Ryo Haraguchi

若年者の頻脈性不整脈および心臓突然死の原因の1つである Wolff-Parkinson-White (WPW) 症候群は，心臓内の正常な刺激伝導路とは別に先天的に心房と心室とをつなぐ副伝導路が存在する疾患である．これまでに我々は心房筋・心室筋・副伝導路からなる数理モデルを構築した上で，コンピュータシミュレーションにより，副伝導路の大きさ・心房・心室の導電率・副伝導路の導電率が副伝導路を介した伝導にどのような影響を与えるのかをsource-sink の概念に基づいて明らかにした．しかしながら，イオンチャネル電流と伝導の実際との関連は明らかではない．そこで我々は年齢によるイオンチャネル電流の差異を模擬できる膜電位モデルを構築した上で，心房・心室・副伝導路のイオンチャネル電流が副伝導路を介した伝導にどのような影響を与えるのかについてコンピュータシミュレーションによる検討を行なった．それにより，小児・成人・老年いずれの場合においても，イオンチャネル電流の変化は副伝導路を介した伝導に影響を及ぼさないという結果が得られた．本研究の結果は，副伝導路における伝導の成立およびWPW症候群の顕在化はsource-sink関係が支配的な要因であることを示唆している．

<sec xml:lang="en"> <title>Background</title> <p xml:lang="en">Detection of the fiber orientation pattern of the myocardium using diffusion tensor magnetic resonance imaging lags ≈12 weeks of gestational age (WGA) behind fetal myocardial remodeling with invasion by the developing coronary vasculature (8 WGA). We aimed to use diffusion tensor magnetic resonance imaging tractography to characterize the evolution of fiber architecture in the developing human heart from the later embryonic period. </sec> <sec xml:lang="en"> <title>Methods and Results</title> <p xml:lang="en">Twenty human specimens (8–24 WGA) from the Kyoto Collection of Human Embryos and Fetuses, including specimens from the embryonic period (Carnegie stages 20–23), were used. Diffusion tensor magnetic resonance imaging data were acquired with a 7T magnetic resonance system. Fractional anisotropy and helix angle were calculated using standard definitions. In all samples, the fibers ran helically in an organized pattern in both the left and right ventricles. A smooth transmural change in helix angle values (from positive to negative) was detected in all 16 directions of the ventricles. This feature was observed in almost all small (Carnegie stage 23) and large samples. A higher fractional anisotropy value was detected at the outer side of the anterior wall and septum at Carnegie stage 20 to 22, which spread around the ventricular wall at Carnegie stage 23 and in the early fetal samples (11–12 WGA). The fractional anisotropy value of the left ventricular walls decreased in samples with ≥13 WGA, which remained low (≈0.09) in larger samples. </sec> <sec xml:lang="en"> <title>Conclusions</title> <p xml:lang="en">From the human late embryonic period (from 8 WGA), the helix angle arrangement of the myocardium is comparable to that of the adult, indicating that the myocardial structure blueprint, organization, and integrity are already formed. </sec>

The mechanism underlying WPW syndrome features accessory conduction between the atrium and ventricle. We recently visualized the histological morphology of the accessory pathway using a three-dimensional image reconstruction technique. However, the morphological and electrophysiological details of an accessory pathway are unclear. Here, we performed computer simulations of anterograde and retrograde accessory pathway conduction using a simplified wall model. We investigated the relationships among the bundle size of the accessory pathway, intercellular conductivity, and accessory conduction. We found that increasing the intercellular conductivity of the atria and ventricle promotes such conduction. By contrast, we found that increasing intercellular conductivity of the accessory pathway prevents accessory conduction. Source-sink theory may explain the first points; an electrotonic effect may explain the second one. Our findings provide new insights into the morphological and electrophysiological details of the accessory pathway.

Electrical excitation conduction abnormalities at the right ventricular outflow tract (RVOT) are one of the arrhythmogenic substrates despite normal heart. However, how much delay at the RVOT develops ventricular arrhythmias is not quantitatively investigated. In this study, we constructed a three-dimensional human ventricular model including 20 million myocardial units to investigate the role of conduction delay in the RVOT on initiation and maintenance of the ventricular arrhythmias. Electrical coupling conductance between two units in the conduction delay zone and size of conduction delay zone could be freely changed. Ventricular arrhythmia inducibility in the heart with conduction delay zone around the RVOT was higher compared with the heart with conduction delay the right ventricular free wall. Anatomical complexities and electrophysiological heterogeneity around the RVOT might act as important role in induction spiral wave reentry to transfer to ventricular arrhythmia.

