{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:26:18Z","timestamp":1767374778554,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["397484323"],"award-info":[{"award-number":["397484323"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background\/Objectives: While the presence of inflammatory processes in stenotic aortic valves is acknowledged, no systematic characterization of the systemic immune reaction upon aortic valve stenosis (AS) has been performed yet. The hypothesis of this study was that AS induces a systemic inflammatory reaction linked with local processes in the heart. Methods: Murine wire injury (WI) to induce AS, or sham surgery, were performed prior to the 4-week assessment of AS severity, left ventricular (LV) function and hypertrophy with echocardiography (echo). Organ weights, levels of leukocytes, cytokines and costimulatory molecules in blood, heart, and peripheral immune organs (spleen, liver, lymph nodes), and immune cell uptake of Cy5-labelled perfluorocarbon nanoemulsions were measured. Results: Trends towards correlation were found between organ weights, myocardial immune cells and echo. Cytokine mRNA levels trended mainly towards an increase in heart and regional lymph nodes and a reduction in spleen and liver, and correlation with echo was more homogeneous after WI. Unchanged cytokine protein levels in myocardium and plasma trended to correlate with echo. A homogeneous pattern was found for echo and costimulatory molecule correlation, while PFC uptake by lymphatic cells was reduced upon AS. Conclusions: The results suggest a link between number and activation state of leukocytes in peripheral organs and cardiac processes in AS. Considering the pathological value of inflammation, it is crucial that future studies investigate if a modulation of the systemic inflammatory reaction relieves severity of AS and opposes development of heart failure.<\/jats:p>","DOI":"10.3390\/cells14120883","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T08:18:06Z","timestamp":1749629886000},"page":"883","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Wire Injury-Induced Moderate Aortic Valve Stenosis in Mice Is Accompanied by a Chronic Systemic Inflammatory Reaction"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6876-6035","authenticated-orcid":false,"given":"Katrin","family":"Becker","sequence":"first","affiliation":[{"name":"Cardiovascular Research Laboratory, Department of Cardiology, Pulmonary Diseases and Vascular Medicine, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University, 40225 D\u00fcsseldorf, Germany"},{"name":"Institute for Molecular Cardiology, Medical Faculty, University Hospital D\u00fcsseldorf, Heinrich-Heine University, 40225 D\u00fcsseldorf, Germany"},{"name":"Faculty of Medicine, University Hospital Cologne, University of Cologne, 50937 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Aluru, J.S., Barsouk, A., Saginala, K., Rawla, P., and Barsouk, A. (2022). Valvular Heart Disease Epidemiology. Med. Sci., 10.","key":"ref_1","DOI":"10.3390\/medsci10020032"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e599","DOI":"10.1016\/S2666-7568(22)00168-4","article-title":"Counting the cost of premature mortality with progressively worse aortic stenosis in Australia: A clinical cohort study","volume":"3","author":"Stewart","year":"2022","journal-title":"Lancet Healthy Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1007\/s10741-023-10312-7","article-title":"Acute advanced aortic stenosis","volume":"28","author":"Avvedimento","year":"2023","journal-title":"Heart Fail. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1056\/NEJMra1313875","article-title":"Aortic-Valve Stenosis\u2014From Patients at Risk to Severe Valve Obstruction","volume":"371","author":"Otto","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1161\/ATVBAHA.119.313067","article-title":"Aortic Valve Stenosis: From Basic Mechanisms to Novel Therapeutic Targets","volume":"40","author":"Goody","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1002\/ehf2.12837","article-title":"Inflammatory signatures are associated with increased mortality after transfemoral transcatheter aortic valve implantation","volume":"7","author":"Hoffmann","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1093\/cvr\/cvx011","article-title":"An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy","volume":"113","author":"Frati","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.lfs.2013.03.014","article-title":"Myocardial hypertrophy is associated with inflammation and activation of endocannabinoid system in patients with aortic valve stenosis","volume":"92","author":"Duerr","year":"2013","journal-title":"Life Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1016\/j.bbamcr.2016.01.003","article-title":"mTOR, cardiomyocytes and inflammation in cardiac hypertrophy","volume":"1863","author":"Xu","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2764","DOI":"10.2337\/diacare.26.10.2764","article-title":"Relation of left ventricular hypertrophy to inflammation and albuminuria in adults with type 2 diabetes: The strong heart study","volume":"26","author":"Palmieri","year":"2003","journal-title":"Diabetes Care"},{"key":"ref_11","first-page":"5063","article-title":"Systemic inflammation is associated with myocardial fibrosis, diastolic dysfunction, and cardiac hypertrophy in patients with hypertrophic cardiomyopathy","volume":"9","author":"Fang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_12","first-page":"37","article-title":"T cell homing and exercise","volume":"13","author":"Mooren","year":"2007","journal-title":"Exerc. Immunol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.molimm.2004.06.040","article-title":"Chemokine-Mediated Control of T Cell Traffic in Lymphoid and Peripheral Tissues","volume":"42","author":"Ebert","year":"2005","journal-title":"Molecular Immunology"},{"key":"ref_14","first-page":"56","article-title":"Lymphocyte migration: An essential step in understanding the effects of vaccination","volume":"98","author":"Pabst","year":"1997","journal-title":"Behring Inst. Mitt."