A new approach to an old algorithm for the Simulation of Isinglike Systems
The importance and need for an integrative mathematical modeling approach in the biological and medical fields is currently well recognized. Such an approach is crucial in understanding the complexity of hierarchical biological systems increasingly revealed by active researches in molecular and cellular biology. Particularly in cardiac functioning, modeling must cover such diverse phenomena as solid mechanics, fluid dynamics, electricity and biochemistry. Recent advancements in computational science and the development of high-performance computers have enabled the creation of multi-scale, multi-physics simulation heart models using the finite element method. Although whole heart or ventricular models of electrophysiology involving electro-mechanics with or without blood flow dynamics have been reported, to our knowledge no single model has yet succeeded in completely reproducing the behavior of the heart from the subcellular to whole organ levels. In this article, we present a brief methodology-focused review on some of the essential components for multi-scale, multi-physics heart modeling. A perspective of heart modeling in the era of high performance computing is also presented.
Recent studies have revealed that Ca(2+) not only regulates the contraction of cardiomyocytes, but can also function as a signaling agent to stimulate ATP production by the mitochondria. However, the spatiotemporal resolution of current experimental techniques limits our investigative capacity to understand this phenomenon. Here, we created a detailed three-dimensional (3D) cardiomyocyte model to study the subcellular regulatory mechanisms of myocardial energetics. The 3D cardiomyocyte model was based on the finite-element method, with detailed subcellular structures reproduced, and it included all elementary processes involved in cardiomyocyte electrophysiology, contraction, and ATP metabolism localized to specific loci. The simulation results were found to be reproducible and consistent with experimental data regarding the spatiotemporal pattern of cytosolic, intrasarcoplasmic-reticulum, and mitochondrial changes in Ca(2+); as well as changes in metabolite levels. Detailed analysis suggested that although the observed large cytosolic Ca(2+) gradient facilitated uptake by the mitochondrial Ca(2+) uniporter to produce cyclic changes in mitochondrial Ca(2+) near the Z-line region, the average mitochondrial Ca(2+) changes slowly. We also confirmed the importance of the creatine phosphate shuttle in cardiac energy regulation. In summary, our 3D model provides a powerful tool for the study of cardiac function by overcoming some of the spatiotemporal limitations of current experimental approaches.
Large deformation, nonlinear stress relaxation behavior was examined in the molten state for two types of ABS polymers, with one type containing well-dispersed rubber particles and the other, agglomerated rubber particles. These different morphologies were accomplished by adjusting the chemical composition of poly(styrene-co-acrylonitrile) (SAN) grafted on the rubber particles, such that the acrylonitrile content of the grafted SAN is equal to or different from that of the matrix SAN. The time-strain separability was found for the nonlinear relaxation of the matrix/grafted SAN chains in those ABS polymers. In the ABS polymer containing randomly dispersed rubber particles, the damping function h(γ) of the SAN chains was more strongly dependent on the strain γ than h(γ) of the pure matrix SAN chains. This difference was attributed to the filler effect in that ABS polymer. In contrast, in the ABS polymers containing networks of the agglomerated rubber particles, the SAN chains exhibited less γ-dependent h(γ) that is close to the pure matrix chains, possibly due to lack of the filler effect in large pockets formed in this network.
The friction of filled rubber on a rough surface is mainly determined by the rubber viscoelasticity and the surface property of multiple-scale asperities that can be represented by the power spectral density of the surface profile (i.e., power spectrum of surface roughness). This paper investigates a prediction model of rubber friction on dry and wet surfaces with large roughness under lightly squeezing, and finds a high stationary friction coefficient that depends on sliding speed. To this end, we demonstrated friction testing at low velocities with carbon-black-filled rubber and a hard substrate having self-affine surface roughness. From the experiment results, we estimated the hysteresis friction coefficient related to energy dissipation resulting from cyclic deformations of the viscoelastic rubber by applying the theory developed by Persson [(J. Chem. Phys. 115, 3840 (2001)]. We discussed the additional factor, an adhesion force, which also increases the friction coefficient. We concluded that the hysteresis loss of rubber viscoelastic deformation contributes most of the friction force, accounting for the nonlinear viscoelastic behavior of filled rubber, and that the operative surface wavelength extends to the order of micrometers.
T-tubules in mammalian ventricular myocytes constitute an elaborate system for coupling membrane depolarization with intracellular Ca(2+) signaling to control cardiac contraction. Deletion of t-tubules (detubulation) has been reported in heart diseases, although the complex nature of the cardiac excitation-contraction (E-C) coupling process makes it difficult to experimentally establish causal relationships between detubulation and cardiac dysfunction. Alternatively, numerical simulations incorporating the t-tubule system have been proposed to elucidate its functional role. However, the majority of models treat the subcellular spaces as lumped compartments, and are thus unable to dissect the impact of morphological changes in t-tubules. We developed a 3D finite element model of cardiomyocytes in which subcellular components including t-tubules, myofibrils, sarcoplasmic reticulum, and mitochondria were modeled and realistically arranged. Based on this framework, physiological E-C coupling was simulated by simultaneously solving the reaction-diffusion equation and the mechanical equilibrium for the mathematical models of electrophysiology and contraction distributed among these subcellular components. We then examined the effect of detubulation in this model by comparing with and without the t-tubule system. This model reproduced the Ca(2+) transients and contraction observed in experimental studies, including the response to beta-adrenergic stimulation, and provided detailed information beyond the limits of experimental approaches. In particular, the analysis of sarcomere dynamics revealed that the asynchronous contraction caused by a large detubulated region can lead to impairment of myocyte contractile efficiency. These data clearly demonstrate the importance of the t-tubule system for the maintenance of contractile function.
Experimental characterization of two cardiac mitochondrial subpopulations, namely, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), has been hampered by technical difficulties, and an alternative approach is eagerly awaited. We previously developed a three-dimensional computational cardiomyocyte model that integrates electrophysiology, metabolism, and mechanics with subcellular structure. In this study, we further developed our model to include intracellular oxygen diffusion, and determined whether mitochondrial localization or intrinsic properties cause functional variations. For this purpose, we created two models: one with equal SSM and IFM properties and one with IFM having higher activity levels. Using these two models to compare the SSM and IFM responses of [Ca(2+)], tricarboxylic acid cycle activity, [NADH], and mitochondrial inner membrane potential to abrupt changes in pacing frequency (0.25-2 Hz), we found that the reported functional differences between these subpopulations appear to be mostly related to local [Ca(2+)] heterogeneity, and variations in intrinsic properties only serve to augment these differences. We also examined the effect of hypoxia on mitochondrial function. Under normoxic conditions, intracellular oxygen is much higher throughout the cell than the half-saturation concentration for oxidative phosphorylation. However, under limited oxygen supply, oxygen is mostly exhausted in SSM, leaving the core region in an anoxic condition. Reflecting this heterogeneous oxygen environment, the inner membrane potential continues to decrease in IFM, whereas it is maintained to nearly normal levels in SSM, thereby ensuring ATP supply to this region. Our simulation results provide clues to understanding the origin of functional variations in two cardiac mitochondrial subpopulations and their differential roles in maintaining cardiomyocyte function as a whole.
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