Targeting cardiac myosin in HFrEF: mechanism, clinical evidence, and the role of omecamtiv mecarbil

Abstract

The morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) remain high despite significant advances in treatment. Current guideline-directed medical therapies (GDMT) primarily target neurohormonal pathways. However, traditional positive inotropes, which enhance contractility, are limited by adverse events including increased myocardial oxygen consumption and arrhythmogenesis. Omecamtiv Mecarbil (OM) is a first-in-class selective cardiac myosin activator that addresses this gap by directly targeting the cardiac sarcomere. OM binds to cardiac myosin, stabilizing it in a force-generating state, thereby prolonging systolic ejection time and improving contractility without increasing intracellular calcium or heart rate. The Phase III GALACTIC-HF trial, which enrolled over 8,200 patients with HFrEF, reported an 8% relative risk reduction in the composite endpoint of heart failure events or cardiovascular death (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.86–0.99, P = 0.025). This benefit was primarily driven by a reduction in heart failure hospitalizations, with no significant difference in cardiovascular mortality. Subgroup analysis revealed that the clinical benefit was most pronounced in patients with a left ventricular ejection fraction (LVEF) of ≤ 28%. OM was generally well-tolerated, with a safety profile comparable to placebo, though it possesses a narrow therapeutic window, with higher plasma concentrations associated with an increased risk of ischemic events. In summary, OM represents a novel, mechanistically distinct therapeutic option for symptomatic HFrEF patients, particularly those with severe systolic dysfunction, who remain at high risk despite optimized GDMT.

Introduction

Heart failure (HF) is a chronic, progressive syndrome characterized by the heart’s inability to pump sufficient blood to meet the body’s metabolic demands. It remains a global health challenge, affecting approximately 64.3 million people worldwide as of 2021, with a prevalence of 1–2% among adults in developed countries [1, 2]. Heart failure with reduced ejection fraction (HFrEF), defined by a left ventricular ejection fraction (LVEF) of 40% or less, accounts for at least half of all HF cases. It is important to note that while HFrEF is broadly defined as LVEF ≤ 40%, major clinical trials, including GALACTIC-HF, often enroll patients with more severe systolic dysfunction (e.g., LVEF ≤ 35%).

The core pathophysiology of HFrEF involves a decline in myocardial contractility, which triggers a cascade of compensatory mechanisms, including neurohormonal activation and adverse ventricular remodeling. While these mechanisms initially maintain cardiac output, the resulting increase in cardiac wall stress and myocardial oxygen demand ultimately leads to reduced contractile efficiency, further myocardial injury, and cardiomyocyte death [3]. Despite decades of therapeutic advancements, many patients with HFrEF still experience disease progression and fail to achieve full recovery, underscoring the persistent need for novel treatment strategies [4]. Directly targeting the sarcomere to improve contractility represents a potentially disease-modifying approach distinct from neurohormonal blockade.

Current management of HFrEF is founded on two main therapeutic pillars. The first, and most effective, involves the inhibition of detrimental neurohormonal activation through agents such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor-neprilysin inhibitors (ARNi), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). The second pillar, historically less successful for long-term use, attempts to enhance cardiac contractility. Traditional positive inotropic agents, such as beta-adrenergic agonists and phosphodiesterase inhibitors, achieve this by increasing the intracellular calcium concentration in cardiomyocytes [5]. However, this calcium-centric mechanism is associated with significant drawbacks, including increased heart rate, elevated myocardial oxygen consumption, and a heightened risk of arrhythmias, which have been linked to increased long-term mortality [5].

Omecamtiv mecarbil (OM) represents a new class of therapeutics: the selective cardiac myosin activators (or “myotropes”). OM augments cardiac contractility by directly targeting the sarcomere, the fundamental contractile unit of the cardiomyocyte. It selectively binds to cardiac myosin, increasing the number of myosin heads that can bind to the actin filament and initiate a power stroke at the beginning of systole [6, 7]. In chronic HFrEF patients, OM treatment has been shown to increase left ventricular systolic ejection time and stroke volume, decrease left ventricular systolic and diastolic volumes (suggesting beneficial reverse cardiac remodeling), and reduce plasma natriuretic peptide levels and heart rate, all with less neurohormonal activation [7, 8].

The Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial is the first large-scale study to test whether selective enhancement of cardiac contractility could translate into improved clinical outcomes in HFrEF. Given OM’s mechanism, which avoids adverse effects on blood pressure, heart rate, kidney function, or potassium levels, the trial was able to enroll a broad and diverse patient population, including many who would have been excluded from other contemporary HF trials [3]. The trial hypothesized that OM could safely improve symptoms, prevent clinical heart failure events, and delay cardiovascular death in patients with HFrEF Figs. 1 and 2.

Fig. 1.

The Contractile Apparatus and Site of OM Action

Fig. 2.

Myosin ATPase Cycle

While prior publications have examined specific aspects of omecamtiv mecarbil including molecular mechanism, individual clinical trials, or subgroup analyses such as age-based outcomes (Lu et al., 2026) [9] the present review provides a comprehensive, integrated framework spanning from sarcomere biology to clinical implementation. We synthesize preclinical and clinical data, compare OM with all major inotrope classes, propose practical patient selection criteria, and outline future directions including next-generation myotropes. This holistic approach is designed to serve both basic scientists and practicing clinicians.

