Takashi Ashihara

Publications of Takashi Ashihara

• The role of fibroblasts in complex fractionated electrograms during persistent/permanent atrial fibrillation: implications for electrogram-based catheter ablation.

  Authors: Takashi Ashihara, Ryo Haraguchi, Kazuo Nakazawa, Tsunetoyo Namba, Takanori Ikeda, Yuko Nakazawa, Tomoya Ozawa, Makoto Ito, Minoru Horie, Natalia A Trayanova

  Circulation research. 12/2011; 110(2):275-84.

  Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF).Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear. Because atrial fibrosis is associated with persistent/permanent AF, we hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation. We used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone. Fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/permanent AF. Our findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.

• Mechanisms of Defibrillation Failure

  Authors: Takashi Ashihara, Jason Constantino, Natalia A. Trayanova

  09/2011;

  ISBN: 978-953-307-666-9

• Regional cooling facilitates termination of spiral-wave reentry through unpinning of rotors in rabbit hearts.

  Authors: Masatoshi Yamazaki, Haruo Honjo, Takashi Ashihara, Masahide Harada, Ichiro Sakuma, Kazuo Nakazawa, Natalia Trayanova, Minoru Horie, Jérôme Kalifa, José Jalife, Kaichiro Kamiya, Itsuo Kodama

  Heart rhythm : the official journal of the Heart Rhythm Society. 08/2011; 9(1):107-14.

  Moderate global cooling of myocardial tissue was shown to destabilize 2-dimensional (2-D) reentry and facilitate its termination. This study sought to test the hypothesis that regional coolingModerate global cooling of myocardial tissue was shown to destabilize 2-dimensional (2-D) reentry and facilitate its termination. This study sought to test the hypothesis that regional cooling destabilizes rotors and facilitates termination of spontaneous and DC shock-induced subepicardial reentry in isolated, endocardially ablated rabbit hearts. Fluorescent action potential signals were recorded from 2-D subepicardial ventricular myocardium of Langendorff-perfused rabbit hearts. Regional cooling (by 5.9°C ± 1.3°C) was applied to the left ventricular anterior wall using a transparent cooling device (10 mm in diameter). Regional cooling during constant stimulation (2.5 Hz) prolonged the action potential duration (by 36% ± 9%) and slightly reduced conduction velocity (by 4% ± 4%) in the cooled region. Ventricular tachycardias (VTs) induced during regional cooling terminated earlier than those without cooling (control): VTs lasting >30 seconds were reduced from 17 of 39 to 1 of 61. When regional cooling was applied during sustained VTs (>120 seconds), 16 of 33 (48%) sustained VTs self-terminated in 12.5 ± 5.1 seconds. VT termination was the result of rotor destabilization, which was characterized by unpinning, drift toward the periphery of the cooled region, and subsequent collision with boundaries. The DC shock intensity required for cardioversion of the sustained VTs decreased significantly by regional cooling (22.8 ± 4.1 V, n = 16, vs 40.5 ± 17.6 V, n = 21). The major mode of reentry termination by DC shocks was phase resetting in the absence of cooling, whereas it was unpinning in the presence of cooling. Regional cooling facilitates termination of 2-D reentry through unpinning of rotors.

• Identification and functional characterization of KCNQ1 mutations around the exon 7-intron 7 junction affecting the splicing process.

  Authors: Keiko Tsuji-Wakisaka, Masaharu Akao, Takahiro M Ishii, Takashi Ashihara, Takeru Makiyama, Seiko Ohno, Futoshi Toyoda, Kenichi Dochi, Hiroshi Matsuura, Minoru Horie

  Biochimica et biophysica acta. 07/2011; 1812(11):1452-9.

