Hiroyuki Inoue

All Publications

• Modeling reduced contractility and impaired desmosome assembly due to plakophilin-2 deficiency using isogenic iPS cell-derived cardiomyocytes STEM CELL REPORTS Inoue, H., Nakamura, S., Higo, S., Shiba, M., Kohama, Y., Kondo, T., Kameda, S., Tabata, T., Okuno, S., Ikeda, Y., Li, J., Liu, L., Yamazaki, S., Takeda, M., Ito, E., Takashima, S., Miyagawa, S., Sawa, Y., Hikoso, S., Sakata, Y. 2022; 17 (2): 337-351

  Abstract

  Loss-of-function mutations in PKP2, which encodes plakophilin-2, cause arrhythmogenic cardiomyopathy (AC). Restoration of deficient molecules can serve as upstream therapy, thereby requiring a human model that recapitulates disease pathology and provides distinct readouts in phenotypic analysis for proof of concept for gene replacement therapy. Here, we generated isogenic induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) with precisely adjusted expression of plakophilin-2 from a patient with AC carrying a heterozygous frameshift PKP2 mutation. After monolayer differentiation, plakophilin-2 deficiency led to reduced contractility, disrupted intercalated disc structures, and impaired desmosome assembly in iPSC-CMs. Allele-specific fluorescent labeling of endogenous DSG2 encoding desmoglein-2 in the generated isogenic lines enabled real-time desmosome-imaging under an adjusted dose of plakophilin-2. Adeno-associated virus-mediated gene replacement of PKP2 recovered contractility and restored desmosome assembly, which was sequentially captured by desmosome-imaging in plakophilin-2-deficient iPSC-CMs. Our isogenic set of iPSC-CMs recapitulates AC pathology and provides a rapid and convenient cellular platform for therapeutic development.

  View details for DOI 10.1016/j.stemcr.2021.12.016

  View details for Web of Science ID 000767587200002

  View details for PubMedID 35063130

  View details for PubMedCentralID PMC8828557

• Overhanging Bioresorbable Vascular Scaffold Observed on Angioscopy 1 Year After Implantation CIRCULATION JOURNAL Inoue, H., Okamura, A., Iwamoto, M., Sumiyoshi, A., Tanaka, K., Takayasu, K., Kawamura, K., Koyama, Y., Inoue, K., Iwakura, K., Fujii, K., Sakata, Y., Nagai, H. 2020; 84 (9): 1605

  View details for DOI 10.1253/circj.CJ-20-0315

  View details for Web of Science ID 000563764000025

  View details for PubMedID 32684538

• Burden and Long Firing of Premature Atrial Contraction Early After Catheter Ablation Predict Late Recurrence of Atrial Fibrillation CIRCULATION JOURNAL Inoue, H., Tanaka, N., Tanaka, K., Ninomiya, Y., Hirao, Y., Oka, T., Okada, M., Kitagaki, R., Takayasu, K., Koyama, Y., Okamura, A., Iwakura, K., Fujii, K., Sakata, Y., Inoue, K. 2020; 84 (6): 894-901

  Abstract

  Associations between characteristics of premature atrial contraction (PAC) 6 months after catheter ablation (CA) and later recurrence are not known. We investigated the effects of PAC characteristics on long-term outcomes of initially successful atrial fibrillation (AF) ablation.Methods and Results:In all, 378 patients (mean age 61 years, 21% female, 67% paroxysmal AF) who underwent initial radiofrequency CA for AF without recurrence up to 24-h Holter monitoring 6 months after the procedure were reviewed retrospectively. The calculated number of PAC/24 h and the length of the longest PAC run during Holter recording were analyzed. After 4.3±1.2 years (mean±SD) follow-up, 123 (32.5%) patients experienced late recurrence. Patients with recurrence had significantly more PAC/24 h (median [interquartile range] 110 [33-228] vs. 42 [16-210]; P<0.01) and a longer longest PAC run (5 [2-8] vs. 3 [1-5]; P<0.01) than those without. Receiver operating characteristic curve analysis indicated 58 PAC/24 h and a longest PAC run of 5 were optimal cut-off values for predicting recurrence. After adjusting for previously reported predictors of late recurrence, frequent PAC (≥58/24 h) and longest PAC run ≥5 were found to be independent predictors of late recurrence (hazard ratios [95% confidence intervals] 1.93 [1.24-3.02; P<0.01] and 1.81 [1.20-2.76; P<0.01], respectively).Six months after successful AF ablation, both frequent PAC and long PAC run are independent predictors of late recurrence.

