Treatments targeting inotropy

Christoph Maack, Thomas Eschenhagen, Nazha Hamdani, Frank R. Heinze, Alexander R. Lyon, Dietmar J. Manstein, Joseph Metzger, Zoltan Papp, Carlo G. Tocchetti, M. Birhan Yilmaz, Stefan D. Anker, Jean Luc Balligand, Johann Bauersachs, Dirk Brutsaert, Lucie Carrier, Stefan Chlopicki, John G. Cleland, Rudolf A. De Boer, Alexander Dietl, Rodolphe FischmeisterVeli Pekka Harjola, Stephane Heymans, Denise Hilfiker-Kleiner, Johannes Holzmeister, Gilles De Keulenaer, Giuseppe Limongelli, Wolfgang A. Linke, Lars H. Lund, Josep Masip, Marco Metra, Christian Mueller, Burkert Pieske, Piotr Ponikowski, Arsen Risti, Frank Ruschitzka, Petar M. Seferovi, Hadi Skouri, Wolfram H. Zimmermann, Alexandre Mebazaa

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesteraseinhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2þ. 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-contraction 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.

Original languageEnglish (US)
Pages (from-to)3626-3640D
JournalEuropean heart journal
Volume40
Issue number44
DOIs
StatePublished - Nov 21 2019

Bibliographical note

Funding Information:
C.M. is supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 894, TRR-219, and Ma 2528/7-1), the German Federal Ministry of Education and Science (BMBF; 01EO1504) and the Corona foundation. J.M.M. is supported by grants from the NIH. C.G.T. is supported by grants of Federico II University-Ricerca d Ateneo. J.L.B. is supported by Fonds National de la Recherche Scientifique and European Union (UE Horizon2020 GA634559. A.D. is supported by the German Cardiac

Funding Information:
Conflict of interest: C.M. serves as an advisor to Servier and received speaker honoraria from Servier, Boehringer Ingelheim, Bayer, Bristol Myers Squibb, Pfizer, Daiichi Sankyo, Novartis and Berlin Chemie. T.E. is co-founder of spin-off company EHT Technologies GmbH. F.R.H. received grants from Sanofi, Novartis and Menarini. A.R.L. reports personal fees from Novartis, AMGEN and Servier. D.J.M. holds Patent EP2277124 B1 issued to Medizinische Hochschule Hannover and TU Dresden. J.M.M. has a patent pending. Z.P. received speaker honoraria from Orion Pharma. C.G.T. received speaker honoraria from Alere and is co-inventor of the Canadian patent no. 2,613,477: “Thiol Sensitive Positive Inotropes”, issued on Dec 3, 2013. M.B.Y. reports on institutional honoraria from Novartis, Bayer Healthcare and Amgen. S.D.A. received fees for trial / registry steering committee work and advisory boards from Bayer, Boehringer Ingelheim, Novartis, Servier, Stealth, and Vifor, and reports on grants for IITs from Abbott Vascular and Vifor. J.L.B. is advisor to Sanofi and Amgen. J.B. received personal fees from Orion, Novartis and Abiomed. J.G.C. serves in the steering committee for GALACTIC (Amgen/Cytokinetics) and is Chief Investigator for IDDEA-HF (Stealth Biopharmaceuticals). He received grants and/or personal fees from Novartis and Servier. R.A.d.B. is a minority shareholder of scPharmaceuticals, Inc., and received personal fees from MandalMed Inc, Novartis, and Servier. The UMCG, which employs R.A.d.B., has received research grants and/or fees from AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Roche, Trevena, and ThermoFisher GmbH. V.P.H. received consultation fees from Orion Pharma. L.H.L. received research grants and/or consultation fees from Orion Pharma, Amgen, Novartis, Boehringer Ingelheim, Vifor Pharma, Astra Zeneca, Merck and Sanofi. J.M. is consultant for Cardiorentis, advisor for Novartis, and received travel grants from Boehringer Ingelheim, Novartis and Menarini. M.M. received consulting honoraria from Amgen, Bayer, Novartis and Servier. C.Mu. received research grants from Abbott, ALERE, Astra Zeneca, Beckman Coulter, Biomerieux, BRAHMS, Critical Diagnostics, Ortho Diagnostics, Roche, Siemens and Singulex, as well as speaker/consulting honoraria from Abbott, ALERE, Astra Zeneca, Biomerieux, BMS, Boehringer Ingelheim, BRAHMS, Cardiorentis, Duke University, Novartis, Roche, Sanofi, Singulex, Siemens, and Zurich Heart House. A.R. received grants from Servier, Actavis, Boehringer Ingelheim, Astra Zeneca and Bayer, and reports on personal fees from Pfizer, Merck, Berlin Chemie, AstraZeneca, Hemofarm Stada, Krka Pharma and Roche Diagnostics. F.R. reports on personal fees (talks) from SJM, Novartis, Servier, Zoll, Bayer and Abbott and serves as an advisor to AstraZeneca, Sanofi, Amgen, Roche, Pfizer and BMS. He received honoraria of steering committee meetings from Fresenius, Vifor and Cardiorentis. W.H.Z. received honoraria for lectures from Daiichi-Sankyo and is founder and advisor of myriamed GmbH and Repairon GmbH. A.M. received honoraria (lectures) from Orion, Servier, Abbott, Novartis, and is a consultant for BMS, Cardiorentis, Roche and Sphyngotec. All other authors declared no conflict of interest.

Funding Information:
Society (DGK) and institutional research grants of the University Hospital Regensburg (ReForM-A/B). C.Mu. received research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, the European Union, the Cardiovascular Research Foundation Basel, Basel University and the University Hospital Basel. W.H.Z. is supported by the DZHK (German Center for Cardiovascular Research), the BMBF, the DFG (ZI 708/10-1, SFB 937 A18, SFB 1002 C04/01 and IRTG 1816 RP12), and Foundation Leducq.

Publisher Copyright:
© 2018 The Author(s).

Keywords

  • Acute decompensated heart failure
  • Adrenergic receptors
  • Calcium
  • Cardiogenic shock
  • Contractility
  • Energetics
  • Excitation-contraction coupling
  • Heart failure
  • Inotropes
  • Levosimendan
  • Mitochondria
  • Nitroxyl
  • Omecamtiv mecarbil
  • Sarcomeres

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