The myosin activator omecamtiv mecarbil: a promising new inotropic agent1
Abstract
Heart failure has emerged as a major cause of mortality over the past several decades, with its prevalence steadily increasing. Current therapeutic approaches are largely confined to suppressing sympathetic nervous system activity and the renin–angiotensin system, often in conjunction with diuretics. This limited strategy stems from the potential for long-term adverse effects associated with inotropic agents, despite their proven effectiveness in improving cardiac function when used for short periods. Positive inotropic agents encompass inhibitors of the Na+/K+ pump, $\beta$-receptor agonists, and phosphodiesterase inhibitors. In theory, Ca2+ sensitizers could also enhance cardiac contractility without leading to problematic Ca2+ overload; however, their mechanism of action is frequently complicated by additional, pleiotropic effects that can extend beyond their primary target. Recently, a novel positive inotropic agent, omecamtiv mecarbil, which acts as a myosin activator, has been developed. Omecamtiv mecarbil directly binds to the $\beta$-myosin heavy chain. This binding enhances cardiac contractility by increasing the number of active, force-generating cross-bridges, and it is presumed to do so without significant off-target effects. This review synthesizes recent findings from both in vivo and in vitro studies on omecamtiv mecarbil, offering a detailed discussion of its molecular mechanism of action. Based on the accumulating clinical data, omecamtiv mecarbil appears to be a promising new therapeutic tool for the management of systolic heart failure.
Keywords: inotropic agents, calcium sensitizer, cardiac myosin activator, omecamtiv mecarbil, CK-1827452, cardiac contractility, heart failure.
Résumé
L’insuffisance cardiaque est devenue une cause majeure de mortalité au cours des dernières décennies, avec une prévalence en constante augmentation. La thérapie actuelle est principalement limitée à la suppression de l’activité sympathique et du système rénine-angiotensine, souvent associée à l’utilisation de diurétiques. Cette restriction stratégique est due aux effets secondaires potentiels à long terme des agents inotropes, malgré leur efficacité avérée sur la fonction cardiaque lorsqu’ils sont utilisés sur de courtes périodes. Les inotropes positifs incluent les inhibiteurs de la pompe Na+/K+, les agonistes des récepteurs $\beta$ et les inhibiteurs de phosphodiestérases. Théoriquement, les sensibilisateurs de Ca2+ peuvent également augmenter la contractilité cardiaque sans entraîner de surcharge de Ca2+ ; cependant, leur mécanisme d’action est fréquemment compliqué par d’autres effets pléiotropes. Récemment, un nouvel agent inotrope positif, l’activateur de la myosine, appelé omecamtiv mecarbil, a été développé. L’omecamtiv mecarbil se lie directement à la chaîne lourde de la $\beta$-myosine et augmente la contractilité cardiaque en augmentant le nombre de ponts transversaux générant une force active, probablement sans effets hors cible majeurs. Cet article de synthèse se concentre sur les résultats obtenus récemment in vivo et in vitro avec l’omecamtiv mecarbil et examine en détail ses mécanismes d’action au niveau moléculaire. Selon les données cliniques disponibles, l’omecamtiv mecarbil représente un nouvel outil très prometteur pour le traitement de l’insuffisance cardiaque systolique.
Mots-clés : agents inotropes, sensibilisateur de calcium, activateur de la myosine cardiaque, omecamtiv mecarbil, CK-1827452, contractilité cardiaque, insuffisance cardiaque.
Current therapeutic strategies against heart failure
Heart failure is medically diagnosed when the heart is unable to deliver the necessary cardiac output to meet the body’s demands. This complex condition can be classified from various perspectives, such as systolic versus diastolic dysfunction, left versus right heart failure, and compensated versus decompensated states, with clearly defined criteria for its progression. From a therapeutic standpoint, the most critical distinction lies between acute and chronic forms of heart failure. In cases of acute heart failure, effectively enhancing the heart’s pumping function using inotropic agents becomes paramount, even if these agents carry potential long-term drawbacks. Conversely, for chronic heart failure, the therapeutic strategy can be quite different; suppression of neurohormonal compensation might actually extend lifespan and improve the patient’s quality of life.
