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. Author Summary Mitral valve regurgitation is a common heart disease in which a malfunctioning valve allows part of the blood pumped by the heart to flow in the wrong direction. This condition overloads the heart by making it pump more blood volume than normal; the heart temporarily adapts by growing in mass and volume, but if untreated the condition can ultimately lead to heart failure and death. The most effective treatment is to surgically repair the valve; however, in many patients heart function deteriorates even after a successful surgery. Many researchers have studied this condition by experimentally overloading the hearts of dogs and rats, producing large amounts of data on the resulting geometric, mechanical, and biologic changes. Yet it has been difficult to translate those studies into effective selection and timing of treatment in all patients. In this work we integrate experimental data reported from 70 research articles on experimental volume overload through a simple model of heart mechanics and a more complex model of the molecular signaling pathways inside heart cells. We use a statistical approach to calibrate the computational model, so that it can predict not only average responses but also the degree of expected uncertainty for each prediction. We then use the model to explore how the heart responds to different combinations of drugs and hormones, and potential treatments during overload.