  KCNQ1 gene encodes the delayed rectifier K(+) channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. WeKCNQ1 gene encodes the delayed rectifier K(+) channel in cardiac muscle, and its mutations cause long QT syndrome type 1 (LQT1). Especially exercise-related cardiac events predominate in LQT1. We previously reported that a KCNQ1 splicing mutation displays LQT1 phenotypes. We identified novel mutation at the third base of intron 7 (IVS7 +3A>G) in exercise-induced LQT1 patients. Minigene assay in COS7 cells and RT-PCR analysis of patients' lymphocytes demonstrated the presence of exon 7-deficient mRNA in IVS7 +3A>G, as well as c.1032G>A, but not in c.1022C>T. Real-time RT-PCR demonstrated that both IVS7 +3A>G and c.1032G>A carrier expressed significant amounts of exon-skipping mRNAs (18.8% and 44.8% of total KCNQ1 mRNA). Current recordings from Xenopus oocytes injected cRNA by simulating its ratios of exon skipping displayed a significant reduction in currents to 64.8 ± 4.5% for IVS7 +3A>G and to 41.4 ± 9.5% for c.1032G>A carrier, respectively, compared to the condition without splicing error. Computer simulation incorporating these quantitative results revealed the pronounced QT prolongation under beta-adrenergic stimulation in IVS7 +3A>G carrier model. Here we report a novel splicing mutation IVS7 +3A>G, identified in a family with mild form LQT1 phenotypes, and examined functional outcome in comparison with three other variants around the exon 7-intron 7 junction. In addition to c.1032G>A mutation, IVS7 +3A>G generates exon-skipping mRNAs, and thereby causing LQT1 phenotype. The severity of clinical phenotypes appeared to differ between the two splicing-related mutations and to result from the amount of resultant mRNAs and their functional consequences.

• Roles of subcellular Na+ channel distributions in the mechanism of cardiac conduction.

  Authors: Kunichika Tsumoto, Takashi Ashihara, Ryo Haraguchi, Kazuo Nakazawa, Yoshihisa Kurachi

  Biophysical journal. 02/2011; 100(3):554-63.

  The gap junction and voltage-gated Na(+) channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na(+) channelThe gap junction and voltage-gated Na(+) channel play an important role in the action potential propagation. The purpose of this study was to elucidate the roles of subcellular Na(+) channel distribution in action potential propagation. To achieve this, we constructed the myocardial strand model, which can calculate the current via intercellular cleft (electric-field mechanism) together with gap-junctional current (gap-junctional mechanism). We conducted simulations of action potential propagation in a myofiber model where cardiomyocytes were electrically coupled with gap junctions alone or with both the gap junctions and the electric field mechanism. Then we found that the action potential propagation was greatly affected by the subcellular distribution of Na(+) channels in the presence of the electric field mechanism. The presence of Na(+) channels in the lateral membrane was important to ensure the stability of propagation under conditions of reduced gap-junctional coupling. In the poorly coupled tissue with sufficient Na(+) channels in the lateral membrane, the slowing of action potential propagation resulted from the periodic and intermittent dysfunction of the electric field mechanism. The changes in the subcellular Na(+) channel distribution might be in part responsible for the homeostatic excitation propagation in the diseased heart.

• Modeling defibrillation of the heart: approaches and insights.

  Authors: Natalia Trayanova, Jason Constantino, Takashi Ashihara, Gernot Plank

  IEEE reviews in biomedical engineering. 01/2011; 4:89-102.

  Cardiac defibrillation, as accomplished nowadays by automatic, implantable devices (ICDs), constitutes the most important means of combating sudden cardiac death. While ICD therapy has proved to beCardiac defibrillation, as accomplished nowadays by automatic, implantable devices (ICDs), constitutes the most important means of combating sudden cardiac death. While ICD therapy has proved to be efficient and reliable, defibrillation is a traumatic experience. Thus, research on defibrillation mechanisms, particularly aimed at lowering defibrillation voltage, remains an important topic. Advancing our understanding towards a full appreciation of the mechanisms by which a shock interacts with the heart is the most promising approach to achieve this goal. The aim of this paper is to assess the current state-of-the-art in ventricular defibrillation modeling, focusing on both numerical modeling approaches and major insights that have been obtained using defibrillation models, primarily those of realistic ventricular geometry. The paper showcases the contributions that modeling and simulation have made to our understanding of the defibrillation process. The review thus provides an example of biophysically based computational modeling of the heart (i.e., cardiac defibrillation) that has advanced the understanding of cardiac electrophysiological interaction at the organ level and has the potential to contribute to the betterment of the clinical practice of defibrillation.

