{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:39:45Z","timestamp":1790617185390,"version":"4.1.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 \u03bcg\/kg bolus followed by 0.1\/0.2 \u03bcg\/kg\/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>The placebo group showed a 9% (P = 0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuro-mechanical efficiency of the diaphragm during loading improved by 21% (P &amp;lt; 0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P &amp;lt; 0.05).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201107-1268oc","type":"journal-article","created":{"date-parts":[[2011,9,30]],"date-time":"2011-09-30T07:38:23Z","timestamp":1317368303000},"page":"90-95","source":"Crossref","is-referenced-by-count":115,"title":["The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function"],"prefix":"10.1093","volume":"185","author":[{"given":"Jonne","family":"Doorduin","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer A.","family":"Sinderby","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Critical Care Medicine, University of Toronto"},{"name":"Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Beck","sequence":"additional","affiliation":[{"name":"Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto"},{"name":"Department of Pediatrics, St. Michael's Hospital, University of Toronto, Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick F.","family":"Stegeman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Radboud University Nijmegen Medical Centre, The Netherlands"},{"name":"Faculty of Human Movement Sciences, Research Institute MOVE, VU University, Amsterdam, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hieronymus W. H.","family":"van Hees","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes G.","family":"van der Hoeven","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo M. A.","family":"Heunks","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,1,1]]},"reference":[{"key":"2026032101081022300_bib1","doi-asserted-by":"crossref","first-page":"R127","DOI":"10.1186\/cc9094","article-title":"Increased duration of mechanical ventilation is associated with decreased diaphragmatic force: a prospective observational study","volume":"14","author":"Hermans","year":"2010","journal-title":"Crit Care"},{"key":"2026032101081022300_bib2","doi-asserted-by":"crossref","first-page":"H819","DOI":"10.1152\/ajpheart.00085.2007","article-title":"Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats","volume":"293","author":"van Hees","year":"2007","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2026032101081022300_bib3","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1164\/rccm.200701-020PP","article-title":"Diaphragm muscle fiber dysfunction in chronic obstructive pulmonary disease: toward a pathophysiological concept","volume":"175","author":"Ottenheijm","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1164\/rccm.2206020","article-title":"Disorders of the respiratory muscles","volume":"168","author":"Laghi","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib5","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1164\/rccm.200210-1246OC","article-title":"Is weaning failure caused by low-frequency fatigue of the diaphragm?","volume":"167","author":"Laghi","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib6","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1097\/00003246-200107000-00005","article-title":"Measurement of twitch transdiaphragmatic, esophageal, and endotracheal tube pressure with bilateral anterolateral magnetic phrenic nerve stimulation in patients in the intensive care unit","volume":"29","author":"Watson","year":"2001","journal-title":"Crit Care Med"},{"key":"2026032101081022300_bib7","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1164\/ajrccm.160.2.9810081","article-title":"Diaphragm strength in chronic heart failure","volume":"160","author":"Hughes","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib8","doi-asserted-by":"crossref","first-page":"1799","DOI":"10.1056\/NEJM199712183372503","article-title":"Cellular adaptations in the diaphragm in chronic obstructive pulmonary disease","volume":"337","author":"Levine","year":"1997","journal-title":"N Engl J Med"},{"key":"2026032101081022300_bib9","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1164\/rccm.200502-262OC","article-title":"Diaphragm dysfunction in chronic obstructive pulmonary disease","volume":"172","author":"Ottenheijm","year":"2005","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib10","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1164\/rccm.200605-721OC","article-title":"Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease","volume":"174","author":"Ottenheijm","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib11","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1056\/NEJMoa070447","article-title":"Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans","volume":"358","author":"Levine","year":"2008","journal-title":"N Engl J Med"},{"key":"2026032101081022300_bib12","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1164\/rccm.200805-732OC","article-title":"Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease","volume":"179","author":"van Hees","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib13","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00424-009-0744-1","article-title":"EMD 57033 partially reverses ventilator-induced diaphragm muscle fibre calcium desensitisation","volume":"459","author":"Ochala","year":"2010","journal-title":"Pflugers Arch"},{"key":"2026032101081022300_bib14","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/S0140-6736(02)09455-2","article-title":"Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial","volume":"360","author":"Follath","year":"2002","journal-title":"Lancet"},{"key":"2026032101081022300_bib15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0014-2999(97)01108-4","article-title":"Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes","volume":"333","author":"Yokoshiki","year":"1997","journal-title":"Eur J Pharmacol"},{"key":"2026032101081022300_bib16","first-page":"A4244","article-title":"The calcium sensitizer levosimendan improves contractility and neuromechanical coupling of the diaphragm in healthy subjects [abstract]","volume":"183","author":"Doorduin","year":"2011","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib17","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1023\/B:MCBI.0000049141.37823.19","article-title":"The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin c","volume":"266","author":"Sorsa","year":"2004","journal-title":"Mol Cell Biochem"},{"key":"2026032101081022300_bib18","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1111\/j.1476-5381.2010.01048.x","article-title":"Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure","volume":"162","author":"van Hees","year":"2011","journal-title":"Br J