Contributions of mechanical loading and hormonal changes to eccentric hypertrophy during volume overload: A Bayesian...

Area of Science:

• Cardiovascular Biology
• Systems Biology
• Computational Biology

Background:

• Primary mitral regurgitation (MR) causes left ventricular (LV) mechanical alterations and eccentric hypertrophy.
• Current treatments for MR offer symptom relief, but surgical intervention is needed for functional recovery.
• Suboptimal surgical timing leads to post-operative systolic dysfunction in 20% of MR patients.

Purpose of the Study:

• To better understand the hypertrophic process in ventricular volume overload (VO).
• To improve and personalize the management of MR by clarifying hypertrophy drivers.
• To develop a predictive model for cardiac hypertrophy interventions.

Main Methods:

• A Bayesian approach was used to integrate data from 70 studies on experimental VO in dogs and rats.
• A logic-based network model of myocyte hypertrophic signaling was calibrated using this integrated data.
• The model's predictions were validated against 43 independent studies.

Main Results:

• The calibrated model predicts that neurohormonal response, not myocyte strain, primarily drives hypertrophy in experimental VO.
• Myocardial tissue stretch increases initially but is compensated by early remodeling.
• The model accurately reproduced various experimental outcomes, including drug interventions.

Conclusions:

• Neurohormonal signaling plays a critical role in VO-induced cardiac hypertrophy.
• This modeling approach offers a quantitative framework for predicting responses to interventions in complex cardiac hypertrophy.
• Improved understanding of hypertrophy mechanisms can personalize MR management and improve surgical outcomes.