Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiovascular disease, affecting approximately 1 in 200–500 individuals worldwide and representing a leading cause of heart failure, arrhythmias, and sudden cardiac death in the young [1, 2]. Despite significant advances in genetic mechanisms leading to HCM, treatment strategies have for decades remained confined to symptom control using $\beta$-blockers, non-dihydropyridine calcium channel blockers, and disopyramide, or invasive septal reduction therapy in refractory cases [3, 4]. These approaches, while effective in reducing symptoms and outflow gradients, fail to address the fundamental molecular mechanism of HCM: sarcomeric hypercontractility, increased binding probability of actin-myosin and inefficient energetics.

The identification of pathogenic variants in sarcomere genes, particularly myosin heavy chain 7 (MYH7) and myosin-binding protein C (MYBPC3), established HCM as a primary disease of the contractile apparatus [5]. This recognition shifted therapeutic aspirations from symptomatic palliation toward disease-specific intervention. Over the past decade, insights into cross-bridge kinetics and actin–myosin interaction have culminated in the development of selective cardiac myosin inhibitors (CMIs). By directly modulating myosin ATPase activity, these agents reduce excessive cross-bridge formation, increase myosin in super-relaxed state (SRX) thereby normalize contractility, and mitigate left ventricular outflow tract (LVOT) obstruction [6]. Mavacamten, the first-in-class myosin inhibitor, provided proof-of-concept that targeted sarcomere modulation could alter the natural history of HCM. Parallel development of aficamten, a next-generation myosin inhibitor with different pharmacokinetics, has reinforced the therapeutic potential of sarcomere modulation [7]. Together, these advances mark a paradigm shift in the management of HCM. For the first time, a pharmacological therapy targets the underlying molecular pathophysiology rather than its downstream consequences. Myosin inhibition has thus emerged as a revolutionary game changer, bridging the gap between genetic discovery and clinical translation (Fig. 1). This review summarizes the historical evolution of myosin inhibitors, synthesizes evidence from pivotal trials, and highlights future directions including use in non-obstructive HCM, pediatric populations, and novel sarcomere-targeting agents.

Fig. 1.

Timeline of milestones in hypertrophic cardiomyopathy (HCM). Key advances are shown from the first clinical description (1869) and early surgical/interventional therapies (myectomy, 1964; alcohol septal ablation, 1994) to the modern era of cardiac myosin inhibitors, with landmark trials illustrating the paradigm shift from invasive to disease-specific pharmacological therapy. Created in Illustrae (https://illustrae.co/)

The defining hallmark of HCM is sarcomeric hypercontractility, a direct consequence of pathogenic variants in genes encoding thick and thin filament proteins, most notably MYH7 and MYBPC3 [8]. At the cellular level, these variants increase the proportion of myosin heads available for actin interaction, thereby augmenting force generation but impairing diastolic relaxation and myocardial energetics [6, 9]. For mutation elusive obstructive HCM, the mechanism is not as well understood, but response to myosin inhibition seems comparable as shown in recent clinical trials. The resulting hyperdynamic contractile state promotes left ventricular hypertrophy, microvascular ischemia, fibrosis, and ultimately heart failure [10, 11, 12].

Cardiac myosin exists in a continuum of conformational states. In the SRX, myosin heads are sequestered along the thick filament backbone, minimizing adenosine triphosphate (ATP) turnover and conserving energy. In contrast, the disordered relaxed state (DRX) exposes myosin heads, increasing their probability of actin engagement and cross-bridge formation [13, 14]. Genetic variants destabilize the SRX conformation, shifting the balance toward DRX, thereby driving hypercontractility and energetic inefficiency [14, 15].

Selective CMIs, including mavacamten and aficamten, act by stabilizing the SRX state and reducing the number of myosin heads available for cross-bridge cycling (Fig. 2). This allosteric modulation of myosin ATPase activity normalizes contractility, improves diastolic filling, and reduces LVOT gradients [6]. Unlike traditional negative inotropes, which blunt adrenergic signaling ($\beta$-blockers), calcium entry (verapamil), or sodium conductance (disopyramide), CMIs directly target the sarcomere, providing the first disease-specific pharmacological therapy for HCM. Disease-modifying preclinical studies demonstrated that chronic myosin inhibition not only corrects hypercontractility but also attenuates pathological hypertrophy and fibrosis, restoring myocardial energetics and efficiency [16]. Importantly, early human data from cardiac magnetic resonance imaging (MRI) substudies suggest reductions in left ventricular mass and improvements in filling dynamics during long-term therapy [17]. These findings raise the possibility that CMIs may act not only as symptom-modifying but also as disease-modifying therapies, capable of altering the natural trajectory of HCM.

Fig. 2.

