Papers - Katsumata, Yoshinori

Visualization of the electrophysiologically defined junction between the superior vena cava and right atrium

Nishiyama N., Hashimoto K., Yamashita T., Miyama H., Fujisawa T., Katsumata Y., Kimura T., Fukuda K., Takatsuki S.

Journal of Cardiovascular Electrophysiology (Journal of Cardiovascular Electrophysiology)  31 ( 8 ) 1964 - 1969 2020.08

ISSN  10453873

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© 2020 Wiley Periodicals LLC Introduction: An electrical superior vena cava (SVC) isolation from the right atrium (RA) sometimes can be challenging. For a safe and efficient SVC isolation, we aimed to visualize the accurate position of the SVC-RA junction on a three-dimensional (3D) mapping system using the decremental conduction properties of the SVC-RA junction in patients with atrial fibrillation (AF). Methods: This study consisted of 15 consecutive AF patients (11 males, age 59 ± 10 years). A 3D mapping catheter was positioned in the SVC-RA junction region while delivering a single extra-stimulus from the right atrial appendage (RAA), to discriminate the RA and SVC potentials. The electrophysiological SVC-RA junction was defined as the most proximal points where the SVC potentials were recorded, which were tagged on the 3D mapping system around the SVC-RA junction, where radiofrequency energy applications were applied. Results: Around the SVC-RA junction, 9 ± 2 points were tagged on the 3D mapping system. The highest and lowest SVC-RA junction points were located on the anterior wall and posterior wall, respectively. The difference in the level between the highest and lowest SVC-RA junction points was 16.2 ± 6.3 mm. A successful SVC isolation was obtained in all patients without any complications. Conclusion: The plane of the electrophysiologically defined SVC-RA junction was not perpendicular to the body axis, but slanted due to the anterior side being higher. Recognizing the precise location of the SVC-RA junction would contribute to a safe and efficacious SVC isolation.

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Discrepancy in recognition of symptom burden among patients with atrial fibrillation

Katsumata Y., Kimura T., Kohsaka S., Ikemura N., Ueda I., Fujisawa T., Nakajima K., Nishiyama T., Aizawa Y., Oki T., Suzuki M., Heidenreich P.A., Fukuda K., Takatsuki S.

American Heart Journal (American Heart Journal)  226   240 - 249 2020.08

ISSN  00028703

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© 2020 Elsevier Inc. Our aim was to investigate the variability in physician recognition of atrial fibrillation (AF)-related symptoms, which greatly contributes to the management of AF patients. Methods and Results: A total of 1493 newly-referredAF patients (67 ± 11 y/o, 1057 men) consecutively registered in an outpatient-based Japanese multicenter database (KiCS-AF) from September 2012 to December 2016 were analyzed. Self-reportedAF symptom burden was assessed via symptom and daily activities domains within the Atrial Fibrillation Effect on QualiTy-of-life (AFEQT) questionnaire. Physician symptom under-recognition (UR) was defined as no subjective complaints recorded in the medical records despite AFEQT score of <80; and physician's apparent over-recognition (OvR) was defined as documentation of subjective complaints despite total AFEQT score of ≥80. There was poor agreement between patient-reported and physicians-estimated symptom burden (kappa 0.28, 95% CI 0.23 to 0.33). In the logistic regression analysis, age> 75 (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.13–2.62), male sex (OR, 1.82; 95% CI, 1.22–2.74), and persistent/permanent AF (OR 2.54/3.36; CI, 1.63–3.99/1.91–5.89, respectively) were predictors of UR. Conversely, heart failure (OR, 2.46; 95% CI, 1.44–4.25) and treatment in an ablation facility (OR, 1.43; 95% CI, 1.02–2.02) were associated with greater odds of OvR in addition to age, sex, and type of AF. Conclusions: Discordance in recognition of AF symptom burden by physicians was frequent in AF patients seen in outpatient management and involved both patient- and physician-related factors.

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Successful Surgical Treatment Combined With Infliximab in a Patient With Acute Aortic Regurgitation Caused by Behçet Disease

Kawakubo Y., Katsumata Y., Komuro J., Shiraishi Y., Yuasa S., Itabashi Y., Kohno T., Fukuda K.

Canadian Journal of Cardiology (Canadian Journal of Cardiology)  36 ( 7 ) 1161.e3 - 1161.e5 2020.07

ISSN  0828282X

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© 2020 Canadian Cardiovascular Society Standard aortic valve replacement for aortic regurgitation caused by Behçet disease (BD) is frequently complicated by postoperative recurrent prosthetic valve detachment. Tumour necrosis factor (TNF) α is known to be associated with higher inflammation activities. Therefore, the concomitant use of immunomodulatory agents with TNFα inhibitors may be the key to a better outcome. This is a case report of a 46-year-old woman with severe acute aortic regurgitation due to BD. Immunosuppressive therapy including the TNFα inhibitor infliximab, which has not been reported for perioperative use to date, resulted in the prompt remission of inflammation, leading to the success of Bentall surgery.

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Pharmacokinetics of a single inhalation of hydrogen gas in pigs

Sano M., Ichihara G., Katsumata Y., Hiraide T., Hirai A., Momoi M., Tamura T., Ohata S., Kobayashi E.

