Diversity Supplement: Multiscale Modeling of Inherited Cardiomyopathies and Therapeutic Interventions

Familial cardiomyopathies cause long-term geometrical and functional changes in the heart. Hypertrophic disease is typically associated with larger myocytes, thicker ventricular walls, myocyte disarray, and fibrosis. It’s not yet clear how the mutations that impact myosin function scale up to induce these multiscaled effects. The parent grant proposed to develop growth and remodeling laws that couple tissue-level deformation to long-term changes in molecular-level structure and function (via alterations in myosin kinetics, sarcomere number/size, and fibrosis). This will allow the model to evolve over time, either remodeling in response to deleterious mutations, or reverse remodeling (that is, undergoing beneficial changes) as a result of therapeutic interventions. One of the key phenotypes listed above, which is not explored in depth in the parent grant, is the development of myocyte disarray in the ventricular wall. This disorganization of myofibers can lead to detrimental changes in the deformation patterns in the heart, which will ultimately degrade global pump function. It has been shown in patients with hypertrophic cardiomyopathy (HCM) that regional myofiber disarray is linked to ventricular hypokinesis (cite). Despite this clinical relevance, few studies have tried to address the growth and remodeling laws that are needed to characterize myofiber reorientation in the presence of HCM. The research planned in this supplement seeks to overcome these limitations and develop a new growth and remodeling law that will relate changes in myocardial microstructure (via myofiber disarray) and ventricular strain patterns. This new law will enhance the ongoing work in the parent grant by coupling changes in ventricular wall volume (parent grant) to deformation driven changes in myofiber orientation (supplement). Together, this law will more accurately capture the structural alterations caused by HCM. To achieve this, the following aims are proposed for the supplement period: Aim 1: Quantify myofiber disarray with diffusion tensor (DT) MRI at the same time points as the strain patterns collected with DENSE MRI. It should be noted that the DENSE MRI data is currently being collected as part of the parent grant. The DT MRI data will be collected at multiple time points to capture the evolution of myofiber disarray. Aim 2: Implement a new growth and remodeling law into the finite element framework to account for myofiber reorientation. The finite element code is organized in a modular way, which will allow for seamless integration of the new growth and remodeling law with what is currently implemented from the parent grant.