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1111\/j.1600-065X.2009.00782.x","article-title":"Molecular mechanism and function of CD40\/CD40L engagement in the immune system","volume":"229","author":"Elgueta","year":"2009","journal-title":"Immunol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/stem.5530120502","article-title":"The activation antigen CD69","volume":"12","author":"Ziegler","year":"1994","journal-title":"Stem Cells"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5989","DOI":"10.1073\/pnas.0700946104","article-title":"Costimulatory ligand CD70 is delivered to the immunological synapse by shared intracellular trafficking with MHC class II molecules","volume":"104","author":"Keller","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"13967","DOI":"10.1073\/pnas.93.24.13967","article-title":"Costimulatory function and expression of CD40 ligand, CD80, and CD86 in vascularized murine cardiac allograft rejection","volume":"93","author":"Hancock","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s00392-019-01413-1","article-title":"Graded murine wire-induced aortic valve stenosis model mimics human functional and morphological disease phenotype","volume":"108","author":"Niepmann","year":"2019","journal-title":"Clin. Res. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00395-022-00936-5","article-title":"Multiparametric MRI identifies subtle adaptations for demarcation of disease transition in murine aortic valve stenosis","volume":"117","author":"Quast","year":"2022","journal-title":"Basic Res. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1161\/ATVBAHA.113.302610","article-title":"A novel mouse model of aortic valve stenosis induced by direct wire injury","volume":"34","author":"Honda","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"doi-asserted-by":"crossref","unstructured":"Staal, A.H.J., Becker, K., Tagit, O., Koen van Riessen, N., Koshkina, O., Veltien, A., Bouvain, P., Cortenbach, K.R.G., Scheenen, T., and Fl\u00f6gel, U. (2020). In vivo clearance of 19F MRI imaging nanocarriers is strongly influenced by nanoparticle ultrastructure. Biomaterials, 261.","key":"ref_22","DOI":"10.1016\/j.biomaterials.2020.120307"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1002\/sim.7263","article-title":"Analysis of small sample size studies using nonparametric bootstrap test with pooled resampling method","volume":"36","author":"Dwivedi","year":"2017","journal-title":"Stat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8","DOI":"10.4097\/kjae.2016.69.1.8","article-title":"Nonparametric statistical tests for the continuous data: The basic concept and the practical use","volume":"69","author":"Nahm","year":"2016","journal-title":"Korean J. Anesthesiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.tjem.2018.08.001","article-title":"User\u2019s guide to correlation coefficients","volume":"18","author":"Akoglu","year":"2018","journal-title":"Turk. J. Emerg. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s12195-011-0197-4","article-title":"Regulation of Hepatic Cell Mobilization in Experimental Myocardial Ischemia","volume":"4","author":"Liu","year":"2011","journal-title":"Cell. Mol. Bioeng."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1093\/eurheartj\/ehv453","article-title":"Innate immune cells in ischaemic heart disease: Does myocardial infarction beget myocardial infarction?","volume":"37","author":"Nahrendorf","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.jjcc.2015.05.002","article-title":"Presence of B cells within aortic valves in patients with aortic stenosis: Relation to severity of the disease","volume":"67","author":"Natorska","year":"2016","journal-title":"J. Cardiol."},{"doi-asserted-by":"crossref","unstructured":"Mo, F., Luo, Y., Yan, Y., Li, J., Lai, S., and Wu, W. (2021). Are activated B cells involved in the process of myocardial fibrosis after acute myocardial infarction? An in vivo experiment. BMC Cardiovasc. Disord., 21.","key":"ref_29","DOI":"10.1186\/s12872-020-01775-9"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2022.954936","article-title":"Role of B cells as antigen presenting cells","volume":"13","author":"Rastogi","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1161\/CIRCULATIONAHA.113.007101","article-title":"CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload","volume":"129","author":"Laroumanie","year":"2014","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1148\/radiol.2452061973","article-title":"Left ventricular functional assessment in mice: Feasibility of high spatial and temporal resolution ECG-gated blood pool SPECT","volume":"245","author":"Chin","year":"2007","journal-title":"Radiology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.ijcard.2018.12.076","article-title":"Small molecule-mediated inhibition of CD40-TRAF6 reduces adverse cardiac remodelling in pressure overload induced heart failure","volume":"279","author":"Bosch","year":"2019","journal-title":"Int. