{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:04:02Z","timestamp":1785420242348,"version":"3.56.0"},"reference-count":103,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union Road Federation","award":["PNRR-POC-2023-12378186"],"award-info":[{"award-number":["PNRR-POC-2023-12378186"]}]},{"award":["PNRR-POC-2023-12378186"],"award-info":[{"award-number":["PNRR-POC-2023-12378186"]}],"id":[{"id":"https:\/\/ror.org\/02qcxga94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute heart failure (AHF) and cardiogenic shock (CS) remain major causes of cardiovascular morbidity, mortality, and healthcare utilization worldwide. Although inotropic agents are central to the management of low-output states, their clinical utility is fundamentally constrained by mechanisms that increase myocardial oxygen consumption, disrupt calcium homeostasis, and promote arrhythmogenesis, without improving long-term outcomes. These limitations reflect not only pharmacological shortcomings, but a broader conceptual reliance on amplification of intracellular calcium flux as the primary means of augmenting contractility. While effective in increasing cardiac output, this strategy imposes substantial energetic and electrophysiological costs and fails to address key abnormalities of the failing myocardium, including impaired calcium recirculation and diastolic dysfunction. Istaroxime is a first-in-class agent that combines Na+\/K+-ATPase inhibition with enhancement of sarcoplasmic reticulum Ca2+-ATPase (sarcoplasmic reticulum Ca2+-ATPase isoform 2a (SERCA2a)) function, thereby modulating both calcium availability and reuptake. This dual mechanism promotes a more coordinated pattern of excitation\u2013contraction coupling, integrating systolic augmentation with improved diastolic relaxation. Early clinical studies demonstrate a distinct hemodynamic profile characterized by increased stroke volume, preservation of heart rate, and stabilization or elevation of arterial pressure. These properties suggest a potential role for istaroxime in specific hemodynamic phenotypes, particularly hypotensive AHF and early cardiogenic shock, where conventional inotropes are limited by tachycardia or vasodilatory effects. However, current evidence is limited to phase II studies focused on hemodynamic endpoints, and the impact of istaroxime on survival, organ function, and disease progression remains unknown. Istaroxime represents a mechanistically distinct approach to inotropic therapy, shifting the paradigm from calcium amplification toward partial restoration of calcium cycling. Its clinical relevance will depend on whether this strategy can translate into improved patient outcomes\u2014an objective that has thus far eluded the entire class of inotropic agents.<\/jats:p>","DOI":"10.3390\/ijms27135779","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Istaroxime in Acute Heart Failure and Early Cardiogenic Shock: A Calcium-Cycling Approach to Inotropic Therapy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-1645","authenticated-orcid":false,"given":"Beata","family":"Krasi\u0144ska","sequence":"first","affiliation":[{"name":"Department of Hypertensiology, Angiology, and Internal Medicine, Poznan University of Medical Sciences, 1\/2 D\u0142uga Street, 61-848 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7141-2561","authenticated-orcid":false,"given":"Giuseppe","family":"Maria Raffa","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"},{"name":"Department of Precision Medicine in Medical Surgical and Critical Area (Me.Pre.C.C.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-1965","authenticated-orcid":false,"given":"Calogera","family":"Pisano","sequence":"additional","affiliation":[{"name":"Department of Research, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"},{"name":"Department of Precision Medicine in Medical Surgical and Critical Area (Me.Pre.C.C.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nuzzi","sequence":"additional","affiliation":[{"name":"Department of Clinical Cardiology and Heart Failure, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3383-9657","authenticated-orcid":false,"given":"Paolo","family":"Manca","sequence":"additional","affiliation":[{"name":"Department of Clinical Cardiology and Heart Failure, IRCCS ISMETT (Mediterranean Institute for Transplantation and Advanced Specialized Therapies), 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6563-0877","authenticated-orcid":false,"given":"Krzysztof J.","family":"Filipiak","sequence":"additional","affiliation":[{"name":"The Centre of Postgraduate Medical Education, 99\/103 Marymoncka Street, 01-813 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansur","family":"Rahnama","sequence":"additional","affiliation":[{"name":"Department