Contributions of mechanical loading and hormonal changes to eccentric hypertrophy during volume overload: A Bayesian analysis using logic-based network models

Primary mitral regurgitation (MR) is a pathology that alters mechanical loading on the left ventricle, triggers an array of compensatory neurohormonal responses, and induces a distinctive ventricular remodeling response known as eccentric hypertrophy. Drug therapies may alleviate symptoms, but only mitral valve repair or replacement can provide significant recovery of cardiac function and dimensions. Questions remain about the optimal timing of surgery, with 20% of patients developing systolic dysfunction post-operatively despite being treated according to the current guidelines. Thus, better understanding of the hypertrophic process in the setting of ventricular volume overload (VO) is needed to improve and better personalize the management of MR. To address this knowledge gap, we employ a Bayesian approach to combine data from 70 studies on experimental volume overload in dogs and rats and use it to calibrate a logic-based network model of hypertrophic signaling in myocytes. The calibrated model predicts that growth in experimental VO is mostly driven by the neurohormonal response, with an initial increase in myocardial tissue stretch being compensated by subsequent remodeling fairly early in the time course of VO. This observation contrasts with a common perception that volume-overload hypertrophy is driven primarily by increased myocyte strain. The model reproduces many aspects of 43 studies not used in its calibration, including infusion of individual hypertrophic agonists alone or in combination with various drugs commonly employed to treat heart failure, as well as administration of some of those drugs in the setting of experimental volume overload. We believe this represents a promising approach to using the known structure of an intracellular signaling network to integrate information from multiple studies into quantitative predictions of the range of expected responses to potential interventions in the complex setting of cardiac hypertrophy driven by a combination of hormonal and mechanical factors.