  View details for DOI 10.1253/circj.CJ-19-0976

  View details for Web of Science ID 000537219400007

  View details for PubMedID 32188830

• Multiplexed measurement of cell type-specific calcium kinetics using high-content image analysis combined with targeted gene disruption BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Tabata, T., Masumura, Y., Higo, S., Kunimatsu, S., Kameda, S., Inoue, H., Okuno, S., Ogawa, S., Takashima, S., Watanabe, M., Miyagawa, S., Hikoso, S., Sakata, Y. 2022; 637: 40-49

  Abstract

  Kinetic analysis of intracellular calcium (Ca2+) in cardiomyocytes is commonly used to determine the pathogenicity of genetic mutations identified in patients with dilated cardiomyopathy (DCM). Conventional methods for measuring Ca2+ kinetics target whole-well cultured cardiomyocytes and therefore lack information concerning individual cells. Results are also affected by heterogeneity in cell populations. Here, we developed an analytical method using CRISPR/Cas9 genome editing combined with high-content image analysis (HCIA) that links cell-by-cell Ca2+ kinetics and immunofluorescence images in thousands of cardiomyocytes at a time. After transfecting cultured mouse cardiomyocytes that constitutively express Cas9 with gRNAs, we detected a prolonged action potential duration specifically in Serca2a-depleted ventricular cardiomyocytes in mixed culture. To determine the phenotypic effect of a frameshift mutation in PKD1 in a patient with DCM, we introduced the mutation into Cas9-expressing cardiomyocytes by gRNA transfection and found that it decreases the expression of PKD1-encoded PC1 protein that co-localizes specifically with Serca2a and L-type voltage-gated calcium channels. We also detected the suppression of Ca2+ amplitude in ventricular cardiomyocytes with decreased PC1 expression in mixed culture. Our HCIA method provides comprehensive kinetic and static information on individual cardiomyocytes and allows the pathogenicity of mutations to be determined rapidly.

  View details for DOI 10.1016/j.bbrc.2022.10.088

  View details for Web of Science ID 000904705300006

  View details for PubMedID 36375249

• Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2 Δ160E-Induced Cardiomyopathy. Circulation. Genomic and precision medicine Kondo, T., Higo, S., Shiba, M., Kohama, Y., Kameda, S., Tabata, T., Inoue, H., Okuno, S., Ogawa, S., Nakamura, S., Takeda, M., Ito, E., Li, J., Liu, L., Kuramoto, Y., Lee, J. K., Takashima, S., Miyagawa, S., Sawa, Y., Hikoso, S., Sakata, Y. 2022; 15 (5): e003522

  Abstract

  The Δ160E mutation in TNNT2, which encodes troponin T, is a rare pathogenic variant identified in patients with hypertrophic cardiomyopathy and is associated with poor prognosis. Thus, a convenient human model recapitulating the pathological phenotype caused by TNNT2 Δ160E is required for therapeutic development.We identified a heterozygous in-frame deletion mutation (c.478_480del, p.Δ160E) in TNNT2 in a patient with familial hypertrophic cardiomyopathy showing progressive left ventricular systolic dysfunction, leading to advanced heart failure. To investigate the pathological phenotype caused by Δ160E, we generated a set of isogenic induced pluripotent stem cells carrying the heterozygous Δ160E, homozygously corrected or homozygously introduced Δ160E using genome editing and differentiated them into cardiomyocytes (Hetero-Δ160E-, wild type-, and Homo-Δ160E-induced pluripotent stem cells [iPSC]-derived cardiomyocytes [iPSC-CMs]).Hetero-Δ160E-iPSC-CMs exhibited prolonged calcium decay, relaxation impairment, and hypertrophy compared to wild type-iPSC-CMs. Notably, these phenotypes were further exacerbated in Homo-Δ160E-iPSC-CMs. Overexpression of R-GECO-fused Δ160E mutant troponin T prolonged decay time and time to peak of the myofilament-localized calcium transient in iPSC-CMs, indicating that sarcomeric calcium retention with Δ160E may affect intracellular calcium concentration. High-content imaging analysis detected remarkable nuclear translocation of NFATc1, especially in Homo-Δ160E-iPSC-CMs, indicating that the Δ160E mutation promotes hypertrophic signaling pathway in a dose-dependent manner. Increased phosphorylation of CaMKIIδ (calcium/calmodulin-dependent protein kinase IIδ) and phospholamban at Thr17 was observed in Homo- and Hetero-Δ160E-iPSC-CMs. Epigallocatechin-3-gallate, a calcium desensitizing compound, shortened prolonged calcium decay and relaxation duration in Δ160E-iPSC-CMs.Isogenic iPSC-CMs recapitulate the prolonged calcium decay, relaxation impairment, and subsequent calcium-regulated signaling pathways caused by the TNNT2 Δ160E mutation and can serve as a human model for therapeutic development to prevent hypertrophic cardiomyopathy pathology.

