Background: Recently, myocardial sheets consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) have been used to clarify the mechanisms of inherited arrhythmias and to evaluate the efficacy of antiarrhythmic drugs. However, whether the electrophysiological properties of the hiPSC-CM are the same as those of the original human cardiomyocytes (hCM) remains unclear. Indeed, hiPSC-CM has automaticity, longer action potential duration (APD), smaller action potential amplitude (APA), and positively shifted diastolic potential (DP). Methods: To clarify this issue, we constructed in silico models of hCM and hiPSC-CM sheets based on the experimental data, and performed simulations of spiral wave (SW) reentry. Then we analyzed the SW behaviors in the in silico myocardial sheets, and also evaluated the effects of IKr blockade. Results: ( 1 )The in silico model of hiPSC-CM had spontaneous activations 0.5-1 Hz, longer APD, smaller APA, and DP positively shifted by∼15 mV. ( 2 )Conduction velocity (CV) in the hiPSC-CM sheet was∼5 cm/s, which was only∼1/10 of the CV in the hCM sheet. ( 3 )Mean cycle length (mCL) of excitations during SW reentry in the hiPSC-CM sheet was∼0.9 Hz, whereas that in the hCM sheet was∼5 Hz and identical to that of human VF. ( 4 )Both CV and mCL during SW reentry in the model of hiPSC-CM sheet were highly consistent with previous experimental data. ( 5 )The mCL of SW reentry in hCM sheet was markedly prolonged by IKr blockade, whereas that in hiPSC-CM sheet was shortened. Conclusion: The SW behavior and the antiarrhythmic drug efficacy in the in silico models of hCM and hiPSC-CM sheets are different. Our findings suggest that such in silico analytical approach might fill the gap between hCM and hiPSC-CM when we apply the hiPSC-CM sheet to clinical practice.
The Purkinje fiber network is one of the specialized excitation conduction systems that ensure coordinated contraction of the ventricles due to faster excitation conduction than other regions of the heart. A recent study identified a mutation in connexin 40 (Cx40), a gap junction isoform predominantly expressed in the His-Purkinje system, in patients with progressive cardiac conduction defect associated with lethal ventricular arrhythmias. This mutation disrupts the formation of gap junction channels in the His-Purkinje system, resulting in a decrease in gap junction conductance. However, the relationship between the reduced gap junction conductance and inducibility and sustainability of arrhythmias in the Purkinje fiber network is not clear. To elucidate the underlying mechanisms, we studied the relationship between cell-to-cell conduction property of the Purkinje fiber network and the initiation of ventricular arrhythmias using computer simulations. We used mathematical action potential models for rabbit Purkinje fiber and ventricular myocyte. Using these models, we constructed simplified anatomical models including action potential models to calculate excitation conduction from the His bundle to ventricular tissue via the Purkinje fiber network and Purkinje-ventricular junctions. Our His-Purkinje-ventricular network models was composed of approximately 13,000 cells, in which neighboring cells were connected by gap junction channels. To simulate mutation in connexin, gap junction conductance was reduced from 5,000 nS (physiological condition) to 10 nS. At lower gap junction conductances, reentrant beats occurred. When one of the reentrant circuits was disconnected, reentrant beats did not persist in some cases, as a consequence of altered excitation conduction dynamics. Our simulation results suggest that both Purkinje fiber network structure and gap junction conductance are important factors for generating arrhythmias in the Purkinje fiber network. In addition, ablation applied to the reentrant circuit in the His-Purkinje-ventricular network is a potential preventive treatment for arrhythmias generated from the Purkinje fiber network.
Many biological findings are continuously reported in the life science area. Most of them are reports on the correlations between some proteins, or correlations between some proteins and macroscopic phenomena such as whole body hemodynamics. In order to understand the underlying mechanisms of the biological systems, simulation and analysis of multiscale biological function models are considered useful. Since the complex calculation schemes are necessary to calculate these models efficiently, it is useful to represent both the biological function models and the calculation schemes in descriptive languages which are readable by the computer programs. In this report, we introduce our simulation system which generates simulation programs from biological function models and calculation schemes both described by description languages. Using our system, we were able to generate simulation programs for a hemodynamic simulation model coupling a ventricular myocyte model and a whole body circulation model, a simulation model that evaluates the changes in action potential of a ventricular myocyte model after drug administration, and a program that calculates the changes in action potential of ventricular myocytes by changing specific parameters.
