Treatments targeting inotropy

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.

Metabolic Alterations in Inherited Cardiomyopathies

“…Heart failure per se can occur as heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF). While the mechanisms of HFpEF are still incompletely resolved, involving alterations of myofilaments and the extracellular matrix that compromise diastolic function [17], the development of HFrEF is caused by derangements of excitation-contraction coupling, where a decreased Ca2+ load of the sarcoplasmic reticulum (SR), with subsequently reduced amplitudes of cytosolic Ca2+ transients is a major cause of systolic dysfunction [18,19]. These alterations in intracellular ion handling disrupt the process of energy supply-and-demand matching by impairing the accumulation of Ca2+ inside mitochondria.…”

Figures of the Heart Failure Association (HFA): Dr. Rudolf de Boer, HFA Board Member (2014–2020), Chair of the Basic Science Section (2016–2018), coordinator of the Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio‐oncology

“…My adoption into ESC and HFA have brought me a lot: I profited both from learning from high‐rank researchers and clinicians as well as from networking. It has been a privilege and very learning to contribute and drive some influential committees and task forces for the development of HFA congresses and meeting programmes, and was able to contribute to position and scientific papers . I am currently member of the Board of the HFA of the ESC since 2014, I have been Chair of the Basic Science Section (2016–2018), I am the coordinator of the HFA Study Group on Heart Failure with Preserved Ejection Fraction, and member of the HFA study groups of Translational Research and Cardio‐oncology.…”

Notch1 protects against myocardial ischaemia‐reperfusion injury via regulating mitochondrial fusion and function

“…Mitochondria are the power centre of cells, which determine whether cells survive or not . A large number of studies have proved that various signal pathways of myocardial protection ultimately target mitochondria . Therefore, it is of great significance to explore the molecular mechanism of myocardial protection based on mitochondria.…”