Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (−)‐noradrenaline

Figures

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  FIGURE 1. Effects of OM on the contractile dynamics of atrial trabeculae. Five different concentrations of OM were tested and compared to control (absence of OM). Time dependent reduction in contractile force (fade) was observed in all trabeculae (A). OM did not increase contractile force, nor reduce fade (p = .). OM produced concentration‐dependent increases in TPF (B) and t 50% (C). At 120 min, there was a significant increase from the control group with 600 nM, 1 µM and 2 µM for both TPF and t 50%. Statistical analysis by one‐way ANOVA test followed by Tukey's multiple comparisons test

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  FIGURE 2. Effects of OM on the contractile dynamics of human failing ventricular trabeculae. Concentration‐dependent increase in TPF (A) and t 50% (B) in human failing ventricle. At 120 min, OM produced a significant increase in TPF (600 nM: p < .001, 2 µM: p < .001) and t 50% (600 nM: p < .001, 2 µM: p < .001). (C) Representative examples of two consecutive contractions from left ventricular trabeculae exposed to different concentrations of OM stimulated at 1 Hz (Green Control, Blue 600 nM, Red 2 µM). Statistical analysis by one‐way ANOVA test followed by Tukey's multiple comparisons test

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  FIGURE 3. Effect of OM on preserving contractile force in ventricular trabeculae. (A) All trabeculae produced a time‐dependent reduction in contractile strength. Sub‐group analysis revealed the left (B) ventricular (p < .001), but not right (C) ventricular trabeculae in the OM groups exhibited preservation of contractile force. Statistical analysis by linear mixed effects modelling followed by Bonferroni's multiple comparison adjustment

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  FIGURE 4. Effect of OM on force of contraction following incubation with 1 µM (−)‐noradrenaline (NA). Following 1 µM (−)‐noradrenaline (NA), there was no significant difference in contractile force between groups at baseline (see NA bar) (p = .66). At 120 min, contractile force was maintained in trabeculae incubated with OM (600 nM and 2 µM), whilst the control group displayed a significant reduction in force (*p = .005). There was a significant difference in the contractile force achieved at 120 min between control versus 2 µM OM (p < .001) control versus 600 nM OM (p = .02). Statistical analysis by one‐way ANOVA test followed by Tukey's multiple comparisons test was performed

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  FIGURE 5. Arrhythmia protocol. Following incubation with OM at 60 bpm (1 Hz), stimulators were turned off, and trabeculae observed for spontaneous contractions (*). There was no increase in spontaneous contractions (p > .05), statistical analysis using Kruskal‐Wallis test

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  FIGURE 6. Conservation of the inotropic effects of (−)‐noradrenaline in the presence of OM. OM (600 nM or 2 µM) does not affect the potency or maximal inotropic effect of (−)‐noradrenaline. This finding was reproduced with all trabeculae (A) and when analysing left (B) and right (C) ventricular trabeculae separately (p > .05). An ordinary one‐way ANOVA test followed by Tukey's multiple comparisons test was performed

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  FIGURE 7. Opposing diastolic effects of noradrenaline and OM in both left and right ventricular trabeculae. Concentration‐dependent effects of (−)‐noradrenaline on TPF (A) and t 50% (B) in left and right ventricular trabeculae previously exposed to OM. In both figures, basal represents the TPF and t 50% of trabeculae before exposure to any compound, there was no significant difference between groups (TPF: p = .65, t 50%: p = .91). ± OM represents the TPF and t 50% after 120 min of exposure to ±OM. ISO reflects maximal β‐AR (β1 − AR + β2 − AR) activity. (−)‐Noradrenaline had powerful lusitropic effects on the control group (Green), which were not exposed to OM, significantly reducing TPF and t 50% below baseline. Trabeculae exposed to 2 µM and 600 nM OM had an increase in TPF and t 50% prior to the addition of (−)‐noradrenaline. Despite maximal β‐AR effect, the TPF and t 50%, remained greater than basal for 2 µM OM, whilst 600 nM also exhibited a significant reduction