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Journal articleSchmiedmayer P, Johnson A, Schuetz N, et al., 2026,
Design and rationale of the my heart counts cardiovascular health study: a large-scale, fully digital biobank, and randomized trial of large language model-driven coaching of physical activity.
, Am J Prev Cardiol, Vol: 28BACKGROUND: Cardiovascular disease remains the leading cause of global morbidity and mortality. The original My Heart Counts smartphone application demonstrated the feasibility of large-scale, fully digital recruitment and trial conduct, but was limited by platform exclusivity and the need for human experts to create text-based behavioral interventions. METHODS: The next-generation My Heart Counts smartphone application is a prospective, observational cohort study with an embedded randomized crossover trial, evaluating personalized text-based coaching prompts, available in both English and Spanish. All study and trial operations will be conducted via the My Heart Counts smartphone application, re-designed using the open-source Stanford Spezi framework to support iOS, with a planned Android release in 2027. The target enrollment is N = 15,000 adults across the United States and United Kingdom. The study establishes a comprehensive digital biobank by synthesizing passive mobile health data (steps, flights climbed, heart rate, sleep, workouts), raw sensor data (e.g., accelerometry), longitudinal clinical surveys, active tasks (6-minute walk test and 12-minute Cooper run test), electrocardiograms (ECG), and electronic health record (EHR) data integrated via HL7 FHIR protocols. The embedded trial evaluates the effect of text-based coaching prompts generated by a large language model (LLM) grounded in the Transtheoretical Model of Change on daily physical activity, as compared to generic prompts. PLANNED ANALYSIS: The primary endpoint of the randomized crossover trial is change in daily step count between LLM-driven and generic text-based intervention arms, analyzed using mixed-effects models. Secondary endpoints include change in mean active minutes and calorie burn over each intervention week. Other exploratory analyses include the changes in submaximal (6-minute walk test) and maximal (Cooper 12-minute run test) cardiorespiratory fitness, changes to sensor-derived biom
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Journal articleYin S, Mayr U, Barallobre-Barreiro J, et al., 2026,
Aortic Stenosis Hyalectan Remodeling Revealed by Proteomics and Glycoproteomics.
, Arterioscler Thromb Vasc BiolBACKGROUND: 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 differentiation, as evidenced by inc
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Journal articleNaghavi N, Barbaro L, Griffiths M, et al., 2026,
Development of a hemolysis filter system for the selective removal of free hemoglobin, heme and iron from blood envisaged for use in extracorporeal circuits
, Scientific Reports, ISSN: 2045-2322Hemolysis, the rupture of red blood cells, releases hemoglobin, heme, 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 heme), 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 heme, 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 articleKardys I, Mayr M, Mair J, et al., 2026,
Proteomics profiling for cardiovascular risk prediction: transforming clinical care.
, Eur Heart J Acute Cardiovasc Care, Vol: 15, Pages: 481-483 -
Journal articleSharma T, Fall T, Sayols-Baixeras S, et al., 2026,
Linking Lipidomics to Vulnerable Coronary Plaques: A PROSPECT II Substudy.