Despite considerable therapeutic advancements in the management of chronic heart failure over the past few decades, progress in the treatment of acute heart failure has been relatively limited. Historically, digitalis glycosides were among the first agents employed to enhance cardiac performance. These compounds function by inhibiting the activity of the Na+/K+ pump located in the cell’s surface membrane. This inhibition leads to a reduction in the transmembrane Na+ gradient, which, in turn, results in an increase in cellular Ca2+ levels via the Na+/Ca2+ exchange mechanism. While these glycosides exhibit beneficial acute effects, their long-term efficacy in improving contractility has been questioned. More significantly, they frequently show substantial proarrhythmic activity due attributed to the potential for Ca2+ overload within cardiac cells. Indeed, the development of delayed afterdepolarizations has been commonly reported in patients experiencing digitalis intoxication.
Positive inotropic action can also be elicited by activating the cardiac $\beta$-adrenergic receptors, which represents the natural physiological mechanism for increasing cardiac output through an elevated heart rate, enhanced contractility (positive inotropy), and improved relaxation (lusitropy). The entry of Ca2+ into cardiomyocytes is markedly augmented by the protein kinase A-dependent phosphorylation of L-type Ca2+ channels. The accelerated rate of Ca2+ sequestration into the sarcoplasmic reticulum (SR), a process mediated by the phosphorylation of phospholamban by protein kinase A, is also crucial. This leads to a reduction in diastolic Ca2+ concentration but an elevation in systolic Ca2+ concentration due to the increased Ca2+ content within the SR, further augmented by the positive effect of synchronizing SR Ca2+ release through $\beta$-adrenergic stimulation.
Unfortunately, sympathomimetic agents, despite their inotropic benefits, are also strongly proarrhythmic for several reasons. Firstly, the increase in intracellular Ca2+ concentration can lead to the generation of delayed afterdepolarizations. Furthermore, early afterdepolarizations, which can manifest as serious cardiac arrhythmias like torsade de pointes, are also triggered by $\beta$-adrenergic activators under both in vitro and in vivo conditions. This explains why $\beta$1-receptors are generally better suppressed than activated over longer time scales in chronic heart failure. Secondly, $\beta$-adrenergic activation increases myocardial oxygen consumption, which is detrimental for a failing heart already operating under metabolic stress. However, selective activation of $\beta$3-adrenergic receptors, which operate via the NO/cGMP pathway, might mitigate the unfavorable consequences of cardiac remodeling and therefore hold promise in the treatment of heart failure.
Similar to $\beta$-adrenergic activation, the inhibition of the phosphodiesterase (PDE) enzyme offers another avenue to increase contractile force. This is because cAMP levels can be elevated either by boosting its production or by decreasing its breakdown. Amrinone and milrinone were among the pioneering molecules used as positive inotropic agents that acted by inhibiting PDE. However, this strategy presents two major challenges. The first largely mirrors the issues seen with $\beta$-adrenergic agonists: the resulting Ca2+ overload significantly increases the propensity for arrhythmias. Secondly, because cardiomyocytes contain multiple PDE isoenzymes, each possessing a distinct signal transduction pathway and compartmentalization profile, selective inhibition of a single isoenzyme may be necessary to achieve targeted effects and avoid unwanted consequences. Suppression of the PDE-III isoform has been widely employed in heart failure treatment with varying degrees of success.
Beyond the increased arrhythmia risk due to Ca2+ overload, a shared concern with $\beta$-adrenergic agonists and PDE inhibitors is their tendency to escalate the ATP utilization of the working myocardium. This occurs because an increased rate of Ca2+ cycling necessitates that more Ca2+ be actively removed from the cytoplasm within a given timeframe under these conditions. Such an increase in energy demand can be particularly detrimental in chronic heart failure, where the failing heart often operates under suboptimal metabolic conditions. Recently, a novel strategy focusing on “RyR2 stabilization” has emerged. This approach is predicated on the understanding that, in certain forms of heart failure, the RyR2 channel becomes leaky, allowing Ca2+ to escape from the sarcoplasmic reticulum during diastole. This leakage severely impairs the heart’s pump function, as it leads to an elevated diastolic Ca2+ level (contributing to diastolic failure) combined with a reduced sarcoplasmic reticulum Ca2+ content (contributing to systolic failure). Ryanodine receptor stabilizers, by effectively suppressing this diastolic Ca2+ leak, are believed to improve contractile performance while simultaneously reducing the heart’s energy demand.