Mechanism of action

Cardiac contraction is driven by the cardiac myosin ATPase cycle, a molecular mechanism that converts the chemical energy from ATP hydrolysis into mechanical force. The cycle begins when ATP binds to the actin-bound myosin head, causing the actomyosin complex to dissociate. Myosin then hydrolyzes ATP into adenosine diphosphate (ADP) and inorganic phosphate (Pi), transitioning into a high-energy, pre-power stroke (PPS) conformation, which is primed to generate force [9]. In this state, the myosin head is dissociated and bound to ADP and Pi. The motor subsequently rebinds to actin, initiating the force-generating power stroke and triggering the release of Pi. This transition to strong binding and subsequent Pi release is the rate-limiting step in the cycle in the presence of actin. During the power stroke, the light chain-binding domain rotates, resulting in a displacement that pulls the actin filament. The subsequent release of ADP limits cross-bridge detachment and sets the rate of unloaded shortening, before the myosin returns to the strongly bound rigor state [9].

Omecamtiv mecarbil (OM) is a selective cardiac myosin activator that stabilizes the PPS state by binding to a specific allosteric site, often referred to as the “PPS pocket.” The location of this buried pocket, which only forms when the myosin motor has a primed lever arm, explains the drug’s high selectivity for cardiac myosin. Structurally, OM acts as a bridge, forming extensive interactions with the N-terminal subdomain, the relay helix, and the converter domain. This binding stabilizes the lever arm in a fully primed position, which is essential for initiating contraction [10].

By stabilizing the PPS state, OM kinetically shifts the equilibrium of the recovery stroke and ATP hydrolysis toward the ADP-Pi-bound state. This action leads to the accumulation of cardiac myosin heads with a primed lever arm before the start of cardiac contraction, thereby increasing the population of heads ready to bind to the actin filament. This stabilization prevents the non-productive turnover of ATP (release of ADP and Pi) in the absence of interaction with the actin filament. Consequently, OM increases the number of myosin heads (force generators) available to bind to the actin filament and initiate a power stroke at the beginning of systole, augmenting cardiac contractility [10].

OM is fundamentally differentiated from calcium-dependent inotropes (calcitropes) and conventional myofilament calcium sensitizers due to its molecular target and its independence from calcium signaling. Traditional calcitropes, such as beta-agonists, catecholamines, and phosphodiesterase inhibitors, increase myocardial contractile force by mobilizing calcium and increasing intracellular Ca²⁺ concentrations, often via cyclic adenosine monophosphate (cAMP) signaling. This mechanism is associated with adverse effects, including increased myocardial oxygen demand, arrhythmias, and poor long-term clinical outcomes [11, 12]. In contrast, OM is classified as a cardiac myotrope because it acts as an allosteric modulator that directly targets and activates cardiac myosin, bypassing the Ca²⁺ signaling cascade.

While calcitropes enhance contractility primarily by increasing the rate of force generation (dP/dt), OM’s stabilization of the myosin PPS state leads to a significant increase in the duty ratio—the fraction of the ATPase cycle during which myosin is strongly bound to actin. This stabilization increases the number of myosin heads entering the force-producing state, resulting in the prolongation of contraction time and systolic ejection time, without a significant increase in the rate of force development [11, 12, 13]. This mechanism allows OM to improve myocardial performance more efficiently and, importantly, without the characteristic pro-arrhythmic risks and energy-wasting effects linked to Ca²⁺ cycling seen with PDE inhibitors [11, 12].

OM exhibits unique cardioselectivity through its specific binding affinity for the human beta-cardiac myosin heavy chain (MyHC-7) isoform. This specificity is crucial as OM is designed to enhance contractile force by directly modulating the cardiac molecular motor [13]. The residues critical for OM interaction (e.g., Y164, H666, N711, and I713) are strictly conserved in cardiac myosin but are often not conserved in non-cardiac myosin II isoforms (e.g., smooth muscle or skeletal muscle), ensuring its selective action on the heart [13, 14].

It is worth noting that while OM enhances systolic function without raising intracellular calcium, preclinical studies have shown that supra-therapeutic concentrations can induce diastolic dysfunction and electromechanical alternans in animal models. This narrow therapeutic window where efficacy is achieved at 200–1000 ng/mL but diastolic impairment may emerge at higher levels has guided dose selection in clinical trials and underscores the importance of therapeutic drug monitoring.

Preclinical and clinical trials

The clinical efficacy of OM in HFrEF was established through a robust program of preclinical and clinical studies.

• Preclinical Studies

Preclinical investigations demonstrated OM’s ability to augment cardiac performance across various animal models. In conscious dogs with systolic HF, OM prolonged systolic ejection time, increased cardiac output, and reduced left ventricular (LV) dimensions [17]. Studies in rats with chronic aortic regurgitation (AR) showed that OM reduced LV wall stress and elevated systolic performance [18]. Furthermore, OM demonstrated a significant improvement in myocardial dysfunction and neurological outcomes following resuscitation in a rat model [19]. These studies in dogs and rats highlighted OM’s narrow therapeutic range, with optimal systolic function improvement observed between 600 and 1200 µg/kg, which informed the target plasma concentrations for human trials. Importantly, in vivo studies noted the occurrence of diastolic dysfunction at higher therapeutic doses, providing crucial guidance for subsequent clinical trial design [20, 21].