• Sketch-based Dynamic Illustration of Fluid Systems.

  Authors: Bo Zhu, Michiaki Iwata, Ryo Haraguchi, Takashi Ashihara, Nobuyuki Umetani, Takeo Igarashi, Kazuo Nakazawa

  ACM Trans. Graph. 01/2011; 30:134.

• Bepridil facilitates early termination of spiral-wave reentry in two-dimensional cardiac muscle through an increase of intercellular electrical coupling.

  Authors: Hiroki Takanari, Haruo Honjo, Yoshio Takemoto, Tomoyuki Suzuki, Sara Kato, Masahide Harada, Yusuke Okuno, Takashi Ashihara, Tobias Opthof, Ichiro Sakuma, Kaichiro Kamiya, Itsuo Kodama

  Journal of pharmacological sciences. 01/2011; 115(1):15-26.

  Bepridil is effective for conversion of atrial fibrillation to sinus rhythm and in the treatment of drug-refractory ventricular tachyarrhythmias. We investigated the effects of bepridil onBepridil is effective for conversion of atrial fibrillation to sinus rhythm and in the treatment of drug-refractory ventricular tachyarrhythmias. We investigated the effects of bepridil on electrophysiological properties and spiral-wave (SW) reentry in a 2-dimensional ventricular muscle layer of isolated rabbit hearts by optical mapping. Ventricular tachycardia (VT) induced in the presence of bepridil (1 µM) terminated earlier than in the control. Bepridil increased action potential duration (APD) by 5% - 8% under constant pacing and significantly increased the space constant. There was a linear relationship between the wavefront curvature (κ) and local conduction velocity: LCV = LCV₀ - D·κ (D, diffusion coefficient; LCV₀, LCV at κ = 0). Bepridil significantly increased D and LCV₀. The regression lines with and without bepridil crossed at κ = 20 - 40 cm⁻¹, resulting in a paradoxical decrease of LCV at κ > 40 cm⁻¹. Dye transfer assay in cultured rat cardiomyocytes confirmed that bepridil increased intercellular coupling. SW reentry in the presence of bepridil was characterized by decremental conduction near the rotation center, prominent drift, and self-termination by collision with boundaries. These results indicate that bepridil causes an increase of intercellular coupling and a moderate APD prolongation, and this combination compromises wavefront propagation near the rotation center of SW reentry, leading to its drift and early termination.

• Transmural dispersion of repolarization determines scroll wave behavior during ventricular tachyarrhythmias.

  Authors: Ryo Haraguchi, Takashi Ashihara, Tsunetoyo Namba, Kunichika Tsumoto, Shingo Murakami, Yoshihisa Kurachi, Takanori Ikeda, Kazuo Nakazawa

  Circulation journal : official journal of the Japanese Circulation Society. 12/2010; 75(1):80-8.

