A drug for a genetic heart muscle disease may be effective for a broader range of patients than previously thought, after researchers uncovered a new molecular mechanism behind one of the most common forms of the disease.

Researchers said in a study published in the journal Nature Cardiovascular Research that the drug mavacamten, an inhibitor of cardiac myosin protein, was able in experimental models on mice and lab-grown human heart tissue to reduce pathological changes associated with hypertrophic cardiomyopathy (HCM), even when the genetic mechanism causing the disease was different from the mechanism the drug was originally developed to target.

Hypertrophic cardiomyopathy is a genetic disease that causes abnormal thickening of the heart muscle, and may make the heart contract with excessive force or have difficulty relaxing between beats.

In some cases, the disease can cause serious heart rhythm disturbances, heart failure, or sudden death, especially in young people and athletes.

Hypertrophic cardiomyopathy

Estimates suggest that hypertrophic cardiomyopathy affects approximately 1 in 200 to 500 people, and is often associated with mutations in genes that control proteins responsible for heart muscle contraction, particularly the MYH7 and MYBPC3 genes.

The new research focuses on the MYBPC3 gene, which produces a protein called cardiac myosin-binding protein C. This protein plays an important role in regulating the movement of myosin, the molecular motor that helps heart muscle cells contract.

It was previously known that some mutations in this gene reduce the amount of protein in the heart, disrupting the natural balance of myosin activity and making the heart muscle overly active. However, there was more uncertainty about another type of mutation that does not reduce protein levels but changes how it works.

To study this type, researchers developed a mouse model carrying a mutation called R502W, which is a common mutation associated with hypertrophic cardiomyopathy in humans. Mice carrying this mutation showed clear signs of disease, including cardiac hypertrophy, tissue fibrosis, impaired heart function, and increased contractile force.

The researchers said the surprise was that the protein amount and location within heart cells remained normal. This means the disease here did not arise from a protein deficiency, but from a more subtle defect: the mutation weakened the natural interaction between protein C and myosin, driving more myosin molecules into an active state capable of generating contraction.

According to the study, it seemed as if a fine brake within the heart muscle was no longer working efficiently. Instead of some contraction engines remaining in a resting state, more were ready to work, leading to excessive contraction and gradual stress on the heart muscle.

Factors Reducing Heart Efficiency

The researchers also found that the mutation increased the sensitivity of heart muscle to calcium, a key element in triggering contraction. With the weakened interaction between protein C and myosin and increased calcium sensitivity, contractile force increased pathologically.

The team tested the effect of mavacamten in this new model, as well as in another model based on the absence of protein C itself. In both cases, the treatment reduced pathological remodeling of the heart muscle, a process that includes hypertrophy, fibrosis, and structural changes that make the heart less efficient over time.

The drug also helped return some myosin to a more quiescent, less active state within the heart muscle, consistent with its known mechanism as a cardiac myosin inhibitor. Additional experiments on engineered human heart tissue carrying the same mutation showed that mavacamten reduced excessive contractile force.

The significance of the findings is that they suggest the drug may be beneficial not only in cases where the disease results from a deficiency in protein quantity, but also when the problem lies in protein function and its interaction with myosin.

This could theoretically expand the category of patients who could benefit from myosin inhibition.

The researchers said that preclinical data, along with previously published evidence, support the idea that mavacamten may be effective in carriers of different disease-causing mutations in the MYH7 and MYBPC3 genes.

They added that variability in some patients' response to the drug may not necessarily be due solely to the mutation type, but to other factors such as disease stage, environmental factors, or additional genetic variations.

However, the study remains at the preclinical stage; it did not prove that all patients carrying these mutations will respond the same way, nor did it directly test expanded use of the drug in a large clinical trial designed for that purpose. But it provides a biological explanation that helps understand why the drug might work across different disease pathways.