• Clinical Trials

Phase I and Pharmacokinetic Studies The first-in-man Phase I study by Teerlink et al. in 2011 demonstrated a dose- and concentration-dependent augmentation of LV systolic function with OM, with a maximum tolerated dose of 0.5 mg/kg. The study identified myocardial ischemia as a dose-related toxicity resulting from an excessive increase in systolic ejection time [22]. A subsequent population pharmacokinetic–pharmacodynamic (PK–PD) study established OM’s two-compartment model with first-order oral absorption, a half-life of approximately 18.5 h, and an oral bioavailability of around 90%. This study confirmed a strong correlation between OM concentration and systolic ejection time [23].

Phase II Trials Two Phase II trials explored OM in different settings:

• ATOMIC-HF: This double-blind, multicenter, randomized study included 606 hospitalized patients with acute decompensated HFrEF (LVEF ≤ 40%) and tested intravenous (IV) OM. While the study showed no significant improvement in the primary outcome of dyspnea compared to placebo, it did report a concentration-related prolongation of systolic ejection time (SET) and a reduction in LV end-systolic dimensions, with a safety profile similar to placebo [24].

• COSMIC-HF: This study assessed oral OM in 448 patients with chronic HFrEF over 20 weeks. The findings confirmed OM’s tolerability compared to placebo and demonstrated positive effects on SET, stroke volume, and left ventricular end-diastolic diameter, suggesting enhanced cardiac function and beneficial reverse remodeling [8].

Phase III Trials

• GALACTIC-HF: This landmark Phase III, randomized, double-blind, placebo-controlled trial enrolled 8,256 patients with symptomatic HFrEF (LVEF ≤ 35%) and a median follow-up of 21.8 months. The primary composite outcome was the time to a first heart failure event (hospitalization or urgent visit) or cardiovascular death. The primary outcome occurred in 37.0% of the OM group (1,523 of 4,120 patients) versus 39.1% in the placebo group (1,607 of 4,112 patients) (Hazard ratio [HR]: 0.92; 95% CI, 0.86 to 0.99; P = 0.025). This represented an 8% relative risk reduction in the composite endpoint, which was primarily driven by a reduction in heart failure events, while CV-related deaths did not significantly decrease (HR 0.99, P = 0.86). Subgroup analysis revealed that the greatest efficacy and benefit were observed in patients with an LVEF of ≤ 28%. The safety profile was comparable between the OM and placebo groups, with no increased risk of ischemic events or ventricular tachycardia, indicating a favorable electrophysiologic safety profile [16].

• METEORIC-HF: This Phase III trial assessed the effect of oral OM on exercise capacity in 276 HFrEF patients over 20 weeks. The primary outcome, change in peak VO₂ (a measure of exercise capacity), showed no significant difference between the OM and placebo groups (–0.24 mL/kg/min vs. 0.21 mL/kg/min) [25]. The negative value for OM suggests a slight decline in peak VO₂, contrasting with a slight improvement in the placebo group, indicating that OM’s clinical benefit is related to a reduction in heart failure events rather than an enhancement of exercise capacity.

The key findings from the major clinical trials are summarized in Tables 1 and 2.

Table 1.

Comparison of Inotropic Mechanisms

Feature	Omecamtiv Mecarbil [11]	Dobutamine [11]	Levosimendan [12]
Mechanism Class	Cardiac Myotrope [11]	Cardiac Calcitrope [11]	Hybrid/Mixed Mechanism (Calcium sensitizer + Inodilator) [12]
Molecular Target	Cardiac Myosin (beta-MyHC-7 isoform) [13]	beta-adrenergic receptors [11]	Cardiac Troponin C, Phosphodiesterase-3, and K < sub> ATP</sub> channels [12]
Effect on Ca²⁺ Levels	Independent of intracellular Ca²⁺ concentration. Enhances calcium sensitivity [13, 15]	Increases intracellular Ca²⁺ levels [11]	Modulates contractile force without altering Ca²⁺ transients via Ca²⁺ sensitization. PDE inhibition can increase Ca²⁺ fluxes at higher doses [11, 12]
Primary Inotropic Effect	Allosteric modulator stabilizing the Pre-Powerstroke (PPS) state. Increases number of force-producing myosin heads and augments myosin duty ratio [11, 13]	Increases cAMP and PKA, enhancing Ca²⁺ levels. Leads to accelerated fiber shortening (increased dP/dt) [11]	Calcium sensitization of the contractile force. Vasodilation complements inotropy (Inodilator) [12]
Other Key Effects	Increased systolic ejection time [15]. Slows cross-bridge kinetics/force development [13]. Reduced NT-proBNP levels [8]	Increased myocardial O₂ demand/consumption [11]. Increased Chronotropic effects [11]. Promotes Ca²⁺ desensitization [12]	Potent vasodilation via opening potassium channels [12]. Cardioprotective effects [12]. Does not impair diastolic function/lusitropy [12]
Clinical Outcome (Mortality)	Reduced incidence of composite primary outcome (HF events + CV death) [16]	Associated with increased mortality during prolonged use [11]	Mixed results: large trials (SURVIVE, REVIVE) were neutral. Meta-analyses suggest potential mortality reduction [11, 12]

Table 2.