Mechanism of action of cardiac myosin inhibitors (CMIs). Balanced distribution of myosin heads between the super-relaxed (SRX) and disordered relaxed (DRX) states, permitting normal contractility and efficient relaxation (A). In hypertrophic cardiomyopathy (HCM), destabilization of the SRX state increases myosin head availability for cross-bridge formation, resulting in hypercontractility, diastolic dysfunction, and impaired energetics (B). CMIs such as mavacamten and aficamten stabilize the SRX state, reduce excessive cross-bridge cycling, and restore energetic efficiency (C). Schematic chemical structures of mavacamten and aficamten are shown (D). Created in Illustrae (https://illustrae.co/)

The translation of myosin inhibition from mechanistic insight to clinical application has been remarkable. Within little more than a decade, selective CMIs have advanced from preclinical proof-of-concept to phase 3 trials demonstrating meaningful clinical benefit in obstructive HCM.

The introduction of CMIs into clinical practice has been accompanied by close attention to safety, tolerability, and monitoring requirements. While both mavacamten and aficamten demonstrate consistent efficacy across pivotal trials, their pharmacokinetic properties, potential for left ventricle (LV) systolic dysfunction, and regulatory frameworks necessitate careful implementation. A key safety consideration is the potential for transient reductions in LVEF, reflecting the intended negative inotropic mechanism. In EXPLORER-HCM, VALOR-HCM, and MAVA-LTE, between 5% and 14% of mavacamten-treated patients experienced a reduction in LVEF 50% [20, 22, 31]. In all cases managed per protocol with drug interruption or dose adjustment, systolic function recovered, underscoring the reversibility of this effect. Importantly, all cases managed per protocol with temporary drug interruption or dose adjustment recovered, underscoring the predictable and reversible nature of this effect. By contrast, aficamten’s shorter terminal half-life (about 3.5 days) facilitates more rapid pharmacodynamic reversibility. In REDWOOD-HCM, SEQUOIA-HCM, and FOREST-HCM, transient reductions in LVEF 50% occurred in approximately 3–7% of patients, were consistently reversible with dose adjustment or interruption, and were not associated with clinical heart failure [24, 25, 32]. Notably, in the non-obstructive HCM population enrolled in ODYSSEY-HCM, LVEF 50% occurred more frequently with mavacamten than with placebo (22% vs 2%), highlighting phenotype-specific safety considerations in non-obstructive disease [30]. These findings support the need for structured echocardiographic monitoring during dose titration for both mavacamten and aficamten, as patients receiving either agent remain at risk for transient reductions in LVEF. Although aficamten’s shorter half-life may allow faster pharmacodynamic reversibility, this does not eliminate the need for regular monitoring. However, modest reductions in LVEF observed with both mavacamten and aficamten are an expected pharmacodynamic effect of myosin inhibition and reflect target engagement rather than myocardial injury. These decreases are typically mild, reversible with dose adjustment or brief interruption, and rarely associated with symptoms. A lower incidence of LVEF reduction should not be interpreted as evidence of greater long-term disease-modifying potency. Furthermore, disease stage may influence susceptibility to systolic dysfunction during CMI therapy. Patients with advanced HCM phenotypes, such as those with extensive myocardial fibrosis or borderline systolic function, may theoretically be more vulnerable to LVEF reduction. Further subgroup analyses and dedicated prospective studies are needed to determine whether these factors modify the susceptibility to LVEF reduction during CMI therapy.

Mavacamten is metabolized primarily via Cytochrome P450 2C19 (CYP2C19) and CYP3A4, creating potential for drug-drug interactions with agents such as antiarrhythmics, antifungals, and proton-pump inhibitors [33]. Accordingly, comprehensive medication reconciliation is essential prior to and during therapy. In a recent analysis of real-world data of a post-market approval registry in the US, 99% of patients did not show any clinically relevant interacting medication before initiation of mavacamten. Aficamten, while not yet approved, undergoes minimal CYP-mediated metabolism, which may improve safety in elderly patients and those with polypharmacy [33].

Overall, CMIs have shown a favorable tolerability profile. The most frequently reported adverse events include dizziness, fatigue, and transient reductions in ejection fraction, with no evidence of excess arrhythmias or proarrhythmic risk compared with placebo. Importantly, treatment discontinuation due to adverse events remains low (5%) [31, 32, 34]. Pregnancy and breastfeeding remain areas of caution, as safety data are insufficient; current recommendations advise avoiding CMIs in women of childbearing potential unless effective contraception is ensured [35].

