{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:59:58Z","timestamp":1792094398941,"version":"4.4.0"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRL BO-4264\/1-1"],"award-info":[{"award-number":["GRL BO-4264\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Patients with acute ischemic stroke (AIS) present an increased incidence of systemic inflammatory response syndrome and release of Troponin T coinciding with cardiac dysfunction. The nature of the cardiocirculatory alterations remains obscure as models to investigate systemic interferences of the brain-heart-axis following AIS are sparse. Thus, this study aims to investigate acute cardiocirculatory dysfunction and myocardial injury in mice after reperfused AIS. Ischemic stroke was induced in mice by transient right-sided middle cerebral artery occlusion (tMCAO). Cardiac effects were investigated by electrocardiograms, 3D-echocardiography, magnetic resonance imaging (MRI), invasive conductance catheter measurements, histology, flow-cytometry, and determination of high-sensitive Troponin T (hsTnT). Systemic hemodynamics were recorded and catecholamines and inflammatory markers in circulating blood and myocardial tissue were determined by immuno-assay and flow-cytometry. Twenty-four hours following tMCAO hsTnT was elevated 4-fold compared to controls and predicted long-term survival. In parallel, systolic left ventricular dysfunction occurred with impaired global longitudinal strain, lower blood pressure, reduced stroke volume, and severe bradycardia leading to reduced cardiac output. This was accompanied by a systemic inflammatory response characterized by granulocytosis, lymphopenia, and increased levels of serum-amyloid P and interleukin-6. Within myocardial tissue, MRI relaxometry indicated expansion of extracellular space, most likely due to inflammatory edema and a reduced fluid volume. Accordingly, we found an increased abundance of granulocytes, apoptotic cells, and upregulation of pro-inflammatory cytokines within myocardial tissue following tMCAO. Therefore, reperfused ischemic stroke leads to specific cardiocirculatory alterations that are characterized by acute heart failure with reduced stroke volume, bradycardia, and changes in cardiac tissue and accompanied by systemic and local inflammatory responses.<\/jats:p>","DOI":"10.3389\/fphys.2021.782760","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T23:40:58Z","timestamp":1640043658000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Acute Heart Failure After Reperfused Ischemic Stroke: Association With Systemic and Cardiac Inflammatory Responses"],"prefix":"10.3389","volume":"12","author":[{"given":"Lilian","family":"Vornholz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Nienhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Gliem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Alter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carina","family":"Henning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hakima","family":"Ezzahoini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Wolff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Clasen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tienush","family":"Rassaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Fl\u00f6gel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Kelm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Gerdes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Jander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"B\u00f6nner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1002\/ana.20806","article-title":"Insular involvement in brain infarction increases risk for cardiac arrhythmia and death","volume":"59","author":"Abboud","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1093\/eurheartj\/ehw149","article-title":"ESC working group position paper on myocardial infarction with non-obstructive coronary arteries","volume":"38","author":"Agewall","year":"2017","journal-title":"Eur. Heart J."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1159\/000353875","article-title":"What does elevated high-sensitive troponin I in stroke patients mean: concomitant acute myocardial infarction or a marker for high-risk patients?","volume":"36","author":"Anders","year":"2013","journal-title":"Cerebrovasc. Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1161\/01.STR.0000137607.61697.77","article-title":"Systemic inflammatory response depends on initial stroke severity but is attenuated by successful thrombolysis","volume":"35","author":"Audebert","year":"2004","journal-title":"Stroke"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1161\/01.STR.17.3.472","article-title":"Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination","volume":"17","author":"Bederson","year":"1986","journal-title":"Stroke"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1002\/ana.25073","article-title":"Stroke-induced chronic systolic dysfunction driven by sympathetic overactivity","volume":"82","author":"Bieber","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e34730","DOI":"10.1371\/journal.pone.0034730","article-title":"Resident cardiac immune cells and expression of the ectonucleotidase enzymes CD39 and CD73 after ischemic injury","volume":"7","author":"Bonner","year":"2012","journal-title":"PLoS One"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1161\/CIRCRESAHA.113.300180","article-title":"Ecto-5\u2032-nucleotidase on immune cells protects from adverse cardiac remodeling","volume":"113","author":"Bonner","year":"2013","journal-title":"Circ. Res."