PLoS ONE (PLoS ONE)  15 ( 6 )  2020.06

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© 2020 Sano et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The benefits of inhaling hydrogen gas (H2) have been widely reported but its pharmacokinetics have not yet been sufficiently analyzed. We developed a new experimental system in pigs to closely evaluate the process by which H2 is absorbed in the lungs, enters the bloodstream, and is distributed, metabolized, and excreted. We inserted and secured catheters into the carotid artery (CA), portal vein (PV), and supra-hepatic inferior vena cava (IVC) to allow repeated blood sampling and performed bilateral thoracotomy to collapse the lungs. Then, using a hydrogen-absorbing alloy canister, we filled the lungs to the maximum inspiratory level with 100% H2. The pig was maintained for 30 seconds without resuming breathing, as if they were holding their breath. We collected blood from the three intravascular catheters after 0, 3, 10, 30, and 60 minutes and measured H2 concentration by gas chromatography. H2 concentration in the CA peaked immediately after breath holding; 3 min later, it dropped to 1/40 of the peak value. Peak H2 concentrations in the PV and IVC were 40% and 14% of that in the CA, respectively. However, H2 concentration decay in the PV and IVC (half-life: 310 s and 350 s, respectively) was slower than in the CA (half-life: 92 s). At 10 min, H2 concentration was significantly higher in venous blood than in arterial blood. At 60 min, H2 was detected in the portal blood at a concentration of 6.9–53 nL/mL higher than at steady state, and in the SVC 14–29 nL/mL higher than at steady state. In contrast, H2 concentration in the CA decreased to steady state levels. This is the first report showing that inhaled H2 is transported to the whole body by advection diffusion and metabolized dynamically.

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Palmitate induces cardiomyocyte death via inositol requiring enzyme-1 (IRE1)-mediated signaling independent of X-box binding protein 1 (XBP1)

Yamamoto T., Endo J., Kataoka M., Matsuhashi T., Katsumata Y., Shirakawa K., Isobe S., Moriyama H., Goto S., Shimanaka Y., Kono N., Arai H., Shinmura K., Fukuda K., Sano M.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  526 ( 1 ) 122 - 127 2020.05

ISSN  0006291X

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© 2020 The Authors Overloading of the saturated fatty acid (SFA) palmitate induces cardiomyocyte death. The purpose of this study is to elucidate signaling pathways contributing to palmitate-induced cardiomyocyte death. Palmitate-induced cardiomyocyte death was induced in Toll-like receptor 2/4 double-knockdown cardiomyocytes to a similar extent as wild-type cardiomyocytes, while cardiomyocyte death was canceled out by triacsin C, a long-chain acyl-CoA synthetase inhibitor. These results indicated that palmitate induced cytotoxicity after entry and conversion into palmitoyl-CoA. Palmitoyl-CoA is not only degraded by mitochondrial oxidation but also taken up as a component of membrane phospholipids. Palmitate overloading causes cardiomyocyte membrane fatty acid (FA) saturation, which is associated with the activation of endoplasmic reticulum (ER) unfolded protein response (UPR) signaling. We focused on the ER UPR signaling as a possible mechanism of cell death. Palmitate loading activates the UPR signal via membrane FA saturation, but not via unfolded protein overload in the ER since the chemical chaperone 4-phenylbutyrate failed to suppress palmitate-induced ER UPR. The mammalian UPR relies on three ER stress sensors named inositol requiring enzyme-1 (IRE1), PKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Palmitate loading activated only IRE1 and PERK. Knockdown of PERK did not affect palmitate-induced cardiomyocyte death, while knockdown of IRE1 suppressed palmitate-induced cardiomyocyte death. However, knockdown of X-box binding protein 1 (XBP1), the downstream effector of IRE1, did not affect palmitate-induced cardiomyocyte death. These results were validated by pharmacological inhibitor experiments. In conclusion, we identified that palmitate-induced cardiomyocyte death was triggered by IRE1-mediated signaling independent of XBP1.

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Treatment strategies and subsequent changes in the patient-reported quality-of-life among elderly patients with atrial fibrillation: QOL in Elderly Patients with AF

Miura K., Ikemura N., Kimura T., Katsumata Y., Ueda I., Tanimoto K., Ohki T., Shinmura D., Negishi K., Fukuda K., Takatsuki S., Kohsaka S.

American Heart Journal (American Heart Journal)  222   83 - 92 2020.04

ISSN  00028703

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© 2020 Elsevier Inc. Background: Rhythm-control strategy, including catheter ablation (CA) application, constitutes an integral part of atrial fibrillation (AF) management. However, elderly patients are underrepresented in clinical trials, and reports on patient-reported outcome of various rhythm-control treatments remain limited. Therefore, we aimed to investigate the application of a rhythm-control strategy for elderly patients with AF. Methods: Using a prospective, multicenter Japanese registry, we analyzed 733 patients with AF aged ≥70 years who completed the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire at baseline and 1-year visit. Improvement in patient-reported quality-of-life (QOL) was assessed according to their initial treatment strategy. Results: A total of 321 patients (43.8%) were managed with rhythm-control strategy, of which 125 (17.1%) received treatment with antiarrhythmic drugs (AADs) alone and 196 (26.7%) underwent CA. Compared with the rate-control group, the rhythm-control group was younger and less likely to have comorbid conditions but had lower baseline AFEQT-overall summary (OS) scores (71.8 [standard deviation 20.3] vs. 80.0 [standard deviation 16.1]; P < .001). After the first year, AFEQT-OS scores improved regardless of treatment strategies (ie, rate- or rhythm-control). After adjusting for confounders, CA implementation and a lower baseline AFEQT score were associated with meaningful improvement in QOL (changes in AFEQT-OS score ≥5). QOL improvement among subgroups of rhythm-control patients with AADs alone was not clinically meaningful. Conclusions: In contemporary Japanese clinical practice, rhythm-control strategy is widely implemented in elderly patients with AF, and CA use is associated with improvement in QOL in carefully selected patients.

