Cardiovascular Research最新文献

{"title":"Fatty acid synthase in cardiovascular disease: from molecular mechanisms to therapeutic targeting","authors":"Dina Ibrahim, Mohamed S Zaghloul, Bera Koklu, Abdullah Elahi, James L Januzzi, Marc P Bonaca, Mohamed A Zayed","doi":"10.1093/cvr/cvag200","DOIUrl":"https://doi.org/10.1093/cvr/cvag200","url":null,"abstract":"Fatty acid synthase (FAS), the rate-limiting enzyme of de novo lipogenesis, is now recognized as a multifunctional regulator of cardiovascular homeostasis; its roles extend beyond simple FA biosynthesis to encompass calcium signaling, cholesterol trafficking, and inflammatory modulation. This review synthesizes current understanding of FAS molecular biology, tissue-specific expression, and pathophysiological contributions to cardiovascular disease. Circulating FAS (cFAS) associates with lipoproteins and promotes macrophage foam cell formation independently of low-density lipoprotein cholesterol concentration, establishing a novel atherogenic mechanism. cFAS is primarily hepatic in origin and is released under conditions of enhanced de novo lipogenesis and insulin resistance. Adipose tissue may also contribute through extrusion of FAS. In macrophages, Fasn deletion enhances cholesterol efflux through liver X receptor alpha induction and ATP-binding cassette transporter A1 upregulation, reducing atherosclerosis by 20-40% in preclinical models without affecting serum lipids. Vascular smooth muscle cells upregulate FAS during phenotypic switching, facilitating transformation into foam cells within plaques. Clinical studies have established cFAS as a diagnostic biomarker for peripheral arterial disease, with higher concentrations present in affected individuals; elevated cFAS may also discriminate more severe disease. Despite its pathogenic roles in atherosclerosis, cardiac FAS serves essential stress-adaptive functions through calcium/calmodulin-dependent protein kinase II regulation, as cardiac-specific Fasn knockout mice exhibit profound stress intolerance and accelerated aging-related cardiac dysfunction, demonstrating that FAS-mediated de novo lipogenesis is indispensable for myocardial stress responses. This observation necessitates tissue-specific therapeutic approaches. Pharmacological FAS inhibitors, including TVB-2640 (denifanstat), demonstrate acceptable safety profiles in clinical trials and reduce hepatic de novo lipogenesis by 50-70%, while platensimycin reduces atherosclerotic burden in preclinical models. These findings position FAS as both a mechanistic driver and promising therapeutic target for cardiovascular disease. However, the divergent consequences of FAS modulation across tissues underscore the need for targeted delivery strategies that suppress pathological lipogenesis while preserving essential cardiac functions.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"78 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148946721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atherosclerotic plaque fibroblasts derive from adventitial and medial Pdgfra-lineage-positive cells and predominantly maintain fibroblast identity.","authors":"Guanliang Li, Sebastiaan E J Asselberghs, Baixue Yu, Cong Feng, Paul-Lennard Mendez, Dimitri Kasakovski, Pieter Goossens, Tia M Ackermans, Renée J H A Tillie, Marion J Gijbels, Lieve Temmerman, He Xu, Marjo M P C Donners, Dlzar A Kheder, Sidrah Maryam, Han Jin, Chenyi Xue, Sikander Hayat, Austin C Conklin, Casey E Romanoski, Mauro Giacca, Clint L Miller, Muredach P Reilly, Ming Chen, Rafael Kramann, Barend Mees, Andrew H Baker, Judith C Sluimer","doi":"10.1093/cvr/cvag183","DOIUrl":"https://doi.org/10.1093/cvr/cvag183","url":null,"abstract":"<p><strong>Aims: </strong>Fibroblasts are mesenchymal cells in the healthy vascular adventitia. In atherosclerosis, single-cell sequencing datasets suggest fibroblasts are abundant in plaques. However, their identity, origin, and fate during plaque progression remain unclear, which we aim to unravel here.