  Ventricular tachyarrhythmia is the leading cause of sudden cardiac death, and scroll wave re-entry is known to underlie this condition. Class III antiarrhythmic drugs are commonly used worldwide toVentricular tachyarrhythmia is the leading cause of sudden cardiac death, and scroll wave re-entry is known to underlie this condition. Class III antiarrhythmic drugs are commonly used worldwide to treat ventricular tachyarrhythmias; however, these drugs have a proarrhythmic adverse effect and can cause Torsade de Pointes or ventricular fibrillation. Transmural dispersion of repolarization (TDR) has been suggested to be a strong indicator of ventricular tachyarrhythmia induction. However, the role of TDR during sustained scroll wave re-entry is poorly understood. The purpose of the present study was to investigate how TDR affects scroll wave behavior and to provide a novel analysis of the mechanisms that sustain tachyarrhythmias, using computer simulations. Computer simulations were carried out to quantify the TDR and QT interval under a variety of I(Ks) and I(Kr) during transmural conduction. Simulated scroll wave re-entries were done under a variety of I(Ks) and I(Kr) in a ventricular wall slab model, and the scroll wave behavior and the filament dynamics (3-dimensional organizing center) were analyzed. A slight increase in TDR, but not in the QT interval, reflected antiarrhythmic properties resulting from the restraint of scroll wave breakup, whereas a marked increase in TDR was proarrhythmic, as a result of scroll wave breakup. The TDR determines the sustainment of ventricular tachyarrhythmias, through control of the scroll wave filament dynamics.

• Tunnel propagation following defibrillation with ICD shocks: hidden postshock activations in the left ventricular wall underlie isoelectric window.

  Authors: Jason Constantino, Yun Long, Takashi Ashihara, Natalia A Trayanova

  Heart rhythm : the official journal of the Heart Rhythm Society. 03/2010; 7(7):953-61.

  After near-defibrillation threshold (DFT) shocks from an implantable cardioverter-defibrillator (ICD), the first postshock activation that leads to defibrillation failure arises focally after anAfter near-defibrillation threshold (DFT) shocks from an implantable cardioverter-defibrillator (ICD), the first postshock activation that leads to defibrillation failure arises focally after an isoelectric window (IW). The mechanisms underlying the IW remain incompletely understood. The goal of this study was to provide mechanistic insight into the origins of postshock activations and IW after ICD shocks, and to link shock outcome to the preshock state of the ventricles. We hypothesized that the nonuniform ICD field results in the formation of an intramural excitable area (tunnel) only in the left ventricular (LV) free wall, through which both pre-existing and new shock-induced wavefronts propagate during the IW. Simulations were conducted using a realistic three dimensional (3D) model of defibrillation in the rabbit ventricles. Biphasic ICD shocks of varying strengths were delivered to 27 different fibrillatory states. After near-DFT shocks, regardless of preshock state, the main postshock excitable area was always located within LV free wall, creating an intramural tunnel. Either pre-existing fibrillatory or shock-induced wavefronts propagated during the IW (duration of up to 74 ms) in this tunnel and emerged as breakthroughs on LV epicardium. Preshock activity within the LV played a significant role in shock outcome: a large number of preshock filaments resulted in an IW associated with tunnel propagation of pre-existing rather than shock-induced wavefronts. Furthermore, shocks were more likely to succeed if the LV excitable area was smaller. The LV intramural excitable area is the primary reason for near-DFT failure. Any intervention that decreases the extent of this area will improve the likelihood of defibrillation success.

• Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome.

  Authors: Hideki Itoh, Tomoko Sakaguchi, Wei-Guang Ding, Eiichi Watanabe, Ichiro Watanabe, Yukiko Nishio, Takeru Makiyama, Seiko Ohno, Masaharu Akao, Yukei Higashi [......] Yuko Nakazawa, Takenori Yao, Hikari Jo, Yoshihisa Sugimoto, Takashi Ashihara, Hideki Hayashi, Makoto Ito, Keiji Imoto, Hiroshi Matsuura, Minoru Horie

  Circulation. Arrhythmia and electrophysiology. 10/2009; 2(5):511-23.

  BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency amongBACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.

• Endothelin-1 as a predictor of atrial fibrillation recurrence after pulmonary vein isolation.

  Authors: Yuko Nakazawa, Takashi Ashihara, Takayoshi Tsutamoto, Makoto Ito, Minoru Horie

  Heart rhythm : the official journal of the Heart Rhythm Society. 06/2009; 6(6):725-30.