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Adrenal cortex hypoxia modulates aldosterone production in heart failure

Yamashita K., Ito K., Endo J., Matsuhashi T., Katsumata Y., Yamamoto T., Shirakawa K., Isobe S., Kataoka M., Yoshida N., Goto S., Moriyama H., Kitakata H., Mitani F., Fukuda K., Goda N., Ichihara A., Sano M.

Biochemical and Biophysical Research Communications (Biochemical and Biophysical Research Communications)  524 ( 1 ) 184 - 189 2020.03

ISSN  0006291X

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© 2020 The Authors Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells. In H295R cells (a human adrenocortical cell line), hypoxia-induced β3-adrenergic receptor expression. Hypoxia-mediated β3-adrenergic receptor expression augmented aldosterone production by facilitating hydrolysis of lipid droplets though ERK-mediated phosphorylation of hormone-sensitive lipase, also known as cholesteryl ester hydrolase. Hypoxia also accelerated the synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase, thereby increasing the cholesterol ester content in lipid droplets. Thus, hypoxia enhanced aldosterone production by zona glomerulosa cells via promotion of the accumulation and hydrolysis of cholesterol ester in lipid droplets. In conclusion, hypoxic zona glomerulosa cells with heart failure show enhanced aldosterone production via increased catecholamine responsiveness and activation of cholesterol trafficking, irrespective of the renin-angiotensin system.

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Mexiletine shortens the QT interval in a pedigree of KCNH2 related long QT syndrome

Fujisawa T., Aizawa Y., Katsumata Y., Kimura K., Hashimoto K., Yamashita T., Miyama H., Kimura T., Kosaki K., Takatsuki S., Shimizu W., Fukuda K.

Journal of Arrhythmia (Journal of Arrhythmia)  36 ( 1 ) 193 - 196 2020.02

ISSN  18804276

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© 2020 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society. A 23-year-old female had been suffering from recurrent syncopal episodes during sleep since her childhood. She had a family history of sudden death and her QTc interval was remarkably prolonged to 537 ms A Holter ECG revealed torsade de pointes, corresponding to syncope. She was started on mexiletine and her QTc interval shortened. Her symptoms were controlled after β-blockers and Ca-blockers were added. A genetic analysis with a next generation sequencer identified a frameshift mutation at the C terminus of the KCNH2 gene. Here we present a type 2 long QT syndrome case in which mexiletine was effective.

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Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension

Hiraide T., Kataoka M., Suzuki H., Aimi Y., Chiba T., Isobe S., Katsumata Y., Goto S., Kanekura K., Yamada Y., Moriyama H., Kitakata H., Endo J., Yuasa S., Arai Y., Hirose N., Satoh T., Hakamata Y., Sano M., Gamou S., Kosaki K., Fukuda K.

Journal of Heart and Lung Transplantation (Journal of Heart and Lung Transplantation)  39 ( 2 ) 103 - 112 2020.02

ISSN  10532498

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© 2019 International Society for Heart and Lung Transplantation BACKGROUND: A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. METHODS: Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. RESULTS: The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs 93%, respectively; p < 0.001). CONCLUSIONS: Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

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Symptom burden and treatment perception in patients with atrial fibrillation, with and without a family history of atrial fibrillation

Fujisawa T., Kimura T., Kohsaka S., Ikemura N., Katsumata Y., Miyama H., Nakajima K., Nishiyama T., Aizawa Y., Kanki H., Nagami K., Fukuda K., Takatsuki S.

Heart and Vessels (Heart and Vessels)   2020

ISSN  09108327

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© 2020, Springer Japan KK, part of Springer Nature. Atrial fibrillation (AF) is known to aggregate within family and might be associated with a lower quality-of-life (QoL). We evaluated the association between a family history (FHx) of AF and patient-reported symptom burden and perception towards treatment. We performed a retrospective analysis in a cohort of 1285 newly diagnosed patients with AF. Patients completed the atrial fibrillation effect on quality of life (AFEQT) questionnaire at the time of registration and at the 1-year follow-up. Patients who had a first-degree relative with AF were classified into the FHx group. Baseline characteristics and AFEQT scores were compared between groups, and a multivariate analysis was used to evaluate the independent association between FHx and QoL. Overall, 15.9% of patients (n = 204) had a positive AF FHx. Compared to the non-FHx group, the FHx group had an earlier onset of AF (60.2 ± 12.0 years vs. 64.5 ± 12.1 years; P < 0.05) and lower AFEQT overall summary (AFEQT-OS) score at baseline (73.9 ± 17.8 vs. 77.0 ± 16.8; P < 0.05). After adjustment for clinical background, a positive FHx was independently associated with a worse QoL (changes in AFEQT-OS score = − 3.18; 95% confidence interval: − 5.67 to − 0.69; P = 0.012). No between-group difference in AFEQT-OS scores was noted at the 1-year follow-up. An FHx of AF was associated with a lower QoL, which could be improved by therapeutic intervention in patients with AF. Recognizing the presence of an FHx of AF is important to predict patient’s symptom load and treatment acceptance.