</p><p><strong>Approach and results: </strong>To robustly define fibroblast identity, origin, and fate, we employed meta-analyses of 54 single-cell RNA sequencing libraries, including murine smooth muscle cell (Myh11) and endothelial cell (EC) (Cdh5) lineage reporter mice with and without atherosclerosis; human control and atherosclerotic arteries; and murine adventitia and atherosclerotic plaques processed separately from low-density lipoprotein (LDL) receptor knockout (Ldlr-/-) mice. These meta-analyses showed that murine and human plaque fibroblast identity was robustly defined by Pdgfra, Pi16, Cygb, and Serpinf1 mRNA. Ninety-five percent of plaque fibroblasts do not derive from the Myh11 lineage, while no Cdh5-lineage-positive cells were present in the fibroblast cluster. We identified five murine arterial fibroblast subsets in atherosclerotic murine aorta: progenitor fibroblasts, matrix fibroblasts, inflammatory fibroblasts, an EC-like fibroblast subset, detected in both adventitia and plaques, and Col5a3+ fibroblasts, unique to the adventitia. We next studied fibroblast identity, origin, and fate using pseudotime analysis and Pdgfra-CreERT2/tdTomato lineage reporter mice (Pdgfra Lin+). Healthy Pdgfra Lin+ reporter mice showed predominant adventitial tdTomato expression, and infrequent medial and intimal Pdgfra Lin+ cells co-expressing MYH11 and PECAM1, respectively. The Pdgfra Lin+ plaque area increased with diet duration. Pdgfra Lin+ cells largely maintain fibroblast identity in the plaque, while <10% co-express SMC markers (MYH11, SM22α), or contribute to ACTA2+ cap cells. ECs gaining mesenchymal markers are transcriptionally distinct from Cdh5-lineage-negative fibroblasts gaining EC markers. Plaque-resident EC-like fibroblasts displayed a mesenchymal-to-endothelial transition transcriptome, which was induced in human primary fibroblasts in vitro by starvation, and dampened or reversed by IL1B, TGFB1, TGFB3, and oxidized LDL. Cross-species integration showed that all murine plaque fibroblasts were conserved in human atherosclerosis, with one additional subset partially resembling murine subsets, and three human-specific subsets. Importantly, human fibroblast subsets differentially correlated to human plaque traits, with EC-like fibroblasts correlating to plaque instability.</p><p><strong>Conclusion: </strong>Our results indicate that 95% of plaque-residing fibroblasts are Myh11 Lin- Plaque fibroblasts have a dual origin, predominantly adventitial Pdgfra Lin+ progenitor fibroblasts, with a minor contribution from medial Pdgfra Lin+  Myh11+ SMCs. Most plaque fibroblasts maintain fibroblast identity. Murine plaque fibroblast subsets were con","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 1 modulation unlocks the therapeutic potential of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in calcific aortic valve stenosis.","authors":"Vincenza Valerio, Ilaria Massaiu, Matteo Franchi, Antoine Rimbert, Zoé Begué-Racapé, Mattia Chiesa, Veronika A Myasoedova, Valentina Rusconi, Francesca Bertolini, Donato De Giorgi, Alice Bonomi, Sergio Pirola, Marco Zanobini, Paola Di Pietro, Albino Carrizzo, Michele Ciccarelli, Romain Capoulade, Stefano Genovese, Paolo Poggio","doi":"10.1093/cvr/cvag199","DOIUrl":"https://doi.org/10.1093/cvr/cvag199","url":null,"abstract":"<p><strong>Background: </strong>Calcific aortic valve stenosis (AS) affects 3% of older adults and lacks medical treatment. The deacetylase Sirtuin 1 (SIRT1) could be involved in many pathways linked to AS progression. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucose-lowering agents, have been shown to reduce cardiovascular events (likely via SIRT1), but their possible benefits in AS are unknown. Our study aims to uncover the role of SIRT1 in AS progression and assess the benefit of SGLT2i to slow down the aortic valve fibro-calcification processes.