Aiming to understanding how disease phenotypes apparent at the whole-organism scale emerge from molecular, cellular, tissue, organ, and organ-system interactions, we have assembled multi-scale (lumped-parameter and distributed) models for cardiovascular systems components, using the models to construct and assess competing hypotheses [1-3] and analyze data from rodent models , other species , and humans [5-14]. Cardiac models and model components developed by this group, and of particular relevance to the studies proposed here, include new models of rodent myocyte excitation-contraction coupling [15-22], myofilament interactions [23-25], and signal transduction [26, 27], as well as new multi-scale continuum models of ventricular electrophysiology , mechanics , growth and remodeling in ventricular hypertrophy [30-32]. In parallel we have developed modules for simulating components for metabolic processes (e.g., [33-44]), gas exchange ([45-47]), and solute transport in the body [48-50] in a self-consistent computational framework. We are now realizing the utility of all of this foundational work by applying integrated models in current and proposed studies. For example, a recent study pulls some of these pieces together to determine how metabolic changes observed in heart failure are sufficient to cause systolic dysfunction and whole-body heart failure symptoms and how myosin activating drugs affect the disease phenotype . We have also translated these technologies to the clinic by developing patient-specific models of cardiac electromechanics [12-14] that have shown exciting potential to improve prediction of therapeutic outcomes in patients with dyssynchronous heart failure.
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