{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:39:34Z","timestamp":1784554774212,"version":"3.55.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":911,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Austrian Society of Cardiology and the Ludwig Boltzmann Institute for Cardiovascular Research"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Ischaemia\u2013reperfusion injury (IRI) following myocardial infarction remains a challenging topic in acute cardiac care and consecutively arising heart failure represents a severe long-term consequence. The extent of neutrophil infiltration and neutrophil-mediated cellular damage are thought to be aggravating factors enhancing primary tissue injury. Toll-like receptor 9 was found to be involved in neutrophil activation as well as chemotaxis and may represent a target in modulating IRI, aspects we aimed to illuminate by pharmacological inhibition of the receptor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Forty-nine male adult Sprague\u2013Dawley rats were used. IRI was induced by occlusion of the left coronary artery and subsequent snare removal after 30 min. Oligonucleotide (ODN) 2088, a toll-like receptor 9 (TLR9) antagonist, control-ODN, or DNase, were administered at the time of reperfusion and over 24 h via a mini-osmotic pump. The hearts were harvested 24 h or 4 weeks after left coronary artery occlusion and immunohistochemical staining was performed. Echocardiography was done after 1 and 4 weeks to determine ventricular function. Inhibition of TLR9 by ODN 2088 led to left ventricular wall thinning (P = 0.003) in association with drastically enhanced neutrophil infiltration (P = 0.005) and increased markers of tissue damage. Additionally, an up-regulation of the chemotactic receptor CXCR2 (P = 0.046) was found after TLR9 inhibition. No such effects were observed in control-ODN or DNase-treated animals. We did not observe changes in monocyte content or subset distribution, hinting towards neutrophils as the primary mediators of the exerted tissue injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our data indicate a TLR9-dependent, negative regulation of neutrophil infiltration. Blockage of TLR9 appears to prevent the down-regulation of CXCR2, followed by an uncontrolled migration of neutrophils towards the area of infarction and the exertion of disproportional tissue injury resulting in potential aneurysm formation. In comparison with previous studies conducted in TLR\u2212\/\u2212 mice, we deliberately chose a transient pharmacological inhibition of TLR9 to highlight effects occurring in the first 24 h following IRI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ehf2.14403","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T03:07:57Z","timestamp":1684206477000},"page":"2375-2385","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Short-Term Toll-Like Receptor 9 Inhibition Leads to Left Ventricular Wall Thinning After Myocardial Infarction"],"prefix":"10.1093","volume":"10","author":[{"given":"Max","family":"Lenz","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kiss","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]},{"name":"Center for Biomedical Research, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Haider","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Salzmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mira","family":"Brekalo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin A.","family":"Krychtiuk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ouafa","family":"Hamza","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Huber","sequence":"additional","affiliation":[{"name":"3rd Medical Department for Cardiology and Emergency Medicine, Faculty of Medicine, Wilhelminenhospital and Sigmund Freud University , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hengstenberg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno K.","family":"Podesser","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Wojta","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]},{"name":"Core Facility Imaging, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4819-3190","authenticated-orcid":false,"given":"Philipp J.","family":"Hohensinner","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]},{"name":"Center for Biomedical Research, Medical University of Vienna , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter S.","family":"Speidl","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna , Vienna ,","place":["Austria"]},{"name":"Ludwig Boltzmann Institute for Cardiovascular Research , Vienna ,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,16]]},"reference":[{"key":"2026012114091812200_ehf214403-bib-0001","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"2026012114091812200_ehf214403-bib-0002","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/eurheartj\/ehz859","article-title":"European Society of Cardiology: Cardiovascular Disease Statistics 2019","volume":"41","author":"Timmis","year":"2020","journal-title":"Eur Heart