</p><p><strong>Methods: </strong>RNA-seq data of human aortic valve specimens were collected from the ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VIC) were generated by CRISPR/Cas9. Real-time PCR, immunofluorescence, and calcification assays were used to characterise mutant VICs. Conditioned medium experiments were implemented to evaluate SGLT2i effect on cellular cross-talk and calcification. Diabetic patients' data from the Lombardy regional healthcare database, treated with sulphonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. Cumulative incidence of hospitalisation for non-rheumatic aortic valve disease was assessed by Kaplan-Meier and Fine and Gray models were used to estimate subdistribution hazard ratios.</p><p><strong>Results: </strong>RNA-seq showed that SIRT1 could be an upstream regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular-matrix remodelling, and calcification by modulating key transcription factors. Moreover, calcification assays further support this role, revealing an increased calcification in SIRT1 KD VICs and a concomitant decrease in VIC SIRT1 Over when compared to wild type. Then, exploring SGLT2i impact on calcification, we showed that VICs cultured in SGLT2i-treated-endothelial medium exhibited reduced calcification associated with endothelial-increased nitric oxide levels, while SIRT1 inhibition enhanced VIC calcification. The real-world data analysis revealed that SGLT2i-treated group had a lower incidence of hospitalised patients for non-rheumatic aortic valve disease compared to SU-treated group.</p><p><strong>Conclusions: </strong>Our data identify SIRT1 as an upstream regulator of fibro-calcific processes in AS and suggest that SGLT2i may slow the aortic valve degeneration through SIRT1 modulation. These findings support SGLT2i as a potential therapeutic strategy for AS prevention and care.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular smooth muscle cell-derived osteoprotegerin drives pulmonary arterial hypertension via AKT activation and is attenuated by monoclonal antibody therapy.","authors":"Merve Keles, Laura E West, Nadine D Arnold, Astrid Weiss, Nadiya V Mykytyuk, Julia Baldauf, Josephine A Pickworth, Amira A Zawia, Helena A Turton, Megan F Allen, Clemens Ruppert, A A Roger Thompson, Sheila E Francis, Ralph T Schermuly, Allan Lawrie","doi":"10.1093/cvr/cvag197","DOIUrl":"https://doi.org/10.1093/cvr/cvag197","url":null,"abstract":"<p><strong>Aim: </strong>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.</p><p><strong>Methods and results: </strong>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 proliferation and migration of human PASMC. These results align with emerging data implicating OPG in cellular senescence and vascular aging.</p><p><strong>Conclusion: </strong>Together, these findings highlight VSMC-derived OPG as a critical mediator of pulmonary vascular remodelling in PAH pathogenesis and suggest that targeting OPG via a therapeutic antibody is mediated through PI3K-Akt signalling.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular nexus glia regulates vascular homeostasis and undergoes dynamic remodelling in deep vein thrombosis.","authors":"Kunhua Yang, Cheng Huang, Xuefeng Shi, Yumin Wu, Yi Lu, Yang Hu, Yuqiang Liu, Zhihui Qi, Ruizhe Tang, Jiaoyan Ren, Jie Xu, Fu-Li Xiang, Zhongxing Wang, Maojin Yao","doi":"10.1093/cvr/cvag180","DOIUrl":"https://doi.org/10.1093/cvr/cvag180","url":null,"abstract":"<p><strong>Aims: </strong>The cardiovascular system is tightly regulated by the nervous system, yet while cardiac nexus glial cells are known modulators of physiology, the identity and functional significance of glial populations within the vasculature remain poorly defined. We hypothesized that a specialized population of vascular glial cells exists in the adventitia and undergoes molecular and morphological remodelling under pathological stress.