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A high BNP level predicts an improvement in exercise tolerance after a successful catheter ablation of persistent atrial fibrillation

Katsumata Y., Tamura Y., Kimura T., Kohsaka S., Sadahiro T., Nishiyama T., Aizawa Y., Azuma K., Fukuda K., Takatsuki S.

Journal of Cardiovascular Electrophysiology (Journal of Cardiovascular Electrophysiology)  30 ( 11 ) 2283 - 2290 2019.11

ISSN  10453873

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© 2019 Wiley Periodicals, Inc. Introduction: Restoration of sinus rhythm (SR) by catheter ablation (CA) of atrial fibrillation (AF) improves exercise tolerance. However, it is still unclear what characteristics of patients are contributing to an improvement in exercise tolerance after CA of AF without heart failure. Methods and results: This study consisted of 51 consecutive patients with persistent or long-standing persistent AF without heart failure who were restored to SR for over 6 months by a successful CA. Exercise tolerance was evaluated by cardiopulmonary exercise testing before and 3 and 6 months after CA. The clinical characteristics contributing to an improvement in exercise tolerance was elucidated. The peak oxygen uptake (VO2)% significantly increased from 101.4 ± 20.3% to 110.9 ± 19.9% 3 months after the CA (P <.001). The improvement rate in the peak VO2% exhibited a positive correlation to the baseline brain natriuretic peptide (BNP; ρ = 0.39, P <.01), but not to the age, AF duration, left ventricular ejection fraction, or left atrial size. The linear regression analysis revealed that the baseline BNP was an independent predictor of an improvement in the peak VO2% (coefficients = 0.32; 95% confidence interval = 0.08, 0.54; P =.01). The peak VO2% improved significantly in the patients whose baseline BNP level was greater than 100 pg/mL, compared to the others (P <.01). These favorable findings were also observed 6 months after the CA. Conclusion: Elimination of persistent AF by CA was associated with an improvement in exercise tolerance. This was particularly true in patients with high BNP values at baseline.

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A Cluster Analysis of the Japanese Multicenter Outpatient Registry of Patients With Atrial Fibrillation

Inohara T., Piccini J.P., Mahaffey K.W., Kimura T., Katsumata Y., Tanimoto K., Inagawa K., Ikemura N., Ueda I., Fukuda K., Takatsuki S., Kohsaka S.

American Journal of Cardiology (American Journal of Cardiology)  124 ( 6 ) 871 - 878 2019.09

ISSN  00029149

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© 2019 Elsevier Inc. Recently, cluster analysis was used to identify unique clinically relevant phenotypes of atrial fibrillation (AF) in a cohort from the United States (US) and classified clusters according to the presence of comorbid behavioral disorders, those with conduction disorders, or atherosclerotic comorbidities. Whether these phenotypes are consistent in AF cohorts outside the US remains unknown. Thus, we sought to conduct a cluster analysis in a cohort of Japanese AF patients. We conducted a cluster analysis of phenotypic data (46 variables) in an AF patient cohort recruited from 11 Japanese sites participating in the KiCS-AF Registry. Overall, 2,458 AF patients (median [IQR] age, 68.0 [60.0 to 76.0]; 30.3% female; median [IQR] CHA2DS2-Vasc, 2 [1, 3]) were analyzed. Similar to the US cohort, atherosclerotic comorbidities were identified as distinguishing factors to characterize clusters. Distribution of AF type and left atrial (LA) size substantially varied and was the key feature for cluster formation. CHA2DS2-Vasc score also contributed to cluster formation, although behavioral disorders and/or conduction disorders did not readily characterize clusters. Subsequently, the cohort was classified into 3 clusters: (1) Younger paroxysmal AF (n = 1,190); (2) Persistent/permanent AF with LA enlargement (n = 1,143); and (3) Atherosclerotic comorbid AF in elderly patients (N = 125). In conclusion, conventional classifications, such as atherosclerotic risk factors and CHA2DS2-Vasc score contributed to cluster formation in mutually, whereas in nonatherosclerotic clusters, AF type or LA size rather than the presence or absence of behavior risk factors or sinus node dysfunction (tachy-brady syndrome) seemed to contribute to cluster formation in the Japanese cohort.

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Discrepancy between patient-reported quality of life and the prognostic assessment of Japanese patients hospitalized with acute heart failure

Shoji S., Shiraishi Y., Sawano M., Katsumata Y., Yuasa S., Kohno T., Fukuda K., Spertus J., Kohsaka S.

