Effects of omecamtiv mecarbil and mavacamten in isolated human atrium

Figures

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  Fig. 1. Scheme: Potential mechanism(s) of action of omecamtiv mecarbil and mavacamten-461 in the human cardiomyocytes. Stimulation of the activity of β-adrenoceptors (β-AR) by isoprenaline leads via stimulatory GTP-binding proteins (Gs) to an increase of adenylyl cyclase (AC) activity. Adenylyl cyclase increases the formation of 3′,5′-cyclic adenosine monophosphate (cAMP) that stimulates cAMP-protein kinase (PKA). PKA phosphorylates and thus activates inter alia phospholamban (PLB) at the amino acid serine 16, the inhibitory subunit of troponin (TnI), the ryanodine receptor (RYR), and the L-type calcium channel (LTCC). Calcium cations (Ca2+) are stored on calsequestrin (CSQ) in the sarcoplasmic reticulum and are released via RYR from the sarcoplasmic reticulum (SR). These released Ca2+ bind to troponin C (TnC) on thin myofilaments, and as a result, systolic force is augmented. In cardiac diastole, Ca2+ concentrations fall because Ca2+ is pumped into the SR via the SR-calcium ATPase (SERCA). The activity of SERCA is increased when phospholamban is phosphorylated on amino acid serine 16. Negative inotropic effects can be used to treat HOCOM (hypertrophic obstructive cardiomyopathy) like…

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  Fig. 2. Original recordings of force of contraction of paced human right atrial preparations. A No positive inotropic effect of omecamtiv mecarbil was noted in human atrium. First, calcium ions (Ca2+) were cumulatively applied. Then washout was preformed thrice. Thereafter, omecamtiv mecarbil (10 nM to 10 µM) was cumulatively applied. Additionally, without washout, Ca2+ was applied again. B A negative inotropic effect of mavacamten-461 was noted in human atrium. Mavacamten-461 (10 nM to 10 µM) was cumulatively applied. C Antiadrenergic effects of omecamtiv mecarbil in human atrium. First, 10 nM isoprenaline was applied. When a plateau was reached, OME (10 nM to 10 µM) was cumulatively applied. Note that under these conditions, OME clearly exhibits an antiadrenergic negative inotropic effect. Vertical bars indicate force in millinewton (mN). Horizontal bars indicate incubation times in minutes (min)

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  Fig. 3. Effects of omecamtiv mecarbil (OME) on time parameters of contraction in human and mouse atrial preparations. OME prolongs the duration of contraction. Ordinates: normalized force of contraction (% of maximum effect). Abscissae: time of contraction in milliseconds (ms). A After control contractions in human atrial preparations (Ctr), isoprenaline (10 nM) shortened the duration of contraction, and additionally applied OME prolonged duration of contraction. B In contrast, in human atrial preparations, calcium ions (Ca2+) prolonged duration of contraction that was much more prolonged by additionally applied OME. C Similarly, in mouse left atrial preparations, OME prolonged duration of contraction alone and even more in the additional presence of Ca2+

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  Fig. 4. Effects of mavacamten-461 (MYK-461) on time parameters of contraction in human and mouse atrial preparations. MYK-461 shortens the duration of contraction. Ordinates: normalized force of contraction (% of maximum effect). Abscissae: time of contraction in milliseconds (ms). A After control contractions in human atrial preparations (Ctr), calcium ions (Ca2+) prolonged the duration of contraction, and additionally applied MYK-461 shortened duration of contraction. B In contrast, in human atrial preparations, isoprenaline shortened duration of contraction that was further shortened by MYK-461. C Similarly, in mouse left atrial preparations, Ca2+ prolonged duration of contraction alone, and additionally applied MYK-461 prolonged even more the duration of muscle contraction in the additional presence of Ca2+

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  Fig. 5. Concentration-dependent effects of calcium ions alone or in the presence of omecamtiv mecarbil (OME) or mavacamten-461 (MYK-461) on time to peak tension or time of relaxation in electrically stimulated human atrial preparations. Calcium ions (Ca2+) were cumulatively applied alone or in the presence of OME (A) or MYK-461 (B). Abscissae: concentration of calcium ions in millimolar concentrations (mM). Numbers in brackets indicate number of experiments. *p < 0.05 versus pre-drug value (Ctr) set as 100%

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  Fig. 6. Effect of calcium ions (Ca2+) on the first derivate of force of contraction versus time in human right atrial preparations in the absence or presence of omecamtiv mecarbil (OME) or mavacamten-461 (MYK-461). OME (A) or MYK-461 (B) reduced Ca2+-induced increases in the rate of tension development (dF/dt: ordinates). Abscissae: concentration of calcium ions in millimolar concentrations (mM). Numbers in brackets indicate number of experiments. *p < 0.05 versus pre-drug value (Ctr) set as 100%

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  Fig. 7. Omecamtiv mecarbil (OME) did not increase force of contraction in human atrium. A Effect of OME in isolated right atrial preparations from human hearts (red circles) or in isolated left atrial preparations from mice (blue squares). B Effect of calcium ions (Ca2+) alone (circles) or in the presence of OME (squares) on force of contraction in human right atrial preparations. Ordinates: force of contraction in % of pre-drug value (= control: Ctr) Abscissae: decadic logarithm of the concentrations of OME or millimolar (mM) concentrations of Ca2+. *p < 0.05 versus Ctr. Numbers in brackets indicate the number of experiments

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  Fig. 8. Mavacamten-461 (MYK-461) decreased force of contraction in human atrium. A Effects of MYK-461 in human right atrial preparations (red triangles) or mouse left atrial preparations (blue triangles). B Effects of calcium ions (Ca2+) alone (circles) or in the presence of 10 µM MYK-461 (squares) in isolated right atrial preparations from human hearts. Ordinates: force of contraction in % of pre-drug value (= control: Ctr.) Abscissae: decadic logarithm of the concentrations of MYK-461 or millimolar (mM) concentrations of Ca2+. *p < 0.05 versus Ctr. Numbers in brackets indicate the number of experiments