Development of an Integrated Human Model of Electrophysiology and Actin-Myosin Binding to Describe Sarcomere Force Generation in Cardiomyocytes

Abstract

We have developed an integrated human model which links detailed sub-models of sarcomere electrophysiology and actin-myosin kinetics to describe sarcomere force generation. While many published quantitative models connect cardiac electrophysiology to force generation or full heart mechanics, these models typically include a lumped representation of actin-myosin mechanics without sufficient granularity. In order to mechanistically represent both heart failure conditions and treatment strategies which operate at the actin-myosin level, we have developed an integrated multiscale model of sarcomere force generation. Our platform connects published electrophysiology and lumped force generation models to an actin-myosin (AM) model developed based on published data on cardiac myosin modulators. Specifically, the AM model was calibrated to published in vitro data of phosphate release and ATP turnover, and can successfully reproduce the molecular effect of cardiac myosin modulation. We connected this in vitro model with healthy and heart failure phenotypes to describe cardiac force generation before and after therapy. With this multiscale approach we can also simulate sarcomere length-dependent activation, calcium-force relationships, and determine how these simulations are affected in failing myocardium after treatment with cardiac modulators. We demonstrate that models calibrated to data at one scale often need to be adjusted in the context of a multiscale model. For example, the calcium transient produced from a published heart failure electrophysiology model generates little force in the integrated multiscale model, underscoring the continuing challenge of linking in vitro experimental efforts to clinical outputs. We discuss our methods to connect information across scales into one coherent mathematical framework. The final model describes how specific therapeutic interventions at different stages of the actin-myosin cycle will alter sarcomere force generation, which will propagate to changes in clinical outcomes like ejection fraction.