  View details for DOI 10.1161/CIRCGEN.121.003522

  View details for PubMedID 35861968

  View details for PubMedCentralID PMC9584061

• Absence of first-pass isolation is associated with poor pulmonary vein isolation durability and atrial fibrillation ablation outcomes JOURNAL OF ARRHYTHMIA Ninomiya, Y., Inoue, K., Tanaka, N., Okada, M., Tanaka, K., Onishi, T., Hirao, Y., Oka, T., Inoue, H., Takayasu, K., Nakamaru, R., Kitagaki, R., Koyama, Y., Okamura, A., Iwakura, K., Ohishi, M., Fujii, K. 2021; 37 (6): 1468-1476

  Abstract

  Pulmonary vein (PV) reconnection is the main cause of atrial fibrillation (AF) recurrence. This study aimed to examine the effect of first-pass PV isolation (PVI) on PV reconnection frequency during the procedure and on AF ablation outcomes.This retrospective study included 446 patients with drug-refractory AF (370 men, aged 64 ± 10 years) who underwent initial PVI using an open-irrigated contact force catheter between January 2015 and October 2016. We investigated the effect of first-pass PVI on PV reconnection during spontaneous PV reconnection and dormant conduction after an adenosine triphosphate challenge.First-pass PVI was achieved in 69% (617/892) of ipsilateral PVs, of which we observed PV reconnection during the procedure in 134 (22%) PVs. This value was significantly lower than that observed in those without first-pass PVI (50%, 138/275) (P < .0001). We divided the subjects into two groups based on the presence or absence of first-pass PVI in at least one of two ipsilateral PVs: first-pass (n = 383, 86%) and non-first-pass groups (n = 63, 14%). The 2-year AF recurrence-free rate was significantly higher in the first-pass group than in the other group (75% vs 59%, log-rank P = .032). In 78 patients with repeat AF ablation, the PV reconnection rate in the second procedure was significantly lower in PVs that had first-pass isolation in the first procedure (34% vs 73%, P < .0001).Absence of first-pass PVI was associated with a higher frequency of spontaneous PV reconnection and dormant conduction and poor ablation outcomes. First-pass isolation may be a useful marker for better PVI durability.

  View details for DOI 10.1002/joa3.12629

  View details for Web of Science ID 000692792000001

  View details for PubMedID 34887951

  View details for PubMedCentralID PMC8637089

• Phenotypic recapitulation and correction of desmoglein-2-deficient cardiomyopathy using human-induced pluripotent stem cell-derived cardiomyocytes HUMAN MOLECULAR GENETICS Shiba, M., Higo, S., Kondo, T., Li, J., Liu, L., Ikeda, Y., Kohama, Y., Kameda, S., Tabata, T., Inoue, H., Nakamura, S., Takeda, M., Ito, E., Takashima, S., Miyagawa, S., Sawa, Y., Hikoso, S., Sakata, Y. 2021; 30 (15): 1384-1397

  Abstract

  Desmoglein-2, encoded by DSG2, is one of the desmosome proteins that maintain the structural integrity of tissues, including heart. Genetic mutations in DSG2 cause arrhythmogenic cardiomyopathy, mainly in an autosomal dominant manner. Here, we identified a homozygous stop-gain mutations in DSG2 (c.C355T, p.R119X) that led to complete desmoglein-2 deficiency in a patient with severe biventricular heart failure. Histological analysis revealed abnormal deposition of desmosome proteins, disrupted intercalated disk structures in the myocardium. Induced pluripotent stem cells (iPSCs) were generated from the patient (R119X-iPSC), and the mutated DSG2 gene locus was heterozygously corrected to a normal allele via homology-directed repair (HDR-iPSC). Both isogenic iPSCs were differentiated into cardiomyocytes [induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs)]. Multielectrode array analysis detected abnormal excitation in R119X-iPSC-CMs but not in HDR-iPSC-CMs. Micro-force testing of three-dimensional self-organized tissue rings (SOTRs) revealed tissue fragility and a weak maximum force in SOTRs from R119X-iPSC-CMs. Notably, these phenotypes were significantly recovered in HDR-iPSC-CMs. Myocardial fiber structures in R119X-iPSC-CMs were severely aberrant, and electron microscopic analysis confirmed that desmosomes were disrupted in these cells. Unexpectedly, the absence of desmoglein-2 in R119X-iPSC-CMs led to decreased expression of desmocollin-2 but no other desmosome proteins. Adeno-associated virus-mediated replacement of DSG2 significantly recovered the contraction force in SOTRs generated from R119X-iPSC-CMs. Our findings confirm the presence of a desmoglein-2-deficient cardiomyopathy among clinically diagnosed dilated cardiomyopathies. Recapitulation and correction of the disease phenotype using iPSC-CMs provide evidence to support the development of precision medicine and the proof of concept for gene replacement therapy for this cardiomyopathy.

