Ryo Haraguchi

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.

A shape matching dynamics (SMD) is a robust and efficient elastic model based on geometric constraints. This article introduces our study [1] 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 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.

Background: Recently, myocardial sheets consisting of human induced pluripotent stem cellderived 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, hiPSCCM 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.

Vast histological specimen on cardiovascular disease has been saved since its founding in National Cerebral and Cardiovascular Center. We conduct the project for contributing medical research and education by digitizing those histological specimens. We consider that the digitalization of histological specimens improves the accessibility and raise the value of them. In this study, we propose the improvement on the interpolation method and user-interface for three-dimensional visualization of cardiac conduction system from digital histological specimens.

Rotor ablation has been proposed as the effective treatment for human atrial fibrillation (AF). However, existing mapping systems usually take too much time to visualize activation sequences.Methods: We have developed a novel real-time phase mapping system called “ExTRa Mapping” to detect unstable rotors during AF. Based on bipolar signals of a 20-pole spiral-shaped ring catheter, action potential temporal dynamics was numerically estimated. Results: Unstable rotors during in silico AF were reconstructed by ExTRa Mapping (Fig). ExTRa Mapping could identify unstable rotors during clinical AF by creating phase maps on a real-time basis.Conclusion: ExTRa Mapping could open a new avenue for identifying unstable rotors during AF ablation.

In this study, we have noted that the schema drawing by doctors plays a very important role as storage of nonverbal information, share, and understanding methods. And there, we research and develop the technology needed for the database construction to combining character information (medical information) and visual information (schema) for congenital heart disease. In order to realize the cooperation of the schema and disease name, we use the vector schema that can be handled information visually as an interface for linkage. And we report that developed the prototype system that enables collaboration with the clinical information and the vector schema.

Vast histological specimen on cardiovascular disease has been saved since its founding in National Cerebral and Cardiovascular Center. We conduct the project for contributing medical research and education by digitizing those histological specimens. We consider that the digitalization of histological specimens improves the accessibility and raise the value of them. In this study, we visualize the part of cardiac conduction system using the digital image of serial histological specimens of a human heart.

Heartbeat is controlled by action potentials generated from pacemaker of the heart, the sinoatrial node. Atrial fibrillation(AF)is a common arrhythmia characterized by disordering atrial activity. AF generate a blood clot in atria, and it can cause cerebral infarction. In the treatment of AF, heart rate control is achieved by applying drugs into the atrioventricular node connecting atria and ventricles electrically. However, the detail of the mechanisms is unknown. In this study, we investigated the mechanisms of heart rate control during AF using computer simulation. Our simulation results indicate different mechanisms to control ventricular rate during AF with two drugs.