, Arterioscler Thromb Vasc BiolBACKGROUND: Lipidomics, the comprehensive profiling of circulating lipid species, has emerged as a powerful tool to investigate metabolic alterations underlying coronary atherosclerosis. Understanding the mechanisms driving high-risk vulnerable plaque formation and progression to myocardial infarction remains a key therapeutic priority. This study investigates associations between circulating lipid metabolites and imaging-defined features of vulnerable coronary plaque. METHODS: Following revascularization, patients with myocardial infarction underwent 3-vessel coronary artery imaging with near-infrared spectroscopy and intravascular ultrasound to assess nonflow-limiting plaques for lipid core burden index and plaque burden. Multivariable models evaluated associations between 424 lipid metabolites in plasma, quantified by mass spectrometry, pan-coronary lipid, pan-coronary plaque burden, and high-risk vulnerable plaque measures (maximum lipid core burden index within any 4-mm segment across the entire lesion ≥324.7 and plaque burden ≥70%) in 877 patients. Findings were validated in the SCAPIS study (Swedish Cardiopulmonary Bioimage Study) using coronary computed tomography angiography-based measures of coronary artery calcium score and segment involvement score. RESULTS: We identified 156 significant associations (P<0.05) between lipid metabolites and coronary plaque characteristics across 39 metabolic pathways. Sphingomyelins were inversely associated with all plaque metrics, and 1-palmitoyl-2-oleoyl-GPE (16:0/18:1), a phosphatidylethanolamine, was positively associated with all plaque metrics. After correcting for multiple testing, 27 lipid species across 7 pathways remained significant (q<0.05). The majority were linked to pan-coronary lipid burden, with the strongest inverse association observed for sphingomyelin d18:1/22:1, d18:2/22:0, and d16:1/24:1. Similar inverse patterns were seen for select dihydrosphingomyelins and fatty acid dicarboxylates. I
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Journal articleIssitt T, Kagugbe GW, Toe QK, et al., 2026,
Iron Compartmentalisation and Vascular Endothelial Cell Dysfunction.
, Antioxidants (Basel), Vol: 15, ISSN: 2076-3921Iron is essential for life, but its safe use by the body depends on it being kept within tightly controlled compartments. When this compartmentalisation is disrupted-through haemolysis, saturation of scavenger proteins, or dysregulation of the hepcidin-ferroportin axis-damaging iron species accumulate in the circulation and within vascular cells, with potentially serious consequences for endothelial function. This review explores the mechanisms by which iron dysregulation compromises vascular endothelial cell biology across a range of disease states, including haemolytic anaemias, atherosclerosis, cerebrovascular disease, extracorporeal circulatory support, and iatrogenic iron loading. Common pathological themes emerge: depletion of nitric oxide bioavailability, oxidative stress, endothelial activation, and in chronic settings, vascular remodelling. The review subsequently focuses in depth on the pulmonary vasculature, where dysregulated iron compartmentalisation has emerged as a key contributor to the pathogenesis of pulmonary hypertension. Here, iron-driven mitochondrial dysfunction, smooth muscle cell proliferation, and iron-dependent lipid peroxidation via ferroptosis are discussed as mechanistic drivers of pulmonary vascular remodelling. The therapeutic implications of targeting iron handling in pulmonary hypertension are considered, including modulation of the hepcidin-ferroportin axis. Together, the evidence presented highlights disordered iron compartmentalisation as a unifying pathological thread across vascular disease and a compelling target for intervention.
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Journal articleAlharbi R, Keles M, Fernandez N, et al., 2026,
KLF6 activation marks an angiogenic and apoptosis resistant endothelial phenotype in pulmonary arterial hypertension
, Communications Biology, ISSN: 2399-3642 -
Journal articleBarallobre-Barreiro J, Mayr M, 2026,
Proteomic insights into bi-atrial remodelling in persistent atrial fibrillation.
, Cardiovasc Res, Vol: 122, Pages: 958-959 -
Journal articleMarchetti M, Meloni M, Anwar M, et al., 2026,
Correction: Marchetti et al. MicroRNA-24-3p Targets Notch and Other Vascular Morphogens to Regulate Post-ischemic Microvascular Responses in Limb Muscles. Int. J. Mol. Sci. 2020, 21, 1733.
, Int J Mol Sci, Vol: 27In the original publication [...].
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Journal articleToe QK, Issitt T, Quinlan GJ, et al., 2026,
The Interplay Between IL-6, Hepcidin, and BMPR2 Signalling in Pulmonary Arterial Hypertension: Mechanistic Insights Into Vascular Remodelling.