An alternative inotropic strategy involves increasing the “efficacy” of the Ca2+ signal. This means either generating more force from a given rise in cytosolic Ca2+, or requiring less Ca2+ to produce a specific level of force. Ca2+ sensitizers achieve this by increasing the affinity of troponin C for Ca2+, thereby improving the mechanical performance of the myocardium without significantly increasing its oxygen demand. Since, at least in theory, Ca2+ cycling is not enhanced by these agents, the intracellular Ca2+ level and the associated incidence of arrhythmias should not be elevated. Pimobendan and levosimendan, the most recognized conventional Ca2+ sensitizers, also exhibit phosphodiesterase inhibitory actions. Theoretically, the combined effects of Ca2+ sensitization and PDE inhibition might offer clinical advantages. This is because the PDE-dependent component could counteract a predictable diastolic dysfunction that might otherwise result from pure Ca2+ sensitization. The hemodynamic effects of levosimendan are further complicated by its ability to open ATP-sensitive K+ channels in vascular smooth muscle cells, which leads to vasodilation. Moreover, the activation of these channels, located in the mitochondrial membrane, has been shown to exert cardioprotective effects. Collectively, it is likely that all these mechanisms contribute to the overall therapeutic benefits observed with levosimendan. The term positive inotropy with a “downstream mechanism” of action refers to a specific form of Ca2+ sensitization, where the myocardial systolic force is enhanced through direct modifications of the molecular events within the actin–myosin cycle.
Myosin activators — new strategy for increasing contractility
As previously discussed, each of the currently known inotropic strategies is hampered by certain drawbacks. An ideal inotropic agent would ideally possess several key characteristics: it should selectively enhance cardiac contractility, manifesting as positive inotropic and lusitropic actions without inducing chronotropic (heart rate), dromotropic (conduction velocity), or bathmotropic (excitability) responses. Furthermore, it should not increase the heart’s energy demand, and, most importantly, it should not heighten the propensity for arrhythmias. An additional beneficial trait would be for its positive inotropic action to be augmented under pathological conditions, such such as in a failing heart. Given that these objectives have not been fully achieved by interventions acting upstream of Ca2+–troponin binding, research efforts have increasingly focused on the downstream steps of muscle contraction. The binding of Ca2+ to troponin C initiates a cascade of protein–protein interactions that ultimately culminate in force generation. Indeed, modulating these specific steps offers numerous opportunities to regulate contractility. Among these strategies, the application of myosin activators likely represents the most promising approach. These compounds enhance the force of contraction by directly interacting with the myosin heavy chain. Omecamtiv mecarbil is the pioneering selective cardiac myosin activator that operates via this mechanism.
The initial molecule identified for its ability to increase the ATPase activity of myosin was CK-0156636. Subsequent modifications led to CK-1032100, where the substitution of a nitrate group for fluorine improved the molecule’s water solubility, thereby reducing its binding to plasma proteins. CK-1122534 was the first agent demonstrated to increase fractional shortening in rat ventricular myocardium; however, this compound also activated ATP-sensitive K+ channels. CK-1213296 rectified this particular side effect but was found to inhibit the CYP 1A2 enzyme. All these undesirable side effects were successfully eliminated in CK-1317138. The culmination of this optimization process led to the development of CK-1827452, which is now known as omecamtiv mecarbil. This refined molecule proved to be an order of magnitude more potent than its precursor, CK-1317138.
In vitro and in vivo effects of omecamtiv mecarbil
Omecamtiv mecarbil exerts its positive inotropic effect through highly selective binding to the S1 domain of the cardiac $\beta$-myosin heavy chain. This binding occurs specifically at a region where the relay helix and converter domain converge at the base of the force-producing lever arm. The interaction of omecamtiv mecarbil at this site induces a conformational change within the nucleotide-binding domain of the myosin head. This conformational alteration contributes to the allosteric activation of myosin’s enzymatic and mechanical properties. As a direct consequence of this allosteric modulation of the myosin nucleotide-binding domain, omecamtiv mecarbil has been shown to accelerate the release of inorganic phosphate, a step that is otherwise rate-limiting in the actomyosin cycle. This acceleration is due to an increased ATPase activity of the myosin heavy chain, which, in turn, speeds up the transition rate from the weakly bound to the strongly bound configuration of actin-associated myosin heads by reducing the energy barrier between these states. This effect ultimately results in an increased number of force-generating cross-bridges within the sarcomere, directly correlating with an enhancement of force generation.