</p><p><strong>Methods and results: </strong>By analysing human and murine single-cell RNA sequencing (scRNA-seq) datasets, we identified a conserved population of glial cells in large vessels. Using hGFAP-Cre;tdTomato reporter mice and the Mosaic Analysis with Double Markers (MADM) system, we characterized these vascular nexus glia (VNGs) as an extensive reticular network in the adventitia that are in contact with sympathetic nerve fibres. To investigate functional necessity, we ablated the epigenetic regulator Suz12 in the GFAP lineage, which impaired VNG development and triggered vascular metabolic dysregulation. Cross-tissue transcriptomic integration revealed that VNGs possess a unique metabolic and stress-response signature compared to other glial subtypes. In a murine deep vein thrombosis model, time-resolved scRNA-seq and tissue clearing mapped a biphasic phenotypic transition. During thrombosis development, VNGs exhibit profound plasticity, undergoing morphological retraction and transitioning from a neuro-supportive state to an activated profile characterized by extracellular matrix reorganization and pro-fibrotic signalling.</p><p><strong>Conclusion: </strong>Our study identifies VNGs as a ubiquitous glial network within the vascular adventitia essential for homeostatic maintenance. By uncovering their Suz12-dependent development and dynamic remodelling during thrombotic injury, we provide a new conceptual framework for the neuro-vascular interface in venous thromboembolic disease.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148905241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNMT3A-driven clonal haematopoiesis induces semaphorin 4A-dependent endothelial activation in heart failure.","authors":"Mariana Shumliakivska, Inga Hemmerling, Sebastian Cremer, Klara Kirschbaum, Marina Scheller, Xue Li, Carsten Müller-Tidow, Florian Leuschner, David John, Wesley Tyler Abplanalp, Andreas M Zeiher, Stefanie Dimmeler, Guillermo Luxán","doi":"10.1093/cvr/cvag192","DOIUrl":"https://doi.org/10.1093/cvr/cvag192","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Very-long chain fatty acids increase cell membrane thickness and impair mitochondrial function of aortic smooth muscle cells: implications for early vascular ageing.","authors":"Aleksandra Hliwa-Ślazyk, Magdalena Narajczyk, Magdalena Dzitkowska-Zabielska, Marika Franczak, Tomasz Sledzinski, Krzysztof Narkiewicz, Adriana Mika","doi":"10.1093/cvr/cvag191","DOIUrl":"https://doi.org/10.1093/cvr/cvag191","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148879192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechano-sensing channels PIEZO1 and PIEZO2 regulate mitral valve serotonin-mediated homeostasis and pathophysiology","authors":"Stanley J Stachelek, Emily J Hauber, Xiaoqiu Yang, Devin W Laurence, Vitali Rusinkevich, Peiran Lu, Estibaliz Castillero, Benjamin B Pressly, Claire Brady, Nikia T Toomey, Ilia Fishbein, Alexis Martinez, Alireza Mohammad Karim, Ephraim Jacobson, Dov Levine, Shawnaleh Cada, Kenneth B Margulies, Kenneth C Bedi, George M Anderson, Abba M Krieger, Liming Pei, Giovanni Ferrari, Robert J Levy","doi":"10.1093/cvr/cvag190","DOIUrl":"https://doi.org/10.1093/cvr/cvag190","url":null,"abstract":"Aims Mitral regurgitation (MR) pathophysiology involves increased serotonin (5-HT) receptor (HTR) expression and signaling, together with reduced 5-HT transporter (SLC6A4) expression in mitral valve interstitial cells (MVIC). The mechanosensitive calcium channels, PIEZO1 and PIEZO2, regulate cellular responses to a variety of mechanical conditions; however, PIEZO1 and PIEZO2 have not been studied in MR. We investigated the hypothesis that PIEZO1 and PIEZO2 mediate, through 5-HT mechanisms both homeostasis in normal mitral valves (nMV) and in the pathophysiology of MR. Methods and Results Immunofluorescence and Western blots demonstrated the presence of PIEZO1 and PIEZO2 in samples of explanted human nMV and MR. MVIC derived from nMV and MR leaflets also expressed PIEZO1 and PIEZO2. Single-cell RNA sequencing (scRNA-seq) analyses of nMV and MR leaflet samples from 9 MR and 5 nMV cases identified 7 different cell types: Endothelial cells, smooth muscle cells, T-cells, macrophages, and three distinct MVIC phenotypes, VIC1, VIC2, and VIC3. MVIC together comprised 97% of all valve cells, irrespective of valve pathology. In addition, scRNA-seq of nMV and MR leaflets demonstrated MVIC PIEZO1 and PIEZO2 expression, together with HTR2B and SLC6A4. MVIC cultures, with no added 5-HT, demonstrated that PIEZO1 activation with its agonist, Yoda1, increased