Heart and Vessels (Heart and Vessels)  34 ( 9 ) 1464 - 1470 2019.09

ISSN  09108327

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© 2019, Springer Japan KK, part of Springer Nature. Patient-reported quality of life (PRQL) is a primary therapeutic target for patients with chronic heart failure (HF) and is associated with long-term prognosis. However, its utility in hospitalized HF (HHF) patients in the acute setting remains unclear. We aimed to assess the utility of PRQL (the Kansas City Cardiomyopathy Questionnaire [KCCQ]) in HHF patients and its association with long-term prognosis as well as with the clinical risk score (Get With The Guidelines-Heart Failure [GWTG-HF] risk score). PRQL was evaluated using the KCCQ in consecutive 114 HHF patients. Its association with the composite outcome of all-cause mortality or HF readmission within the first year after discharge was analyzed. Furthermore, its distribution by the clinical risk score (GWTG-HF) was evaluated using Pearson’s correlation coefficient. The median KCCQ was 34.9, but was widely distributed (interquartile range 23.7–56.8). After adjustment for known prognostic indicators, the KCCQ was not an independent predictor of the composite outcome within the first year (group with high vs. low KCCQ scores: hazard ratio, 0.67; 95% confidence interval 0.26–1.71). There was no significant correlation between the KCCQ and the GWTG-HF risk score. In conclusion, PRQL during the acute phase of HF was significantly impaired and also varied widely, irrespective of patient characteristics or severity. PRQL assessment and risk prediction for HHF patients in the acute setting seemed to provide two distinct types of information for health care providers.

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Sirt1 counteracts decrease in membrane phospholipid unsaturation and diastolic dysfunction during saturated fatty acid overload

Yamamoto T., Endo J., Kataoka M., Matsuhashi T., Katsumata Y., Shirakawa K., Yoshida N., Isobe S., Moriyama H., Goto S., Yamashita K., Ohto-Nakanishi T., Nakanishi H., Shimanaka Y., Kono N., Shinmura K., Arai H., Fukuda K., Sano M.

Journal of Molecular and Cellular Cardiology (Journal of Molecular and Cellular Cardiology)  133   1 - 11 2019.08

ISSN  00222828

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© 2019 Elsevier Ltd Background: The fatty acid (FA)composition of membrane phospholipid reflects at least in part dietary fat composition. Saturated FA (SFA)suppress Sirt1 activity, while monounsaturated FA (MUFA)counteract this effect. Objective: We explored a role of Sirt1 in homeostatic control of the fatty acid composition of membrane phospholipid in the presence of SFA overload. Methods and results: Sirt1 deficiency in cardiomyocytes decreased the expression levels of liver X receptor (LXR)-target genes, particularly stearoyl-CoA desaturase-1 (Scd1), a rate-limiting enzyme in the cellular synthesis of MUFA from SFA, increased membrane SFA/MUFA ratio, and worsened left ventricular (LV)diastolic function in mice fed an SFA-rich high fat diet. In cultured cardiomyocytes, Sirt1 knockdown (KD)exacerbated the palmitate overload-induced increase in membrane SFA/MUFA ratio, which was associated with decrease in the expression of LXR-target genes, including Scd1. Forced overexpression of Scd1 in palmitate-overloaded Sirt1KD cardiomyocytes lowered the SFA/MUFA ratio. Nicotinamide mononucleotide (NMN)increased Sirt1 activity and Scd1 expression, thereby lowering membrane SFA/MUFA ratio in palmitate-overloaded cardiomyocytes. These effects of NMN were not observed for Scd1KD cardiomyocytes. LXRα/βKD exacerbated palmitate overload-induced increase in membrane SFA/MUFA ratio, while LXR agonist T0901317 alleviated it. NMN failed to rescue Scd1 protein expression and membrane SFA/MUFA ratio in palmitate-overloaded LXRα/βKD cardiomyocytes. The administration of NMN or T0901317 showed a dramatic reversal in membrane SFA/MUFA ratio and LV diastolic function in SFA-rich HFD-fed mice. Conclusion: Cardiac Sirt1 counteracted SFA overload-induced decrease in membrane phospholipid unsaturation and diastolic dysfunction via regulating LXR-mediated transcription of the Scd1 gene.

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Influence of long term administration of tofogliflozin on chronic inflammation of visceral adipose tissue in mice with obesity induced by a high-fat diet

Shirakawa K., Yano W., Inoue K., Katsumata Y., Endo J., Sano M.

PLoS ONE (PLoS ONE)  14 ( 1 )  2019.07

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© 2019 Shirakawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. We previously found that senescence of cluster of differentiation 4 (CD4) T cells is accelerated in the visceral adipose tissue (VAT) of mice with diet-induced obesity (DIO) due to a high-fat diet (HFD), and that these senescent-Associated T cells cause chronic inflammation of visceral adipose tissue through secretion of osteopontin, provoking systemic insulin resistance. In this study, we examined whether the development of chronic inflammation and senescence-Associated T cells in VAT of DIO mice was improved by long-Term weight loss after switching to normal chow (NC) or by administration of a sodium glucose cotransporter 2 inhibitor (tofogliflozin). Wild-Type mice were fed an HFD for 26 weeks from 4 weeks old. At 30 weeks of age, half of these DIO mice were switched to NC with or without 0.005% tofogliflozin for 38 weeks. The other mice remained on the HFD with or without 0.005% tofogliflozin for 38 weeks. When DIO mice were switched to NC, their weight decreased to that of mice kept on NC since weaning. After 38 weeks (68 weeks of age), chronic inflammation of the VAT subsided with disappearance of senescence-Associated T cells. In the HFD groups, the carbohydrate intake per mouse was half or less of that in the NC group, and urinary glucose excretion by the effect of tofogliflozin was lower in the HFD mice than in the NC mice. Mice that remained on the HFD showed no improvement in chronic inflammation in VAT, possibly because urinary glucose excretion was not sufficiently promoted by tofogliflozin due to the low carbohydrate intake. Thus, no improvement in glucose metabolism or weight loss was observed in these mice.

