapitulating key features of human CAVD. Single-cell RNA sequencing and in vitro experiments linked versican to activated valve interstitial cells, while aggrecan colocalized with calcification markers in osteoblast-like cells. Pentraxin 3 was bound to hyaluronan and accumulated in calcified AVs. ADAMTS5 deficiency was sufficient to cause intact versican accumulation and promote valve interstitial cell activation, accompanied by increased
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Journal articleTakov K, Penkov S, Pechlaner R, et al., 2026, , Atherosclerosis, Vol: 420
BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is described as a low-density lipoprotein-like particle, but recent work suggests heterogeneity, including triglyceride (TG)-rich features. We investigated whether native Lp(a) carries an apolipoprotein E (APOE)-associated TG signature, whether it is remodeled postprandially, and whether Lp(a)-associated TG species are linked to cardiovascular risk. METHODS: Plasma Lp(a) was immunocaptured under native conditions and analyzed by proteomics in patients with high Lp(a) (n = 15) and lipidomics in healthy volunteers (n = 9). Lp(a) produced in HepG2 cells was characterized using immunoprecipitation, density gradient ultracentrifugation, microsomal triglyceride transfer protein inhibition, and fatty acid loading. Matched fasting and postprandial samples assessed Lp(a) lipidome remodeling (n = 6). The relationship between Lp(a)-associated TGs and cardiovascular risk was examined in the community-based Bruneck Study (n = 623). RESULTS: Direct plasma Lp(a) immunocapture showed APOE enrichment, confirmed by proteomics, immunoblotting, reverse APOE immunocapture, and size-exclusion chromatography followed by Lp(a) immunoprecipitation. In vitro, HepG2 cells secreted APOE-containing Lp(a) that was more buoyant than apolipoprotein B (APOB)-only particles and less affected by lomitapide or fatty acid loading. The Lp(a) lipidome was more stable postprandially than plasma lipids. Plasma Lp(a) depletion reduced 35 lipid species, predominantly TGs, including TG(52:3) and TG(52:4), previously linked to incident cardiovascular disease. TG reduction following Lp(a) depletion correlated with attenuation of cardiovascular risk after Lp(a) adjustment in the Bruneck Study, supporting a clinically relevant TG signature of native Lp(a). CONCLUSIONS: Native plasma Lp(a) carries a defined TG signature that is relatively stable postprandially and linked to incident cardiovascular disease.
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Journal articleMacko A, Pecon-Slattery J, Shovlin CL, 2026, , QJM: An International Journal of Medicine, ISSN: 1460-2725
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Recent genetic data suggest hereditary haemorrhagic telangiectasia (HHT) is 2–12 times more common than the clinically ascertained prevalence, potentially above the ‘rare disease’ designation threshold, and undermining clinical predictions for asymptomatic individuals diagnosed by genetic testing.</jats:p> </jats:sec> <jats:sec> <jats:title>Aim</jats:title> <jats:p>To test, we examined if missense variants in HHT disease-causing genes may have been misclassified as pathogenic (LP/P) or benign (B/LB).</jats:p> </jats:sec> <jats:sec> <jats:title>Design</jats:title> <jats:p>Evaluation of ClinVar-annotated missense variants in ENG, ACVRL1 and SMAD4.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Human-independent methods using CodeXome for pan-primate evolutionary history, and AlphaMissense which incorporates AlphaFold predictions for protein misfolding were used to validate/reclassify pathogenic and benign missense variants</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>ClinVar annotations were commonly conservative with 35–90% of rare missense substitutions in ENG, ACVRL1 and SMAD4 classified as variants of uncertain significance. CodeXome identified 92% of ClinVar-annotated B/LB variants were shared with other primate species, supporting their benign classification. AlphaMissense metrics stro