of Dental Surgery, Medical University of Lublin, 6 Chod\u017aki Street, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4213-8708","authenticated-orcid":false,"given":"Anna","family":"Olasi\u0144ska-Wi\u015bniewska","sequence":"additional","affiliation":[{"name":"Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, 1\/2 D\u0142uga Street, 61-848 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5478-3245","authenticated-orcid":false,"given":"Mariusz","family":"Kowalewski","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Centre of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior, 02-507 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2798-1959","authenticated-orcid":false,"given":"Zbigniew","family":"Krasi\u0144ski","sequence":"additional","affiliation":[{"name":"Department of Vascular, Endovascular Surgery, Angiology and Phlebology, Poznan University of Medical Sciences, 1\/2 D\u0142uga Street, 61-848 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Suwalski","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Centre of Postgraduate Medical Education, Central Clinical Hospital of the Ministry of Interior, 02-507 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Grywalska","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Medical University of Lublin, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8080-2764","authenticated-orcid":false,"given":"Tomasz","family":"Urbanowicz","sequence":"additional","affiliation":[{"name":"Cardiac Surgery and Transplantology Department, Poznan University of Medical Sciences, 1\/2 D\u0142uga Street, 61-848 Pozna\u0144, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"ref_1","first-page":"e72106","article-title":"Cardiac Failure and Cardiogenic Shock: Insights Into Pathophysiology, Classification, and Hemodynamic Assessment","volume":"16","author":"Siopi","year":"2024","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Baudry, G., Bourdin, J., Mocan, R., Hugon-Vallet, E., Pozzi, M., Jobb\u00e9-Duval, A., Paulo, N., Rossignol, P., Sebbag, L., and Girerd, N. (2022). Prognosis of Advanced Heart Failure Patients according to Their Hemodynamic Profile Based on the Modified Forrester Classification. J. Clin. Med., 11.","DOI":"10.3390\/jcm11133663"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1016\/j.jacc.2025.02.018","article-title":"2025 Concise Clinical Guidance: An ACC Expert Consensus Statement on the Evaluation and Management of Cardiogenic Shock: A Report of the American College of Cardiology Solution Set Oversight Committee","volume":"85","author":"Sinha","year":"2025","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","first-page":"e895","article-title":"2022 AHA\/ACC\/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"145","author":"Heidenreich","year":"2022","journal-title":"Circulation"},{"key":"ref_5","first-page":"165","article-title":"Acute Heart Failure: From The Emergency Department to the Intensive Care Unit","volume":"42","author":"Sheehan","year":"2024","journal-title":"Cardiol. Clin."},{"key":"ref_6","first-page":"510","article-title":"Acute decompensated heart failure: Contemporary medical management","volume":"36","author":"Joseph","year":"2009","journal-title":"Tex. Heart Inst. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cardfail.2024.01.012","article-title":"Modes of Death in Patients with Cardiogenic Shock in the Cardiac Intensive Care Unit: A Report from the Critical Care Cardiology Trials Network","volume":"30","author":"Berg","year":"2024","journal-title":"J. Card. Fail."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"EVIDoa2300323","DOI":"10.1056\/EVIDoa2300323","article-title":"Prognostic Factors Associated with Mortality in Cardiogenic Shock\u2014A Systematic Review and Meta-Analysis","volume":"3","author":"Jung","year":"2024","journal-title":"NEJM Evid."},{"key":"ref_9","unstructured":"Blumer, V., Sinha, S.S., Carnicelli, A.P., Isseh, I.N., Gage, A., Rali, A.S., Guilliod, C., Hickey, G.W., Bernhardt, A.M., and Wilcox, J.E. (2026). Cardiogenic Shock Survivorship: A Multidisciplinary Approach Across the Continuum of Care. J. Am. Coll. Cardiol., Epub ahead of print."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1161\/CIRCULATIONAHA.124.068203","article-title":"Survivorship After Cardiogenic Shock","volume":"151","author":"Hall","year":"2025","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.amjcard.2026.02.024","article-title":"Cardiogenic Shock: A State-of-the-Art Review","volume":"266","author":"Samuels","year":"2026","journal-title":"Am. J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2015","DOI":"10.1111\/j.1476-5381.2011.01588.x","article-title":"Use of inotropes and vasopressor agents in critically ill patients","volume":"165","author":"Bangash","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Cheko, J., Patsalis, N., Kreutz, J., Divchev, D., Chatzis, G., Schieffer, B., and Markus, B. (2023). The Impact of Positive Inotropic Therapy on Hemodynamics and Organ Function in Acute Heart Failure: A Differentiated View. J. Pers. Med., 14.","DOI":"10.3390\/jpm14010017"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Profire, B.