  View details for DOI 10.1093/hmgAdab127

  View details for Web of Science ID 000731099700002

  View details for PubMedID 33949662

  View details for PubMedCentralID PMC8283207

• Clinical significance of left ventricular reverse remodeling after catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction JOURNAL OF CARDIOLOGY Okada, M., Tanaka, N., Oka, T., Tanaka, K., Ninomiya, Y., Hirao, Y., Yoshimoto, I., Inoue, H., Kitagaki, R., Onishi, T., Koyama, Y., Okamura, A., Iwakura, K., Sakata, Y., Fujii, K., Inoue, K. 2021; 77 (5): 500-508

  Abstract

  Left ventricular (LV) reverse remodeling (LVRR) after catheter ablation of atrial fibrillation (AFCA) has not been fully described. This study investigated the predictors and clinical outcomes of LVRR after AFCA in patients with LV systolic dysfunction.Of 3319 consecutive patients who underwent first-time AFCA between January 2012 and October 2019, 376 with a baseline LV ejection fraction of <50% were retrospectively evaluated. They were subjected to 256-slice multidetector computed tomography (MDCT) scanning at baseline and 3 months after AFCA. The LVRR was defined as a decrease in the LV end-systolic volume of ≥15%.The prevalence of LVRR was 83% (n = 306). Multivariate logistic regression analysis including age, body mass index, diabetic status, beta-blocker use, and LV diastolic diameter revealed that the predictors of LVRR were non-paroxysmal atrial fibrillation (AF) (odds ratio, 2.68; 95% confidence interval, 1.42-5.05; p = 0.002) and absence of apparent underlying structural heart disease (4.81; 2.31-10.0; p <0.001). The prevalence of LVRR differed depending on AF recurrence pattern prior to the post-MDCT [no episode vs. paroxysmal episode (lasting <7 days) vs. persistent episode (lasting ≥7 days), 84% vs. 81% vs. 63%, respectively, p = 0.023]. During a median follow-up of 32 months, the incidence of paroxysmal form of AF recurrence was similar, whereas persistent form of AF recurrence was less frequent in patients with LVRR (10.5% vs. 18.6%, p = 0.018). Heart failure hospitalizations (2.3% vs. 15.7%, p <0.001), cardiovascular deaths (0.7% vs. 4.3%, p = 0.015), and all-cause deaths (1.3% vs. 5.7%, p = 0.018) were similarly less frequent in those with LVRR.LVRR after AFCA, which was predicted by non-paroxysmal AF without any apparent structural heart disease at baseline, was associated with persistent form of AF recurrence prior to the evaluation. LVRR was associated with favorable clinical outcomes.

  View details for DOI 10.1016/j.jjcc.2020.11.007

  View details for Web of Science ID 000634399300010

  View details for PubMedID 33272779

• A case of pulseless electrical activity due to takotsubo syndrome following radiofrequency catheter ablation for atrial fibrillation. Journal of cardiology cases Oka, T., Tanaka, K., Inoue, H., Ninomiya, Y., Tanaka, K., Hirao, Y., Tanaka, N., Okada, M., Takayasu, K., Kitagaki, R., Koyama, Y., Okamura, A., Iwakura, K., Fujii, K., Inoue, K. 2020; 22 (6): 294-298

  Abstract

  A 51-year-old man with normal left ventricular ejection fraction (LVEF) underwent radiofrequency catheter ablation (RFCA) for long-standing persistent atrial fibrillation (AF). After isolating the pulmonary veins (PV), we attempted to ablate multiple non-PV AF triggers evoked by isoproterenol and performed repetitive intracardiac electrical cardioversion under considerable dose of barbiturate. Finally, administration of pilsicainide was required to maintain sinus rhythm. Sixty minutes after the procedure, initiation of development of rapid ST-segment elevation was observed on the continuous electrocardiogram monitor and the patient complained of general fatigue. There was occurrence of complete atrioventricular block and he immediately fell into pulseless electrical activity (PEA). Cardiopulmonary resuscitation was initiated and a percutaneous cardiopulmonary system (PCPS) was provided. Echocardiogram showed severe biventricular systolic dysfunction. Although ST-segment change sustained, emergent coronary angiography was normal. Left ventriculogram showed apical to mid ventricular akinesia and preserved basal contractibility, which was typical of takotsubo syndrome (TS). Fortunately, he recovered completely; the PCPS was weaned on day 5, and the LVEF normalized within 2 weeks without any neurological disorders. This is the first case report of PEA due to TS following AF ablation. TS due to stressors of RFCA procedure should be recognized as a possible life-threatening complication. .