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Importance of the vein of Marshall involvement in mitral isthmus ablation

Fujisawa T., Kimura T., Nakajima K., Nishiyama T., Katsumata Y., Aizawa Y., Fukuda K., Takatsuki S.

PACE - Pacing and Clinical Electrophysiology (PACE - Pacing and Clinical Electrophysiology)  42 ( 6 ) 617 - 624 2019.06

ISSN  01478389

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© 2019 Wiley Periodicals, Inc. Background: Epicardiac conduction via the vein of Marshall (VOM) can bypass the mitral isthmus (MI) line, making MI ablation difficult. This study aimed to assess the contribution of the VOM in achieving MI conduction block. Methods: This study included 143 consecutive patients with nonparoxysmal atrial fibrillation who underwent initial MI ablation. They were retrospectively classified into two groups, a VOM-guided group (n = 28) and a conventional group (n = 115), according to the use of a 2-Fr electrode catheter inserted in the VOM. The acute success rate of achieving MI block and the ablation data were assessed. When the bidirectional block was verified exclusively in the VOM or coronary sinus (CS) electrodes, we defined it as a pseudo MI block. In the VOM-guided group, we ascertained the complete MI block, verified both in the VOM and CS electrodes. Results: In the VOM-guided group, the pseudoblock was observed in 33.3% of the patients during MI ablation. With significantly less radiofrequency energy (19 322.6 ± 11 352.8 vs 25 389.3 ± 19 951.9, P = 0.04), we achieved a similar level of success rate in MI ablation in the VOM-guided group (96.4% vs 91.3%, P = 0.36). Notably, after achieving complete MI block, atrial burst pacing induced two perimitral flutters in the VOM-guided group, which were successfully terminated by the additional radiofrequency application. Conclusions: Assessment of electrical conduction through the VOM could clarify the existence of a pseudo MI conduction block. However, the existence of a slow conduction through the MI could be detected only after induction of perimitral atrial tachycardia with atrial programmed stimulation.

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Pressure overload inhibits glucocorticoid receptor transcriptional activity in cardiomyocytes and promotes pathological cardiac hypertrophy

Matsuhashi T., Endo J., Katsumata Y., Yamamoto T., Shimizu N., Yoshikawa N., Kataoka M., Isobe S., Moriyama H., Goto S., Fukuda K., Tanaka H., Sano M.

Journal of Molecular and Cellular Cardiology (Journal of Molecular and Cellular Cardiology)  130   122 - 130 2019.05

ISSN  00222828

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© 2019 Glucocorticoid receptor (GR) is abundantly expressed in cardiomyocytes. However, the role of GR in regulating cardiac hypertrophy and heart failure in response to pressure overload remains unclear. Cardiomyocyte-specific GR knockout (GRcKO) mice, mineralocorticoid receptor (MR) knockout (MRcKO), and GR and MR double KO (GRMRdcKO) mice were generated using the Cre-lox system. In response to pressure overload, GRcKO mice displayed worse cardiac remodeling compared to control (GR f/f ) mice, including a greater increase in heart weight to body weight ratio with a greater increase in cardiomyocytes size, a greater decline in left ventricular contractility, and higher reactivation of fetal genes. MRcKO mice showed a comparable degree of cardiac remodeling compared to control (MR f/f ) mice. The worse cardiac remodeling in pressure overloaded GRcKO mice is not due to compensatory activation of cardiomyocyte MR, since pressure overloaded GRMRdcKO mice displayed cardiac remodeling to the same extent as GRcKO mice. Pressure overload suppressed GR-target gene expression in the heart. Although plasma corticosterone levels and subcellular localization of GR (nuclear/cytoplasmic GR) were not changed, a chromatin immunoprecipitation assay revealed that GR recruitment onto the promoter of GR-target genes was significantly suppressed in response to pressure overload. Rescue of the expression of GR-target genes to the same extent as sham-operated hearts attenuated adverse cardiac remodeling in pressure-overloaded hearts. Thus, GR works as a repressor of adverse cardiac remodeling in response to pressure overload, but GR-mediated transcription is suppressed under pressure overload. Therapies that maintain GR-mediated transcription in cardiomyocytes under pressure overload can be a promising therapeutic strategy for heart failure.

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Assessment of Sex Differences in the Initial Symptom Burden, Applied Treatment Strategy, and Quality of Life in Japanese Patients With Atrial Fibrillation

Ikemura N., Kohsaka S., Kimura T., Ueda I., Katsumata Y., Nishiyama T., Aizawa Y., Tanimoto K., Momiyama Y., Akaishi M., Mitamura H., Fukuda K., Spertus J.A., Takatsuki S.