\u0218., Lupa\u0219cu, F.G., St\u0103tescu, C., \u0218orodoc, V., Sasc\u0103u, R.A., Profire, L., and \u0218orodoc, L. (2025). Heart Failure Biomarkers-Pathophysiology, Diagnosis, Prognosis and Clinical Relevance. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199740"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Iorio, A.M., Luc\u00e0, F., Pozzi, A., Rao, C.M., Di Fusco, S.A., Colivicchi, F., Grimaldi, M., Oliva, F., and Gulizia, M.M. (2024). Inotropic Agents: Are We Still in the Middle of Nowhere?. J. Clin. Med., 13.","DOI":"10.3390\/jcm13133735"},{"key":"ref_16","first-page":"CD009669","article-title":"Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome","volume":"1","author":"Schumann","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1146\/annurev-physiol-060121-041653","article-title":"Adrenergic Regulation of Calcium Channels in the Heart","volume":"84","author":"Papa","year":"2022","journal-title":"Annu. Rev. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Vald\u00e9s, \u00c1., Treuer, A.V., Barrios, G., Ponce, N., Fuentealba, R., Dulce, R.A., and Gonz\u00e1lez, D.R. (2018). NOX Inhibition Improves \u03b2-Adrenergic Stimulated Contractility and Intracellular Calcium Handling in the Aged Rat Heart. Int. J. Mol. Sci., 19.","DOI":"10.20944\/preprints201804.0190.v1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"274","DOI":"10.52601\/bpr.2024.240906","article-title":"\u03b2-adrenergic regulation of Ca2+ signaling in heart cells","volume":"10","author":"Yang","year":"2024","journal-title":"Biophys. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11795468221075064","DOI":"10.1177\/11795468221075064","article-title":"A Clinical Update on Vasoactive Medication in the Management of Cardiogenic Shock","volume":"16","author":"Shankar","year":"2022","journal-title":"Clin. Med. Insights Cardiol."},{"key":"ref_21","first-page":"2108","article-title":"Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock","volume":"385","author":"Gibson","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_22","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":"ref_23","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 failure","volume":"1","author":"Packer","year":"2013","journal-title":"JACC Heart Fail."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1016\/j.jacc.2019.02.051","article-title":"Cardiac Calcitropes, Myotropes, and Mitotropes: JACC Review Topic of the Week","volume":"73","author":"Psotka","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_25","first-page":"676","article-title":"Inotropic therapies in heart failure and cardiogenic shock: An educational review","volume":"10","author":"DesJardin","year":"2021","journal-title":"Eur. Heart J. Acute Cardiovasc. Care"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/CRD.0000000000000598","article-title":"Istaroxime: A Novel Therapeutic Agent for Acute Heart Failure","volume":"33","author":"Newbury","year":"2025","journal-title":"Cardiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1002\/ejhf.1843","article-title":"Istaroxime in acute heart failure: The holy grail is at HORIZON?","volume":"22","author":"Chioncel","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s10741-019-09873-3","article-title":"SERCA2a: A key protein in the Ca2+ cycle of the heart failure","volume":"25","author":"Liu","year":"2020","journal-title":"Heart Fail. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.yjmcc.2024.10.008","article-title":"Another-regulin regulates cardiomyocyte calcium handling via integration of neuroendocrine signaling with SERCA2a activity","volume":"197","author":"Hassel","year":"2024","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_30","first-page":"e41084","article-title":"Safety and Efficacy of Istaroxime in Patients With Acute Heart Failure: A Meta-Analysis of Randomized Controlled Trials","volume":"15","author":"Rawat","year":"2023","journal-title":"Cureus"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/13543784.2026.2618978","article-title":"Istaroxime\u2014Update of data in early cardiogenic shock and decompensated heart failure","volume":"35","author":"Florek","year":"2026","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1016\/j.ahj.2009.03.007","article-title":"Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: Results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: A Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial","volume":"157","author":"Shah","year":"2009","journal-title":"Am. Heart J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1002\/ehf2.15102","article-title":"Safety and efficacy of up to 60 h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial","volume":"12","author":"Biegus","year":"2025","journal-title":"ESC Heart Fail."