  View details for DOI 10.1016/j.jccase.2020.08.001

  View details for PubMedID 33304425

  View details for PubMedCentralID PMC7718526

• Adeno-associated virus-mediated gene delivery promotes S-phase entry-independent precise targeted integration in cardiomyocytes SCIENTIFIC REPORTS Kohama, Y., Higo, S., Masumura, Y., Shiba, M., Kondo, T., Ishizu, T., Higo, T., Nakamura, S., Kameda, S., Tabata, T., Inoue, H., Motooka, D., Okuzaki, D., Takashima, S., Miyagawa, S., Sawa, Y., Hikoso, S., Sakata, Y. 2020; 10 (1): 15348

  Abstract

  Post-mitotic cardiomyocytes have been considered to be non-permissive to precise targeted integration including homology-directed repair (HDR) after CRISPR/Cas9 genome editing. Here, we demonstrate that direct delivery of large amounts of transgene encoding guide RNA (gRNA) and repair template DNA via intra-ventricular injection of adeno-associated virus (AAV) promotes precise targeted genome replacement in adult murine cardiomyocytes expressing Cas9. Neither systemic injection of AAV nor direct injection of adenovirus promotes targeted integration, suggesting that high copy numbers of single-stranded transgenes are required in cardiomyocytes. Notably, AAV-mediated targeted integration in cardiomyocytes both in vitro and in vivo depends on the Fanconi anemia pathway, a key component of the single-strand template repair mechanism. In human cardiomyocytes differentiated from induced pluripotent stem cells, AAV-mediated targeted integration fluorescently labeled Mlc2v protein after differentiation, independently of DNA synthesis, and enabled real-time detection of sarcomere contraction in monolayered beating cardiomyocytes. Our findings provide a wide range of applications for targeted genome replacement in non-dividing cardiomyocytes.

  View details for DOI 10.1038/s41598-020-72216-y

  View details for Web of Science ID 000573753400004

  View details for PubMedID 32948788

  View details for PubMedCentralID PMC7501291

• Outcomes After Atrial Fibrillation Ablation in Patients With Premature Atrial Contractions Originating From Non-Pulmonary Veins JACC-CLINICAL ELECTROPHYSIOLOGY Nakamaru, R., Okada, M., Tanaka, N., Tanaka, K., Ninomiya, Y., Hirao, Y., Oka, T., Inoue, H., Takayasu, K., Koyama, Y., Okamura, A., Iwakura, K., Rakugi, H., Sakata, Y., Fujii, K., Inoue, K. 2019; 5 (11): 1319-1327

  Abstract

  The aim of this study was to examine the relationship between residual premature atrial contractions (PACs) originating from non-pulmonary veins (PVs), which do not initiate atrial fibrillation (AF), and AF recurrence after ablation.Residual atrial ectopic beats that trigger AF from non-PVs (non-PV AF triggers) after catheter ablation are among the major causes of AF recurrence. However, little is known about the impact of non-PV PACs on AF recurrence.This retrospective study included 565 consecutive patients who underwent first-time AF ablation at our institution. After PV isolation, we infused isoproterenol to provoke non-PV AF triggers and/or non-PV PACs. We excluded 26 patients with non-PV AF triggers and 3 patients who underwent ablation of non-PV PACs, and finally analyzed 536 patients. Non-PV PACs were defined as ectopic beats that were constantly observed with the same intra-atrial activation patterns from non-PVs.Residual non-PV PACs during the procedure were observed in 112 patients (21%). There was no significant difference in the AF recurrence rate between patients with non-PV PACs (35 of 112, 31%) and those without (145 of 424, 34%; log-rank p = 0.69), during a median follow-up of 670 days. Age- and sex-adjusted hazards for AF recurrence were also similar between the 2 groups.The similar AF recurrence rate in patients with and without non-PV PACs suggests that the additional ablation of non-PV PACs has limited effect on AF recurrence.