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.4110\/in.2016.16.1.26","article-title":"Involvement of immune cell network in aortic valve stenosis: Communication between valvular interstitial cells and immune cells","volume":"16","author":"Lee","year":"2016","journal-title":"Immune Netw."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14803","DOI":"10.1038\/ncomms14803","article-title":"Temporal and tissue-specific requirements for T-lymphocyte IL-6 signalling in obesity-associated inflammation and insulin resistance","volume":"8","author":"Xu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4699","DOI":"10.1182\/blood-2009-07-230631","article-title":"IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production","volume":"115","author":"Maeda","year":"2010","journal-title":"Blood"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1002\/eji.201040673","article-title":"IL-10 produced by activated human B cells regulates CD4+ T-cell activation in vitro","volume":"40","author":"Bouaziz","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_38","first-page":"376","article-title":"Interleukin-10 inhibits motility in murine and human B lymphocytes","volume":"82","author":"Clinchy","year":"1994","journal-title":"Immunology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4545","DOI":"10.4049\/jimmunol.151.9.4545","article-title":"Human IL-10 is a chemoattractant for CD8+ T lymphocytes and an inhibitor of IL-8-induced CD4+ T lymphocyte migration","volume":"151","author":"Jinquan","year":"1993","journal-title":"J. Immunol."},{"doi-asserted-by":"crossref","unstructured":"Yang, S., Wang, J., Brand, D.D., and Zheng, S.G. (2018). Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front. Immunol., 9.","key":"ref_40","DOI":"10.3389\/fimmu.2018.00784"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1161\/CIRCULATIONAHA.120.045536","article-title":"Transcatheter Aortic Valve Implantation Represents an Anti-Inflammatory Therapy Via Reduction of Shear Stress-Induced, Piezo-1-Mediated Monocyte Activation","volume":"142","author":"Baratchi","year":"2020","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.jtcvs.2011.04.044","article-title":"Myocardial Remodeling With Aortic Stenosis and Following Aortic Valve Replacement- Mechanisms and Future Prognostic Implications","volume":"143","author":"Yarbrough","year":"2012","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1161\/HYPERTENSIONAHA.107.093120","article-title":"Relation of left ventricular hypertrophy with systemic inflammation and endothelial damage in resistant hypertension","volume":"50","author":"Salles","year":"2007","journal-title":"Hypertension"},{"doi-asserted-by":"crossref","unstructured":"Medenwald, D., Dietz, S., Tiller, D., Kluttig, A., Greiser, K.H., Loppnow, H., Thiery, J., Nuding, S., Russ, M., and Fahrig, A. (2014). Inflammation and echocardiographic parameters of ventricular hypertrophy in a cohort with preserved cardiac function. Open Heart, 1.","key":"ref_44","DOI":"10.1136\/openhrt-2013-000004"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1161\/CIRCULATIONAHA.107.737890","article-title":"In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging","volume":"118","author":"Ding","year":"2008","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1016\/j.jacc.2017.01.025","article-title":"Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study","volume":"69","author":"Yan","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1001\/jama.2018.18077","article-title":"Association of Renin-Angiotensin Inhibitor Treatment with Mortality and Heart Failure Readmission in Patients with Transcatheter Aortic Valve Replacement","volume":"320","author":"Inohara","year":"2018","journal-title":"J. Am. Med. Assoc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcvm.2023.1234368","article-title":"Renin\u2013angiotensin system inhibitors reduce cardiovascular mortality in hypertensive patients with severe aortic stenosis undergoing transcatheter aortic valve implantation: Insights from the EffecTAVI registry","volume":"10","author":"Basile","year":"2023","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1006\/viro.1996.0555","article-title":"Effects of the estrous cycle on local humoral immune responses and protection of intranasally immunized female mice against herpes simplex virus type 2 infection in the genital tract","volume":"224","author":"Gallichan","year":"1996","journal-title":"Virology"},{"key":"ref_50","first-page":"364310","article-title":"Animal Models of Calcific Aortic Valve Disease","volume":"2011","author":"Sider","year":"2011","journal-title":"Int. J. Inflam."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/12\/883\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:50:01Z","timestamp":1760032201000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/12\/883"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":50,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["cells14120883"],"URL":"https:\/\/doi.org\/10.3390\/cells14120883","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,6,11]]}}}