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s12968-015-0118-0","article-title":"Myocardial T2 mapping reveals age- and sex-related differences in volunteers","volume":"17","author":"Bonner","year":"2015","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1007\/s12975-017-0520-z","article-title":"MiR-126 affects brain-heart interaction after cerebral ischemic stroke","volume":"8","author":"Chen","year":"","journal-title":"Transl. Stroke Res."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1161\/CIRCRESAHA.117.311170","article-title":"Brain-heart interaction: cardiac complications after stroke","volume":"121","author":"Chen","year":"","journal-title":"Circ. Res."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1136\/jnnp.2004.037531","article-title":"Insular lesions, ECG abnormalities, and outcome in acute stroke","volume":"76","author":"Christensen","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1080\/01616412.1997.11740874","article-title":"Monofilament intraluminal middle cerebral artery occlusion in the mouse","volume":"19","author":"Clark","year":"1997","journal-title":"Neurol. Res."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3498","DOI":"10.1161\/STROKEAHA.113.002470","article-title":"N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARgamma agonist rosiglitazone","volume":"44","author":"Cuartero","year":"2013","journal-title":"Stroke"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.jns.2014.12.007","article-title":"Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area?","volume":"348","author":"De Raedt","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1161\/01.STR.0000251441.89665.bc","article-title":"Stroke-induced immunodepression: experimental evidence and clinical relevance","volume":"38","author":"Dirnagl","year":"2007","journal-title":"Stroke"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1016\/j.freeradbiomed.2015.10.409","article-title":"Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function","volume":"89","author":"Erkens","year":"2015","journal-title":"Free Radic. Biol. Med."},{"key":"ref18","doi-asserted-by":"publisher","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":"Flogel","year":"2008","journal-title":"Circulation"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1111\/ene.12233","article-title":"White blood cell count is an independent predictor of outcomes after acute ischaemic stroke","volume":"21","author":"Furlan","year":"2014","journal-title":"Eur. J. Neurol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"H733","DOI":"10.1152\/ajpheart.2000.279.2.H733","article-title":"Phenotypic screening for heart rate variability in the mouse","volume":"279","author":"Gehrmann","year":"2000","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"e006025","DOI":"10.1161\/CIRCIMAGING.116.006025","article-title":"Cardiovascular magnetic resonance relaxometry predicts regional functional outcome after experimental myocardial infarction","volume":"10","author":"Haberkorn","year":"2017","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1093\/eurheartj\/ehx393","article-title":"2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC)","volume":"39","author":"Ibanez","year":"2018","journal-title":"Eur. Heart J."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"3175","DOI":"10.1161\/STROKEAHA.113.001714","article-title":"Ischemic stroke brain sends indirect cell death signals to the heart","volume":"44","author":"Ishikawa","year":"2013","journal-title":"Stroke"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2392","DOI":"10.1161\/ATVBAHA.107.149476","article-title":"Sphingosine-1-phosphate analogue FTY720 causes lymphocyte redistribution and hypercholesterolemia in ApoE-deficient mice","volume":"27","author":"Klingenberg","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1002\/ana.24906","article-title":"Stroke in right dorsal anterior insular cortex is related to myocardial injury","volume":"81","author":"Krause","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jneumeth.2009.07.029","article-title":"Functional testing in a mouse stroke model induced by occlusion of the distal middle cerebral artery","volume":"184","author":"Lubjuhn","year":"2009","journal-title":"J. Neurosci. Methods"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1093\/cvr\/cvw024","article-title":"Temporal neutrophil polarization following myocardial infarction","volume":"110","author":"Ma","year":"2016","journal-title":"Cardiovasc. Res."