Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure

Area of Science:

• Cardiovascular Physiology
• Biophysics
• Computational Biology

Background:

• 2 -deoxy-ATP (dATP) is known to improve cardiac function, but the underlying mechanisms and therapeutic efficacy at low concentrations are unclear.
• Understanding how dATP modulates cardiac contractility is crucial for developing treatments for heart failure.

Purpose of the Study:

• To elucidate the multiscale mechanisms by which dATP improves ventricular function.
• To investigate how small fractions of dATP enhance cardiac performance from molecular to organ levels.

Main Methods:

• Utilized a multiscale computational modeling approach, integrating atomistic simulations, Markov state modeling, and organ-scale simulations.
• Analyzed actomyosin association, sarcomere mechanics, myocyte Ca[Formula: see text] dynamics, and biventricular mechanoenergetics.

Main Results:

• dATP significantly increased the actomyosin association rate (1.9-fold) and the pool of myosin heads available for crossbridge cycling.
• Mechanosensing and cooperativity were identified as key mechanisms for dATP's effect at low fractions, increasing force development (1.3-fold).
• In a heart failure model, dATP improved ejection fraction by 16% and energy efficiency by 1%.

Conclusions:

• Small amounts of dATP can substantially enhance cardiac contractility through increased crossbridge cycling efficiency and improved Ca[Formula: see text] handling.
• This study provides a comprehensive multiscale analysis of dATP's mechanism of action, offering insights into potential therapeutic strategies for heart failure.