  View details for DOI 10.1016/j.jacep.2019.08.002

  View details for Web of Science ID 000602735000012

  View details for PubMedID 31753439

• Multiple Shifts of the Earliest Retrograde Atrial Activation Site Along the Tricuspid Annulus During the Fast-Slow Form of Atrioventricular Nodal Reentrant Tachycardia by Radiofrequency Modification INTERNATIONAL HEART JOURNAL Okada, M., Tanaka, K., Matsunaga-Lee, Y., Ninomiya, Y., Hirao, Y., Oka, T., Tanaka, N., Inoue, H., Iwakura, K., Fujii, K., Inoue, K. 2019; 60 (3): 761-767

  Abstract

  A 70-year-old woman was admitted for treatment of supraventricular tachycardia. Ventriculoatrial conduction was revealed through programmed ventricular stimulation; the coronary sinus ostium (CSos) was the earliest atrial activation site. The fast-slow forms of atrioventricular nodal reentrant tachycardia (AVNRT) were induced by ventricular extra-stimuli. During tachycardia, the earliest atrial activation site was located at the bottom of CSos. Radiofrequency (RF) energy application to this site resulted in the delay of local electrical potential, prolongation of tachycardia cycle length, and a shift of the earliest retrograde activation site to the roof of CSos. Subsequent ablation induced a similar shift to the inferior tricuspid annulus and to the right posterior septum. Finally, RF energy application to the right posterior septum resulted in the termination of tachycardia, which was not induced afterward. Multiple shifts in the earliest retrograde atrial activation site along the tricuspid annulus after each slow pathway ablation suggested that annular tissue plays a substantial role as a substrate for AVNRT.

  View details for DOI 10.1536/ihj.18-406

  View details for Web of Science ID 000469753300037

  View details for PubMedID 31105149

• Comparison of the Safety and Efficacy of Automated Annotation-Guided Radiofrequency Ablation and 2nd-Generation Cryoballoon Ablation in Paroxysmal Atrial Fibrillation CIRCULATION JOURNAL Tanaka, N., Tanaka, K., Ninomiya, Y., Hirao, Y., Oka, T., Okada, M., Inoue, H., Nakamaru, R., Takayasu, K., Kitagaki, R., Koyama, Y., Okamura, A., Iwakura, K., Sakata, Y., Fujii, K., Inoue, K. 2019; 83 (3): 548-555

  Abstract

  Automated ablation lesion annotation with optimal settings for parameters including contact force (CF) and catheter stability may be effective for achieving durable pulmonary vein isolation. Methods and Results: We retrospectively examined 131 consecutive patients who underwent initial catheter ablation (CA) for paroxysmal atrial fibrillation (PAF) by automatic annotation system (VISITAG module)-guided radiofrequency CA (RFCA) (n=61) and 2nd-generation cryoballoon ablation (CBA) (n=70) in terms of safety and long-term efficacy. The automatic annotation criteria for the RFCA group were as follows: catheter stability range of motion ≤1.5 mm, duration ≥5 s, and CF ≥5 g. We ablated for >20 s with a force-time integral >150 gs at each site, before moving to the next site. Each interlesion distance was <6 mm. Procedural complications were more frequent in the CBA group (1.6% vs. 10.0%, P=0.034). Across a median follow-up of 2.98 years, 88.5% and 70.0% of patients in the RFCA and CBA groups, respectively, were free from recurrence (log-rank test, P=0.0039). There was also a significant difference in favor of RFCA with respect to repeat ablations (3.3% vs. 24.3%, log-rank test, P=0.0003).RF ablation guided by an automated algorithm that includes CF and catheter stability parameters showed better long-term outcomes than CBA in the treatment of patients with PAF without increasing complications.

  View details for DOI 10.1253/circj.CJ-18-1035

  View details for Web of Science ID 000459390900009

  View details for PubMedID 30726801

• Usefulness of Failed Electrical Cardioversion for Early Recurrence After Catheter Ablation for Atrial Fibrillation as a Predictor of Future Recurrence AMERICAN JOURNAL OF CARDIOLOGY Nakamaru, R., Tanaka, N., Okada, M., Tanaka, K., Ninomiya, Y., Hirao, Y., Oka, T., Inoue, H., Koyama, Y., Okamura, A., Iwakura, K., Rakugi, H., Sakata, Y., Fujii, K., Inoue, K. 2019; 123 (5): 794-800