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1002\/ejhf.2629","article-title":"Safety and efficacy of istaroxime in patients with acute heart failure-related pre-cardiogenic shock\u2014A multicentre, randomized, double-blind, placebo-controlled, parallel group study (SEISMiC)","volume":"24","author":"Metra","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3627","DOI":"10.1093\/eurheartj\/ehad195","article-title":"2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure","volume":"44","author":"McDonagh","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wu, J., Liao, M., Dai, T., Liu, G., Zhang, J., Zhu, Y., Xu, L., and Zhao, J. (2026). The Landscape of SERCA2 in Cardiovascular Diseases: Expression Regulation, Therapeutic Applications, and Emerging Roles. Biomolecules, 16.","DOI":"10.3390\/biom16020188"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1517\/14712590903321462","article-title":"Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure","volume":"10","author":"Lipskaia","year":"2010","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1002\/ejhf.1557","article-title":"Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials","volume":"21","author":"Ahmad","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e029787","DOI":"10.1161\/JAHA.123.029787","article-title":"State of Shock: Contemporary Vasopressor and Inotrope Use in Cardiogenic Shock","volume":"12","author":"Bloom","year":"2023","journal-title":"J. Am. Heart Assoc."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Forzano, I., Mone, P., Mottola, G., Kansakar, U., Salemme, L., De Luca, A., Tesorio, T., Varzideh, F., and Santulli, G. (2022). Efficacy of the New Inotropic Agent Istaroxime in Acute Heart Failure. J. Clin. Med., 11.","DOI":"10.3390\/jcm11247503"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Parinandi, N.L., and Hund, T.J. (2022). Calcium-Dependent Signaling in Cardiac Myocytes. Cardiovascular Signaling in Health and Disease [Internet], Springer.","DOI":"10.1007\/978-3-031-08309-9"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2038","DOI":"10.1016\/j.bpj.2010.08.016","article-title":"Synergy between CaMKII substrates and \u03b2-adrenergic signaling in regulation of cardiac myocyte Ca(2+) handling","volume":"99","author":"Soltis","year":"2010","journal-title":"Biophys. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e399","DOI":"10.1097\/CCM.0000000000002101","article-title":"Calcium\/Calmodulin Protein Kinase II-Dependent Ryanodine Receptor Phosphorylation Mediates Cardiac Contractile Dysfunction Associated With Sepsis","volume":"45","author":"Gonano","year":"2017","journal-title":"Crit. Care Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"S443","DOI":"10.33549\/physiolres.934805","article-title":"Structure-function relationships and modifications of cardiac sarcoplasmic reticulum Ca2+-transport","volume":"70","author":"Nusier","year":"2021","journal-title":"Physiol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.yjmcc.2016.06.007","article-title":"CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift","volume":"98","author":"Uchinoumi","year":"2016","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1161\/CIRCRESAHA.125.325387","article-title":"Interplay Between Ryanodine Receptor Arrangement and Function: Implications for (Patho)physiological Control of Calcium Release","volume":"137","author":"Gonano","year":"2025","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.yjmcc.2011.12.003","article-title":"Pathophysiology of the cardiac late Na current and its potential as a drug target","volume":"52","author":"Moreno","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1007\/s12551-020-00736-y","article-title":"Sarcoplasmic reticulum calcium mishandling: Central tenet in heart failure?","volume":"12","author":"Denniss","year":"2020","journal-title":"Biophys. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Khalid, A., Ahmed, A.B., Gill, R., Shaikh, T., Khorsandi, J., and Kia, A. (2025). Molecular Mechanisms of L-Type Calcium Channel Dysregulation in Heart Failure. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26125738"},{"key":"ref_50","first-page":"149","article-title":"Pathophysiology of Acute and Chronic Right Heart Failure","volume":"38","author":"Thandavarayan","year":"2020","journal-title":"Cardiol. Clin."