J"},{"key":"2026012114091812200_ehf214403-bib-0003","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1161\/CIRCRESAHA.114.302744","article-title":"Reperfusion strategies in acute coronary syndromes","volume":"114","author":"Bagai","year":"2014","journal-title":"Circ Res"},{"key":"2026012114091812200_ehf214403-bib-0004","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1097\/SHK.0000000000000044","article-title":"Neutrophils--a key component of ischemia-reperfusion injury","volume":"40","author":"Schofield","year":"2013","journal-title":"Shock"},{"key":"2026012114091812200_ehf214403-bib-0005","doi-asserted-by":"crossref","first-page":"496","DOI":"10.3389\/fphys.2014.00496","article-title":"Ischemia\/reperfusion activates myocardial innate immune response: the key role of the toll-like receptor","volume":"5","author":"Vilahur","year":"2014","journal-title":"Front Physiol"},{"key":"2026012114091812200_ehf214403-bib-0006","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s10557-020-06946-6","article-title":"The role of extracellular DNA and histones in Ischaemia-reperfusion injury of the myocardium","volume":"34","author":"Shah","year":"2020","journal-title":"Cardiovasc Drugs Ther"},{"key":"2026012114091812200_ehf214403-bib-0007","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/s41419-019-1718-7","article-title":"TLR9 is essential for HMGB1-mediated post-myocardial infarction tissue repair through affecting apoptosis, cardiac healing, and angiogenesis","volume":"10","author":"Liu","year":"2019","journal-title":"Cell Death Dis"},{"key":"2026012114091812200_ehf214403-bib-0008","doi-asserted-by":"crossref","first-page":"H1485","DOI":"10.1152\/ajpheart.00481.2016","article-title":"Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation","volume":"311","author":"Omiya","year":"2016","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026012114091812200_ehf214403-bib-0009","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.bbrc.2019.05.150","article-title":"Ablation of toll-like receptor 9 attenuates myocardial ischemia\/reperfusion injury in mice","volume":"515","author":"Kitazume-Taneike","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"2026012114091812200_ehf214403-bib-0010","doi-asserted-by":"crossref","DOI":"10.1161\/JAHA.113.000629","article-title":"The TLR9 ligand, CpG-ODN, induces protection against cerebral ischemia\/reperfusion injury via activation of PI3K\/Akt signaling","volume":"3","author":"Lu","year":"2014","journal-title":"J Am Heart Assoc"},{"key":"2026012114091812200_ehf214403-bib-0011","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1002\/1521-4141(200205)32:5<1212::AID-IMMU1212>3.0.CO;2-D","article-title":"Inhibitory oligonucleotides specifically block effects of stimulatory CpG oligonucleotides in B cells","volume":"32","author":"Stunz","year":"2002","journal-title":"Eur J Immunol"},{"key":"2026012114091812200_ehf214403-bib-0012","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ijcard.2019.03.003","article-title":"Remote ischemic perconditioning attenuates adverse cardiac remodeling and preserves left ventricular function in a rat model of reperfused myocardial infarction","volume":"285","author":"Pilz","year":"2019","journal-title":"Int J Cardiol"},{"key":"2026012114091812200_ehf214403-bib-0013","volume-title":"Steady State Concentration","author":"Cascella","year":"2023"},{"key":"2026012114091812200_ehf214403-bib-0014","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jconrel.2007.03.016","article-title":"Improved systemic pharmacokinetics, biodistribution, and antitumor activity of CpG oligodeoxynucleotides complexed to endogenous antibodies in vivo","volume":"120","author":"Palma","year":"2007","journal-title":"J Control Release"},{"key":"2026012114091812200_ehf214403-bib-0015","doi-asserted-by":"crossref","first-page":"H500","DOI":"10.1152\/ajpheart.00381.2014","article-title":"Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy","volume":"308","author":"Ge","year":"2015","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026012114091812200_ehf214403-bib-0016","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1097\/QCO.0b013e328344f50f","article-title":"Inflammation and cardiac outcome","volume":"24","author":"Hohensinner","year":"2011","journal-title":"Curr Opin Infect Dis"},{"key":"2026012114091812200_ehf214403-bib-0017","doi-asserted-by":"crossref","first-page":"C797","DOI":"10.1152\/ajpcell.00330.2020","article-title":"Monocyte recruitment and fate specification after myocardial infarction","volume":"319","author":"Mentkowski","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026012114091812200_ehf214403-bib-0018","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00395-019-0740-3","article-title":"Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction","volume":"114","author":"Hofbauer","year":"2019","journal-title":"Basic Res Cardiol"},{"key":"2026012114091812200_ehf214403-bib-0019","doi-asserted-by":"crossref","first-page":"937","DOI":"10.15252\/emmm.201506083","article-title":"The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment","volume":"8","author":"Schloss","year":"2016","journal-title":"EMBO