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"2560","DOI":"10.1161\/STROKEAHA.108.536086","article-title":"Cardiac dysfunction after left permanent cerebral focal ischemia: the brain and heart connection","volume":"40","author":"Min","year":"2009","journal-title":"Stroke"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1264","DOI":"10.1161\/CIRCULATIONAHA.115.018547","article-title":"Coronary angiographic findings in acute ischemic stroke patients with elevated cardiac troponin: The Troponin Elevation in Acute Ischemic Stroke (TRELAS) Study","volume":"133","author":"Mochmann","year":"2016","journal-title":"Circulation"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1161\/01.STR.30.5.981","article-title":"C-reactive protein and outcome after ischemic stroke","volume":"30","author":"Muir","year":"1999","journal-title":"Stroke"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"6523","DOI":"10.4049\/jimmunol.176.11.6523","article-title":"Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages","volume":"176","author":"Offner","year":"2006","journal-title":"J. Immunol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/0006-8993(90)91796-J","article-title":"Cardiac chronotropic organization of the rat insular cortex","volume":"533","author":"Oppenheimer","year":"1990","journal-title":"Brain Res."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1002\/cphy.c140076","article-title":"The insular cortex and the regulation of cardiac function","volume":"6","author":"Oppenheimer","year":"2016","journal-title":"Compr. Physiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1038\/nprot.2008.138","article-title":"Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats","volume":"3","author":"Pacher","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1084\/jem.20021098","article-title":"Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation","volume":"198","author":"Prass","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1938","DOI":"10.1016\/j.jstrokecerebrovasdis.2015.05.005","article-title":"Early dynamics of P-selectin and interleukin 6 predicts outcomes in ischemic stroke","volume":"24","author":"Pusch","year":"2015","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1016\/j.ijcard.2014.10.036","article-title":"Prognostic relevance of cardiac troponin T levels and their dynamic changes measured with a high-sensitivity assay in acute ischaemic stroke: analyses from the TRELAS cohort","volume":"177","author":"Scheitz","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/0006-8993(86)90973-X","article-title":"Changes in plasma catecholamine levels after insula damage in experimental stroke","volume":"375","author":"Smith","year":"1986","journal-title":"Brain Res."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S1474-4422(11)70291-5","article-title":"Cardiovascular and neurological causes of sudden death after ischaemic stroke","volume":"11","author":"Soros","year":"2012","journal-title":"Lancet Neurol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1161\/CIRCRESAHA.116.308446","article-title":"Heart-brain axis: effects of neurologic injury on cardiovascular function","volume":"120","author":"Tahsili-Fahadan","year":"2017","journal-title":"Circ. Res."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1056\/NEJMoa1406761","article-title":"Clinical features and outcomes of Takotsubo (stress) cardiomyopathy","volume":"373","author":"Templin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1307","DOI":"10.1161\/01.STR.30.7.1307","article-title":"Effects of stroke localization on cardiac autonomic balance and sudden death","volume":"30","author":"Tokgozoglu","year":"1999","journal-title":"Stroke"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/s00395-013-0330-8","article-title":"Endothelial NOS (NOS3) impairs myocardial function in developing sepsis","volume":"108","author":"van de Sandt","year":"2013","journal-title":"Basic Res. Cardiol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1212\/01.wnl.0000342471.07290.07","article-title":"Impact of cardiac complications on outcome after aneurysmal subarachnoid hemorrhage: a meta-analysis","volume":"72","author":"van der Bilt","year":"2009","journal-title":"Neurology"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1002\/jcsm.12335","article-title":"Experimental ischaemic stroke induces transient cardiac atrophy and dysfunction","volume":"10","author":"Veltkamp","year":"2019","journal-title":"J. Cachexia. Sarcopenia Muscle"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"e2234","DOI":"10.1038\/cddis.2016.140","article-title":"The emerging role of toll-like receptor 4 in myocardial inflammation","volume":"7","author":"Yang","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.ijcard.2014.12.116","article-title":"Takotsubo cardiomyopathy, a new concept of cardiomyopathy: clinical features and pathophysiology","volume":"182","author":"Yoshikawa","year":"2015","journal-title":"Int. J. Cardiol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1007\/s00392-015-0928-y","article-title":"Safety of percutaneous coronary intervention in patients with acute ischemic stroke\/transient ischemic attack and acute coronary syndrome","volume":"105","author":"Zeus","year":"2016","journal-title":"Clin. Res. Cardiol."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.782760\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T23:41:03Z","timestamp":1640043663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.782760\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":48,"alternative-id":["10.3389\/fphys.2021.782760"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.782760","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,21]]},"article-number":"782760"}}