MVIC Ca2+ uptake. This was inhibited by PIEZO1-siRNA, and Dooku1, a Yoda1 antagonist, but not PIEZO2-siRNA or noncoding-RNA. Additional MVIC studies revealed that in static MVIC cultures, PIEZO1 activation with Yoda1 downregulated SLC6A4, upregulated HTR2B, and increased 5-HT levels and protein synthesis. Cyclic tension MVIC bioreactor studies showed that either PIEZO1-siRNA or PIEZO2-siRNA mitigated tension induced SLC6A4 downregulation and increased collagen synthesis; only PIEZO2-siRNA mitigated both static and cyclic tension-induced MVIC 5-HT production. Conclusions Our findings have identified a novel link between mechano-transduction, 5-HT production and receptor signaling, and collagen synthesis, suggesting PIEZO1, PIEZO2, and downstream 5-HT pathways as potential therapeutic targets for mitigating MR progression.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"43 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-specific associations of the plasma-proteome with incident coronary artery disease","authors":"Vincent Q Sier, Kristina Dimitrova, Erna H A B Peters, Wouter P M van der Loo, Ko Willems van Dijk, Diana van Heemst, Wilhelmina H Bax, Paul H A Quax, Gerard Pasterkamp, Michal Mokry, J Wouter Jukema, Raymond Noordam, Margreet R de Vries","doi":"10.1093/cvr/cvag186","DOIUrl":"https://doi.org/10.1093/cvr/cvag186","url":null,"abstract":"Aims The etiology of coronary artery Disease (CAD) appears different for men and women, yet insights into underlying sex-specific biological mechanisms are limited. We integrated genomic and proteomic analyses to investigate sex-specific associations of the plasma-proteome with CAD. Methods and Results In 40,829 UK Biobank participants (free-of-CAD, baseline-365 days thereafter; 55% women; mean age 56.9 ± 8.1 years), we examined associations between 2,922 plasma proteins and incident CAD over a median follow-up of 13.7 years (IQR 13.1-14.4) using multivariable-adjusted Cox proportional hazards models. Sex-specific analyses identified 440 female exclusive and 32 male exclusive proteins associated with incident CAD (FDR-corrected p &amp;lt; 0.05), revealing distinct pathway enrichments, including innate immune response in women and angiogenesis in men. Causality was assessed through combined and sex-stratified two-sample Mendelian randomization (MR) using inverse-variance-weighted analyses with genome wide association summary statistics from 422,108 men (61,969 cases) and 521,695 women (27,128 cases) (UK Biobank, FinnGen freeze 9). Integration of direct sex-protein interaction analyses with sex-combined MR identified 59 proteins with evidence for sex-specific causal effects. Four proteins demonstrated concordant directionality in sex-stratified MR analyses (n = 943,803) and multivariable regression models, namely CDKN2D, MYH9, and SKAP2 (women), and CTSH (men). To assess translational relevance, prioritized targets were further evaluated in secondary major adverse cardiovascular events among carotid endarterectomy patients (MACE; Athero-Express) and acute myocardial infarction (AMI; MISSION!) using plasma proteomics and ELISA. After further top-target identification in the context of MACE and AMI, clinical drug candidates were identified through a machine learning framework, including CTSH (men), and TNFRSF4 (both sexes). Conclusions We identified sex-specific associations of proteins and biological pathways with incident CAD. Whereas the majority of proteins had consistent associations in both men and women, our findings suggest a degree of sex-specific pathogenesis with evidence for potential causality, opening new alleys for tailored prevention strategies and clinical cardiovascular risk management.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"184 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148877309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early encounters with hypertrophic cardiomyopathy.","authors":"Eugene Braunwald","doi":"10.1093/cvr/cvag094","DOIUrl":"https://doi.org/10.1093/cvr/cvag094","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}