},{"key":"ref_51","first-page":"161","article-title":"Right Heart Failure: A Hemodynamic Review","volume":"38","author":"Viray","year":"2020","journal-title":"Cardiol. Clin."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"111434","DOI":"10.5492\/wjccm.v14.i4.111434","article-title":"Pathophysiology and management of right ventricular failure in critically ill patients: A narrative review","volume":"14","author":"Kermanian","year":"2025","journal-title":"World J. Crit. Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e578","DOI":"10.1161\/CIR.0000000000000560","article-title":"Evaluation and Management of Right-Sided Heart Failure: A Scientific Statement From the American Heart Association","volume":"137","author":"Konstam","year":"2018","journal-title":"Circulation"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Levitt, C.V., Williams, C.A., Ahari, J., and Pourmand, A. (2024). Approach to Decompensated Right Heart Failure in the Acute Setting. J. Clin. Med., 13.","DOI":"10.3390\/jcm13030869"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"24097","DOI":"10.1038\/s41598-021-03317-5","article-title":"The effect of levosimendan on right ventricular function in patients with heart dysfunction: A systematic review and meta-analysis","volume":"11","author":"Hu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.jchf.2021.01.015","article-title":"Levosimendan Improves Hemodynamics and Exercise Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial","volume":"9","author":"Burkhoff","year":"2021","journal-title":"JACC Heart Fail."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3966","DOI":"10.1002\/ehf2.15448","article-title":"Haemodynamic effects of istaroxime in SCAI stage B HF-related cardiogenic shock: Insights from the SEISMiC trial","volume":"12","author":"Pagnesi","year":"2025","journal-title":"ESC Heart Fail."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13395-021-00280-7","article-title":"The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) pump: A potential target for intervention in aging and skeletal muscle pathologies","volume":"11","author":"Xu","year":"2021","journal-title":"Skelet. Muscle"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s10741-009-9153-y","article-title":"Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond","volume":"14","author":"Teerlink","year":"2009","journal-title":"Heart Fail. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/FJC.0000000000000113","article-title":"Inotropes and inodilators for acute heart failure: Sarcomere active drugs in focus","volume":"64","author":"Nagy","year":"2014","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1111\/bph.12278","article-title":"Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition","volume":"169","author":"Ferrandi","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"102759","DOI":"10.1016\/j.redox.2023.102759","article-title":"The mitochondrial calcium uniporter (MCU) activates mitochondrial respiration and enhances mobility by regulating mitochondrial redox state","volume":"64","author":"Weiser","year":"2023","journal-title":"Redox Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"171398","DOI":"10.1016\/j.scitotenv.2024.171398","article-title":"The mystery of methylmercury-perturbed calcium homeostasis: AMPK-DRP1-dependent mitochondrial fission initiates ER-mitochondria contact formation","volume":"923","author":"Hu","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_64","first-page":"100461","article-title":"Ultrastructure analysis of mitochondria, lipid droplet and sarcoplasmic reticulum apposition in human heart failure","volume":"13","author":"Latchman","year":"2025","journal-title":"J. Mol. Cell. Cardiol. Plus"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Popoiu, T.A., Maack, C., and Bertero, E. (2023). Mitochondrial calcium signaling and redox homeostasis in cardiac health and disease. Front. Mol. Med., 3.","DOI":"10.3389\/fmmed.2023.1235188"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"102997","DOI":"10.1016\/j.jaccas.2024.102997","article-title":"Effects of Cardiac Contractility Modulation in a Patient With Heart Failure and High Arrhythmic Burden","volume":"30","author":"Ottaviani","year":"2025","journal-title":"JACC Case Rep."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Pironti, G., Maack, C., Andersson, D.C., and Lund, L.H. (2026). Emerging therapeutic directions for inotropic therapy in heart failure. Med, Epub ahead of print.","DOI":"10.1016\/j.medj.2026.101073"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"248320","DOI":"10.1100\/2012\/248320","article-title":"Activation of \u03b2-adrenoceptors by dobutamine may induce a higher expression of peroxisome proliferator-activated receptors \u03b4 (PPAR\u03b4) in neonatal rat cardiomyocytes","volume":"2012","author":"Chou","year":"2012","journal-title":"Sci. World J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1111\/bcpt.12385","article-title":"Milrinone for the Treatment of Acute Heart Failure After Acute Myocardial Infarction: A Systematic Review and Meta-Analysis","volume":"117","author":"Tang","year":"2015","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1161\/01.RES.0000256354.95791.f1","article-title":"Overview of PDEs and their regulation","volume":"100","author":"Omori","year":"2007","journal-title":"Circ. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1592\/phco.24.14.1366.43145","article-title":"Levosimendan, a new calcium-sensitizing inotrope for heart failure","volume":"24","author":"Ng","year":"2004","journal-title":"Pharmacotherapy"},{"key":"ref_72","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":"Linkels","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/FJC.0000000000000636","article-title":"Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper","volume":"73","author":"Herpain","year":"2019","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1111\/jcpt.12067","article-title":"Pharmacology of levosimendan: Inotropic, vasodilatory and cardioprotective effects","volume":"38","author":"Pathak","year":"2013","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Abuelazm, M., Ali, S., AlBarakat, M.M., Mahmoud, A., Tanashat, M., Suilik, H.A., Abdelazeem, B., and Bra\u0161i\u0107, J.R. (2023). Istaroxime for Patients with Acute Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Diseases, 11.","DOI":"10.3390\/diseases11040183"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e018833","DOI":"10.1161\/JAHA.120.018833","article-title":"Cellular Mechanisms Underlying the Low Cardiotoxicity of Istaroxime","volume":"10","author":"Racioppi","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.yjmcc.2011.02.008","article-title":"Role and mechanism of subcellular Ca2+ distribution in the action of two inotropic agents with different toxicity","volume":"50","author":"Alemanni","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1093\/cvr\/cvab123","article-title":"SERCA2a stimulation by istaroxime improves intracellular Ca2+ handling and diastolic dysfunction in a model of diabetic cardiomyopathy","volume":"118","author":"Torre","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1007\/s12551-018-0442-3","article-title":"Role of ion channels in heart failure and channelopathies","volume":"10","author":"Rahm","year":"2018","journal-title":"Biophys. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Husti, Z., Varr\u00f3, A., and Baczk\u00f3, I. (2021). Arrhythmogenic Remodeling in the Failing Heart. Cells, 10.","DOI":"10.3390\/cells10113203"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Cumberland, M.J., Riebel, L.L., Roy, A., O\u2019Shea, C., Holmes, A.P., Denning, C., Kirchhof, P., Rodriguez, B., and Gehmlich, K. (2022). Basic Research Approaches to Evaluate Cardiac Arrhythmia in Heart Failure and Beyond. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.806366"},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Cardona, K., Trenor, B., and Giles, W.R. (2016). Changes in Intracellular Na+ following Enhancement of Late Na+ Current in Virtual Human Ventricular Myocytes. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167060"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1161\/01.CIR.0000016701.85760.97","article-title":"Intracellular Na(+) concentration is elevated in heart failure but Na\/K pump function is unchanged","volume":"105","author":"Despa","year":"2002","journal-title":"Circulation"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Nagy, N., T\u00f3th, N., and N\u00e1n\u00e1si, P.P. (2022). Antiarrhythmic and Inotropic Effects of Selective Na+\/Ca2+ Exchanger Inhibition: What Can We Learn from the Pharmacological Studies?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232314651"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s10741-009-9136-z","article-title":"Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na-K-ATPase inhibition: A new promising treatment for acute heart failure syndromes?","volume":"14","author":"Khan","year":"2009","journal-title":"Heart Fail. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1002\/ejhf.1743","article-title":"Treatment with 24\u2009hour istaroxime infusion in patients hospitalised for acute heart failure: A randomised, placebo-controlled trial","volume":"22","author":"Carubelli","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.healun.2025.05.013","article-title":"Safety and efficacy intravenous istaroxime up to 60 hours for patients with pre-cardiogenic shock","volume":"44","author":"Biegus","year":"2025","journal-title":"J. Heart Lung Transplant."