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A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity\/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation\u2013contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1093\/eurheartj\/ehy600","type":"journal-article","created":{"date-parts":[[2018,9,17]],"date-time":"2018-09-17T07:15:02Z","timestamp":1537168502000},"page":"3626-3644","source":"Crossref","is-referenced-by-count":200,"title":["Treatments targeting inotropy"],"prefix":"10.1093","volume":"40","author":[{"given":"Christoph","family":"Maack","sequence":"first","affiliation":[{"name":"Comprehensive Heart Failure Center, University Clinic W\u00fcrzburg , Am Schwarzenberg 15, W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Eschenhagen","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf (UKE) , Hamburg, Germany"},{"name":"Partner site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Centre for Cardiovascular Research) , Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazha","family":"Hamdani","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Physiology, Ruhr University Bochum , Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R","family":"Heinzel","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9 University Medicine , Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander R","family":"Lyon","sequence":"additional","affiliation":[{"name":"NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute , Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dietmar J","family":"Manstein","sequence":"additional","affiliation":[{"name":"Institute for Biophysical Chemistry, Hannover Medical School , Hannover, Germany"},{"name":"Division for Structural Biochemistry, Hannover Medical School , Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Metzger","sequence":"additional","affiliation":[{"name":"Department of Integrative Biology & Physiology, University of Minnesota Medical School , Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology , Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo G","family":"Tocchetti","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, Federico II University , Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Birhan","family":"Yilmaz","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Cumhuriyet University , Sivas, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan D","family":"Anker","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Pneumology, University Medical Center G\u00f6ttingen and DZHK (German Center for Cardiovascular Research) , G\u00f6ttingen, Germany"},{"name":"Division of Cardiology and Metabolism - Heart Failure, Cachexia and Sarcopenia, Department of Internal Medicine and Cardiology , Berlin-Brandenburg Center for Regenerative Therapies (BCRT) at Charit\u00e9 University Medicine, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Luc","family":"Balligand","sequence":"additional","affiliation":[{"name":"Institut de Recherche Exp\u00e9rimentale et Clinique (IREC), Pole of Pharmacology and Therapeutics (FATH) , Universite Catholique de Louvain and Cliniques Universitaires Saint-Luc, Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johann","family":"Bauersachs","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School , Carl-Neuberg-Str. 1, Hannover D-30625, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Brutsaert","sequence":"additional","affiliation":[{"name":"University of Antwerp Emeriti Professor, , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf (UKE) , Hamburg, Germany"},{"name":"Partner site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Centre for Cardiovascular Research) , Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Chlopicki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Medical College , Jagiellonian University, Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G","family":"Cleland","sequence":"additional","affiliation":[{"name":"University of Hull, Kingston upon Hull , UK"},{"name":"National Heart and Lung Institute, Royal Brompton and Harefield Hospitals NHS Trust , Imperial College, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Dietl","sequence":"additional","affiliation":[{"name":"Klinik und Poliklinik f\u00fcr Innere Medizin II, Universit\u00e4tsklinikum Regensburg , Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodolphe","family":"Fischmeister","sequence":"additional","affiliation":[{"name":"Inserm UMR-S 1180, Univ. Paris-Sud, Universit\u00e9 Paris-Saclay , Ch\u00e2tenay-Malabry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veli-Pekka","family":"Harjola","sequence":"additional","affiliation":[{"name":"Emergency Medicine, University of Helsinki, Helsinki , Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Heymans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, CARIM , Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denise","family":"Hilfiker-Kleiner","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School , Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Holzmeister","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Centre Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"de Keulenaer","sequence":"additional","affiliation":[{"name":"Laboratory of Physiopharmacology (University of Antwerp) and Department of Cardiology , ZNA Hospital, Antwerp, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Sciences, Second University of Naples , Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang A","family":"Linke","sequence":"additional","affiliation":[{"name":"Institute of Physiology II, University of M\u00fcnster , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars H","family":"Lund","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Medicine, Karolinska Institutet , Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Masip","sequence":"additional","affiliation":[{"name":"Intensive