  Abstract

  Early recurrence of atrial arrhythmia (ERAA) during a blanking period after catheter ablation (CA) for atrial fibrillation (AF) does not always result in subsequent AF recurrence. We investigated whether failed electrical cardioversion (ECV) during the blanking period was associated with recurrence. A total of 1,240 consecutive patients who underwent first-time CA for AF at our institution between March 2012 and March 2016 were investigated. Among the 517 patients (42%) who experienced ERAA, 262 underwent ECV. Failure or success of ECV was defined according to the current expert consensus statement. Failed ECV was defined as failure to terminate AF and/or relapse into AF within 30 seconds after transient sinus rhythm conversion by ECV with a shock energy of 270 J in this study. Of the patients, 254 (97%) with restored sinus rhythm were included, and 8 who experienced sustained AF afterward and discontinued the rhythm-control strategy were excluded. We divided the 254 patients into the following 2 groups on the basis of failed or successful ECV: failed-ECV (n = 105; at least 1 failed ECV but experienced successful ECV at a later date nevertheless) and successful-ECV (n = 149, no failed ECV) groups. At the median follow-up period of 610 days after CA, the recurrence rate was higher in the failed-ECV group than in the successful-ECV group (76.2% vs 45.6%, log-rank p < 0.001). After adjustment for baseline differences, failed ECV was found to be a significant predictor of recurrence in the multivariate model (p < 0.001). In conclusion, failed ECV for ERAA was an independent predictor of future recurrence.

  View details for DOI 10.1016/j.amjcard.2018.11.039

  View details for Web of Science ID 000460997500014

  View details for PubMedID 30558757

• Left Atrial Reverse Remodeling After Catheter Ablation of Nonparoxysmal Atrial Fibrillation in Patients With Heart Failure With Reduced Ejection Fraction AMERICAN JOURNAL OF CARDIOLOGY Oka, T., Inoue, K., Tanaka, K., Ninomiya, Y., Hirao, Y., Tanaka, N., Okada, M., Inoue, H., Nakamaru, R., Koyama, Y., Okamura, A., Iwakura, K., Sakata, Y., Fujii, K. 2018; 122 (1): 89-96

  Abstract

  The efficacy of catheter ablation (CA) of nonparoxysmal atrial fibrillation (PAF) in patients with left ventricular systolic dysfunction is controversial. We investigated the outcomes of CA for non-PAF in patients with reduced left ventricular ejection fraction (LVEF) and the impact of early left atrial (LA) reverse remodeling on these outcomes. A total of 251 consecutive patients who underwent CA for non-PAF were divided into 2 groups (reduced: preoperative LVEF ≤55%, LVEF: 46.5 ± 8.7%, n = 63; normal: >55%, 65.8 ± 5.8%, n = 188). We analyzed the 4-year atrial fibrillation- or atrial tachycardia (AT)-free survival rate and assessed changes in LVEF, hemodynamics, and LA reverse remodeling at the end of a 90-day blanking period. We also evaluated LA reverse remodeling in patients with and without recurrence. The atrial fibrillation- or AT-free survival rates were similar (reduced vs normal 48% vs 42%, p = 0.32). The reduced group exhibited significant LVEF improvement (before vs after, 46.5 ± 8.7% vs 58.4 ± 11.5%, p<0.001), reduced mitral regurgitation, and spectral tissue Doppler-derived index, and had greater percent maximum left atrial volume reduction (reduced vs normal 25.3 ± 18.2% vs 19.3 ± 16.2%, p = 0.014). Percent maximum left atrial volume reduction was greater in patients without recurrence (with recurrence vs without recurrence 17.3 ± 16.7% vs 25.4 ± 16.1%, p<0.001). In conclusion, the efficacy of non-PAF CA in patients with reduced LVEF was comparable with that in patients with normal LVEF. Greater LA reverse remodeling in these patients suggests an association with a reduced recurrence rate.

  View details for DOI 10.1016/j.amjcard.2018.03.026

  View details for Web of Science ID 000437808600014

  View details for PubMedID 29703439

• Efficacy and Safety of Figure-of-Eight Suture for Hemostasis After Radiofrequency Catheter Ablation for Atrial Fibrillation CIRCULATION JOURNAL Okada, M., Inoue, K., Tanaka, K., Ninomiya, Y., Hirao, Y., Oka, T., Tanaka, N., Inoue, H., Nakamaru, R., Koyama, Y., Okamura, A., Iwakura, K., Sakata, Y., Fujii, K. 2018; 82 (4): 956-+

