A heart muscle disease starts while the heart is at rest
In an inherited form of heart muscle thickening, something already goes wrong when the heart is simply at rest. That changes how we think about treatment.
Hypertrophic cardiomyopathy (HCM) is a condition in which the heart muscle becomes too thick, causing symptoms like breathlessness, fatigue, and in severe cases sudden cardiac arrest. It is caused by mutations in genes that control heart muscle proteins. Research has traditionally focused on what goes wrong during contraction.
The researchers, publishing in eLife, investigated what already goes wrong in the resting state with a well-known mutation: R403Q in the MYH7 gene. They used a technique called polarized second-harmonic generation (pSHG) microscopy, which maps the organization of muscle proteins without damaging the tissue. They found that a larger fraction of the heart muscle molecules (myosin) exist in an actively available state, even when the heart is not contracting.
Higher energy use at rest
This has a concrete consequence: the heart muscle consumes more energy at rest than normal. The researchers also measured elevated ATPase activity, a measure of energy use in the muscle cell, in affected tissue. That elevated energy consumption appears to result from both a population shift toward more active myosin molecules and increased activity per myosin molecule.
The link to aging is indirect but relevant. Heart disease is the most common cause of death in later life. Understanding how the heart muscle is already strained at rest by genetic variants offers opportunities for earlier intervention. HCM also frequently manifests after middle age.
Existing drugs help, but incompletely
The researchers also tested two existing compounds: a myosin activator and an inhibitor (mavacamten). Both equalized the difference in myosin organization between affected and healthy tissue. Yet resting energy consumption remained elevated even at high concentrations of the activator. This suggests current treatments do not fully correct the mechanism. These findings are so far limited to animal tissue (minipigs). Translation to humans requires further research.
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