Book of Abstracts - New Frontiers 2022

Abstracts of poster presentations

INVESTIGATION OF THE EFFECT OF THE NOVEL MYOSIN ACTIVATOR DANICAMTIV ON THE CONTRACTILITY AND Ca 2+ TRANSIENTS OF ISOLATED LEFT VENTRICULAR CARDIOMYOCYTES F. Sárkány 1 , A. P. Ráduly 1 , A. Tóth 1 , Z. Papp 1 , Z. Csanádi 1 , B. Horváth 2 , N. Szentandrássy 2 , A. Borbély 1 Division of Clinical Physiology, Institute of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; 2 Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Introduction: Advanced stage systolic heart failure (HFrEF) remains a disease with a very poor prognosis. Its treatment is based on improving cardiac systolic dysfunction and myocardial contractility. Our current research has focused on a new pharmacological agent, danicamtiv directly influencing the cross-bridge cycle. Aim: To study the effects of danicamtiv on the contractility and Ca 2+ transients in isolated left ventricular cardiomyocytes. Methods: The effects of danicamtiv were investigated on freshly isolated left ventricular canine cardiomyocytes. Cells were loaded with Fura-2 AM calcium sensitive fluorescent dye before the experiments. Different concentrations of danicamtiv (10 nM - 2 µM) were applied in the experiments. Cell contraction was induced by field stimulation (0.5-0.1 Hz), then a set-up capable of recording the shortening of the sarcomere length as well as the changes in intracellular Ca2+ concentration simultaneously was used. Results: In the presence of 0.5 Hz stimulation and 2 µM danicamtiv, both the contraction duration (2.0±0.7 s vs. 0.8±0.2 s, mean±SEM, P<0.05) and the systolic ejection time were prolonged (1.6±0.6 s vs. 0.6±0.1 s, P<0.05), while the kinetics of contraction and relaxation were both decelerated (0.21±0.19 µm/s vs. 0.94±0.49 µm/s and 0.22±0.18 µm/s vs. 1.30±0.75 µ m/s, P<0.05, respectively) (n=18). Treatment with 2 µM danicamtiv showed a positive ionotropic effect: a shortening could be observed in diastolic (1.59±0.13 µm vs. 1.90±0.03 µm P<0.05, n=18), as well as in systolic sarcomere lengths (1.46±0.08 µm vs. 1.68±0.0 µm P<0.05, n=18). The lowest effective danicamtiv concentration was 0.01 µM. Danicamtiv treatment was not associated with an increase in intracellular Ca2+ concentration, regardless of the frequency of stimulation. Conclusion: Our results suggest that the positive inotropic effect of danicamtiv is accompanied by a significant reduction in resting sarcomere length of isolated cardiomyocytes and deceleration of relaxation kinetics, which may impair diastolic function. All these may limit the clinical efficacy of this novel myosin activator agent.

Keywords: positive inotropy, HFrEF, danicamtiv, myosin activator

Funding:Project no. TKP2020-NKA-04 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the 2020 4.1.1-TKP2020 funding scheme.

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