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Journal articleYogeswaran A, Fünderich M, Kiely DG, et al., 2026, , Chest
BACKGROUND: Pulmonary vascular diseases are characterized by mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR), both reflecting the steady-flow component of right ventricular (RV) afterload while neglecting pulsatile elements. Pulmonary artery compliance (PAC) and arterial elastance (Ea) capture complementary aspects of pulmonary vascular load, whereas stroke volume index (SVI) reflects RV functional adaptation. The prognostic significance of these integrated parameters remains incompletely understood, particularly in early-stage disease. RESEARCH QUESTION: Do PAC, Ea, and SVI predict mortality independently of PVR in patients with mild pulmonary hypertension (PH) and across the full spectrum of PH? STUDY DESIGN AND METHODS: Using the international PVRI GoDeep meta-registry, we first evaluated the prognostic relevance of PAC, Ea, and SVI in patients with mild PH, defined as a mPAP > 20 mm Hg and < 25 mm Hg. Subsequently, these analyses were extended to the overall PH population across the full spectrum of disease severity. Subgroup analyses were performed according to PH etiology. PAC was calculated as the ratio of stroke volume to pulmonary arterial pulse pressure, and Ea as end-systolic pressure divided by stroke volume. RESULTS: In patients with mild PH (n = 1,097), neither mPAP nor PVR predicted mortality (both P > .05). In contrast, Ea, PAC, SVI, and heart rate demonstrated independent prognostic value. Expanding the analysis to 16,899 patients across PH groups 1-5, these parameters remained significantly associated with survival, independent of PVR/total pulmonary resistance and after adjustment for multiple potential confounders. Consistent findings were observed across etiological subgroups and idiopathic pulmonary arterial hypertension/heritable pulmonary arterial hypertension. INTERPRETATION: Parameters integrating pulsatile vascular load and interdependent RV function possess predictive power independent of PVR/total p
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Journal articleKhamis R, 2026,
Effects of walnut consumption on anti-MDA-LDL antibodies and immunoglobulins in the WAHA randomized trial
, JACC: Advances, ISSN: 2772-963XBackground: Higher total serum IgG levels have been associated with protection from cardiovascular events in the ASCOT Trial. Antibodies against Ox-LDL have also been linked to favourable clinical and vascular imaging outcomes. Objective: To determine whether regular walnut consumption influences circulating immunoglobulins, malondialdehyde-modified low-density lipoprotein (MDA-LDL), a highly immunogenic form of Ox-LDL, and antibodies against MDA-LDL. Methods: The Walnuts and Healthy Aging (WAHA) study was a two-centre, randomised controlled trial conducted in Spain and the USA. Adults aged 63-79 years were assigned to a walnut-enriched diet or a control diet excluding walnuts for two years. Serum total IgG, total IgM, MDA-LDL as well as IgG and IgM anti MDA-LDL antibodies were measured by enzyme-linked immunoassays in 474 participants. Results: Baseline immunoglobulin concentrations differed substantially by study centre. Participants from the USA had 25% lower total IgM and IgG concentrations than participants from Spain. Walnut consumption increased total serum IgG by 11% in the US cohort (95% CI: 0-24%; p=0.04), while pooled analysis showed a 6% increase across both cohorts (95% CI: 0-12%; p=0.04). Over the two-year study period, total IgM and both IgG and IgM anti-MDA-LDL concentrations declined significantly in both control and intervention groups. Conclusion: Long-term walnut consumption was associated with a modest increase in total serum IgG but had no significant effect on total IgM, MDA-LDL, or antibodies against MDA-LDL. Baseline IgG and IgM concentrations were substantially lower among US participants, suggesting that geographic, environmental, social, or genetic factors may modulate immune biomarkers independently of dietary intervention.