不整脈の起源となる心室性期外収縮の治療を行うためには、期外収縮の起源を同定する必要がある。本研究では、12誘導心電図から再構成したベクトル心電図の特徴量について検討した。(著者抄録)

【背景】脳梗塞や心不全を引き起こす心房細動(AF)には，肺静脈異常興奮を隔離するカテーテルアブレーション（心筋焼灼）が標準術式である．しかし，慢性化したAFにその術式はあまり有効でなく，AFのリアルタイム映像化に基づく新たな治療戦略が模索されている．【方法】標準術式に抵抗性を示すAFの患者に対し，我々が開発したリアルタイム臨床不整脈映像化システム（ExTRa Mapping）を適用した．心内電位に基づきAFを瞬時に映像化した上で，維持機構であるローター（機能的な興奮旋回）をミニマルな焼灼で制御し(図)，長期予後を含めた臨床的有効性を検討した．【結果】(1)映像化されたAFは，不定在かつ不安定な動態を示す複数ローターで構成され，心房内に偏在するローターの存在確率には時間的再現性があった．(2)従来は心筋を瘢痕化させる強い焼灼が求められたが，AF維持機構を修飾しローターを制御するには，心筋を軽く変性させるミニマル焼灼でも十分なことが，本術後フォローで判明したAF根治率の高さ（79%）から推察された．【結語】標準術式抵抗性AFに対する新たなアブレーション治療戦略の構築に，AFのリアルタイム映像化によるローター制御が有用と強く示唆された．

心臓突然死の原因となる心室細動の発生メカニズムとして，心筋組織内の電気的興奮伝播の不均一性が考えられている．しかしながら，メカニズムの詳細については不明な点が多い．我々の研究グループでは，長年，心臓形状モデルを用いた電気的興奮伝播のシミュレーション研究を行ってきている．本研究では，心室形状モデルを用い，スーパーコンピュータによる電気的興奮伝播のシミュレーションを実行し，電気的興奮伝播が遅延する領域の部位，大きさ，遅延の程度と不整脈の誘発性および持続性との関係について，心電図と位相特異性との観点から検討した．その結果，右室流出路における電気的興奮伝播の遅延は，他の領域に遅延がある場合と比較して，心室性不整脈の誘発性が高いことが明らかとなった．本セッションでは，シミュレーションによる不整脈研究の成果，将来の不整脈の制御や治療などに向けた展望について議論する．

Myocardial bundles working as accessory pathways in Wolff-Parkinson-White (WPW) syndrome are generally tiny tissues, so elucidating the culprit histology of atrioventricular (AV) myocardial connections requires careful serial sectioning of the AV junction. We performed a postmortem examination of accessory AV myocardial connections in an 84-year-old man who died from pneumonia 20 years after surgical cryoablation for WPW syndrome. Three-dimensional reconstruction images of serial histologic sections revealed accessory AV connections between the atrial and ventricular myocardium in the vicinity of the cryoablation scar. The remnant myocardial bridge was 4 mm wide and made up of multiple discontinuous fibers. This case was informative in that it provided for visualization of the histologic morphology of a remnant bundle of Kent.

Background: Effects of nonparoxysmal atrial fibrillation (non-PAF) ablation targeting complex fractionated atrial electrogram (CFAE) areas and/or low voltage areas (LVAs) are still controversial. Methods and Results: A recently developed online real-time phase mapping system (ExTRa Mapping) was used to conduct LVA mapping and simultaneous ExTRa and CFAE mapping in 28 non-PAF patients after pulmonary vein isolation (PVI). Nonpassively activated areas, in the form of meandering rotors and/or multiple wavelets assumed to contain non-PAF drivers, partly overlapped with CFAE/LVAs but not always coincided with them. Conclusion: Real-time rotor imaging, rather than conventional indirect indicators only, might be very useful for detecting non-PAF drivers.

Background: Intra-atrial electrogram-based modulation of atrial fibrillation (AF) drivers has been proposed as an effective ablation strategy for non-paroxysmal AF (Non-PAF). However, whether the modulated areas really contain real AF drivers is unclear. Methods: A recently-developed AF imaging system (ExTRa Mapping) was applied to 28 Non-PAF patients. Non-passively-activated areas (NPAs) assumed to contain Non-PAF drivers were determined. We investigated the correlation between NPAs and indirect indicators of Non-PAF drivers, and the effectiveness of the NPA ablation. Results: (1) In NPAs, typical wave dynamics during Non-PAF were rotational activations in the forms of meandering rotors and/or multiple wavelets. (2) The NPAs did not always coincide with indirect indicators of Non-PAF drivers, and we found no significant correlation among them (P>0.05). (3) The freedom from Non-PAF after the NPA ablation was 79%. Conclusion: Real-time mapping of AF dynamics, rather than mapping of indirect indicators, might be more useful for detecting Non-PAF drivers.