Key OM Clinical Trials

Trial Name	Phase	Population (N)	Intervention vs. Comparator	Primary Outcome(s)	Key Findings / Comments
Teerlink et al. [22]	I	45 (HF patients & healthy)	IV OM (dose escalation) vs. Placebo	PK/PD relationship & Safety	Dose/concentration-related increase in systolic ejection time and LV function
ATOMIC-HF [24]	II	606 (Acute HFrEF, LVEF ≤ 40%)	IV OM vs. Placebo	Dyspnea improvement; Systolic Ejection Time	No significant dyspnea improvement. Systolic ejection time increased
COSMIC-HF [8]	II	448 (Chronic HFrEF, 20 wks)	Oral OM vs. Placebo	OM plasma concentration; SET, Stroke Volume, LV diameters	Achieved target plasma levels. Increased SET and stroke volume; decreased ventricular diameters.
GALACTIC-HF [16]	III	8,256 (Symptomatic HFrEF, LVEF ≤ 35%)	Oral OM (25, 37.5, 50 mg BID) vs. Placebo	Time to first HF event or CV death	Primary outcome: 37.0% (OM) vs. 39.1% (Placebo); HR 0.92 (0.86–0.99), P = 0.025. Benefit driven by HF events, not CV death. Greatest benefit in LVEF ≤ 28%
METEORIC-HF [25]	III	276 (Chronic HFrEF, 20 wks)	Oral OM vs. Placebo	Change in peak VO₂	No significant difference (-0.24 vs. + 0.21 mL/kg/min). OM does not improve exercise capacity

A recently published subgroup analysis of GALACTIC-HF by Lu et al. (2026) [9] demonstrated that the efficacy and safety of OM were generally consistent across age groups, including patients ≥ 75 years, though younger patients showed a numerically larger treatment effect. These findings support the use of OM across the age spectrum of HFrEF patients meeting other selection criteria.

Safety and tolerability

The safety profile of Omecamtiv Mecarbil (OM) is a critical factor distinguishing it from conventional inotropic agents. Traditional therapies, such as beta-adrenergic agonists and phosphodiesterase inhibitors, enhance contractility via increased intracellular calcium or cyclic adenosine monophosphate (cAMP), but their utility is limited by safety concerns, including pro-arrhythmia, increased myocardial oxygen demand, and increased long-term mortality [11, 26]. OM, as a selective cardiac myosin activator, improves systolic function without directly influencing calcium handling or neurohormonal mechanisms [26].

• Safety Profile

Arrhythmogenic Potential OM enhances contractility by increasing the number of force-generating myosin heads, thereby prolonging systolic ejection time. Since this mechanism bypasses calcium cycling, the increase in intracellular calcium the primary driver of arrhythmia for other inotropes is obviated. Large-scale clinical trials, including COSMIC-HF [8] and GALACTIC-HF [16], have confirmed that OM does not increase the risk of sustained ventricular arrhythmias compared to placebo. While premature ventricular contractions and non-sustained ventricular tachycardia may occur, their rates are not significantly different from controls. This favorable electrophysiology contrasts sharply with agents like dobutamine and milrinone, which markedly increase arrhythmia risk [24].

Cardiac Ischemia Despite its favorable electrophysiologic profile, OM presents a specific safety consideration regarding myocardial ischemia. High plasma concentrations of OM can lead to excessive systolic activation and prolonged ejection time, which may increase myocardial oxygen demand and decrease diastolic coronary perfusion [27]. The COSMIC-HF pharmacokinetic substudy noted that patients with OM plasma levels exceeding the therapeutic threshold experienced higher frequencies of ischemic events, including elevated myocardial injury markers and angina [8]. This observation underscores the critical need for therapeutic drug monitoring.

Troponin Elevation A dose-dependent, low-grade elevation in cardiac troponin I or T levels has been observed with OM [28]. In GALACTIC-HF, a ≥ 50% increase in high-sensitivity cardiac troponin I occurred in 17.1% of OM patients vs. 12.5% on placebo, and a ≥ 100% increase in 8.5% vs. 5.3%, respectively [28]. Importantly, these increases were generally not associated with clinical signs of myocardial infarction, ECG changes, or clear ischemic episodes. Instead, they are thought to reflect small differences in ventricular workload and sarcomere activation. Although troponin levels increased slightly in a subset of GALACTIC-HF patients, this was not linked to higher rates of adverse cardiovascular events [16, 28]. Clinicians must interpret any troponin elevation cautiously within the context of a heart failure population and consider interrupting dosing if significant elevations occur without another clear cause.