, Pulm Circ, Vol: 16, ISSN: 2045-8932Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary vasoconstriction and vascular remodelling, with mutations in bone morphogenetic protein receptor type 2 (BMPR2) being the most common genetic alteration associated with the disease. While inflammatory mediators like interleukin-6 (IL-6) and the iron-regulatory hormone hepcidin have been implicated in vascular remodelling, their interaction with BMPR2 signalling remains poorly understood. This study investigated how IL-6 and hepcidin influence BMPR2 expression and downstream signalling in human pulmonary arterial endothelial cells (hPAECs). Using qPCR and Western blot analyses, we demonstrated that both IL-6 and hepcidin significantly reduced BMPR2 mRNA and protein levels in hPAECs. Intriguingly, despite this reduction, SMAD1/5 phosphorylation remained active, suggesting compensatory signalling through alternative receptor complexes. Treatment with IL-6 and hepcidin upregulated inhibitors of differentiation (ID) protein expression, mimicking the effects observed with BMPR2 knockdown. These findings reveal a novel regulatory axis involving IL-6, hepcidin, and BMPR2 in PAH pathogenesis, where IL-6 and hepcidin promote vascular remodelling through both BMPR2-dependent and independent mechanisms. These results suggest that therapeutic strategies targeting this axis, particularly those aimed at rebalancing BMP/TGF-β signalling, may hold promise for treating PAH.
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Journal articlePericleous C, Strauss E, Arachchillage DJ, 2026,
Endothelial dysfunction in APS: advancing pathophysiological understanding to improve management.
, Curr Opin Immunol, Vol: 100Endothelial dysfunction (ED) is a hallmark of antiphospholipid syndrome (APS) driven by chronic antiphospholipid antibody (aPL) exposure. Beyond acute thrombotic events, ED contributes to atherosclerosis, vascular remodelling, stenosis and multi-organ manifestations, positioning the endothelium as a putative target for disease monitoring and therapeutic intervention. In this review, we integrate new experimental and clinical studies with emerging data presented at recent international meetings that advance our understanding of endothelial pathophysiology in APS. These studies reveal novel APS vascular endotypes and convergence between aPL-driven endothelial thromboinflammation, endothelial-to-mesenchymal transition, extracellular matrix remodelling and aberrant cell growth pathways across arterial, venous and capillary territories, and multiple organs. We discuss evolving approaches to assess endothelial health, including circulating biomarkers, endothelial colony-forming cells, and non-invasive functional and imaging-based tools. Finally, we highlight the need to integrate early detection, aggressive cardiovascular risk modification and precision medicine to mitigate ED and improve long-term outcomes in APS.
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Journal articleLundby A, Van Eyk JE, Mayr M, et al., 2026,
Consensus statement on mass spectrometry-based proteomic analysis of cardiac tissue.
, Nat Cardiovasc Res, Vol: 5, Pages: 526-540Mass spectrometry-based cardiac proteomics provides direct molecular insight into cardiac physiology and disease. While plasma proteomics has advanced biomarker discovery, the analysis of cardiac tissue is essential for mechanistic understanding and therapeutic target identification; however, proteomic investigation of cardiac tissue faces unique challenges, including limited sample availability, regional heterogeneity, variability in collection and processing, and inconsistent reporting practices that hinder reproducibility and data integration. Here, we provide a practical framework for designing and conducting mass spectrometry-based proteomic studies of cardiac tissue and primary cardiac cells. We outline best practices and key considerations for sample handling, experimental design, data acquisition, quality control and statistical analysis. This guideline aims to support cardiac researchers in generating robust and reproducible proteomics datasets that advance our understanding of cardiac biology in both physiological and pathological contexts.
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Journal articleNaser J, Fogell NA, Patel M, et al., 2026,
Experimental comparisons of optical coherence tomography-based versus angiography-based time-averaged wall shear stress estimations.
