Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations

TY - JOUR

T1 - Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations

AU - Rhoden, Alexandra

AU - Schulze, Thomas

AU - Pietsch, Niels

AU - Christ, Torsten

AU - Hansen, Arne

AU - Eschenhagen, Thomas

PY - 2022/3/1

Y1 - 2022/3/1

N2 - Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.NEW & NOTEWORTHY We developed a novel setup allowing precise control of preload of EHT and characterized effects of the myosin activator OM. OM not only exerted contraction-slowing and positive inotropic effects but also increased diastolic tension. Effect size and direction varied between species, auxotonic and isometric conditions, concentration, and time. We also observed OM-induced increase of mitochondrial ROS, which has not been observed before and may explain part of the effects on contractility.

AB - Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function, and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analysis of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared with effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time to peak under all conditions (maximally two- to threefold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increased under isometric conditions, again with biphasic concentration dependency. Diastolic tension concentration dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.NEW & NOTEWORTHY We developed a novel setup allowing precise control of preload of EHT and characterized effects of the myosin activator OM. OM not only exerted contraction-slowing and positive inotropic effects but also increased diastolic tension. Effect size and direction varied between species, auxotonic and isometric conditions, concentration, and time. We also observed OM-induced increase of mitochondrial ROS, which has not been observed before and may explain part of the effects on contractility.

KW - Adenosine Triphosphate/metabolism

KW - Animals

KW - Calcium/metabolism

KW - Cardiotonic Agents/pharmacology

KW - Cell Line

KW - Cells, Cultured

KW - Cellular Reprogramming Techniques/methods

KW - Humans

KW - Induced Pluripotent Stem Cells/cytology

KW - Mitochondria, Heart/drug effects

KW - Myocardial Contraction

KW - Myocytes, Cardiac/cytology

KW - Rats

KW - Rats, Wistar

KW - Reactive Oxygen Species/metabolism

KW - Urea/analogs & derivatives

U2 - 10.1152/ajpheart.00534.2021

DO - 10.1152/ajpheart.00534.2021

M3 - SCORING: Journal article

C2 - 35030072

VL - 322

SP - H373-H385

JO - AM J PHYSIOL-HEART C

JF - AM J PHYSIOL-HEART C

SN - 0363-6135

IS - 3

ER -