Background The atrioventricular (AV) node is the only compartment that conducts an electrical impulse between the atria and the ventricles. The main role of the AV node is to facilitate efficient pumping by conducting excitation slowly between the two chambers as well as reduce the ventricular rate during atrial fibrillation (AF). Methods Using computer simulations, we investigated excitation conduction from the right atrium to the bundle of His during high-rate atrial excitation with or without partial blocking of the calcium or potassium ionic current. Results Our simulations revealed differences in rate reduction and repolarization effects between calcium and potassium current blocking and high degree of potassium current blocking required to reduce the ventricular rate during AF. Conclusions Our simulation results explain why potassium current blockers are not recommended for controlling ventricular rate during AF.

This chapter presents examples of medical image understanding algorithms using computational anatomy models explained in Chap. 2. After the introductory in Sect. 3.1, Sect. 3.2 shows segmentation algorithms for vertebrae, ribs, and hip joints. Segmentation algorithms for skeletal muscle and detection algorithms for lymph nodes are explained in Sects. 3.3 and 3.4, respectively. Section 3.5 deals with algorithms for understanding organs/tissues in the head and neck regions and starts with computational neuroanatomy, followed by analysis and segmentation algorithms for white matter, brain CT, oral regions, fundus oculi, and retinal optical coherence tomography (OCT). Algorithms useful in the thorax, specifically for the lungs, tracheobronchial tree, vessels, and interlobar fissures from a thoracic CT volume, are presented in Sect. 3.6. Section 3.7 provides algorithms for breast ultrasound imaging, i.e., mammography and breastMRI. Cardiac imaging algorithms in an echocardiographic image sequence and MR images as well as coronary arteries in a CT volume are explained in Sect. 3.8. Section 3.9 deals with segmentation algorithms of abdominal organs, including the liver, pancreas, spleen, kidneys, gastrointestinal tract, and abdominal blood vessels, followed by anatomical labeling of segmented vessels.

<p>Background: Modulation of atrial fibrillation (AF) drivers after pulmonary-vein-isolation (PVI) has been proposed as one of the effective ablation strategies for non-paroxysmal AF (Non-PAF). However, the effectiveness is still controversial because optimal method for detecting AF drivers is unsolved. Methods: We developed an in silico and AI-integrated online real-time phase mapping system called "ExTRa Mapping" to quickly visualize AF wave dynamics. We applied the system to 24 Non-PAF patients and calculated non-passively activated period-to-recording time ratio (%NP). Results: ExTRa Mapping was not conducted in 8 patients because no AF was induced after PVI. In remaining 16 patients, ExTRa Mapping uncovered the non-passively activated areas (NPA) assumed to contain AF drivers. Acute effectiveness of the ExTRa Mapping-guided NPA (ExTRa-NPA) ablation was confirmed by %NP decrease; 65±12% to 36±20%. Non-recurrence rate of the ExTRa-NPA ablation was 81% for 7.7±4.0 months. Conclusion: ExTRa-NPA ablation might improve the long-term outcome of the Non-PAF ablation.</p>

<p>Our research group have been conducting simulation studies for analyzing arrhythmia such as sick sinus syndrome, atrial fibrillation, ventricular tachycardia and fibrillation using multi-scale heart models with personal computer and supercomputer. One purpose of our simulation studies is to stratify the arrhythmic risk non-invasively using computer simulation. Recent study has shown that conduction delay around the right ventricular outflow tract is one of the mechanisms to induce ventricular arrhythmias such as Brugada syndrome. Our findings from computer simulation suggest that our model may be useful to stratify the arrhythmic risk in the Brugada syndrome. In this symposium, we will present our simulation scheme and recent progresses. In addition, we would like to discuss our future prospect and the possibility of computer simulation.</p>

<p>Effectiveness of electrogram-based ablation for chronic atrial fibrillation (CAF) is still controversial.</p><p>Methods: To develop a new approach to driver ablation, we recently developed a novel online rapid CAF visualization system (ExTRa Mapping), and conducted catheter ablation in 15 CAF patients.</p><p>Results: (1) ExTRa Mapping demonstrated no stationary rotors. Instead, regions with passive activations and/or non-passive activations (multiple wavelets and meandering rotors) were observed. (2) ExTRa-guided ablation targeting non-passive activations terminated the CAF or reduced the CAF inducibility.</p><p>Conclusion: The ExTRa Mapping could open a new avenue for CAF ablation.</p>