JAMA network open (JAMA network open)  2 ( 3 )  2019.03

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Importance: The clinical characteristics and outcomes of women and men with atrial fibrillation (AF) are reported to be different. However, whether sex-related differences extend to patients' symptom burden and perceived quality of life (QOL) or the management pattern of AF has been rarely studied, particularly in Asian countries. Objective: To assess the differences in symptoms, treatment, and QOL between Japanese female and male patients with AF. Design, Setting, and Participants: Retrospective cohort study using data from the multicenter outpatient registry Keio Interhospital Cardiovascular Studies-Atrial Fibrillation (KiCS-AF), which collects information regarding health status and the treatment of patients with newly diagnosed or referred AF. One-year follow-up data were available for 1534 patients at 11 referral centers in the Tokyo, Japan, area who were enrolled between September 2012 and December 2015. All data available up to the 1-year follow-up examination through July 31, 2017, were included. Main Outcomes and Measures: Sex, symptoms, AF treatment, and QOL as determined by Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaires at their initial visit and 1 year later. Results: Of 1534 patients, 1076 (70.1%) were men. Compared with men, women were more likely to be older (median age, 73 years [interquartile range {IQR}, 65-78 years] vs 65 years [IQR, 57-73 years], P < .001) and have higher median brain-type natriuretic peptide levels (102.8 pg/mL [IQR, 47.3-235.5 pg/mL] vs 74.1 pg/mL [IQR, 28.5-150.5 pg/mL], P < .001). Women also had lower median AFEQT overall summary scores than men (75 [IQR, 61-85] vs 80 [IQR, 69-90]; P < .001) but similar treatment satisfaction at baseline. During follow-up, women were less likely to be treated with a rhythm control strategy (48.1% [n = 214] vs 58.0% [n = 621], P < .001), including catheter ablation of AF (adjusted hazard ratio, 0.77 [95% CI, 0.62-0.95]; P = .02). At 1-year follow-up, women and men had improved QOL scores, regardless of their baseline characteristics (eg, age or brain-type natriuretic peptide levels) or treatment strategies, yet the sex gap persisted and grew (adjusted change in AFEQT overall summary score during 12 months, 5.89 [95% CI, 2.24-9.54] in women vs 8.94 [95% CI, 5.59-12.30] in men; P = .02). Conclusions and Relevance: In contemporary Japanese clinical practice among unselected patients with AF, women were initially seen with greater QOL impairment, and the sex gap grew 1 year after presentation. The present study underscores the need for focused efforts to better understand and close this observed sex gap over the initial year of treatment for patients with AF.

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Artificial intelligence to predict needs for urgent revascularization from 12-leads electrocardiography in emergency patients

Goto S., Kimura M., Katsumata Y., Goto S., Kamatani T., Ichihara G., Ko S., Sasaki J., Fukuda K., Sano M.

PLoS ONE (PLoS ONE)  14 ( 1 )  2019.01

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Copyright: © 2019 Goto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background :Patient with acute coronary syndrome benefits from early revascularization. However, methods for the selection of patients who require urgent revascularization from a variety of patients visiting the emergency room with chest symptoms is not fully established. Electrocardiogram is an easy and rapid procedure, but may contain crucial information not recognized even by well-trained physicians. Objective: To make a prediction model for the needs for urgent revascularization from 12-lead electrocardiogram recorded in the emergency room. Method: We developed an artificial intelligence model enabling the detection of hidden information from a 12-lead electrocardiogram recorded in the emergency room. Electrocardiograms obtained from consecutive patients visiting the emergency room at Keio University Hospital from January 2012 to April 2018 with chest discomfort was collected. These data were splitted into validation and derivation dataset with no duplication in each dataset. The artificial intelligence model was constructed to select patients who require urgent revascularization within 48 hours. The model was trained with the derivation dataset and tested using the validation dataset. Results: Of the consecutive 39,619 patients visiting the emergency room with chest discomfort, 362 underwent urgent revascularization. Of them, 249 were included in the derivation dataset and the remaining 113 were included in validation dataset. For the control, 300 were randomly selected as derivation dataset and another 130 patients were randomly selected for validation dataset from the 39,317 who did not undergo urgent revascularization. On validation, our artificial intelligence model had predictive value of the c-statistics 0.88 (95% CI 0.84-0.93) for detecting patients who required urgent revascularization. Conclusions: Our artificial intelligence model provides information to select patients who need urgent revascularization from only 12-leads electrocardiogram in those visiting the emergency room with chest discomfort.

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Endothelial-mesenchymal transition drives expression of CD44 variant and xCT in pulmonary hypertension

Isobe S., Kataoka M., Endo J., Moriyama H., Okazaki S., Tsuchihashi K., Katsumata Y., Yamamoto T., Shirakawa K., Yoshida N., Shimoda M., Chiba T., Masuko T., Hakamata Y., Kobayashi E., Saya H., Fukuda K., Sano M.