  BACKGROUND: A considerable rate of atrial fibrillation (AF) recurrence is one of the major limitations of pulmonary vein isolation (PVI). Although endothelin-1 (ET-1) is involved in atrialBACKGROUND: A considerable rate of atrial fibrillation (AF) recurrence is one of the major limitations of pulmonary vein isolation (PVI). Although endothelin-1 (ET-1) is involved in atrial remodeling, it is unknown whether plasma ET-1 level before PVI can be used as a predictive factor for AF recurrence. OBJECTIVE: The goal of this study was to clarify whether the plasma ET-1 level, before PVI, can be used as a predictive factor for AF recurrence after PVI. METHODS: Fifty-one patients without structural heart disease who underwent PVI for symptomatic and drug-refractory paroxysmal/persistent AF were included in the study. Neurohumoral factors were measured, and transthoracic echocardiography was performed before and 6 months after each PVI. Mean left atrial (LA) pressure and arterial blood pressure (BP) were evaluated just before PVI. AF recurrence was detected by 12-lead electrocardiogram (ECG), Holter ECG, and event ECG monitor recordings, 3 to 6 months after PVI. RESULTS: Among plasma levels of ET-1, atrial and brain natriuretic peptides, renin, angiotensin II, and aldosterone before PVI, only ET-1 was significantly higher in the recurrence group compared with the nonrecurrence group (2.15 +/- 0.51 vs. 1.65 +/- 0.35 pg/ml, P < .001). Both mean LA pressure and diastolic BP in the recurrence group were significantly higher than in the nonrecurrence group (mean LA pressure, 10 +/- 3 vs. 8 +/- 3 mm Hg, P < .01; diastolic BP, 82 +/- 11 vs. 71 +/- 12 mm Hg, P < .01). The plasma ET-1 level and mean LA pressure were correlative. Multiple logistic regression analyses showed that higher levels of plasma ET-1 and diastolic BP were significant prognostic predictors of AF recurrence 3 to 6 months after PVI (P < .01 and P < .05, respectively). CONCLUSION: Our findings suggest that the plasma ET-1 level before PVI could be a crucial predictor of AF recurrence 3 to 6 months after PVI.

• Hydroxyzine, a First Generation H(1)-Receptor Antagonist, Inhibits Human Ether-a-go-go-Related Gene (HERG) Current and Causes Syncope in a Patient With the HERG Mutation.

  Authors: Tomoko Sakaguchi, Hideki Itoh, Wei-Guang Ding, Keiko Tsuji, Iori Nagaoka, Yuko Oka, Takashi Ashihara, Makoto Ito, Yoshihiro Yumoto, Naoko Zenda, Yukei Higashi, Youichi Takeyama, Hiroshi Matsuura, Minoru Horie

  Journal of pharmacological sciences. 01/2009;

  QT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiacQT prolongation, a risk factor for arrhythmias, can result from genetic variants in one (or more) of the genes governing cardiac repolarization as well as intake of drugs known to affect a cardiac K(+) channel encoded by human ether-a-go-go-related gene (HERG). In this paper, we will report a case of drug-induced long QT syndrome associated with an H(1)-receptor antagonist, hydroxyzine, in which a mutation was identified in the HERG gene. After taking 75 mg of hydroxyzine for several days, a 34-year-old female began to experience repetitive syncope. The deleterious effect of hydroxyzine was suspected because QTc interval shortened from 630 to 464 ms after cessation of the drug. Later on, the patient was found to harbor an A614V-HERG mutation. By using the patch-clamp technique in the heterologous expression system, we examined the functional outcome of the A614V mutation and confirmed a dominant-negative effect on HERG expression. Hydroxyzine concentration-dependently inhibited both wild-type (WT) and WT/A614V-HERG K(+) currents. Half-maximum block concentrations of WT and WT/A614V-HERG K(+) currents were 0.62 and 0.52 muM, respectively. Thus, accidental combination of genetic mutation and intake of hydroxyzine appeared to have led to a severe phenotype, probably, syncope due to torsade de pointes.

• Dynamic Change in ST-Segment and Spontaneous Occurrence of Ventricular Fibrillation in Brugada Syndrome With a Novel Nonsense Mutation in the SCN5A Gene During Long-Term Follow-up.

