Theme 1: Andrew McCulloch


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Multi-Scale Modeling of the Heart: Past, Present and Future

The heart was one of the first organ systems to attract interest in multi-scale computational modeling. In 2006, our goal was to develop models of ventricular electromechanics that spanned form cellular mechanisms to organ scale electrophysiology, mechanics and regulation and to use this models to understand genotype-phenotype relations in mice. Genetically engineered mouse models have us the opportunity to validate these models and gain new mechanistic insights into normal cardiac physiology and the molecular basis of disease. Since then, we have seen important progress in three major areas: (1) Extending these multi-scale models in space and time to include subcellular and atomistic detail. The use of molecular dynamics, molecular electrostatics and Brownian dynamics is allowing us to identify thermodynamic and kinetic parameters of Markov state models that could previously only be estimated or deduced indirectly from empirical data. (2) Extending these multi-scale models to the longer time-scales of cardiac growth and remodeling in development and disease and linking organ scale models of remodeling to underlying cellular mechanisms via systems models of mechanotransduction and agent-based models of multi-cellular activity and interactsion. (3) Extending from models of experimental animals to patient-specific models of heart disease such as congestive heart failure. I will briefly review this progress and point to future directions and opportunities.




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