The human heart beats as a result of multiscale nonlinear dynamics coupling subcellular to whole organ processes, achieving electrophysiologically-driven mechanical contraction. Computational cardiac modelling and simulation have achieved a great degree of maturity, both in terms of mathematical models of underlying biophysical processes and the development of simulation software. In this study, we present the detailed description of a human-based physiologically-based, and fully-coupled ventricular electromechanical modelling and simulation framework, and a sensitivity analysis focused on its mechanical properties. The biophysical detail of the model, from ionic to whole-organ, is crucial to enable future simulations of disease and drug action. Key novelties include the coupling of state-of-the-art human-based electrophysiology membrane kinetics, excitation-contraction and active contraction models, and the incorporation of a pre-stress model to allow for pre-stressing and pre-loading the ventricles in a dynamical regime. Through high performance computing simulations, we demonstrate that 50% to 200% - 1000% variations in key parameters result in changes in clinically-relevant mechanical biomarkers ranging from diseased to healthy values in clinical studies. Furthermore mechanical biomarkers are primarily affected by only one or two parameters. Specifically, ejection fraction is dominated by the scaling parameter of the active tension model and its scaling parameter in the normal direction ( k ort 2 ); the end systolic pressure is dominated by the pressure at which the ejection phase is triggered ( P ej ) and the compliance of the Windkessel fluid model ( C ); and the longitudinal fractional shortening is dominated by the fibre angle ( ϕ ) and k ort 2 . The wall thickening does not seem to be clearly dominated by any of the considered input parameters. In summary, this study presents in detail the description and implementation of a human-based coupled electromechanical modelling and simulation framework, and a high performance computing study on the sensitivity of mechanical biomarkers to key model parameters. The tools and knowledge generated enable future investigations into disease and drug action on human ventricles.

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