  Authors: Mihoko Kawamura, Tomoya Ozawa, Takenori Yao, Takashi Ashihara, Yoshihisa Sugimoto, Takafumi Yagi, Hideki Itoh, Makoto Ito, Takeru Makiyama, Minoru Horie

  Circulation journal : official journal of the Japanese Circulation Society. 01/2009;

  A 67-year-old male underwent genetic testing under the diagnosis of Brugada syndrome because of recurrent ventricular fibrillation with coincident ST-segment elevation in either right precordial,A 67-year-old male underwent genetic testing under the diagnosis of Brugada syndrome because of recurrent ventricular fibrillation with coincident ST-segment elevation in either right precordial, inferior leads or both since the age of 55 years. Screening of gene mutations using denaturing high-performance liquid chromatography (DHPLC) and direct sequencing identified a novel nonsense mutation (R179X) of SCN5A in a heterozygous manner. The functional assay for the identified mutation, using a whole-cell patch clamp in the heterologous expression system, revealed that the nonsense mutation, located in the second transmembrane segment of the first domain (DI-S2) of the alpha-subunit, failed to synthesize the complete structure of the cardiac sodium channel, thus causing the non-functional channel. Coding effects by the gene mutation was altered during the 12-year follow-up, which might affect the clinical features of the patient through the ion channel density in the ventricle, dynamics of repolarization abnormality and conduction disturbance.

• A Sketch-Based Interface for Modeling Myocardial Fiber Orientation that Considers the Layered Structure of the Ventricles.

  Authors: Kenshi Takayama, Takashi Ashihara, Takashi Ijiri, Takeo Igarashi, Ryo Haraguchi, Kazuo Nakazawa

  The journal of physiological sciences : JPS. 11/2008;

  We propose a sketch-based interface for modeling the myocardial fiber orientation required in the electrophysiological simulation of the heart, especially the ventricles. The user can create aWe propose a sketch-based interface for modeling the myocardial fiber orientation required in the electrophysiological simulation of the heart, especially the ventricles. The user can create a volumetric vector field that represents the myocardial fiber orientation in two steps. First, the user defines a depth field over the three-dimensional (3D) ventricular model to create layers of myocardium. Then, the user can peel these layers and draw strokes on them to specify the myocardial fiber orientation in each layer. We represent the 3D ventricular model as a tetrahedral mesh and perform Laplacian smoothing over the mesh vertices to interpolate the vector field defined by the user-drawn strokes. Our method also allows the user to perform deformations on volumetric models of myocardial fiber orientation, which is very important for studying heart disease associated with morphological abnormalities. We created several examples of myocardial fiber orientation and applied them to a simplified simulator to demonstrate the effectiveness of our method.

• A Procedural Method for Modeling the Purkinje Fibers of the Heart.

  Authors: Takashi Ijiri, Takashi Ashihara, Takeshi Yamaguchi, Kenshi Takayama, Takeo Igarashi, Tatsuo Shimada, Tsunetoyo Namba, Ryo Haraguchi, Kazuo Nakazawa

  The journal of physiological sciences : JPS. 11/2008;