Care Department, Consorci Sanitari Integral, University of Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Metra","sequence":"additional","affiliation":[{"name":"Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences , and Public Health, University of Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Cardiovascular Research Institute Basel (CRIB) , University Hospital Basel, University of Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkert","family":"Pieske","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Cardiology, Charit\u00e9 Universit\u00e4tsmedizin Berlin , Campus Virchow Klinikum, Berlin, Germany"},{"name":"Department of Internal Medicine and Cardiology, German Heart Center Berlin, and German Centre for Cardiovascular Research (DZHK) , Partner site Berlin, and Berlin Institute of Health (BIH), Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Ponikowski","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical University, Clinical Military Hospital , Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arsen","family":"Risti\u0107","sequence":"additional","affiliation":[{"name":"Department of Cardiology of the Clinical Center of Serbia and Belgrade University School of Medicine , Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Ruschitzka","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart Centre, University Hospital Zurich , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petar M","family":"Seferovi\u0107","sequence":"additional","affiliation":[{"name":"Serbian Academy of Sciences and Arts , Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hadi","family":"Skouri","sequence":"additional","affiliation":[{"name":"Division of Cardiology, American University of Beirut Medical Centre , Beirut, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfram H","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology and Toxicology, University Medical Center G\u00f6ttingen , G\u00f6ttingen, Germany"},{"name":"German Center for Cardiovascular Research (DZHK) , Partner siteG\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Mebazaa","sequence":"additional","affiliation":[{"name":"H\u00f4pital Lariboisi\u00e8re, Universit\u00e9 Paris Diderot , Inserm U 942, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,10,8]]},"reference":[{"key":"2022102616080269400_ehy600-B1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.jacc.2013.11.053","article-title":"The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries","volume":"63","author":"Ambrosy","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2022102616080269400_ehy600-B2","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1002\/ejhf.890","article-title":"Clinical phenotypes and outcome of patients hospitalized for acute heart failure: the ESC Heart Failure Long-Term Registry","volume":"19","author":"Chioncel","year":"2017","journal-title":"Eur J Heart Fail"},{"key":"2022102616080269400_ehy600-B3","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ejhf.592","article-title":"2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC","volume":"18","author":"Ponikowski","year":"2016","journal-title":"Eur J Heart Fail"},{"key":"2022102616080269400_ehy600-B4","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1056\/NEJM199702203360801","article-title":"Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure","volume":"336","year":"1997","journal-title":"N Engl J Med"},{"key":"2022102616080269400_ehy600-B5","first-page":"380","article-title":"Altered cardiac myocyte Ca regulation in heart failure","volume":"21","author":"Bers","year":"2006","journal-title":"Physiology (Bethesda)"},{"key":"2022102616080269400_ehy600-B6","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1161\/CIRCULATIONAHA.107.728840","article-title":"Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease","volume":"118","author":"Overgaard","year":"2008","journal-title":"Circulation"},{"key":"2022102616080269400_ehy600-B7","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1161\/CIRCRESAHA.111.245092","article-title":"Treatment of chronic heart failure with beta-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology","volume":"109","author":"Bristow","year":"2011","journal-title":"Circ Res"},{"key":"2022102616080269400_ehy600-B8","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1161\/01.RES.0000102042.83024.CA","article-title":"What is the role of beta-adrenergic signaling in heart failure?","volume":"93","author":"Lohse","year":"2003","journal-title":"Circ Res"},{"key":"2022102616080269400_ehy600-B9","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1016\/j.jacc.2014.01.016","article-title":"Inotropes","volume":"63","author":"Francis","year":"2014","journal-title":"J Am Coll Cardiol"},{"key":"2022102616080269400_ehy600-B10","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1097\/CCM.0b013e318232962a","article-title":"Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies","volume":"40","author":"Landoni","year":"2012","journal-title":"Crit Care Med"},{"key":"2022102616080269400_ehy600-B11","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ijcard.2016.02.014","article-title":"Levosimendan meta-analyses: is there a pattern in the effect on mortality?","volume":"209","author":"Pollesello","year":"2016","journal-title":"Int J Cardiol"},{"key":"2022102616080269400_ehy600-B12","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1001\/jama.297.17.1883","article-title":"Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial","volume":"297","author":"Mebazaa","year":"2007","journal-title":"JAMA"},{"key":"2022102616080269400_ehy600-B13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.jchf.2012.12.004","article-title":"Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart 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