The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications

by Selleckchem | Oct 13 2023

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca2+ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations.

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The passage describes an analysis of the inotropic effects of danicamtiv, a direct myosin activator, on cardiac myofilaments. The study investigated the changes in sarcomere length, intracellular calcium levels, and echocardiographic parameters in relation to danicamtiv treatment in both isolated canine cardiomyocytes and anesthetized rats.

In vitro experiments using isolated canine cardiomyocytes showed that increasing concentrations of danicamtiv resulted in a decrease in both systolic and diastolic sarcomere lengths. Contraction and relaxation kinetics also slowed down with higher danicamtiv concentrations. However, intracellular calcium transients remained unchanged, indicating that the drug's effects were not mediated through alterations in calcium handling.

In vivo experiments conducted on anesthetized rats revealed that danicamtiv administration led to significant improvements in left ventricular ejection fraction, fractional shortening, and systolic strain. These findings demonstrated the drug's positive impact on cardiac systolic function. However, several adverse effects on diastolic performance were observed. The systolic ejection time was significantly prolonged, indicating a delay in the ejection of blood from the ventricle. The ratio of diastolic to systolic duration was reduced, suggesting impaired relaxation. Additionally, signs of diastolic dysfunction were observed with higher concentrations of danicamtiv.

In summary, danicamtiv showed promising results in improving cardiac systolic function in both in vitro and in vivo studies. However, its use at higher concentrations was associated with limitations in diastolic performance, including prolonged systolic ejection time and signs of diastolic dysfunction. These findings suggest that careful dosing and monitoring may be necessary to optimize the therapeutic benefits of danicamtiv while minimizing potential adverse effects on diastolic function.