  Abstract

  This study evaluated the safety and efficacy of venous figure-of-eight (FoE) suture to achieve femoral venous hemostasis after radiofrequency (RF) catheter ablation (CA) for atrial fibrillation (AF).Methods and Results:We retrospectively examined 517 consecutive patients undergoing RFCA for AF. The control group (n=247) underwent manual compression for femoral venous hemostasis after sheath removal with 6 h of bed rest. The FoE group (n=270) underwent FoE suture technique with 4 h of bed rest. All patients achieved successful hemostasis within 24 h after CA. Although the incidence of hematoma was similar between the groups, the incidence of rebleeding was lower in the FoE group than in the control group (FoE vs. control, 3.7% vs. 18.6%, P<0.001). The post-procedural use of analgesic and/or anti-emetic agents was less frequent in the FoE group (19.3% vs. 32.0%, P<0.001). On multiple logistic regression analysis after adjustment for age and sex, the use of a vitamin K antagonist (OR, 2.42; 95% CI: 1.18-4.99, P=0.02) and the FoE suture technique (OR, 0.17; 95% CI: 0.08-0.35, P<0.001) were independent predictors of rebleeding after CA.FoE suture technique effectively achieved femoral venous hemostasis after RFCA for AF. It reduced the risk of rebleeding, shortened bed rest duration, and relieved patient discomfort.

  View details for DOI 10.1253/circj.CJ-17-1213

  View details for Web of Science ID 000428079000007

  View details for PubMedID 29375108

• Automated Ablation Annotation Algorithm Reduces Re-conduction of Isolated Pulmonary Vein and Improves Outcome After Catheter Ablation for Atrial Fibrillation CIRCULATION JOURNAL Tanaka, N., Inoue, K., Tanaka, K., Toyoshima, Y., Oka, T., Okada, M., Inoue, H., Nakamaru, R., Koyama, Y., Okamura, A., Iwakura, K., Sakata, Y., Fujii, K. 2017; 81 (11): 1596-1602

  Abstract

  Durable pulmonary vein isolation (PVI) is critical in reducing recurrence after radiofrequency catheter ablation for atrial fibrillation (AF). The VISITAG Module, an automatic annotation system that takes account of catheter stability and contact force (CF), might be useful in accomplishing this.Methods and Results:In 49 patients undergoing VISITAG-guided AF ablation (group A), we set the following automatic annotation criteria: catheter stability range of motion ≤1.5 mm, duration ≥5 s, CF ≥5 g, time ≥25% and tag diameter at 6 mm. We used ablation >20 s and force-time integral >150 gs at each site, then moved to the next site where a new tag appeared that overlapped with the former tag. Results and outcome were retrospectively compared for 42 consecutive patients undergoing CF-guided AF ablation without this algorithm (group B). Successful PVI at completion of the initial anatomical line was more frequent in group A than B (66.3% vs. 36.9%, P=0.0006) while spontaneous PV reconnection was less frequent (14.2% vs. 30.9%, P=0.0014) and procedure time was shorter (138±35 min vs. 180±44 min, P<0.001). One-year success rate off anti-arrhythmic drugs was higher in group A (91.8% vs. 69.1%, log rank P=0.0058).An automated annotation algorithm with an optimal setting reduced acute resumption of left atrium-PV conduction, shortened procedure time, and improved AF ablation outcome.

  View details for DOI 10.1253/circj.CJ-17-0195

  View details for Web of Science ID 000413591500008

  View details for PubMedID 28579576

• Quantitative Assessment of Fluid Accumulation Using Bioelectrical Impedance Analysis in Patients With Acute Decompensated Heart Failure CIRCULATION JOURNAL Sakaguchi, T., Yasumura, K., Nishida, H., Inoue, H., Furukawa, T., Shinouchi, K., Miura, H., Miyazaki, K., Hamano, G., Koide, M., Abe, H., Date, M., Hirooka, K., Koretsune, Y., Kusuoka, H., Yasumura, Y. 2015; 79 (12): 2616-2622

  Abstract

  Acute decompensated heart failure (ADHF) is generally considered to be a problem of fluid volume overload, therefore accurately quantifying the degree of fluid accumulation is of critical importance in assessing whether adequate decongestion has been achieved. The aim of this study was to develop and validate a method to quantify the degree of fluid accumulation in patients with ADHF.Using multi-frequency bioelectrical impedance analysis (BIA), we measured extracellular water (ECW) volume in 130 ADHF patients on admission and at discharge. We also predicted optimal ECW volume using original equations based on data from 60 control subjects without the signs of HF. Measured/predicted (M/P) ratio of ECW in ADHF patients was observed to decrease from 1.26±0.25 to 1.04±0.17 during hospitalization (P<0.001). The amount of ECW volume reduction was significantly correlated with reduction in body weight (r=0.766, P<0.001). On multivariate analysis, higher M/P ratio of ECW at discharge was associated with increased risk of ADHF readmission or cardiac death within 6 months after discharge.Multi-frequency BIA-measured ECW was found to offer valuable information for analyzing the pathophysiology of ADHF, and may be a useful guide in the management of this disease.

  View details for DOI 10.1253/circj.CJ-15-0723

  View details for Web of Science ID 000365763100020

  View details for PubMedID 26477274