Platelet Count Reduction Intermittent, mild, and non-progressive drops in platelet count have been reported with OM, which reversed upon withdrawal of therapy. While the mechanism is unclear, OM’s hematologic safety profile is considered superior to milrinone, which is known to cause thrombocytopenia with long-term use [29].

Diastolic function considerations

Although clinical trials have not identified a significant signal for worsening diastolic function at therapeutic OM concentrations (200–1000 ng/mL), it is important to note that diastolic parameters were not primary or secondary endpoints in COSMIC-HF or GALACTIC-HF. Dedicated echocardiographic substudies assessing tissue Doppler indices (E/e’) or left atrial volume are pending. Patients with significant baseline diastolic dysfunction were not specifically excluded, but subgroup analyses based on diastolic function have not been published. Therefore, while OM appears safe with respect to diastole at approved doses, this remains an area requiring further investigation [30].

Narrow therapeutic window and patient selection

OM is characterized by a narrow therapeutic index. Suboptimal plasma concentrations yield minimal therapeutic effect, while supra-therapeutic levels increase the risk of ischemic complications and toxicity. COSMIC-HF established that optimal therapeutic efficacy is achieved within a plasma concentration range of approximately 200–1000 ng/mL (derived from the oral dosing regimen), with concentrations exceeding 1200 ng/mL associated with increased ischemic adverse effects [8]. This contrasts with the animal dosing ranges (e.g., 600–1200 µg/kg in dogs) that informed early clinical development. Given that OM is metabolized by CYP3A4 and CYP2D6 enzymes, drug–drug interactions can alter exposure, necessitating close dose titration and potentially therapeutic drug monitoring to balance efficacy and safety [26].

Myocardial oxygen consumption (MVO2)

Preclinical studies demonstrate that OM increases MVO2 in a dose-dependent manner through increased resting myosin ATPase activity and prolonged systolic ejection time (Bakkehaug et al., 2015). At therapeutic plasma concentrations (200–1000 ng/mL), the increase in MVO2 is proportional to the gain in contractility, preserving cardiac efficiency. However, at supra-therapeutic levels (> 1200 ng/mL), disproportionate increases in MVO2 occur, correlating with ischemic events and troponin elevations observed in COSMIC-HF. Notably, OM does not increase heart rate, avoiding the chronotropic-mediated MVO2 increases characteristic of β-agonists. Nonetheless, caution is warranted in patients with fixed coronary stenoses or during periods of increased metabolic demand, where supply-demand mismatch could be exacerbated [27].

Tolerability also depends on careful patient selection. OM is best suited for patients with chronic, stable HFrEF who are already optimized on GDMT [16]. Conversely, certain high-risk populations should be excluded:

• Acute decompensated heart failure (ADHF): OM did not show significant benefit and was associated with more adverse events in severely congested patients in the ATOMIC-AHF trial [24, 16].

• Acute coronary syndromes (ACS): OM is avoided in ACS, as increased myocardial work can exacerbate ischemia [16].

• Severe hypertension: Increased afterload in these patients raises systolic stress, increasing the risk of ischemia [16].

• Severe obstructive coronary artery disease: Patients with ischemic cardiomyopathy and significant, untreated coronary stenoses are more prone to oxygen supply-demand imbalance, unlike those with stable, revascularized disease [16].

Hypotension

In GALACTIC-HF, symptomatic hypotension occurred more frequently with OM than placebo (8.2% vs. 6.7%, P = 0.01). This finding is counterintuitive for an inotrope but is explained by baroreceptor-mediated reflex vasodilation in response to improved stroke volume, reduction in neurohormonal vasoconstrictor tone (decreased norepinephrine and NT-proBNP), and additive effects with background GDMT (ACEi/ARNi, beta-blockers, MRAs). The hypotension was generally mild, did not require dose discontinuation in most patients (protocol permitted continued dosing with SBP ≥ 85 mmHg), and was not associated with increased renal dysfunction or syncope [17, 28].

Comparison with other inotropes

Compared to conventional inotropes, OM offers a superior safety profile regarding arrhythmogenesis. The pro-arrhythmic and long-term mortality risks associated with beta-adrenergic agonists (e.g., dobutamine) and phosphodiesterase inhibitors (e.g., milrinone) are linked to their calcium- or cAMP-mediated mechanisms. While levosimendan, a calcium sensitizer, enhances contractility and causes vasodilation, its efficacy is limited by dose-dependent hypotension and reflex tachycardia. OM’s mechanism augmenting actin–myosin cross-bridge cycling time without raising intracellular calcium explains the lower incidence of arrhythmia and the absence of pro-apoptotic calcium overload observed in trials. However, it is important to note that while clinical trials showed no significant signal for diastolic impairment, preclinical data suggest potential diastolic effects at higher exposures [20]. The potential for ischemic events and troponin elevation remains a unique safety concern for OM, warranting continued surveillance.

It is important to recognize that the failing myocardium already exhibits significant derangements in Ca2 + handling, including SR Ca2 + leak and diastolic Ca2 + overload, which contribute to arrhythmogenesis. While OM does not correct these underlying abnormalities, its Ca2 + -independent mechanism ensures that it does not exacerbate them a key distinction from calcitropes, which can further destabilize Ca2 + homeostasis [21] Fig. 3.