  The Purkinje fibers are located in the ventricular walls of the heart, just beneath the endocardium and conduct excitation from the right and left bundle branches to the ventricular myocardium.The Purkinje fibers are located in the ventricular walls of the heart, just beneath the endocardium and conduct excitation from the right and left bundle branches to the ventricular myocardium. Recently, anatomists succeeded in photographing the Purkinje fibers of a sheep, which clearly showed the mesh structure of the Purkinje fibers. In this study, we present a technique for modeling the mesh structure of Purkinje fibers semiautomatically using an extended L-system. The L-system is a formal grammar that defines the growth of a fractal structure by generating rules (or rewriting rules) and an initial structure. It was originally formulated to describe the growth of plant cells, and has subsequently been applied for various purposes in computer graphics such as modeling plants, buildings, streets, and ornaments. For our purpose, we extended the growth process of the L-system as follows: 1) each growing branch keeps away from existing branches as much as possible to create a uniform distribution, and 2) when branches collide, we connect the colliding branches to construct a closed mesh structure. We designed a generating rule based on observations of the photograph of Purkinje fibers and manually specified three terminal positions on a three-dimensional (3D) heart model: those of the right bundle branch, the anterior fascicle, and the left posterior fascicle of the left branch. Then, we grew fibers starting from each of the three positions based on the specified generating rule. We achieved to generate 3D models of Purkinje fibers of which physical appearances closely resembled the real photograph. The generation takes a few seconds. Variations of the Purkinje fibers could be constructed easily by modifying the generating rules and parameters.

• A novel KCNH2 mutation as a modifier for short QT interval.

  Authors: Hideki Itoh, Tomoko Sakaguchi, Takashi Ashihara, Wei-Guang Ding, Iori Nagaoka, Yuko Oka, Yuko Nakazawa, Takenori Yao, Hikari Jo, Makoto Ito, Kazufumi Nakamura, Tohru Ohe, Hiroshi Matsuura, Minoru Horie

  International journal of cardiology. 09/2008;

  In a 34-year-old man showing short QT interval (QTc 329 ms), we identified a novel C-terminal KCNH2 mutation, R1135H. Using a heterologous expression system with CHO cells, the mutant channels wereIn a 34-year-old man showing short QT interval (QTc 329 ms), we identified a novel C-terminal KCNH2 mutation, R1135H. Using a heterologous expression system with CHO cells, the mutant channels were found to display a significantly slow deactivation, which resulted in a gain-of-function for reconstituted 'I(Kr)' channels. This mutation could modify clinical phenotypes for this patient.

• Mutation site dependent variability of cardiac events in Japanese LQT2 form of congenital long-QT syndrome.

  Authors: Iori Nagaoka, Wataru Shimizu, Hideki Itoh, Satoshi Yamamoto, Tomoko Sakaguchi, Yuko Oka, Keiko Tsuji, Takashi Ashihara, Makoto Ito, Hidetada Yoshida, Seiko Ohno, Takeru Makiyama, Yoshihiro Miyamoto, Takashi Noda, Shiro Kamakura, Masaharu Akao, Minoru Horie

  Circulation journal : official journal of the Japanese Circulation Society. 06/2008; 72(5):694-9.

  BACKGROUND: In the LQT2 form of long QT syndrome (LQTS), mutation sites are reported to correlate with clinical phenotypes in Caucasians, but the relationship in Asian patients remains unknown. TheBACKGROUND: In the LQT2 form of long QT syndrome (LQTS), mutation sites are reported to correlate with clinical phenotypes in Caucasians, but the relationship in Asian patients remains unknown. The present study was designed to determine whether the location of KCNH2 mutations would influence the arrhythmic risk in LQT2 patients. METHODS AND RESULTS: In 118 genetically-confirmed LQT2 patients (69 families, 62 KCNH2 mutations), the ECG parameters, Schwartz scores, and the incidence of cardiac events, defined as syncope, aborted cardiac arrest, and sudden cardiac death, were evaluated. To examine the effect of mutation sites, the participants were divided accordingly: pore (n=56) and non-pore (n=62) groups. The corrected QTend interval was significantly greater in the pore than in the non-pore group (QTc; 522+/-63 ms vs 490+/-49 ms, p=0.002). In this study, the clinical course of each of the probands did not differ according to the mutation sites, whereas non-probands carrying the pore site mutation experienced their first cardiac events at significantly younger age than those with the non-pore site mutation (log-rank, p=0.0005). CONCLUSIONS: In a Japanese LQT2 cohort, family members with the pore site mutation were at higher arrhythmic risk than those with the non-pore site mutation.

• Moderate hypothermia increases the chance of spiral wave collision in favor of self-termination of ventricular tachycardia/fibrillation.