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Journal articleMoss BAS, Duregotti E, Yin X, et al., 2026, , J Vis Exp
Vascular smooth muscle cells (SMCs) reside within the medial layer of blood vessels, where they interact with an extracellular matrix (ECM) composed of collagen, elastin, and proteoglycans to maintain vascular structure and function. Aberrant ECM remodeling contributes to multiple vascular diseases; however, conventional two-dimensional culture systems do not adequately recapitulate the three-dimensional (3D) cellular and matrix environment required to study SMC-ECM interactions and matrix remodeling. This protocol describes the generation of engineered vascular tissues (EVTs) from primary human aortic SMCs cultured within fibrin-based 3D hydrogels. Following casting between flexible polydimethylsiloxane posts, EVTs undergo cellular alignment, contraction, and deposit de novo ECM, providing a physiologically relevant platform for studying vascular matrix biology. The protocol details tissue fabrication, culture, harvesting, and downstream analysis of newly deposited ECM by immunofluorescence staining. In addition, a workflow is presented for qualitative and quantitative characterization of EVT-derived proteins using Western blotting and mass spectrometry-based proteomics. Sequential protein extraction enables assessment of soluble and ECM-enriched protein fractions, facilitating in-depth evaluation of ECM composition. This platform provides a reproducible approach for investigating ECM production and remodeling by human SMCs in a 3D environment.
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Journal articleKhawaja SA, Hanna L, Singh A, et al., 2026, , EuroIntervention, Vol: 22, Pages: 883-890
BACKGROUND: Stroke remains a significant concern in patients undergoing transcatheter aortic valve implantation (TAVI). Despite advances in TAVI technology and techniques, stroke rates have remained unchanged, with trials of cerebral embolic protection devices failing to reduce rates. The concept of air emboli has not been previously investigated in TAVI procedures. We hypothesised that gaseous emboli could play a significant role in TAVI and that carbon dioxide (CO2) flushing of the TAVI valves could reduce the incidence of new neurological lesions post-TAVI. AIMS: We aimed to demonstrate the neuroprotective benefits of CO2 flushing in TAVI patients. METHODS: INTERCEPTavi is a single-centre, blinded, randomised controlled pilot trial that studied the effects of flushing TAVI valves with CO2 versus conventional saline on neurological outcomes post-TAVI, assessed using magnetic resonance imaging (MRI) and transcranial Doppler (TCD). Patients with aortic stenosis were randomised after obtaining vascular access. Periprocedural TCD assessed solid and gaseous emboli to the brain. Post-procedure, patients underwent brain MRI to detect lesions. Here, we report the primary outcome of feasibility, as well as the secondary MRI and mechanistic TCD outcomes. RESULTS: A total of 60 patients were recruited and randomised 1:1 to CO2 and saline flushing (TAVI-CO2) versus saline flushing only (TAVI-S). CO2 flushing significantly reduced the average number of lesions per patient (TAVI-CO2: 4 lesions/patient vs TAVI-S: 8.5 lesions/patient; p=0.031). The total infarct area was numerically lower in the TAVI-CO2 group (40.32 mm2 vs 93.20 mm2), although this did not reach statistical significance (p=0.111). Similarly, TCD showed fewer microembolic signals in the TAVI-CO2 arm, primarily due to a reduction in gaseous emboli, but this difference was not statistically significant (p=0.5). CONCLUSIONS: INTERCEPTavi is a pioneering, first-in-human randomised trial that demonstrated that CO2 flu
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Journal articleAkhundova N, Paul R, Fletcher B, et al., 2026, , Journal of Cachexia, Sarcopenia and Muscle, Vol: 17, ISSN: 2190-5991
