Hypertrophic cardiomyopathy, a genetic heart disease that can thicken the cardiac muscle and disrupt its ability to pump efficiently, may have a broader drug treatment than previously understood. In a study spanning genetically engineered mice and human engineered heart tissues, researchers report that mavacamten countered disease-related overactivity caused by two distinct classes of mutations in the MYBPC3 gene. The findings suggest that the drug may work across a wider range of inherited disease mechanisms than its molecular target alone would imply. Rather than treating only one specific genetic defect, mavacamten appeared to restore a more balanced state of the heart’s contractile machinery in models carrying either truncated or missense versions of MYBPC3. The work does not by itself establish how every patient will respond, but it offers a mechanistic explanation for why a drug designed to reduce excessive myosin activity could benefit genetically diverse forms of hypertrophic cardiomyopathy.
The disease arises when mutations alter proteins in the cardiac sarcomere, the microscopic apparatus responsible for contraction. Each heartbeat depends on the coordinated interaction of thick and thin protein filaments, especially myosin and actin. Myosin acts as a molecular motor: powered by ATP, it attaches to actin and generates the force that shortens the sarcomere. Cardiac myosin-binding protein C, or cMyBP-C, helps regulate this process. The protein is encoded by MYBPC3 and binds to myosin within the thick filament, influencing how readily the motor can engage in contraction. When sarcomere activity becomes excessive or poorly regulated, the heart may respond by enlarging its muscle cells and remodeling its structure. That thickening can impair relaxation, raise internal pressures and, in some cases, obstruct blood flow or promote dangerous rhythm disturbances. MYBPC3 is one of the most frequent genes associated with inherited hypertrophic cardiomyopathy, but its variants do not all disrupt the sarcomere in the same way.
Many disease-associated MYBPC3 variants are truncating mutations. These changes create an incomplete version of cMyBP-C or prevent the protein from being produced, leaving the heart with reduced amounts of the regulator. Previous experimental models have commonly focused on this deficiency. The new study instead developed knock-in mice carrying a missense mutation called cMyBP-C p.R502W, in which a single amino-acid substitution changes the protein’s structure without eliminating it. That distinction proved important. Unlike mice carrying cMyBP-C truncations, the R502W animals retained cMyBP-C at normal levels and in its usual location within the sarcomere. Nevertheless, the animals developed pathological myocardial remodeling, demonstrating that a structurally altered protein can cause disease even when the quantity of cMyBP-C appears preserved. The model allowed the researchers to examine a form of hypertrophic cardiomyopathy that more closely reflects the complexity of missense disease variants, rather than treating all MYBPC3 mutations as simple loss of protein.
The investigators found that the R502W substitution weakened the interaction between cMyBP-C and myosin. Under normal conditions, this interaction helps restrain the contractile system. With the mutation, the sarcomere became hypercontractile, meaning it generated excessive force or activated too readily. Two linked changes helped explain the behavior. First, the muscle became more sensitive to calcium ions. Calcium is the central chemical signal that initiates contraction in heart muscle: when calcium levels rise inside a cardiac cell, it enables the contractile proteins to interact; when calcium falls, the muscle should relax. Increased calcium sensitivity means that a given calcium concentration produces a stronger contractile response. Second, the mutant sarcomeres favored an “ON” structural state of myosin. In the ON state, more myosin heads are available to interact with actin. Myosin can also adopt an OFF, or super-relaxed, state in which its heads are folded toward the thick filament and are less available for force generation. The R502W mutation therefore appeared to push the molecular motor toward excessive readiness.
Mavacamten is designed to act directly on cardiac myosin and reduce excessive cross-bridge activity. Its therapeutic effect is associated with stabilizing myosin in a less active, OFF-favored configuration, thereby lowering the number of motors available to engage actin during contraction. In the new experiments, the drug blunted myocardial remodeling in both R502W mice and models lacking cMyBP-C. This result was notable because the underlying defects were not identical. In cMyBP-C-deficient hearts, disease is linked primarily to the loss of a regulatory protein. In R502W hearts, cMyBP-C remained present but interacted abnormally with myosin, while the sarcomere also displayed increased calcium sensitivity and a bias toward the ON state. Despite those differences, mavacamten reduced the pathological response in both settings. The experiments further linked the benefit in R502W hearts to the drug’s ability to restore a greater population of myosin to the OFF state, directly addressing the structural imbalance produced by the mutation.