Fig. 3.

Adverse Event Profile

Place in therapy and guidelines

Omecamtiv mecarbil (OM) is a novel cardiac myotrope that enhances contractility by prolonging systolic ejection time without increasing intracellular calcium or oxygen demand, positioning it uniquely within the heart failure therapeutic landscape [30].

Current Guideline Recommendations.

The clinical role of OM is still evolving, and current international guidelines reflect a cautious approach. The 2022 ACC/AHA/HFSA guideline assigns OM a Class IIb, Level of Evidence B-R recommendation [31]. This classification indicates that OM may be considered for use in specific patients with symptomatic HFrEF. Its benefit is most pronounced in those with severely reduced LVEF (≤ 28%) who remain symptomatic despite optimization on guideline-directed medical therapy (GDMT) [31]. Importantly, guidelines emphasize that OM is not a replacement for standard heart failure therapy but should be considered an adjunct in carefully selected cases [31].

• Regulatory status and dosing

As of late 2024, Omecamtiv Mecarbil has not yet received regulatory approval from the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). The dosing regimen used in the pivotal GALACTIC-HF trial was 25 mg, 37.5 mg, or 50 mg twice daily, titrated based on tolerability and systolic blood pressure (maintaining SBP ≥ 85 mmHg) [16]. If approved, therapeutic drug monitoring to maintain plasma concentrations between 200 and 1000 ng/mL may be recommended to optimize the risk-benefit ratio.

• GALACTIC-HF trial insights

The GALACTIC-HF trial provided the foundational evidence for OM’s clinical utility. The trial, which included 8,256 patients with LVEF ≤ 35% on GDMT, demonstrated an 8% relative risk reduction in the primary composite endpoint (first heart failure event or cardiovascular death) for the OM group compared to placebo. This benefit was primarily driven by a reduction in heart failure hospitalizations and urgent visits, with no significant difference in CV or all-cause mortality [16].

Subgroup analyses from GALACTIC-HF are crucial for defining OM’s place in therapy:

• LVEF: The greatest benefit was observed in patients with severely reduced systolic function (LVEF ≤ 28%), where the hazard ratio was approximately 0.84 [16].

• Biomarkers: Patients with higher baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels indicators of high ventricular wall stress derived a stronger therapeutic effect [32].

• Heart Rhythm: Individuals in sinus rhythm experienced more consistent improvement, whereas the presence of atrial fibrillation or flutter (AF/AFL) appeared to attenuate the treatment effect [32].

• Safety: OM was well tolerated, with no significant increase in ischemic events, arrhythmias, hypotension, renal dysfunction, or hyperkalemia compared with placebo [16].

Integration into GDMT algorithms

OM is a cardiac myotrope, enhancing systolic performance by improving myosin–actin cross-bridge formation, a mechanism distinct from the neurohormonal modulation of the established four pillars of GDMT (beta-blockers, ACEi/ARNI, MRAs, and SGLT2 inhibitors) [33]. Therefore, OM is considered a complementary rather than a substitutive agent.

Within current therapeutic frameworks, OM is viewed as a potential adjunctive or “fifth” agent reserved for a narrowly selected group of patients who remain symptomatic despite optimized GDMT. Expert consensus suggests its potential consideration in advanced or refractory HFrEF (Stage D), or in patients who are unresponsive to other novel options such as vericiguat or ivabradine [33]. Optimization of both pharmacologic and device-based therapies should precede OM initiation.

Ideal patient selection criteria

The most suitable candidates for OM align closely with the characteristics that showed the greatest benefit in GALACTIC-HF:

• Chronic Symptomatic HFrEF: NYHA class II–IV with markedly depressed LVEF (≤ 35%), with the strongest response at LVEF ≤ 28% [16].

• High Cardiac Stress: Evidence of persistent congestion or high ventricular wall stress, reflected by elevated NT-proBNP levels [32].

• Sinus Rhythm: More consistent improvement is seen in patients in sinus rhythm compared to those with AF/AFL [32].

• Hemodynamic Stability: Eligible patients must maintain a systolic blood pressure (SBP) of at least 85 mmHg and an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m² for safety and tolerability [16].

The principal selection parameters are summarized in Table 3.

Table 3.

Ideal Patient Selection Criteria for Omecamtiv Mecarbil

Parameter	Preferred Characteristics	Rationale / Comment
Heart Failure Type	Chronic symptomatic HFrEF (NYHA II–IV)	Reflects the studied population in GALACTIC-HF.
Left Ventricular Ejection Fraction (LVEF)	≤ 35% (greatest benefit at ≤ 28%)	Greater systolic dysfunction correlated with stronger drug effect.
Clinical Status	Persistent symptoms despite optimized GDMT	Indicates refractory heart failure needing adjunct therapy.
Hemodynamic Stability	SBP ≥ 85 mmHg	Ensures safety and tolerability; prevents excessive afterload.
Renal Function	eGFR ≥ 20 mL/min/1.73 m²	Prevents drug accumulation and ensures safe metabolism.
Biomarkers	Elevated NT-proBNP or other indicators of high wall stress	Higher NT-proBNP associated with better outcomes.
Heart Rhythm	Sinus rhythm preferred over atrial fibrillation/flutter	AF/AFL attenuates the treatment benefit.
Clinical Setting	Often post-hospitalization or recent HF event	Reflects real-world applicability from GALACTIC-HF data.
Exclusion Considerations	EF > 35%, acute HF, ACS, severe obstructive CAD, uncontrolled HTN	Limited benefit or increased risk of adverse events.

