Treatments targeting inotropy

Christoph Maack*, Thomas Eschenhagen, Nazha Hamdani, Frank R. Heinzel, 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 Ristic, Frank Ruschitzka, Petar M. Seferovic, Hadi Skouri, Wolfram H. Zimmermann, Alexandre Mebazaa

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

69 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)3626-3640
Number of pages15
JournalEuropean Heart Journal
Volume40
Issue number44
DOIs
Publication statusPublished - 21 Nov 2019

Keywords

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

Cite this