, Int J Cardiovasc Imaging, Vol: 42, Pages: 1029-1043An approach to rapid simulation of time-averaged wall shear stress (TAWSS) on 3D geometries created from 3D Quantitative Coronary Angiography (3D-QCA) methodology has been developed, which enables rapid computational fluid dynamic (CFD) shear stress simulation. We compared TAWSS estimated from 3D-QCA-CFD with optical coherence tomography (OCT)-based CFD simulations in coronary arteries. 15 normal and 5 stenotic coronary arteries in instrumented minipigs were studied. 3D arterial geometries were reconstructed from 3D-QCA and OCT using common centrelines and matched axial positions. Identical boundary conditions were used for both methods through directly measured vessel-specific inlet blood velocities. TAWSS was calculated for axially matched segments (n = 80 for normal arteries; n = 160 for stenotic arteries) and in 3 mm/60° sectors. Mean TAWSS simulation times for 3D-QCA and OCT-based CFD were 17.8 min and ~ 1.5 h respectively. There were significant but numerically small differences in TAWSS for normal arteries (-0.21 ± 0.64 Pa [95%CI -1.04,1.46], p < 0.001), and no significant difference for stenotic arteries (-0.39 ± 3.04 Pa [95%CI -6.35, 5.56], p = 0.25). Axial TAWSS profiles along vessel lengths were similar between the two methods. There is a trend of underestimation by 3D-QCA at higher values of TAWSS compared with OCT, due to differences in geometry dimensions. Similar spatial distributions of TAWSS in both normal and stenotic arteries were observed from co-registered TAWSS maps. This study suggests that 3D-QCA-based TAWSS is feasible in both normal and stenotic arteries and that further clinical evaluation of rapid TAWSS from 3D-QCA is warranted, which may facilitate clinical adoption of TAWSS assessment.
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Journal articleSamaranayake CB, Niglas M, Baxan N, et al., 2026,
Hemodynamic and metabolomic responses to infusion of GLP-1 agonist exenatide in pulmonary arterial hypertension
, JCI Insight, Vol: 11, ISSN: 2379-3708Preclinical studies suggest beneficial effects of GLP-1 agonists in pulmonary arterial hypertension (PAH). This first-in-disease study evaluated acute hemodynamic effects of GLP-1 agonist, exenatide administered i.v. in patients with idiopathic PAH and CTEPH as well as in a PAH rodent model. Seventeen patients (9 idiopathic PAH) received an exenatide infusion during right heart catheterization, which included multisite sampling for circulating metabolites. Acute effects of exenatide were also assessed by cardiac magnetic resonance imaging in monocrotaline (MCT) PAH and control rats. In the clinical study, exenatide was well tolerated, reduced mean pulmonary artery pressure (45 ± 15 mmHg versus 40 ± 18 mmHg), and improved cardiac index (2.1 ± 0.6 L/min versus 2.4 ± 0.9 L/min/m2) and pulmonary vascular resistance (7.8 ± 8.0 WU versus 5.9 ± 5.0 WU) across all patients. Right ventricular (RV) contractility and afterload improved in a subset of patients undergoing pressure-volume measurements. In an exploratory metabolomics analysis, 47 metabolite levels changed after exenatide infusion, predominantly in free fatty acid pathways. Six metabolites with prognostic relevance in PAH within myocardial glycolytic and lipid oxidation pathways were also altered after exenatide. In MCT rats, exenatide improved RV stroke-volume, RV ejection fraction, and RV-arterial coupling. These findings support the further evaluation of exenatide within chronic studies as a potentially novel pulmonary vasodilator therapy.
