Omecamtiv mecarbil exerts differential effects on right ventricular trabecular work in healthy versus pulmonary heart failure rat models, likely driven by disease-related changes in contractile protein phosphorylation.
OM effects in rat RV failure models are hypothesis-generating; leaves open translation to human pulmonary hypertension.
Omecamtiv mecarbil (OM) is a selective cardiac myosin activator. We studied the effects of OM on the characteristics of contractility under mechanical loads of right ventricular trabeculae in control group rats and rats with monocrotaline-induced pulmonary heart failure. Right ventricular hypertrophy was accompanied by an increase in phosphorylation of cardiac myosin-binding protein C (cMyBP-C), troponin T, and troponin I and a decrease in phosphorylation of myosin regulatory light chain. We studied the OM effect in concentrations of 0.2 µM and 1 µM on the “tension–length” loop and the work amount in the intact trabeculae obtained in a physiological contraction mode. To study the OM effect on actin-myosin interaction we analyzed the dependence of the sliding velocities of F-actin and native thin filaments over myosin in an in vitro motility assay on the OM concentrations. The OM effects on the characteristics of contraction of trabeculae from control rats and rats with pulmonary heart failure were different. In the intact rats, OM dose-dependently reduced the work amount of rat trabeculae, but in the rats with pulmonary heart failure, 0.2 µM OM increased it by 8.5 ± 8.7% (p < 0.05, U-test) at 0.5 P/P 0. These differences in the OM effects are explained by an increase in phosphorylation of cMyBP-C and TnI during right ventricular hypertrophy.
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Балакин et al. (2023) studied this question.
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