Adaptive remodeling of the right ventricle in response to pulmonary hypertension: towards physical understanding and prediction

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 DESCRIPTION (provided by applicant): The hypertrophy and remodeling of the heart right ventricle (RV) are key predictors of right heart failure in patients with pulmonary arterial hypertension (PAH) disease. These effects are induced by pressure overload in the RV and are associated with structural and mechanical changes of the RV free wall (RVFW) that eventually results in RV failure. New tools are needed to allow clinicians to use in vivo measurements of RV function into a model that can help predict the progression of this disease. Our long-term objective for this proposal is to improve our understanding on how the RV adapts to PAH, and to develop an experimentally- guided growth and remodeling (G&R) model that captures this adaptation. This model can be "personalized" using in vivo imaging data and thereby has the potential to provide the means for clinicians to predict the progression of RV hypertrophy and evaluate the efficacy of new clinical interventions. Recently, we developed a tissue-level constitutive (stress-strain) model that elucidates the relationship between structural and compositional arrangement in a healthy RVFW and its overall mechanical response; now there is a need to investigate how this arrangement at the cellular-level adapts to a chronic pressure overload, and what effects this adaptation has at tissue- and organ-level behaviors. Towards this goal, we propose to extend our model to a micromechanical model and to account for growth and remodeling response of the RVFW (Aim 1). We will then implement the model within a realistic computational setting and conduct comparisons with results from a rat model (Aim 2). Finally, we will use our model to quantify reversibility in a rat model of PAH subjected to an intervention (Aim 3). Three specific aims of this proposal are then summarized as: 1. Extend our current structural soft tissue constitutive model to a microstructurally accurate 3-D model and to include time-evolving hypertrophy and remodeling adaptation of the RVFW to a pressure overload 2. Develop an anatomically faithful FE model of biventricular rat heart and comparing the simulation results to in vivo data 3. Determine the point of 'no return' along the hypertrophy and remodeling progression by investigating changes in wall stress in a rat model undergoing stem-cell treatment