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Journal articleConstantinescu-Bercu A, Smith KE, Wong SY, et al., 2026,
Von Willebrand factor deficiency impairs angiogenesis via angiopoietin-2: relevance for gut angiodysplasia
, Blood Journal, Vol: 147, Pages: 2541-2553, ISSN: 0006-4971Management of recurrent gastrointestinal (GI) bleeding is a clinical unmet need for patients with von Willebrand disease (VWD) and is linked to the presence of gut vascular malformations (angiodysplasia). We previously demonstrated that von Willebrand factor (VWF) regulates angiogenesis and vascular integrity. VWF controls the storage of the angiogenesis regulator angiopoietin-2 (Angpt-2) in endothelial cells (EC), suggesting a candidate for the genesis of angiodysplasia; however, no direct evidence of the role of Angpt-2 in VWF-dependent angiogenesis is available. Using VWF-deficient human umbilical vein EC (HUVEC) and endothelial colony-forming cells (ECFCs) from patients with severe VWD, we found that loss of VWF resulted in increased Angpt-2 expression through the positive feedback loop Angpt-2–Tie-2–Akt–FOXO1–Angpt-2. In the gut of VWF-deficient mice, Angpt-2 expression was increased, whereas Angpt-1 expression was decreased, suggesting that VWF regulates the Angpt/Tie2 balance in the gut. Moreover, the intestinal vasculature in the jejunum of VWF-deficient mice appeared abnormal, with hypersprouting and lumen formation defects. The findings reveal VWF-deficient mice as a model to study gut angiodysplasia. We investigated sprouting angiogenesis in vitro using a fibrin bead assay and found increased sprouting in VWF-deficient EC. We developed a 3-dimensional microfluidic model of angiogenesis and found that ECFCs from patients with severe VWD exhibit defective remodeling and abnormal lumen formation, reminiscent of the defects in the gut of VWF-deficient mice. Importantly, inhibition of Angpt-2 reduced sprouting in VWF-deficient HUVEC and normalized vascular remodeling in VWD-ECFCs, suggesting that Angpt-2 inhibitors may be effective in patients with VWD with GI bleeding and angiodysplasia.
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Journal articleJones RJ, De Bie EMDD, Deliu N, et al., 2026,
Sotatercept reduces bone morphogenetic protein signaling in patients with pulmonary arterial hypertension.
, Sci Transl Med, Vol: 18Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease where imbalances in the transforming growth factor-β (TGF-β) and bone morphogenetic protein receptor type II (BMPR-II) superfamily pathways have causal roles in hereditary and idiopathic forms of the disease. These pathways are emerging attractive candidates for therapeutic intervention, but there is an unmet need for clinically relevant and practical biomarkers that can measure target engagement, partly because of the inaccessibility of lung tissue in disease for molecular profiling. Here, we explored the surrogate capacity of peripheral blood bone morphogenetic protein (BMP) pathway-specific markers using samples collected in the StratosPHere 1 study using both cell surface assessment of BMPR-II receptor levels and quantitative PCR for the assessment of downstream target engagement. Downstream BMPR-II canonical and noncanonical signaling was measurable and altered in whole blood in both discovery and international replication cohorts, and transcriptomic signatures were clustered by discrete gene modules that associated with clinical outcomes and mortality. We derived a transcriptomic biomarker panel that was repeatable, reproducible, and longitudinally stable for use in early phase, target engagement clinical trials. The biomarker panel was used in a pilot study of nine sotatercept-treated patients with PAH to test the effect of the therapy on the BMP pathway; analysis suggested that sotatercept did not rebalance or increase BMPR-II pathway signaling but rather led to a reduction, possibly due to depletion of circulating BMP9 and BMP10.
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Journal articleKhawaja SA, Hanna L, Singh A, et al., 2026,
A randomized trial of carbon-dioxide flushing to reduce vascular brain injury in patients undergoing TAVI.
