TY - JOUR
T1 - Treatments targeting inotropy
AU - Maack, Christoph
AU - Eschenhagen, Thomas
AU - Hamdani, Nazha
AU - Heinze, Frank R.
AU - Lyon, Alexander R.
AU - Manstein, Dietmar J.
AU - Metzger, Joseph
AU - Papp, Zoltan
AU - Tocchetti, Carlo G.
AU - Yilmaz, M. Birhan
AU - Anker, Stefan D.
AU - Balligand, Jean Luc
AU - Bauersachs, Johann
AU - Brutsaert, Dirk
AU - Carrier, Lucie
AU - Chlopicki, Stefan
AU - Cleland, John G.
AU - De Boer, Rudolf A.
AU - Dietl, Alexander
AU - Fischmeister, Rodolphe
AU - Harjola, Veli Pekka
AU - Heymans, Stephane
AU - Hilfiker-Kleiner, Denise
AU - Holzmeister, Johannes
AU - De Keulenaer, Gilles
AU - Limongelli, Giuseppe
AU - Linke, Wolfgang A.
AU - Lund, Lars H.
AU - Masip, Josep
AU - Metra, Marco
AU - Mueller, Christian
AU - Pieske, Burkert
AU - Ponikowski, Piotr
AU - Risti, Arsen
AU - Ruschitzka, Frank
AU - Seferovi, Petar M.
AU - Skouri, Hadi
AU - Zimmermann, Wolfram H.
AU - Mebazaa, Alexandre
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2019/11/21
Y1 - 2019/11/21
N2 - 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.
AB - 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.
KW - Acute decompensated heart failure
KW - Adrenergic receptors
KW - Calcium
KW - Cardiogenic shock
KW - Contractility
KW - Energetics
KW - Excitation-contraction coupling
KW - Heart failure
KW - Inotropes
KW - Levosimendan
KW - Mitochondria
KW - Nitroxyl
KW - Omecamtiv mecarbil
KW - Sarcomeres
UR - http://www.scopus.com/inward/record.url?scp=85075326564&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85075326564&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehy600
DO - 10.1093/eurheartj/ehy600
M3 - Article
C2 - 30295807
AN - SCOPUS:85075326564
SN - 0195-668X
VL - 40
SP - 3626-3640D
JO - European heart journal
JF - European heart journal
IS - 44
ER -