BackgroundA loss of muscle mass and strength is a marker of poor outcomes following surgery. Changes in muscle gene expression following surgery are likely to contribute to postsurgical muscle loss, but the mechanisms controlling these changes are not known. We have previously shown that miRNAs associate with muscle loss in disease, including surgery, so may contribute to changes in gene expression. We analysed the change in muscle gene expression following surgery and compared it to pre- and postsurgical miRNA expression. We then analysed the effect of one of these miRNAs (miR-675-5p) on gene expression in myoblasts in the presence and absence of an inflammatory stimulus.MethodsDifferential gene expression analysis was performed on RNAseq data from rectus femoris biopsies (n = 18 male patients) pre- and postsurgery. Gene expression was compared with miRNA expression in the same samples to identify patterns of mRNA expression associated with physiology and miRNA expression. The effect of miR-675-5p on gene expression in the presence and absence of TNF-α was determined in LHCN myoblasts by RNAseq.ResultsPostsurgery muscle had increased expression of gene sets associated with TNF-α signalling (2.7-fold) and MYC targets (2.7-fold). Loss of muscle mass and strength associated with MYC target gene sets, but inflammatory gene sets only associated with loss of strength.Comparing miRNA expression with postsurgery gene expression showed that presurgery miR-675-5p expression was most closely associated with postsurgical gene expression, indicating that the presurgery phenotype is important in determining the response to surgery. Presurgery miR-675-5p correlated with change in gene expression in response to surgery (β = 1.30, p < 0.001), such that individuals with the highest presurgery miR-675-5p had the largest change in gene expression in response to surgery.In LHCN myoblasts miR-675-5p increased CCL2 protein rel
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Journal articleShamsi A, Wincup C, Pericleous C, et al., 2026, , Rheumatology (Oxford), Vol: 65
SLE is an established, independent risk factor for cardiovascular disease (CVD), most notably premature atherosclerotic cardiovascular disease (ASCVD). This association is thought to relate to chronic immune-mediated inflammation. Clonal expansion of haematopoietic stem and progenitor cells (HSPCs) with acquired mutations, but no evidence of a blood disorder, is known as clonal haematopoiesis of indeterminate potential (CHIP). CHIP is associated with a pro-inflammatory immune phenotype, driven predominantly by mutant myeloid cells, and is similarly strongly associated with ASCVD. When SLE and CHIP co-occur, there may be synergy of their canonical cellular and molecular inflammatory pathways or even convergence of pathways through shared mechanisms of immune dysregulation, which accelerate CVD. Furthermore, enrichment of HSPC clones carrying CHIP driver mutations has been observed in chronic inflammatory conditions, including SLE. In this review, we explore the emerging role of CHIP in the relationship between SLE and ASCVD, proposing it as a pathogenic nexus in a triangular inflammatory network. Defining these relationships will help early identification of high-risk individuals and facilitate therapeutic targeting of CHIP to mitigate ASCVD complications in SLE patients.
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Journal articleZiverec A, Grangy J, Pécheux Y, et al., 2026, , Mater Today Bio, Vol: 39
The use of articular chondrocytes for cartilage repair is constrained by donor-site morbidity, poor proliferation, and difficulties to maintain a stable phenotype. As a result, nasal chondrocytes (NCs) have recently emerged as an alternative cell source. To better establish the potential of NCs in tissue engineering, we have explored their response to the activation of collagen-binding proteins (integrins, discoidin domain receptors (DDRs) andthe secreted protein acidic cysteine-rich (SPARC)) which are essential to cartilage homeostasis. Ligands for these proteins were synthesized as triple-helical peptides (THPs) that mimic the biological and structural properties of collagen, and were covalently linked to PEG or alginate hydrogels hosting human NCs. Compared to human adipose-tissue mesenchymal stem cells, NCs over-expressed chondrogenic markers, yielding higher Sox9 translocation and type II collagen production. THP ligands significantly improved the expression of key cartilage extracellular matrix components in hydrogels, at both the RNA and protein level, for up to 21 days of culture. In particular, THP ligands for DDRs and SPARC led to increased glycosaminoglycan and collagen deposition. In addition, THPs limited fibrocartilage formation, matrix metalloproteinase 13 expression and chondrocytes hypertrophy after 7 days of culture in hydrogels. This work introduces a biomimetic strategy to drive the early stages of the formation of an engineered cartilage tissue from NCs, by replicating key cell/collagen interactions. It provides a preliminary effort to combine an accessible cell source with functionalized biomaterials for cartilage repair.
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