Cost, access, and real-world considerations

The potential place of OM in therapy will be influenced by factors beyond efficacy, including cost, payer access restrictions, and the need for monitoring. If approved, its cost-effectiveness relative to its modest reduction in HF hospitalizations will be a key determinant of uptake. The potential need for therapeutic drug monitoring could pose a logistical and economic barrier in some healthcare systems. Real-world evidence from registries and post-marketing studies will be crucial to confirm its effectiveness and safety outside the controlled trial environment and to refine patient selection criteria Fig. 4.

Fig. 4.

Integration of Omecamtiv Mecarbil into GDMT for HFrEF

Future directions and novel agents

The success of Omecamtiv Mecarbil (OM) has validated the therapeutic potential of directly targeting the cardiac sarcomere, opening new avenues for drug development in heart failure.

• Next-generation myotropes

Ongoing research is focused on developing next-generation cardiac myosin activators with improved pharmacokinetic profiles and wider therapeutic windows. Danicamtiv (formerly MYK-491) is a novel small molecule that selectively enhances cardiac actomyosin activity, similar to OM, by prolonging contraction while preserving actin–myosin detachment and relaxation, and without impacting Ca²⁺ homeostasis [34]. Evidence suggests danicamtiv engages a myosin site distinct from OM, offering greater selectivity for cardiac over skeletal or smooth muscle myosin [34, 35]. While danicamtiv also accelerates the ATPase turnover rate and increases systolic ejection time (SET) and LVEF, it has shown a broader therapeutic window and a stronger potential to enhance contractility with a lower penalty on lusitropy (relaxation) in engineered human heart tissues compared to OM [35]. However, preclinical and early clinical data on danicamtiv, particularly concerning its diastolic effects, remain limited [35].

• Combination therapies

A significant area for future exploration is the hypothetical synergistic potential of combining cardiac myotropes with other novel HF agents. Diabetes mellitus (DM) and HF are highly coexistent, with DM increasing the risk for HF and influencing outcomes. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, originally approved for type 2 DM, have demonstrated profound cardiovascular benefits in HF that extend beyond their glucose-lowering effects. The combination of a cardiac myosin activator, which improves contractility, and an SGLT-2 inhibitor, which enhances metabolic efficiency and reduces cardiovascular risk factors, presents a potent but as-yet untested area for future clinical investigation [36].

Role in patients with mechanical circulatory support (MCS)

An unexplored area for future investigation is the potential role of OM as adjunctive therapy in patients receiving MCS, including left ventricular assist devices (LVADs) and extracorporeal membrane oxygenation (ECMO). Theoretically, enhancing native ventricular contractility could facilitate weaning from temporary support or improve native ventricular contribution in LVAD patients. However, concerns include potential drug-device interactions, altered pharmacokinetics in critically ill patients, and the risk of supply-demand mismatch in the setting of fixed coronary disease. No clinical trials have addressed this population, representing a significant knowledge gap [34].

• Role in HF with preserved ejection fraction (HFpEF)

OM is not indicated for, nor has it been studied in, patients with heart failure with preserved ejection fraction (HFpEF). The drug’s mechanism enhancing contractility by increasing myosin-actin interaction during systole explains its unsuitability for HFpEF. HFpEF is characterized by preserved systolic function (LVEF ≥ 50%), impaired diastolic function, ventricular stiffness, and filling abnormalities. Since HFpEF patients often have adequate or hypercontractile systolic function, further enhancing contractility with OM would not improve outcomes and could potentially be detrimental [37].

In fact, future research in HFpEF is exploring the opposite pharmacological approach: the use of myosin inhibitors rather than activators. These agents, such as CK-586 (in Phase 2 for HFpEF), aficamptin (preclinical), and mavacamten (approved for obstructive hypertrophic cardiomyopathy and being investigated for HFpEF), aim to reduce hypercontractility and improve diastolic function, highlighting a bifurcated therapeutic strategy based on the underlying HF phenotype [20, 38, 39] Fig. 5.

Fig. 5.

Pipeline of Cardiac Myotropes

Conclusion

Heart failure with reduced ejection fraction (HFrEF) remains a major global health burden, with persistently high rates of mortality and hospitalization despite the widespread use of guideline-directed medical therapy (GDMT). While classical therapies focus on neurohormonal modulation, the introduction of Omecamtiv Mecarbil (OM) marks a significant mechanistic advance by offering a direct approach to increasing cardiomyocyte contractility. OM, a first-in-class selective cardiac myosin activator, achieves this by stabilizing the pre-power stroke state of myosin, thereby augmenting the duration of systole without interfering with intracellular calcium cycling. This unique profile provides a crucial safety advantage over traditional inotropes, which are associated with increased arrhythmogenesis and elevated myocardial oxygen demand.