The aim of this study was to elucidate the effects of myocardial fiber orientation on the deformation of the left ventricular (LV) wall. An LV wall model was constructed by modeling the myocardial fiber structure as an anisotropic hyperelastic material. The shapes of the endocardium and epicardium were assumed to be two spheroids. LV wall deformation by constriction of the myocardial fibers was simulated for three fiber orientations: the myocardial fiber was oriented parallel to the short-axis plane (Case 1) the angle between the myocardial fiber andthe short-axis plane variedlinearly from ＋π/3 in the endocardium to –π/3 in the epicardium (Case 2) andthe myocardial fiber was uniformly orientedat an angle of−π/3 with respect to the short-axis plane (Case 3)．The results showedthat the LV wall deformation was governedby the interaction among the constriction of fibers, the wall deformation as a continuum body, and the geometric constrains of the LV anatomy. Comparing the results of three cases revealedthat the helical structure of fibers contributes to cause a twisting motion and efficient contraction of the LV wall, which produces a heterogeneous distribution of the deformation rates in the LV wall.

Background: Cardiomyocytes located at the ischemic border zone of infarcted ventricle are accompanied by redistribution of gap junctions, which mediate electrical transmission between cardiomyocytes. This ischemic border zone provides an arrhythmogenic substrate. It was also shown that sodium (Na+) channels are redistributed within myocytes located in the ischemic border zone. However, the roles of the subcellular redistribution of Na+ channels in the arrhythmogenicity under ischemia remain unclear. Methods: Computer simulations of excitation conduction were performed in a myofiber model incorporating both subcellular Na+ channel redistribution and the electric field mechanism, taking into account the intercellular cleft potentials. Results: We found in the myofiber model that the subcellular redistribution of the Na+ channels under myocardial ischemia, decreasing in Na+ channel expression of the lateral cell membrane of each myocyte, decreased the tissue excitability, resulting in conduction slowing even without any ischemia-related electrophysiological change. The conventional model (i.e., without the electric field mechanism) did not reproduce the conduction slowing caused by the subcellular Na+ channel redistribution. Furthermore, Na+ channel blockade with the coexistence of a non-ischemic zone with an ischemic border zone expanded the vulnerable period for reentrant tachyarrhythmias compared to the model without the ischemic border zone. Na+ channel blockade tended to cause unidirectional conduction block at sites near the ischemic border zone. Thus, such a unidirectional conduction block induced by a premature stimulus at sites near the ischemic border zone is associated with the initiation of reentrant tachyarrhythmias. Conclusions: Proarrhythmia of Na+ channel blockade in patients with old myocardial infarction might be partly attributable to the ischemia-related subcellular Na+ channel redistribution.

The Purkinje network is one of the electrical excitation conduction systems in the heart and represents the most distal portion of the ventricular conduction system. Gap junction channels provide a pathway for electrical signaling between cells. A recent study identified a mutation that reduces the gap junction conductance in patients with ventricular arrhythmias. To elucidate underlying mechanisms, we studied the relationship between gap junction conductance in the Purkinje network and ventricular arrhythmias using computer simulations. We constructed His-Purkinje-ventricular network models composed of ≈13,000 cells, in which neighbouring cells were connected by gap junction channels. At lower gap junction conductances, reentrant beats occurred. When one of the reentrant circuits was disconnected, reentrant beats did not persist in many cases as a consequence of altering dynamics in excitation conduction. Our simulation results suggest that both Purkinje network structure and gap junction conductance are important factors for generating arrhythmias in the Purkinje network.

Recently, arrhythmia studies have been attempted to use myocardial sheets consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). However, whether the electrophysiological property of hiPSC-CM is consistent with that of original human cardiomyocytes (hCM) is still unclear. In the present study, in silico myocardial sheets of hCM and hiPSC-CM were constructed, and simulations of spiral wave reentry were performed. Then we found that (1) conduction velocity (CV) in the hiPSC-CM sheet was ~5 cm/s, which was ~1/10 of CV in the hCM sheet, (2) mean excitation frequency (mEF) during the spiral wave reentry in the hiPSC-CM sheet was ~0.9Hz, whereas that in the hCM sheet was 5-6Hz identical to real human ventricular fibrillation ~6Hz, and (3) both the CV and mEF in the hiPSC-CM sheet model were very consistent with previous experimental data. Such in silico analytical approach might fill the gap between hiPSC-CM and original hCM sheets.