  Authors: Masahide Harada, Haruo Honjo, Masatoshi Yamazaki, Harumichi Nakagawa, Yuko S Ishiguro, Yusuke Okuno, Takashi Ashihara, Ichiro Sakuma, Kaichiro Kamiya, Itsuo Kodama

  American journal of physiology. Heart and circulatory physiology. 05/2008; 294(4):H1896-905.

  In cardiac arrest due to ventricular fibrillation (VF), moderate hypothermia (MH, 33 degrees C) has been shown to improve defibrillation success compared with normothermia (NR, 37 degrees C) andIn cardiac arrest due to ventricular fibrillation (VF), moderate hypothermia (MH, 33 degrees C) has been shown to improve defibrillation success compared with normothermia (NR, 37 degrees C) and severe hypothermia (SH, 30 degrees C). The underlying mechanisms remain unclear. We hypothesized that MH might prevent reentrant excitations rotating around functional obstacles (rotors) that are responsible for the genesis of VF. In two-dimensional Langendorff-perfused rabbit hearts prepared by cryoablation (n = 13), action potential signals were recorded by a high-resolution optical mapping system. During basic stimulation (2.5-5.0 Hz), MH and SH caused significant prolongation of action potential duration and significant reduction of conduction velocity. Wavelength was unchanged at MH, whereas it was shortened significantly at SH at higher stimulation frequencies (4.0-5.0 Hz). The duration of direct current stimulation-induced ventricular tachycardia (VT)/VF was reduced dramatically at MH compared with NR and SH. The spiral wave (SW) excitations documented during VT at NR were by and large organized, whereas those during VT/VF at MH and SH were characterized by disorganization with frequent breakup. Phase maps during VT/VF at MH showed a higher incidence of SW collision (mutual annihilation or exit from the anatomical boundaries), which caused a temporal disappearance of phase singularity points (PS-0), compared with that at NR and SH. There was an inverse relation between PS-0 period in the observation area and VT/VF duration. MH data points were located in a longer PS-0 period and a shorter VT/VF duration zone compared with SH. MH causes a modification of SW dynamics, leading to an increase in the chance of SW collision in favor of self-termination of VT/VF.

• Tunnel propagation of postshock activations as a hypothesis for fibrillation induction and isoelectric window.

  Authors: Takashi Ashihara, Jason Constantino, Natalia A Trayanova

  Circulation research. 04/2008; 102(6):737-45.

  Comprehensive understanding of the ventricular response to shocks is the approach most likely to succeed in reducing defibrillation threshold. We propose a new theory of shock-inducedComprehensive understanding of the ventricular response to shocks is the approach most likely to succeed in reducing defibrillation threshold. We propose a new theory of shock-induced arrhythmogenesis that unifies all known aspects of the response of the heart to monophasic (MS) and biphasic (BS) shocks. The central hypothesis is that submerged "tunnel" propagation of postshock activations through shock-induced intramural excitable areas underlies fibrillation induction and the existence of isoelectric window. We conducted simulations of fibrillation induction using a realistic bidomain model of rabbit ventricles. Following pacing, MS and BS of various strengths/timings were delivered. The results demonstrated that, during the isoelectric window, an activation originated deep within the ventricular wall, arising from virtual electrodes; it then propagated fully intramurally through an excitable tunnel induced by the shock, until it emerged onto the epicardium, becoming the earliest-propagated postshock activation. Differences in shock outcomes for MS and BS were found to stem from the narrower BS intramural postshock excitable area, often resulting in conduction block, and the difference in the mechanisms of origin of the postshock activations, namely intramural virtual electrode-induced phase singularity for MS and virtual electrode-induced propagated graded response for BS. This study provides a novel analysis of the 3D mechanisms underlying the origin of postshock activations in the process of fibrillation induction by MS and BS and the existence of isoelectric window. The tunnel propagation hypothesis could open a new avenue for interventions exploration to achieve significantly lower defibrillation threshold.