Myosin Modulator Aficamten Inhibits Force by Altering Myosin's Biochemical Activity Without Changing Thick Filament...

Area of Science:

• Cardiovascular Biology
• Muscle Physiology
• Biochemistry

Background:

• Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease.
• Myosin ATPase activity is crucial for cardiac contractility.
• Targeting cardiac myosin is a therapeutic strategy for HCM.

Purpose of the Study:

• To elucidate the biochemical and mechanical effects of aficamten on cardiac muscle.
• To compare aficamten's mechanism with mavacamten.

Main Methods:

• Myofibril mechanical assays were performed.
• Engineered heart tissues were utilized.
• Biochemical assays assessed ATPase activity and nucleotide turnover.

Main Results:

• Aficamten inhibits cardiac myosin ATPase activity by slowing cycling kinetics.
• It decreases force and calcium sensitivity without altering cross-bridge cycling.
• Both aficamten and mavacamten accelerate relaxation in engineered heart tissues, but mavacamten also reduces activation kinetics.

Conclusions:

• Aficamten acts as a cardiac myosin inhibitor by modulating ATPase kinetics.
• Its distinct mechanism from mavacamten offers a potentially differentiated therapeutic profile for HCM.
• Aficamten reduces cardiac contractility through biochemical inhibition leading to altered muscle mechanics.