Mavacamten preserves length-dependent contractility and improves diastolic function in human engineered heart tissue

Area of Science:

• Cardiovascular Research
• Biomedical Engineering
• Pharmacology

Background:

• Engineered heart tissues (EHTs) offer a model for cardiac function but lack comprehensive mechanical characterization.
• Current EHT studies are limited to isometric contractions, hindering realistic assessment of cardiac performance.
• Force-velocity and work loops are crucial for understanding myocardial power and work output.

Purpose of the Study:

• To develop and validate a novel system for generating force-velocity curves and work loops in human EHTs.
• To characterize the effects of mavacamten, a cardiac β-myosin inhibitor, on EHT mechanical function.
• To investigate mavacamten's impact on length- and load-dependent cardiac muscle performance.

Main Methods:

• Developed an adaptive iterative control system for isotonic contractions in human EHTs.
• Generated force-velocity curves to assess power output.
• Created force-length loops to analyze work output during simulated cardiac cycles.

Main Results:

• The system successfully generated force-velocity curves and work loops in human EHTs.
• Mavacamten improved diastolic function by reducing stiffness and relaxation time, supporting its use in hypertrophic cardiomyopathy.
• Mavacamten showed mixed effects on length-dependent performance, attenuating responses at shorter lengths but preserving them at longer lengths.
• Peak power output was reduced and shifted to lower loads in mavacamten-treated EHTs.

Conclusions:

• A robust method for characterizing EHT mechanical function, including isotonic contractions and work loops, has been established.
• Mavacamten demonstrates beneficial effects on diastolic function and reveals novel pharmacological insights into myosin dynamics.
• The findings support mavacamten's therapeutic potential for hypertrophic cardiomyopathy and highlight its effects on intrinsic muscle mechanics.