Experiments conducted in heterologously reconstituted actin–myosin systems revealed that the stimulation of ATPase activity by omecamtiv mecarbil is exclusively observed in the presence of cardiac and slow skeletal muscle myosin isoforms (specifically $\alpha$ and $\beta$), regardless of the origin of the thin filament. In healthy human hearts, the $\beta$ isoform predominates, with a lesser presence of the $\alpha$ isoform, while the $\alpha$ isoform is virtually absent in failing hearts. Importantly, myosins derived from fast skeletal or smooth muscles are not activated by omecamtiv mecarbil, which suggests a “quasi” cardiospecific binding profile for the drug. In fact, omecamtiv mecarbil has been shown to enhance contractility in slow skeletal muscle fibers, such as those found in the diaphragm, which could potentially broaden the therapeutic spectrum of this agent. Consistent with the stabilization of the “strongly bound” configuration of myosin heads, omecamtiv mecarbil reduced the unloaded shortening velocity of porcine and human ventricular myosins when evaluated using an in vitro mobility assay. Since this effect was observed equally with both $\alpha$ and $\beta$ isoforms, it indicates that omecamtiv mecarbil can effectively improve both atrial and ventricular contractility.
An increase in the ATPase activity of the myosin heads would typically be expected to lead to an increased cardiac oxygen consumption. However, because omecamtiv mecarbil does not increase (and actually decreases) the actin-independent release of inorganic phosphate, the overall oxygen consumption of the heart is not anticipated to rise due to the drug. In the absence of extra energy demand related to enhanced Ca2+ cycling, cardiac energy utilization can become more efficient in the presence of omecamtiv mecarbil. Furthermore, the mammalian heart appears robust enough to tolerate myosin motor tuning over extended administration periods. Transgenic rabbits, engineered to possess $\alpha$ and $\beta$ isoforms of myosin in a 1:1 ratio, did not exhibit symptoms of cardiomyopathy; instead, they demonstrated a cardioprotected phenotype in an overdrive-induced heart failure model. Additionally, the lifespan of these transgenic animals was comparable to that of their normal littermates.
Cellular-level studies on the effects of omecamtiv mecarbil revealed an enhancement of fractional shortening in isolated rat cardiomyocytes, notably without any alterations in Ca2+ handling as monitored by fluorescent Ca2+ indicators. Crucially, myosin activation resulted in an increase in both the amplitude and the duration of contractions. Omecamtiv mecarbil also proved effective under in vivo conditions, where fractional shortening was monitored using echocardiography in anesthetized dogs and rats. Interestingly, canine hearts displayed greater sensitivity to omecamtiv mecarbil than rat hearts.
In an in vivo canine model of pacing-induced systolic heart failure, developed after myocardial infarction or chronic pressure overload, omecamtiv mecarbil infusion was shown to significantly enhance left ventricular stroke volume, cardiac output, and systolic ejection time. Concurrently, it led to a reduction in heart rate, total peripheral resistance, and loading pressures. On the other hand, myocardial oxygen consumption and the rate of pressure development were not adversely affected by the drug when compared with traditional inotropes. Furthermore, omecamtiv mecarbil produced a more pronounced augmentation of systolic performance in failing canine hearts than in healthy animals. In contrast to other inotropic agents, including catecholamines, the inotropic action of omecamtiv mecarbil was observed to be enhanced at longer pacing cycle lengths and reduced at shorter pacing cycle lengths in unloaded canine cardiomyocytes.
It is vital to consider that any increase in systolic ejection time might occur at the expense of diastole, potentially impeding ventricular filling and compromising coronary blood flow. However, because intravenous administration of omecamtiv mecarbil has been reported to decrease heart rate, moderate improvements in systolic emptying should not dramatically impair diastolic function or coronary flow. Surprisingly, until recently, no cellular electrophysiological results regarding omecamtiv mecarbil had been published. However, according to preliminary, unpublished data from our laboratory, a relatively high concentration of omecamtiv mecarbil (10 $\mu$mol·L−1) induced small but statistically significant changes in the configuration of canine ventricular action potentials. These alterations included a reduction of phase-1 repolarization, suppression of the plateau amplitude, and a shortening of the action potential duration. While we can only speculate about the involvement of underlying ion currents in the absence of relevant voltage clamp data, a smaller phase-1 amplitude suggests a reduction of the transient outward current ($\text{I}_\text{to}$), and the depression of the plateau potential is consistent with a decreased L-type Ca2+ current. Clearly, further comprehensive electrophysiological studies are indispensable to thoroughly map all possible effects of omecamtiv mecarbil on cardiac ion currents, as even relatively minor shifts in these currents could potentially be proarrhythmic in certain susceptible patient populations.
