Treatments targeting inotropy

Maack, C. et al. (2018) Treatments targeting inotropy. European Heart Journal, ehy600. (doi: 10.1093/eurheartj/ehy600) (PMID:30295807)

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 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–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.

• Item Type: Articles
• Additional 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 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.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John
• Authors: Maack, C., Eschenhagen, T., Hamdani, N., Heinzel, F. R., Lyon, A. R., Manstein, D. J., Metzger, J., Papp, Z., Tocchetti, C. G., Yilmaz, M. B., Anker, S. D., Balligand, J.-L., Bauersachs, J., Brutsaert, D., Carrier, L., Chlopicki, S., Cleland, J. G., de Boer, R. A., Dietl, A., Fischmeister, R., Harjola, V.-P., Heymans, S., Hilfiker-Kleiner, D., Holzmeister, J., de Keulenaer, G., Limongelli, G., Linke, W. A., Lund, L. H., Masip, J., Metra, M., Mueller, C., Pieske, B., Ponikowski, P., Ristić, A., Ruschitzka, F., Seferović, P. M., Skouri, H., Zimmermann, W. H., and Mebazaa, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: European Heart Journal
• Publisher: Oxford University Press
• ISSN: 0195-668X
• ISSN (Online): 1522-9645
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in European Heart Journal ehy600
• Publisher Policy: Reproduced in accordance with the publisher copyright policy