The Phase III GALACTIC-HF trial demonstrated that OM leads to a modest but statistically significant reduction in the composite endpoint of heart failure events and cardiovascular death, driven predominantly by fewer heart failure hospitalizations. The most pronounced benefit is observed in a high-risk subset of patients with more severe systolic dysfunction (LVEF ≤ 28%), recent hospitalization, or persistently elevated natriuretic peptide levels. Importantly, OM achieved these effects with an adequate electrophysiologic safety profile, comparable to placebo, offering a distinct advantage over conventional inotropes.

However, the clinical application of OM requires careful consideration due to its narrow therapeutic range. The risk of ischemia or systolic pressure overload increases with supra-therapeutic plasma levels, necessitating cautious dosing and blood pressure monitoring. Troponin increases are often dose-related and do not always indicate a myocardial infarction; however, they warrant clinical vigilance. Consequently, patient selection is paramount, and OM should generally be avoided in patients with acute coronary syndromes, severe obstructive coronary disease, or uncontrolled hypertension.

OM is currently positioned as a specialized, adjunctive treatment, holding a Class IIb recommendation in ACC/AHA/HFSA guidelines for selected patients with severe HFrEF who remain symptomatic despite optimized GDMT. Clinical implementation should be guided by specialists, supported by algorithms for efficacy and safety monitoring. Looking forward, the field is rapidly advancing with the development of next-generation myosin activators, such as Danicamtiv, which aim for wider therapeutic windows. Furthermore, the exploration of combination therapies, particularly with SGLT2 inhibitors, offers a promising, though speculative, strategy to address both the mechanical and metabolic deficits in HFrEF.

Abbreviations

ACC

American College of Cardiology

HFrEF

Heart Failure with Reduced Ejection Fraction

ACEi

Angiotensin-Converting Enzyme inhibitors

HFSA

Heart Failure Society of America

ACS

Acute Coronary Syndromes

HR

Hazard Ratio

ADP

Adenosine Diphosphate

HTN

Hypertension

ADHF

Acute Decompensated Heart Failure

IV

Intravenous

AF/AFL

Atrial Fibrillation/Atrial Flutter

K_ATP

ATP-sensitive Potassium channels

AHA

American Heart Association

LV

Left Ventricular/Left Ventricle

AR

Aortic Regurgitation

LVEF

Left Ventricular Ejection Fraction

ARNi

Angiotensin Receptor-Neprilysin Inhibitors

METEORIC-HF

Multicenter Exercise Tolerance Evaluation of Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Heart Failure

ATOM IC-HF

Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Heart Failure

mg

Milligrams

ATP

Adenosine Triphosphate

mL

Milliliters

BID

Bis In Die (Twice Daily)

MRA

Mineralocorticoid Receptor Antagonist

BPM

Beats Per Minute

MyHC-7

Myosin Heavy Chain-7

Ca²⁺

Calcium ion

ng/mL

Nanograms per Milliliter

CAD

Coronary Artery Disease

NT-proBNP

N-Terminal pro-B-type Natriuretic Peptide

cAMP

Cyclic Adenosine Monophosphate

NYHA

New York Heart Association

CI

Confidence Interval

OM

Omecamtiv Mecarbil

COSM IC-HF

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure

PDE

Phosphodiesterase

CV

Cardiovascular

Pi

Inorganic Phosphate

CYP

Cytochrome P450

PK-PD

Pharmacokinetic-Pharmacodynamic

DM

Diabetes Mellitus

PKA

Protein Kinase A

dP/dt

Rate of Pressure Change Over Time

PPS

Pre-Power Stroke

ECG

Electrocardiogram

REVIVE

Randomized Evaluation of Intravenous Levosimendan Efficacy

EF

Ejection Fraction

SBP

Systolic Blood Pressure

eGFR

Estimated Glomerular Filtration Rate

SET

Systolic Ejection Time

EMA

European Medicines Agency

SGLT2

Sodium-Glucose Cotransporter-2

FDA

Food and Drug Administration (U.S.)

SURVIVE

Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support

GALACTIC-HF

Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure

VO₂

Volume of Oxygen (oxygen consumption)

GDMT

Guideline-Directed Medical Therapy

HCM

Hypertrophic Cardiomyopathy

HF

Heart Failure

HFpEF

Heart Failure with Preserved Ejection Fraction

Author contributions

Eslam Abady served as the first author and contributed to conceptualization, methodology, data collection, writing of the original draft, project administration, and coordination among co-authors. Mandy Elewa, Kevin Thomas Mathew, Mahmoud Bedair, Suleiman N. Almashaqbeh, Asmaa G. Alwarraqi, Hazem AbuEl-Enien, and Yahya Samadi contributed to data curation, investigation, interpretation, drafting, and revising sections of the manuscript. Khaled Abouelmagd conceived the research idea, supervised the project, contributed to writing and critical revision of the manuscript for important intellectual content, and served as the corresponding author. All authors read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have approved the manuscript and agree with its submission to the journal.

Competing interests

The authors declare no competing interests.