Asuka Hatano

A three-dimensional simulation model of cardiomyocyte integrating excitation-contraction coupling and metabolism.

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.

Multi-scale simulations of cardiac electrophysiology and mechanics using the University of Tokyo heart simulator

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.

Critical role of cardiac t-tubule system for the maintenance of contractile function revealed by a 3D integrated model of cardiomyocytes.

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.

Mitochondrial Colocalization with Ca2+ Release Sites is Crucial to Cardiac Metabolism

In cardiomyocyte subcellular structures, colocalization of mitochondria with Ca2+ release sites is implicated in regulation of cardiac energetics by facilitating Ca2+ influx into mitochondria to modulate the tricarboxylic acid (TCA) cycle. However, current experimental techniques limit detailed examination of this regulatory mechanism. Earlier, we developed a three-dimensional (3D) finite-element cardiomyocyte model featuring a subcellular structure that integrates excitation-contraction coupling and energy metabolism. Here, using this model, we examined the influence of distance between mitochondria and Ca2+ release sites by comparing a normal (50-nm) distance model and a large (200-nm) distance model (LD). The influence of distance was minimal under a low pacing rate (0.25 Hz), but under a higher pacing rate (2 Hz), lower levels of mitochondrial Ca2+ and NADH, elevated phosphate, and suppressed force generation became apparent in the LD model. Such differences became greater when functional impairments (reduced TCA cycle activity, uncoupling effect, and failing excitation-contraction coupling) were additionally imposed. We concluded that juxtaposition of the mitochondria and the Ca2+ release sites is crucial for rapid signal transmission to maintain cardiac-energy balance. The idealized 3D model of cardiac excitation-contraction and metabolism is a powerful tool to study cardiac energetics.

Charge-transfer interatomic potential for investigation of the thermal-oxidation growth process of silicon

A charge-transfer interatomic potential, based on the hybrid-Tersoff potential that incorporates a covalent-ionic mixed-bond nature, was developed to reproduce the growth process of the thermal oxidation of silicon. A fitting process was employed with various reference structures sampled by MD. Actively exploring and learning the wide-range of phase space enabled us to develop a robust interatomic potential. Our interatomic potential reproduced the bulk properties of Si and SiO2 polymorphs well, in addition to the radial distribution function and bond angle distribution of amorphous SiO2. The covalent-ionic mixed-bond nature of the interatomic potential well reproduced the dissociation process of an oxygen molecule on the Si/SiO2 interface. The initial oxidation simulation was performed on the silicon surface. We grew the amorphous SiO2 layer by incorporating the oxygen molecules into the silicon network at the interface. The density of the SiO2 layer and the charge distribution at the interface showed go...

An Integrated Finite Element Simulation of Cardiomyocyte Function Based on Triphasic Theory

In numerical simulations of cardiac excitation-contraction coupling, the intracellular potential distribution and mobility of cytosol and ions have been mostly ignored. Although the intracellular potential gradient is small, during depolarization it can be a significant driving force for ion movement, and is comparable to diffusion in terms of net flux. Furthermore, fluid in the t-tubules is thought to advect ions to facilitate their exchange with the extracellular space. We extend our previous finite element model that was based on triphasic theory to examine the significance of these factors in cardiac physiology. Triphasic theory allows us to study the behavior of solids (proteins), fluids (cytosol) and ions governed by mechanics and electrochemistry in detailed subcellular structures, including myofibrils, mitochondria, the sarcoplasmic reticulum, membranes, and t-tubules. Our simulation results predicted an electrical potential gradient inside the t-tubules at the onset of depolarization, which corresponded to the Na+ channel distribution therein. Ejection and suction of fluid between the t-tubules and the extracellular compartment during isometric contraction were observed. We also examined the influence of t-tubule morphology and mitochondrial location on the electrophysiology and mechanics of the cardiomyocyte. Our results confirm that the t-tubule structure is important for synchrony of Ca2+ release, and suggest that mitochondria in the sub-sarcolemmal region might serve to cancel Ca2+ inflow through surface sarcolemma, thereby maintaining the intracellular Ca2+ environment in equilibrium.

Elucidation of the atomic-scale mechanism of the anisotropic oxidation rate of 4H-SiC between the (0001) Si-face and ( 000 1 ¯) C-face by using a new Si-O-C interatomic potential

Silicon carbide (SiC) is an attractive semiconductor material for applications in power electronic devices. However, fabrication of a high-quality SiC/SiO2 interface has been a challenge. It is well-known that there is a great difference in the oxidation rate between the Si-face and the C-face and that the quality of oxide on the Si-face is greater than that on the C-face. However, the atomistic mechanism of the thermal oxidation of SiC remains to be solved. In this paper, a new Si-O-C interatomic potential was developed to reproduce the kinetics of the thermal oxidation of SiC. Using this newly developed potential, large-scale SiC oxidation simulations at various temperatures were performed. The results showed that the activation energy of the Si-face is much larger than that of the C-face. In the case of the Si-face, a flat and aligned interface structure including Si1+ was created. Based on the estimated activation energies of the intermediate oxide states, it is proposed that the stability of the flat...

Reaction pathway analysis for shuffle-set 60° perfect dislocation in Si

Abstract In this work, the EDIP potential is employed for representing silicon and the shuffle-set 60° perfect dislocation motion is investigated by reaction pathway analysis. There are three possible shuffle-set 60° perfect dislocation core structures named as S1, S2 and S3. The activation energy barriers of the kink migration and nucleation in S1and S2 types are calculated by CI-NEB method. The simulation results show that the critical resolved shear strain of the shuffle-set dislocation in S1 type is around 5%, and the S1 type is the dominate one in the shear strain region of 0 to 5%. During the shear strain from 5to 11.81%, the dislocation moves as the S1 core kink nucleation and migration, meanwhile the S1 dislocation core is in process of transforming into S2. More interestingly, both S1 and S2 dislocation core structures is observed along the dislocation line in this shear strain regime, which could response to the missing observation of long segment dislocation line in the experiment.

A 3D Integrated Model of Cardiomyocytes Revealed the Important Role of Cardiac T-Tubule Structure for the Maintenance of Contractile Function

T-tubules in mammalian ventricular myocytes are invaginations of the surface membrane which couple membrane depolarization with intracellular Ca2+ signaling to facilitate the coordinated 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 have been proposed, 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 arranged realistically. Based on this framework, electrophysiology, E-C coupling, metabolism and mechanical deformation are simulated by simultaneously solving the multiple reaction diffusion equations for Ca2+ and energy metabolites, and the mechanical equilibrium. The model reproduced the Ca2+ transients and contraction observed in experimental studies with and without the t-tubule system and revealed that the asynchronous contraction caused by a large area of detubulated region can impair contractile efficiency.View Large Image | View Hi-Res Image | Download PowerPoint Slide