Pharmacol"},{"key":"2026032101081022300_bib19","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.cardfail.2005.07.001","article-title":"What is the in vivo mechanism of action of levosimendan?","volume":"11","author":"MacGowan","year":"2005","journal-title":"J Card Fail"},{"key":"2026032101081022300_bib20","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1152\/jappl.1998.85.3.1103","article-title":"Does resistive loading decrease diaphragmatic contractility before task failure?","volume":"85","author":"Laghi","year":"1998","journal-title":"J Appl Physiol"},{"key":"2026032101081022300_bib21","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1085\/jgp.98.3.615","article-title":"Changes of myoplasmic calcium concentration during fatigue in single mouse muscle fibers","volume":"98","author":"Westerblad","year":"1991","journal-title":"J Gen Physiol"},{"key":"2026032101081022300_bib22","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1152\/physrev.00015.2007","article-title":"Skeletal muscle fatigue: cellular mechanisms","volume":"88","author":"Allen","year":"2008","journal-title":"Physiol Rev"},{"key":"2026032101081022300_bib23","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s10439-009-9756-4","article-title":"Effect of extracellular potassium accumulation on muscle fiber conduction velocity: a simulation study","volume":"37","author":"Fortune","year":"2009","journal-title":"Ann Biomed Eng"},{"key":"2026032101081022300_bib24","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/0014-2999(95)00872-1","article-title":"The effects of pharmacological modulation of KATP on the guinea-pig isolated diaphragm","volume":"302","author":"Wickenden","year":"1996","journal-title":"Eur J Pharmacol"},{"key":"2026032101081022300_bib25","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1152\/physrev.00027.2009","article-title":"Muscle KATP channels: recent insights to energy sensing and myoprotection","volume":"90","author":"Flagg","year":"2010","journal-title":"Physiol Rev"},{"key":"2026032101081022300_bib26","doi-asserted-by":"crossref","first-page":"17","DOI":"10.7326\/0003-4819-110-1-17","article-title":"Dopamine effects on diaphragmatic strength during acute respiratory failure in chronic obstructive pulmonary disease","volume":"110","author":"Aubier","year":"1989","journal-title":"Ann Intern Med"},{"key":"2026032101081022300_bib27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1056\/NEJM198107303050503","article-title":"Aminophylline improves diaphragmatic contractility","volume":"305","author":"Aubier","year":"1981","journal-title":"N Engl J Med"},{"key":"2026032101081022300_bib28","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1183\/09031936.93.02070652","article-title":"The effect of aminophylline on respiratory and limb muscle contractility in man","volume":"2","author":"Brophy","year":"1989","journal-title":"Eur Respir J"},{"key":"2026032101081022300_bib29","doi-asserted-by":"crossref","first-page":"535","DOI":"10.2165\/00003088-200746070-00001","article-title":"Clinical pharmacology of levosimendan","volume":"46","author":"Antila","year":"2007","journal-title":"Clin Pharmacokinet"},{"key":"2026032101081022300_bib30","doi-asserted-by":"crossref","first-page":"20234","DOI":"10.1016\/S0021-9258(17)30494-5","article-title":"The effect of phosphate and calcium on force generation in glycerinated rabbit skeletal muscle fibers: a steady-state and transient kinetic study","volume":"265","author":"Millar","year":"1990","journal-title":"J Biol Chem"},{"key":"2026032101081022300_bib31","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1097\/00005344-200404000-00011","article-title":"Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart","volume":"43","author":"Kaheinen","year":"2004","journal-title":"J Cardiovasc Pharmacol"},{"key":"2026032101081022300_bib32","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1164\/ajrccm.158.2.9710084","article-title":"The tension-time index and the frequency\/tidal volume ratio are the major pathophysiologic determinants of weaning failure and success","volume":"158","author":"Vassilakopoulos","year":"1998","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib33","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1161\/01.CIR.95.4.910","article-title":"Chronic congestive heart failure elicits adaptations of endurance exercise in diaphragmatic muscle","volume":"95","author":"Tikunov","year":"1997","journal-title":"Circulation"},{"key":"2026032101081022300_bib34","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1183\/09031936.04.00029004","article-title":"Magnetic stimulation for the measurement of respiratory and skeletal muscle function","volume":"24","author":"Man","year":"2004","journal-title":"Eur Respir J"},{"key":"2026032101081022300_bib35","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1136\/thx.49.12.1234","article-title":"Potentiation of diaphragmatic twitch after voluntary contraction in normal subjects","volume":"49","author":"Wragg","year":"1994","journal-title":"Thorax"},{"key":"2026032101081022300_bib36","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1164\/ajrccm.163.4.2005121","article-title":"Changes in respiratory effort sensation over time are linked to the frequency content of diaphragm electrical activity","volume":"163","author":"Sinderby","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2026032101081022300_bib37","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1152\/jappl.1995.79.5.1803","article-title":"Automatic assessment of electromyogram quality","volume":"79","author":"Sinderby","year":"1995","journal-title":"J Appl Physiol"},{"key":"2026032101081022300_bib38","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1152\/jappl.1997.82.4.1370","article-title":"Enhancement of signal quality in esophageal recordings of diaphragm EMG","volume":"82","author":"Sinderby","year":"1997","journal-title":"J Appl Physiol"},{"key":"2026032101081022300_bib39","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/BF02570507","article-title":"Haemodynamic dose-efficacy of levosimendan in healthy volunteers","volume":"47","author":"Lilleberg","year":"1994","journal-title":"Eur J Clin Pharmacol"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/185\/1\/90\/67250422\/ajrccm_185_1_90.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/185\/1\/90\/67250422\/ajrccm_185_1_90.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:08:22Z","timestamp":1774069702000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/185\/1\/90\/8507573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,1]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2012,1,1]]},"published-print":{"date-parts":[[2012,1,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.201107-1268oc","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13365988.14736097","asserted-by":"object"}]},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,1]]},"published":{"date-parts":[[2012,1,1]]}}}