Cardiac impulse propagation is determined by complex interactions between electrical activity of myocardiocytes, intercellular electrical communication and the myocardial tissue structure. A special form of conduction that underlies cardiac arrhythmias, including tachycardia and fibrillation, involves circulating excitation, spiral wave reentry. In this type of impulse propagation, curvature of the propagating excitation wavefront plays additional important roles. This brief review describes results from mathematical simulations and animal experiments to define mechanisms of normal and abnormal impulse conduction in the heart.
A shape matching dynamics (SMD) is a robust and efficient elastic model based on geometric constraints. This article introduces our study  that adopts SMD to visual simulation of cardiac beating motion. In our technique, a heart is represented by a tetrahedral mesh model and a local region is defined at each vertex by connecting its immediate neighbors. During the simulation, we first contract all local regions depending on predefined muscle fiber orientations and contraction rate. Then using SMD, we compute the global shape of the heart model so that it satisfies the contracted local regions. Our technique introduces a fiber-orientation-dependent weighting function to emulate an anisotropic stiffness of myocardium. Since our technique is based on SMD, it is possible to compute cardiac motion in real-time on a commercially available PC.
The accurate propagation of action potentials is indispensable for normal contractile function of the heart. The underlying mechanism of action potential propagation under physiological conditions has been explained by the gap junction responsible for electrical interaction between cardiomyocytes. However, many phenomena under pathological conditions cannot be explained by the gap junctional mechanism. Therefore, the presence of an alternative mechanism besides the gap junctional mechanism has been suggested. In this review, we introduce simulations of action potential propagation in a myofiber model incorporating a novel mechanism resulting from the morphology of cardiomyocytes and the subcellular distributions of functional proteins such as ion channels and transporters, in addition to the conventional gap junctional mechanism. It is possible that the novel conduction mechanism incorporating subcellular distributions of functional proteins plays an important role in homeostasis of excitation propagation in the diseased heart.
Research to understand physiological functions comprehensively from the molecular to the organismal level is now being intensely promoted in physiome and systems biology. Accordingly, development of high-definition physiologically accurate mathematical models is becoming increasingly important. Considering the size and complexity of such models, it is desirable to facilitate research with databases and software applications that allow data sharing and facile integration of wet and dry research. In this article, several software platforms to meet these objectives, including those we are developing, are summarized.
Our research group has conducted many computer simulation studies over the past years, in order to comprehensively understand the electrophysiological phenomena in the heart. By developing high performance computing techniques and visualization technology and by integrating the multilevel knowledge obtained through basic studies from the ion channel level to the organ morphology level, we have simulated the electrical activities of the heart. Actually, incorporating many experimental multilevel data in heart models and executing simulations are difficult tasks. It is necessary to idealize a model as much as possible for realization of an effective and comprehensible simulation. In this article, we report two studies in which one or two thousand units of FSK model designed from the electrophysiological characteristics of ion channels in myocardial cell were linked and large-scale simulations of electrical activities were conducted on a super-computer. The first study was a filament analysis of rotary pivots of scroll wave reentrant arrhythmic activities in a three-dimensional ventricular wall slab model. The results suggested a defensive function against arrhythmia in the heart and a proarrhythmic function caused by degeneration of the defensive function. The second study indicated the dynamics of electrical activities caused by delayed conduction region in the right ventricular outflow tract based on hypothetical Brugada syndrome. Although the three-dimensional ventricular shape model does not sufficiently incorporate detailed physiological properties of the heart, we speculate that this study has generated some inspiring data.
Nasal air flow and temperature were analyzed using a voxel model constructed directly from medical images. The nasal cavities of a healthy male were reconstructed using CT slices in the axial direction at an image resolution of 0.488 mm/pixel and a slice interval of 0.40 mm. The rough surfaces in the image, which were caused by the resolution, were smoothed using a bilinear interpolation algorithm. A voxel-based simulation of inspiratory flow was then performed with a voxel pitch of 0.20 mm. With an interpolation image resolution of 0.163 mm//pixel, the voxel model successfully simulated an overall pressure drop and airflow temperature to the same extent as the conventional boundary-fitted model.