Mol Med"},{"key":"2026012114091812200_ehf214403-bib-0020","doi-asserted-by":"crossref","first-page":"2633","DOI":"10.1097\/CCM.0000000000001311","article-title":"Mitochondrial DNA and toll-like receptor-9 are associated with mortality in critically ill patients","volume":"43","author":"Krychtiuk","year":"2015","journal-title":"Crit Care Med"},{"key":"2026012114091812200_ehf214403-bib-0021","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1007\/s00395-013-0376-7","article-title":"Pre-conditioning with synthetic CpG-oligonucleotides attenuates myocardial ischemia\/reperfusion injury via IL-10 up-regulation","volume":"108","author":"Markowski","year":"2013","journal-title":"Basic Res Cardiol"},{"key":"2026012114091812200_ehf214403-bib-0022","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0104407","article-title":"Toll-like receptor 9-activation during onset of myocardial ischemia does not influence infarct extension","volume":"9","author":"Ohm","year":"2014","journal-title":"PLoS ONE"},{"key":"2026012114091812200_ehf214403-bib-0023","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.bbadis.2012.08.008","article-title":"CpG-ODN, the TLR9 agonist, attenuates myocardial ischemia\/reperfusion injury: involving activation of PI3K\/Akt signaling","volume":"1832","author":"Cao","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"2026012114091812200_ehf214403-bib-0024","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1161\/CIRCULATIONAHA.109.916346","article-title":"Monocytes: protagonists of infarct inflammation and repair after myocardial infarction","volume":"121","author":"Nahrendorf","year":"2010","journal-title":"Circulation"},{"key":"2026012114091812200_ehf214403-bib-0025","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.amjcard.2008.09.085","article-title":"Association of leukocyte and neutrophil counts with infarct size, left ventricular function and outcomes after percutaneous coronary intervention for ST-elevation myocardial infarction","volume":"103","author":"Chia","year":"2009","journal-title":"Am J Cardiol"},{"key":"2026012114091812200_ehf214403-bib-0026","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/0002-8703(86)90461-8","article-title":"Reduction of myocardial infarct size by neutrophil depletion: effect of duration of occlusion","volume":"112","author":"Jolly","year":"1986","journal-title":"Am Heart J"},{"key":"2026012114091812200_ehf214403-bib-0027","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/S0008-6363(99)00187-X","article-title":"The role of neutrophils in myocardial ischemia-reperfusion injury","volume":"43","author":"Jordan","year":"1999","journal-title":"Cardiovasc Res"},{"key":"2026012114091812200_ehf214403-bib-0028","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1182\/blood-2013-07-514992","article-title":"VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia\/reperfusion injury in mice","volume":"123","author":"Savchenko","year":"2014","journal-title":"Blood"},{"key":"2026012114091812200_ehf214403-bib-0029","doi-asserted-by":"crossref","first-page":"2631","DOI":"10.1097\/CCM.0b013e318258fb70","article-title":"Toll-like receptor 9 activation in neutrophils impairs chemotaxis and reduces sepsis outcome","volume":"40","author":"Trevelin","year":"2012","journal-title":"Crit Care Med"},{"key":"2026012114091812200_ehf214403-bib-0030","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1002\/eji.200535806","article-title":"Modulating responsiveness of human TLR7 and 8 to small molecule ligands with T-rich phosphorothiate oligodeoxynucleotides","volume":"36","author":"Jurk","year":"2006","journal-title":"Eur J Immunol"},{"key":"2026012114091812200_ehf214403-bib-0031","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1089\/vim.2016.0103","article-title":"Role of TLR9 in oncogenic virus-produced cancer","volume":"30","author":"Martinez-Campos","year":"2017","journal-title":"Viral Immunol"},{"key":"2026012114091812200_ehf214403-bib-0032","article-title":"Neutrophil extracellular traps in the autoimmunity context","volume":"8","author":"Bruschi","year":"2021","journal-title":"Front Med (Lausanne)"}],"container-title":["ESC Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/10\/4\/2375\/64704698\/eschf_10_4_2375.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eschf\/article-pdf\/10\/4\/2375\/64704698\/eschf_10_4_2375.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T19:10:00Z","timestamp":1769022600000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eschf\/article\/10\/4\/2375\/8285329"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,16]]},"references-count":32,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,5,16]]},"published-print":{"date-parts":[[2023,8,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ehf2.14403","relation":{},"ISSN":["2055-5822"],"issn-type":[{"value":"2055-5822","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8]]},"published":{"date-parts":[[2023,5,16]]},"assertion":[{"value":"2022-12-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}