Treatments targeting inotropy

Eur Heart J. 2019 Nov 21;40(44):3626-3644. doi: 10.1093/eurheartj/ehy600.


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.

Keywords: Acute decompensated heart failure; Adrenergic receptors; Calcium; Cardiogenic shock; Contractility; Energetics; Excitation–contraction coupling; Heart failure; Inotropes; Levosimendan; Mitochondria; Nitroxyl; Omecamtiv mecarbil; Sarcomeres.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Antioxidants / adverse effects
  • Antioxidants / therapeutic use
  • Calcium / metabolism
  • Cardiotonic Agents / adverse effects
  • Cardiotonic Agents / therapeutic use*
  • Case-Control Studies
  • Catecholamines / adverse effects
  • Catecholamines / therapeutic use
  • Clinical Trials as Topic
  • Diastole / drug effects
  • Dobutamine / adverse effects
  • Dobutamine / therapeutic use
  • Dogs
  • Energy Metabolism / drug effects
  • Excitation Contraction Coupling / drug effects*
  • Heart Failure / drug therapy*
  • Heart Failure / mortality
  • Humans
  • Mitochondria / metabolism
  • Models, Animal
  • Myocardial Contraction / drug effects
  • Nitrogen Oxides / adverse effects
  • Nitrogen Oxides / therapeutic use
  • Oxidation-Reduction / drug effects
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / therapeutic use
  • Placebos / administration & dosage
  • Receptors, Adrenergic / drug effects
  • Sarcomeres / drug effects
  • Sarcomeres / metabolism
  • Shock, Cardiogenic / drug therapy*
  • Shock, Cardiogenic / mortality
  • Simendan / adverse effects
  • Simendan / therapeutic use
  • Swine
  • Systole / drug effects
  • Urea / adverse effects
  • Urea / analogs & derivatives
  • Urea / therapeutic use


  • Antioxidants
  • Cardiotonic Agents
  • Catecholamines
  • Nitrogen Oxides
  • Phosphodiesterase Inhibitors
  • Placebos
  • Receptors, Adrenergic
  • omecamtiv mecarbil
  • Simendan
  • Dobutamine
  • Urea
  • nitroxyl
  • Calcium