Clinical trials
Building upon the encouraging preclinical outcomes observed with the myosin activator omecamtiv mecarbil, the drug progressed into a phase I clinical study. The primary objective of this initial trial, conducted in 34 healthy volunteers, was to establish the maximum-tolerated dose and the corresponding plasma concentrations of the drug when administered intravenously over a 6-hour period, once weekly for four weeks. A secondary aim involved evaluating the pharmacodynamic properties of the drug, specifically its effects on left ventricular systolic function as assessed by transthoracic echocardiography, along with its overall safety and tolerability profile. In this first-in-human, dose-escalating investigation, omecamtiv mecarbil effectively enhanced left ventricular systolic function in a dose-dependent manner across doses ranging from 0.005 to 1 mg·kg−1·h−1. Within this dosage range, a direct linear correlation was identified between plasma concentrations of the drug and the systolic ejection time. Importantly, this improvement in the heart’s systolic performance was not associated with any detectable impairment of diastolic function. The maximum-tolerated dose was determined to be 0.5 mg·kg−1·h−1, at which concentration no adverse effects were observed. The dose-limiting toxic effect that emerged was myocardial ischemia, which occurred due to an excessive prolongation of systolic ejection time at the expense of diastolic filling.
A double-blind, randomized, placebo-controlled, dose-ranging phase II trial was subsequently conducted in 45 patients suffering from stable heart failure with left ventricular systolic dysfunction, all of whom were already receiving ACE inhibitor therapy. The main goal of this trial was to evaluate the safety and tolerability of omecamtiv mecarbil within this patient population, who received the drug via infusion for durations of 2, 24, or 72 hours. Omecamtiv mecarbil led to an increase in left ventricular ejection time by up to 80 milliseconds from baseline, while stroke volume showed an increase of up to 9.7 mL. These beneficial changes were also accompanied by a reduction in heart rate of up to 2.7 beats·min−1. Higher plasma concentrations of omecamtiv mecarbil resulted in a decrease in both end-systolic and end-diastolic volumes, by 15 mL and 16 mL respectively. When comparing these findings with the results from the phase I trial, it became evident that the beneficial effects of omecamtiv mecarbil were comparable between healthy individuals and patients with heart failure. The plasma concentration range that was well-tolerated spanned from 0.1 to 1.2 $\mu$g·mL−1. However, at higher plasma levels (1.35 and 1.75 $\mu$g·mL−1), two patients experienced symptoms consistent with myocardial ischemia, which was attributed to an excessive prolongation of systolic ejection time.
A randomized, controlled phase IIb trial, known as ATOMIC-AHF, was carried out to assess the safety and efficacy of omecamtiv mecarbil in patients experiencing acute heart failure. This study ultimately revealed that the omecamtiv mecarbil-induced myosin activation did not achieve its primary endpoint, as no statistically significant effect on dyspnea could be demonstrated. Nevertheless, the study concluded that the administration of omecamtiv mecarbil is clinically safe, and the results showed a tendency towards slowing the progression of heart failure.
More recently, omecamtiv mecarbil was investigated in a cohort of hospitalized patients diagnosed with cardiomyopathy in conjunction with ischemic heart disease, specifically angina pectoris. The objective was to monitor the agent’s safety and tolerability in patients with ischemic cardiomyopathies. This particular combination of conditions was critically important because myocardial ischemia, resulting from an excessive prolongation of systolic ejection time, had already been observed in cases of overdose. In this double-blind, placebo-controlled study, the impact of a 20-hour infusion of omecamtiv mecarbil on cardiac performance during a treadmill exercise test was evaluated. The results indicated that omecamtiv mecarbil, at doses yielding plasma concentrations sufficient to effectively enhance systolic function, was well tolerated even during physical exercise in patients who had ischemic cardiomyopathy and angina. Given that higher concentrations, such as those encountered in an overdose, could indeed lead to ischemic consequences, extreme caution must be exercised with the dosage of omecamtiv mecarbil. This is especially true due to the unknown magnitude of interpersonal variability in drug sensitivity and pharmacokinetics. Data pooled from three distinct clinical trials involving omecamtiv mecarbil were analyzed using a nonlinear mixed-effects model. This analysis aimed to thoroughly investigate the pharmacokinetic properties of the drug and to elucidate the relationship between its plasma concentration and changes in left ventricular outflow tract stroke volume and systolic ejection time. The oral absorption half-life of the drug was determined to be 0.62 hours, and its absolute bioavailability was estimated at 90%, while the elimination half-life extended to 18.5 hours. A direct correlation was observed between plasma concentrations and increases in both stroke volume and ejection time, consistently seen in both healthy volunteers and patients with heart failure. Model-based simulations exploring several immediate-release oral dose regimens (such as 37.5 mg, 50 mg, and 62.5 mg doses administered every 8, 12, and 24 hours, respectively) indicated that a beneficial pharmacodynamic effect could be sustained without leading to excessively high plasma concentrations of omecamtiv mecarbil.