},{"key":"ref_88","first-page":"100524","article-title":"The current use of vasoactive agents in cardiogenic shock related to myocardial infarction and acute decompensated heart failure","volume":"52","author":"Becerra","year":"2025","journal-title":"Am. Heart J. Plus"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3390\/jcm12030846","article-title":"Acute Heart Failure: Diagnostic-Therapeutic Pathways and Preventive Strategies-A Real-World Clinician\u2019s Guide","volume":"12","author":"Mauro","year":"2023","journal-title":"J. Clin. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.jacc.2022.01.018","article-title":"SCAI SHOCK Stage Classification Expert Consensus Update: A Review and Incorporation of Validation Studies: This statement was endorsed by the American College of Cardiology (ACC), American College of Emergency Physicians (ACEP), American Heart Association (AHA), European Society of Cardiology (ESC) Association for Acute Cardiovascular Care (ACVC), International Society for Heart and Lung Transplantation (ISHLT), Society of Critical Care Medicine (SCCM), and Society of Thoracic Surgeons (STS) in December 2021","volume":"79","author":"Naidu","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_91","first-page":"76","article-title":"Society of Cardiovascular Angiography and intervention Stage-B cardiogenic shock: An interventional-heart failure-critical care conundrum","volume":"7","author":"Mehta","year":"2023","journal-title":"IHJ Cardiovasc. Case Rep."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ijcard.2019.09.005","article-title":"A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: An expert panel consensus","volume":"297","author":"Farmakis","year":"2019","journal-title":"Int. J. Cardiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e003800","DOI":"10.1161\/CIRCHEARTFAILURE.116.003800","article-title":"Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations","volume":"10","author":"Butler","year":"2017","journal-title":"Circ. Heart Fail."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1016\/j.jacc.2008.12.079","article-title":"End points for clinical trials in acute heart failure syndromes","volume":"53","author":"Allen","year":"2009","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jointm.2022.12.001","article-title":"The medical treatment of cardiogenic shock","volume":"3","author":"Lescroart","year":"2023","journal-title":"J. Intensive Med."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Kologrivova, I., Kercheva, M., Panteleev, O., and Ryabov, V. (2024). The Role of Inflammation in the Pathogenesis of Cardiogenic Shock Secondary to Acute Myocardial Infarction: A Narrative Review. Biomedicines, 12.","DOI":"10.3390\/biomedicines12092073"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e234","DOI":"10.1097\/MJT.0000000000000920","article-title":"Therapeutic Advances in the Management of Cardiogenic Shock","volume":"26","author":"Chioncel","year":"2019","journal-title":"Am. J. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"133","DOI":"10.15420\/cfr.2019.11.2","article-title":"Inotropes in Acute Heart Failure: From Guidelines to Practical Use: Therapeutic Options and Clinical Practice","volume":"5","author":"Bistola","year":"2019","journal-title":"Card. Fail. Rev."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Njegic, A., Wilson, C., and Cartwright, E.J. (2020). Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias. Front. Physiol., 11.","DOI":"10.3389\/fphys.2020.01068"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1056\/NEJMra2312086","article-title":"Cardiogenic Shock","volume":"394","author":"Thiele","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1016\/j.mcna.2025.04.007","article-title":"Cardiogenic Shock and Temporary Mechanical Circulatory Support","volume":"109","author":"Spaeth","year":"2025","journal-title":"Med. Clin. N. Am."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1136\/heartjnl-2024-324883","article-title":"Mechanical circulatory support for patients with infarct-related cardiogenic shock: A state-of-the-art review","volume":"111","author":"Moller","year":"2025","journal-title":"Heart"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1053\/j.jvca.2024.12.007","article-title":"Mechanical Circulatory Support for Acute Myocardial Infarction Cardiogenic Shock: Review and Recent Updates","volume":"39","author":"Saggu","year":"2025","journal-title":"J. Cardiothorac. Vasc. Anesth."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:08:14Z","timestamp":1783411694000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,26]]},"references-count":103,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135779"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135779","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,26]]}}}