Despite their promise, several important uncertainties and challenges remain in the clinical implementation of CMIs. While MAVA-LTE and FOREST-HCM provide reassuring data over 2–3 years, the long-term consequences of chronic sarcomere inhibition are unknown. Whether lifelong therapy in young patients alters survival, sudden cardiac death risk, or progression to end-stage heart failure remains unanswered. In patients otherwise eligible for SRT, whether CMIs should be offered as first-line alternatives or as a bridge remains debated. VALOR-HCM demonstrated a striking reduction in SRT eligibility, but head-to-head comparisons with surgical myectomy or alcohol septal ablation are lacking [22]. CMI use after acute myocardial infarction raises concern: transient negative inotropy in a myocardium already compromised by ischemic injury could exacerbate pump failure. No study has systematically evaluated post-myocardial infarction (MI) use, and this remains a relative contraindication until further evidence emerges. Similarly, in overdose scenarios, the predictable risk is profound systolic dysfunction; while reversible, optimal management strategies (temporary mechanical support, pharmacological reversal) remain theoretical and require guideline development. Not all HCM patients harbor sarcomere mutations, and treatment response may differ by genotype. Preliminary analyses suggest that sarcomere-positive patients may derive greater structural reverse remodeling, but robust genotype–phenotype–treatment interaction data are limited. Precision cardiology approaches incorporating genetics, imaging, and biomarkers will be essential to refine patient selection. CMIs can be used safely in patients with mild-to-moderate renal impairment (estimated Glomerular Filtration Rate, eGFR $\ge$30), but their safety and efficacy in dialysis-dependent end-stage kidney disease are unstudied and application cannot currently be recommended in dialysis-dependent patients [33]. Dedicated pharmacokinetic and clinical outcome trials are urgently needed to inform dosing, safety, and monitoring strategies in this vulnerable population. High drug costs represent another barrier, particularly in healthcare systems where invasive septal reduction is available and reimbursed. Economic analyses are needed to ensure sustainable, equitable global access. While both mavacamten and aficamten have shown robust efficacy and favorable safety profiles, definitive conclusions about comparative clinical advantages cannot be drawn without a dedicated head-to-head randomized trial. A study designed with safety as the primary endpoint, now that efficacy has been established, would be valuable to determine whether pharmacokinetic differences, such as the shorter half-life of aficamten, translate into meaningful advantages in real-world patient management.

The therapeutic horizon for cardiac myosin inhibition is rapidly expanding. Ongoing studies will determine whether the symptomatic and biomarker improvements observed in early-phase studies translate into robust functional and quality-of-life benefits in non-obstructive HCM. Parallel pediatric and adolescent studies (e.g., CEDAR, SCOUT) are evaluating safety and efficacy in younger patients, where early intervention may prevent maladaptive remodeling and alter lifetime disease trajectory. Beyond classical HCM, CMIs may also have a role in other conditions of hypercontractility. Early exploratory work suggests potential application in heart failure with preserved ejection fraction (HFpEF), where sarcomeric hypercontractility and diastolic dysfunction contribute to pathophysiology [36]. Further investigation will determine whether CMIs can extend benefit into this broader heart failure population.

Integration of CMIs with genetic testing and precision cardiology frameworks could ultimately enable targeted therapy for at-risk mutation carriers before overt disease manifests, opening the door to disease prevention. In parallel, real-world registries and long-term extension studies will be essential to address questions of durability, late safety signals, and cost-effectiveness, and to define their impact on hard outcomes such as progression to heart failure, arrhythmia burden, and mortality.

The positioning of CMIs within current treatment algorithms is becoming increasingly relevant. $\beta$-blockers and non-dihydropyridine calcium channel blockers remain the recommended first-line therapy for symptomatic obstructive HCM, with CMIs and, if symptoms persist, disopyramide or SRT considered as subsequent treatment options. As evidence continues to mature, CMIs may increasingly be used as an early-line option in obstructive HCM. In non-obstructive HCM, their role remains investigational, and careful phenotype-specific patient selection is essential. Integration of CMIs into clinical practice should rely on shared decision-making, taking into account patient goals, comorbidities, and treatment availability.

In conclusion, cardiac myosin inhibitors represent the first truly disease-specific pharmacological therapy for hypertrophic cardiomyopathy. By directly modulating sarcomeric hypercontractility, CMIs achieve outcomes previously attainable only through invasive septal reduction procedures: relief of obstruction, symptomatic improvement, and evidence of structural reverse remodeling. As development extends to non-obstructive disease, pediatric populations, and next-generation molecules, CMIs are poised to fundamentally redefine the standard of care in HCM. While challenges remain—including uncertainties about long-term outcomes, equitable access, and patient selection—myosin inhibition stands as a revolutionary game changer, bridging decades of genetic discovery with tangible clinical translation.

FSH conceived the review, performed the literature search, interpreted the data, drafted the manuscript, and critically revised the final version. EK supported data acquisition and contributed to the critical revision of the manuscript. BM substantial contributions to the conception of the work and critically reviewed the manuscript for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

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This research received no external funding.

FBS has received advisory honoraria as well as speaker and travel honoraria from Bristol Myers Squibb. EK has received speaker honoraria from Bristol Myers. BM reports honoraria for scientific advisory activities, speaking engagements, and travel support from Bristol Myers Squibb and Cytokinetics. Farbod Sedaghat-Hamedani is serving as Guest Editor of this journal. Farbod Sedaghat-Hamedani had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Theodoros Karamitsos.