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

Area of Science:

• Cardiology
• Systems Biology
• Computational Biology

Background:

• Primary mitral regurgitation (MR) leads to left ventricular (LV) remodeling and eccentric hypertrophy.
• Current treatments for MR, including surgery, have limitations, with 20% of patients experiencing post-operative systolic dysfunction.
• Optimal surgical timing for MR remains unclear, necessitating a deeper understanding of the hypertrophic process in ventricular volume overload (VO).

Purpose of the Study:

• To develop a quantitative model of cardiac hypertrophy in response to ventricular volume overload (VO).
• To investigate the primary drivers of hypertrophic growth in experimental VO.
• To predict the effects of interventions in MR-induced cardiac hypertrophy.

Main Methods:

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

Main Results:

• The calibrated model predicts that neurohormonal response, rather than myocyte strain, is the primary driver of hypertrophy in experimental VO.
• Early increases in myocardial tissue stretch are compensated by remodeling relatively early in the VO timeline.
• The model successfully reproduced various experimental outcomes, including responses to hypertrophic agonists and heart failure drugs.

Conclusions:

• This study presents a novel computational approach to model cardiac hypertrophy.
• The findings suggest a greater role for neurohormonal signaling than previously thought in VO-induced hypertrophy.
• The developed model offers a promising tool for predicting patient responses to interventions in MR and cardiac hypertrophy.