, EuroInterventionBACKGROUND: Stroke remains a significant concern in patients undergoing Transcatheter Aortic Valve Implantation (TAVI). Despite advances in TAVI technology and techniques, rates have remained unchanged, with trials of Cerebral embolic protection devices (CEPD) failing to reduce rates. The concept of air emboli has never been previously investigated in TAVI procedures. We hypothesize that gaseous emboli could play a significant role in TAVI and that carbon dioxide (COâ) flushing of the TAVI valves could reduce the incidence of new neurological lesions post-TAVI. AIMS: To demonstrate the neuroprotective benefits of COâ flushing in TAVI. METHODS: INTERCEPTavi is a pilot single centre, blinded, randomized controlled trial that studied the effects of flushing TAVI valves with COâ versus conventional saline on neurological outcomes post TAVI assessed using MRI and transcranial doppler(TCD). Patients with aortic stenosis were randomised after access was obtained. Peri-procedure TCD assessed solid and gas 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 data. RESULTS: 60 patients were recruited and randomised 1:1 to COâ and saline flushing (TAVI-COâ) versus saline flushing only (TAVI-S). COâ flushing significantly reduced the average number of lesions per patient (TAVI-COâ 4 lesions/patient vs TAVI-S 8.5 lesions/patient; P=0.031). The total infarct area was numerically lower in the COâ group (40.32 mm² vs 93.20 mm²), although this did not reach statistical significance (p=0.111). Similarly, Transcranial Doppler (TCD) showed fewer micro-embolic signals in the COâ 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-man randomised trial that demonstrated that COâ
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Journal articlePisacano N, Evans RA, Nutley AS, et al., 2026,
Actin regulation of neutrophil effector mechanisms in health and disease.
, J Leukoc Biol, Vol: 118Neutrophils are central to immune responses in health and disease, and their ability to deform correlates with their functional responses. In health, reorganization of the neutrophil cytoskeleton allows neutrophils to carry out their effector mechanisms. However, in the disease state, dysregulation of neutrophil cytoskeletal properties results in disruption of neutrophil structural integrity, in turn altering their immune response capabilities. We outline how actin and actin polymerization are essential for cell processes, the role of actin in neutrophil function, and how disruption of actin can lead and contribute to a range of disease pathogeneses.
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Journal articlePerry RN, Lenert G, Benavente ED, et al., 2026,
Female-Biased VSMC GRNs Predict MYH9 as Regulator of Fibrous Plaque Phenotype.
, Circ Res, Vol: 138BACKGROUND: Atherosclerosis, an inflammatory driver of coronary artery disease, manifests as unstable atheromatous plaques and stable fibrous plaques. Although atheromatous plaques have been extensively studied, fibrous plaques, particularly in women aged <50 years, where erosion contributes significantly to coronary thrombosis, remain less understood. The molecular mechanisms underlying sex differences in plaque biology, including vascular smooth muscle cell contributions, are incompletely defined. METHODS: Sex-specific gene regulatory networks (GRNs) were constructed from RNA-sequencing data of cultured human vascular smooth muscle cells isolated from 119 male and 32 female heart transplant donors. Network preservation analyses identified female-biased GRNs, which were evaluated in single-cell RNA-sequencing data sets from human carotid atherosclerotic plaques. Bayesian network modeling and proteomic analyses were used to identify and validate regulatory drivers. RESULTS: Two female-biased vascular smooth muscle cell networks, GRNfloralwhite and GRNyellowgreen, were enriched for inflammatory and actin remodeling pathways, respectively. Single-cell RNA-sequencing confirmed sex-specific network activity in plaque vascular smooth muscle cells. Subcellular phenotyping identified a sex-specific gene expression program within GRNyellowgreen enriched for contractile and vascular development pathways. Bayesian network modeling identified MYH9 (myosin heavy chain 9) as a key driver gene. Elevated MYH9 abundance was associated with increased smooth muscle cell content and reduced lipid content in female carotid plaques compared with males, consistent with fibrous plaque features. Proteomic analyses confirmed MYH9 upregulation in female fibrous plaques and association with stable plaque characteristics. CONCLUSIONS: These findings identify MYH9 as a regulator of female-biased fibrous plaque biology and highlight the importance of sex-specific network regulation in atheros
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Journal articleMoncayo CR, Restuadi R, Zhang G, et al., 2026,
Multimodal imaging reveals a lysosomal drug reservoir that drives heterogeneous distribution of PARP inhibitors
, Nature Communications, Vol: 17, ISSN: 2041-1723For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals enrichment of apoptotic and lysosomal signatures in high-drug regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with rucaparib high cells demonstrating increased drug response relative to rucaparib-low. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content alters intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response.
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