Considering all the available data collectively, omecamtiv mecarbil appears to be a highly promising therapeutic approach for the treatment of systolic heart failure, strongly suggesting that the strategy of myosin activation can be effectively translated into clinical practice.
Perspectives
In light of the results discussed, the class of Ca2+ sensitizer agents, according to our current understanding, offers the most suitable therapeutic option for both acute and chronic heart failure. The conventional method of increasing Ca2+ cycling within cardiomyocytes has not been supported by consistently positive therapeutic outcomes, primarily due to the associated increase in energy consumption and heightened propensity for arrhythmias. Theoretically, Ca2+ sensitizers should be free from these undesirable side effects. In the context of acute heart failure, Ca2+ sensitizers alone may very well become the primary therapeutic approach in the future. For chronic heart failure, the judicious application of these drugs, in conjunction with the standard conventional therapy involving $\beta$-blockers, ACE inhibitors, and diuretics, could provide the “pharmacologically suppressed” heart with an opportunity to enhance its mechanical performance. This enhancement has the potential to significantly improve the quality of life for patients. Given that omecamtiv mecarbil is considered a representative of a novel group of Ca2+ sensitizers, the crucial question of whether conventional Ca2+ sensitizers or myosin activators will yield superior therapeutic results must be definitively answered. Further preclinical and clinical studies are essential to fully elucidate and differentiate their potential effects on cardiac oxygen consumption and cardiac rhythm across various cardiac pathologies. It is hoped that thoughtfully designed clinical trials will ultimately help to draw conclusive determinations. The most significant potential drawback associated with omecamtiv mecarbil may involve compromised diastolic filling, a concern that is not mitigated by suppressed PDE activity, unlike in the case of other Ca2+ sensitizers.
As noted previously, no alteration in intracellular Ca2+ transients was observed with omecamtiv mecarbil in ventricular myocytes isolated from rats. This finding was initially considered strong evidence supporting a purely “downstream” mechanism of action for the drug, implying a lack of direct effect on Ca2+ release and reuptake. However, the rat is not an ideal experimental model for this particular aspect, as neither its electrophysiological properties nor its Ca2+ handling mechanisms are entirely analogous to those found in larger mammals, including humans. This concern can be readily addressed by testing omecamtiv mecarbil’s effects on Ca2+ handling in larger mammalian models. The cardioselective nature of omecamtiv mecarbil’s action is generally cited as an advantage, given that myosins from fast skeletal and smooth muscles are unaffected. Nevertheless, the potential therapeutic benefits of omecamtiv mecarbil, particularly those related to facilitating the contractility of slow skeletal muscle, cannot be overstated. Slow-twitch skeletal muscles, such as the diaphragm, possess a myosin composition similar to that found in the heart. Therefore, it is plausible that omecamtiv mecarbil could improve the mechanical performance of the diaphragm and other slow-twitch muscles throughout the body, which could hold significant importance for patients requiring ventilator support or for healthy elderly individuals. Supporting this hypothesis, omecamtiv mecarbil has indeed been shown to facilitate contractility in rat diaphragm in a manner similar to its effects on cardiac myocytes. These experiments clearly underscored the Ca2+ sensitizer properties of omecamtiv mecarbil, evidenced by a slowing of the activation–relaxation kinetics.
Because omecamtiv mecarbil selectively binds to cardiac myosins, it can be utilized for labeling purposes to visualize myosin heads within the heart. Indeed, 18F-labeled analogues of omecamtiv mecarbil have been successfully employed for cardiac myosin imaging using positron emission tomography. This advanced technique, when combined with sarcomere length nanometry, holds the potential to provide unprecedented insights into the intricate mechanics of the contractile machinery of the heart.