Magnetic resonance-guided focused ultrasound (MRgFUS) is becoming one of the foremost treatment options for uterine fibroids and breast cancer. However, for an abdominal organ such as the liver, a target tracking technique to “lock on” to the focal area is required because the organ moves and deforms with respiratory motion. This technique, which is based on the relative displacement of the portal vein using sagittal MR images, is effective for translational motion and deformation because blood flow is visualized as high intensity in MR images using TrueFISP. The aim of this study was to develop a three-dimensional target tracking technique based on the results of an analysis of three-dimensional dynamic information about the portal vein structure. It is difficult to acquire multi-slice images quickly using MR. Therefore, in this study, we propose a method to reconstruct a three-dimensional dynamic model of the liver using multi-slice MR images acquired during slow breathing. Forty-two frames of the image set were acquired during slow breathing. The images were arranged in breathing phase order based on the motion of the diaphragm. Interpolated images were enhanced using a morphology technique and were inserted between the discontinuous frames. Finally, the images were interpolated in isotropic voxels in an out-plane direction. The experimental results demonstrate the feasibility of three-dimensional tracking based on a portal vein tree structure.
We previously reported our attempts to increase local concentration of microbubbles in water flow by acoustic radiation force, with the aim to apply to ultrasound therapy. Because the actual blood vessels are generally structurally complex and contain multiple bifurcations, trapping microbubbles in multiple areas will improve total therapeutic efficiency. However, there is a limitation to the number of ultrasound transducers that can be placed on the body surface, since a single-element transducer produces only one focal point. In this study, we developed a method to trap microbubbles (bubble liposome) that may contain various kinds of drugs in multiple areas by designing a time-shared acoustic field produced by a 2D array transducer at a frequency of 1 MHz. First, we conducted an experiment to trap microbubbles in a straight path of an artificial blood vessel to investigate the relationship between the trapped area and ultrasound parameters. Next, we conducted an experiment to produce a time-shared acoustic field under optimal conditions : maximum sound pressure of 150 kPa-pp and duty ratio of 25% in ultrasound emission. Under these conditions, we succeeded in trapping microbubbles simultaneously in four individual parallel paths with inner diameter of 0.7 mm, in a multi-bifurcated artificial blood vessel model. We also measured the area of trapped microbubbles under a continuous wide acoustic field that covered the area of four paths. Using the same ultrasound power, the time-shared acoustic field had improved trapping efficiency compared to the continuous acoustic field.
Age-related opacity of the lens can happen to anyone. Lens opacity leads to decreased visual function, and damages the quality of life (QOL). It has been reported that lens opacity leads to absorption of blue color with short wavelength. Therefore, we hypothesized that the relationship between decrease in visual function and QOL can be examined if we can measure a person's recognition of blue color. In this study, we develop a visual function evaluation system to measure the blue color differential threshold. This system is implemented on tablet devices and displays a black Japanese character on a blue background. The background color can be changed based on the HSV color system. We conducted a survey on 27 participants aged 23-78 years, using the visual function system to measure the differential threshold and the NEI-VFQ25 vision-related questionnaire as a QOL evaluation tool. Consequently, we found a significant difference in blue contrast sensitivity between young participants and elderly participants. However, there was no correlation between blue contact sensitivity and QOL. In summary, based on the results, we believe that this system can measure blue contrast sensitivity and can be used for evaluating visual function.
In the neuroscience and physiology fields, studies on implantable neural signal detection and transmission systems have clarified the relationship between motor and sensory activities and neural activity. This technique is applicable to handicapped persons in areas of brain-computer interface (BCI) and bionic arm. In this study, we developed a multi-channel neural signal recording system that is capable of measuring neural signals steadily even when the signal amplitude decreases and the noise level increases during long-term measurement. In a previous study, we developed and tested a multi-channel system that simultaneously detected spikes, and calculated the firing frequency. The system comprises a neural signal enhancer with non-linear circuitry and a spike detector. We demonstrated that the performance of the system was sufficient to be used as an embedded spike detector. However, there was an issue that power consumption of the circuit was not optimized. In this study, we reduced the power consumption of the system and evaluated its performance for long term measurements in a rat. The test results with the improved hardware showed that the new system consumes substantially less power than the previous system. The experiments of long-term spike measurement showed that stable spike measurements were possible using a neural signal enhancer with non-linear circuitry.