The researchers also tested the treatment in human engineered heart tissues carrying the R502W variant. These laboratory-built tissues are designed to reproduce selected features of human cardiac muscle, allowing scientists to measure contraction in a controlled setting without studying an entire organ. In those tissues, mavacamten opposed the mutation-associated hypercontractility. The human model strengthened the connection between the mouse findings and human biology, although it remains a simplified system rather than a complete patient heart. Engineered tissues do not fully reproduce the electrical networks, blood supply, immune environment or long-term mechanical stresses present in a living person. Even so, observing the same broad functional effect in human-derived cardiac tissue and in mice is important because it suggests that the mechanism is not limited to one experimental species. The result supports the idea that controlling myosin’s structural state may be useful even when the initiating mutation affects cMyBP-C through an abnormal interaction rather than through outright protein loss.
The study’s central message is that the genetic label alone may not predict the immediate molecular route to disease, but a shared downstream disturbance could still provide a treatment opportunity. Truncating and missense MYBPC3 variants can produce different primary defects: one may reduce the supply of cMyBP-C, while the other may leave the protein in place but impair its binding and regulation. Yet both can ultimately disturb the balance between active and inactive myosin and drive excessive sarcomere performance. Mavacamten appears to act at that convergent point. By reducing the availability of active myosin, it may dampen the mechanical stress that prompts cardiac hypertrophy and remodeling. This is an example of pathway-based treatment: instead of correcting the original DNA sequence, the drug modifies a downstream process that multiple mutations have in common. Such an approach could be especially valuable in inherited diseases where hundreds of distinct variants converge on a smaller number of cellular abnormalities.
The findings also help clarify why a preserved amount of a sarcomeric protein does not necessarily mean preserved function. The R502W mice had normal cMyBP-C levels and localization, but the altered protein no longer regulated myosin correctly. In molecular terms, the mutation changed protein quality rather than protein quantity. This distinction is relevant to genetic diagnosis and disease modeling, because two variants in the same gene may require different experimental systems and could produce different patterns of calcium handling, force generation and structural remodeling. The study’s knock-in design placed the missense change in its normal genomic context, allowing the investigators to observe its effects in a heart that produces the altered protein as part of its native sarcomere. The resulting model therefore provides a platform for testing how specific MYBPC3 variants alter contractile regulation and for examining whether treatments can correct the resulting functional state rather than merely compensate for missing protein.
Mavacamten’s apparent activity across these models does not mean that every person with MYBPC3-related hypertrophic cardiomyopathy will experience the same response, nor does it eliminate the need for clinical assessment and monitoring. Drug effects observed in mice and engineered tissues must be evaluated in patients, whose disease is shaped by age, genetic background, cardiac structure, rhythm, loading conditions and other biological factors. The amount of myosin inhibition must also remain within a therapeutic range: too much reduction in contractility could impair the heart’s ability to pump. The significance of the new work is therefore not a promise of a universal cure, but a clearer mechanistic basis for broader application of a targeted therapy. By showing that mavacamten can oppose hypercontractility generated through distinct MYBPC3-related pathways, the researchers provide evidence that treatment may be guided by convergent sarcomere behavior as well as by the exact mutation.
Published in Nature Cardiovascular Research, the study turns a complicated genetic question into a potentially actionable physiological one: whether the heart’s myosin motors are being driven into an excessively active state. The answer appeared to be yes in both cMyBP-C-deficient and R502W models, even though the molecular routes leading there differed. Mavacamten then acted as a brake, shifting myosin toward its OFF configuration and reducing the remodeling associated with chronic hypercontractility. The work highlights the value of combining genetically precise animal models with human engineered tissues, particularly for disorders in which a single gene can be disrupted in several fundamentally different ways. If future clinical research confirms the relevance of these mechanisms in patients, the findings could broaden the rationale for using myosin-directed therapy in MYBPC3-related hypertrophic cardiomyopathy and help move treatment decisions beyond a simple distinction between “truncating” and “missense” mutations.
Subject of Research: Mavacamten treatment mechanisms in MYBPC3-related hypertrophic cardiomyopathy
Article Title: Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy
Article References: Sen-Martín, L., Fernández-Trasancos, Á., López-Unzu, M.Á. et al. Mavacamten shows broad benefit in human and mouse models of MYBPC3-related hypertrophic cardiomyopathy. Nature Cardiovascular Research 5, 638–657 (2026). https://doi.org/10.1038/s44161-026-00833-3
Image Credits: AI Generated
DOI: 10.1038/s44161-026-00833-3
Keywords: hypertrophic cardiomyopathy, mavacamten, MYBPC3, cardiac myosin, cMyBP-C, sarcomere hypercontractility, missense mutations, truncating mutations, engineered heart tissue
Tags: contractile machinery restorationdrug response in genetic heart conditionsengineered mouse models for cardiomyopathygenetic heart disease treatmenthuman engineered heart tissueshypertrophic cardiomyopathyhypertrophic cardiomyopathy molecular pathwaysinherited cardiomyopathy mechanismsmavacamten therapeutic effectsMYBPC3 gene mutationsmyosin activity regulationsarcomere protein mutations