American Journal of Respiratory Cell and Molecular Biology (American Journal of Respiratory Cell and Molecular Biology)  61 ( 3 ) 367 - 379 2019

ISSN  10441549

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© 2019 by the American Thoracic Society. Pulmonary arterial hypertension (PAH) pathogenesis shares similarities with carcinogenesis. One CD44 variant (CD44v) isoform, CD44v8-10, binds to and stabilizes the cystine transporter subunit (xCT), producing reduced glutathione and thereby enhancing the antioxidant defense of cancer stem cells. Pharmacological inhibition of xCT by sulfasalazine suppresses tumor growth, survival, and resistance to chemotherapy. We investigated whether the CD44v-xCT axis contributes to PAH pathogenesis. CD44v was predominantly expressed on endothelial-to-mesenchymal transition (EndMT)-like cells in the neointimal layer of PAH affected pulmonary arterioles. In vitro, CD44 standard form and CD44v were induced as a result of EndMT. Among human pulmonary artery endothelial cells that have undergone EndMT, CD44v+ cells showed high levels of xCT expression on their cell surfaces and high concentrations of glutathione for survival. This made CD44v+ cells the most vulnerable target for sulfasalazine. CD44v+xCThi cells showed the highest expression levels of proinflammatory cytokines, antioxidant enzymes, antiapoptotic molecules, and cyclin-dependent kinase inhibitors. In the Sugen5416/hypoxia mouse model, CD44v+ cells were present in the thickened pulmonary vascular wall. The administration of sulfasalazine started either at the same time as "Sugen5416" administration (a prevention model) or after the development of pulmonary hypertension (a reversal model) attenuated the muscularization of the pulmonary vessels, decreased the expression of markers of inflammation, and reduced the right ventricular systolic pressure, while reducing CD44v+ cells. In conclusion, CD44v+xCThi cells appear during EndMT and in pulmonary hypertension tissues. Sulfasalazine is expected to be a novel therapeutic agent for PAH, most likely targeting EndMT-derived CD44v+xCThi cells.

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Incidence, clinical characteristics, and long-term outcome of the dilated phase of hypertrophic cardiomyopathy

Aizawa Y., Tanimoto Y., Hirata Y., Fujisawa T., Fukuoka R., Nakajima K., Katsumata Y., Nishiyama T., Kimura T., Yuasa S., Kohno T., Kohsaka S., Murata M., Maekawa Y., Furukawa Y., Takatsuki S., Fukuda K.

Keio Journal of Medicine (Keio Journal of Medicine)  68 ( 4 ) 87 - 94 2019

ISSN  00229717

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© 2018 by The Keio Journal of Medicine. Some patients with hypertrophic cardiomyopathy (HCM) develop systolic dysfunction, called the dilated phase of HCM (d-HCM), which is associated with increased morbidity and mortality. We conducted a retrospective study using an HCM database to clarify the incidence, clinical characteristics, and long-term outcomes of d-HCM. We analyzed an HCM cohort consisting of 434 patients (273 with apical HCM and 161 with non-apical HCM; 18 had obstructive HCM, 16 had dilated HCM, and 127 had other HCM) diagnosed by echocardiography in our hospital between 1991 and 2010. The follow-up period was 8.4 ± 6.7 years. The mean age at final follow-up was 67 ± 14 years, and 304 patients (70%) were men. The mean age of the 16 d-HCM patients at the initial visit was 45 ± 17 years, the age at final follow-up was 59 ± 18 years, and 13 were men. Thirteen d-HCM patients developed atrial fibrillation and six patients developed ischemic stroke. Twelve d-HCM patients were implanted with cardiac devices: one pacemaker, nine implantable cardioverter-defibrillators, and two cardiac resynchronization therapy with defibrillator. Five patients died of progressive heart failure at the age of 61 ± 23 years. The age at the initial visit and final follow-up were lower and the NYHA class, brain natriuretic peptide levels, and left ventricular function at initial evaluation were worse in the d-HCM group. Univariate analysis demonstrated that a lower age at the initial visit was associated with d-HCM (hazard ratio 0.955/1 year increase; 95% CI 0.920–0.991, P = 0.015). In our HCM cohort, the incidence of d-HCM was 4%. A high prevalence of atrial fibrillation and cerebral infarction and poor prognosis were noted in this group, despite patients undergoing medication and device implantation.

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Decrease in membrane phospholipids unsaturation correlates with myocardial diastolic dysfunction

Yamamoto T., Endo J., Kataoka M., Matsuhashi T., Katsumata Y., Shirakawa K., Yoshida N., Isobe S., Moriyama H., Goto S., Yamashita K., Nakanishi H., Shimanaka Y., Kono N., Shinmura K., Arai H., Fukuda K., Sano M.

PLoS ONE (PLoS ONE)  13 ( 12 )  2018.12

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© 2018 Yamamoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Increase in saturated fatty acid (SFA) content in membrane phospholipids dramatically affects membrane properties and cellular functioning. We sought to determine whether exogenous SFA from the diet directly affects the degree of membrane phospholipid unsaturation in adult hearts and if these changes correlate with contractile dysfunction. Although both SFA-rich high fat diets (HFDs) and monounsaturated FA (MUFA)-rich HFDs cause the same degree of activation of myocardial FA uptake, triglyceride turnover, and mitochondrial FA oxidation and accumulation of toxic lipid intermediates, the former induced more severe diastolic dysfunction than the latter, which was accompanied with a decrease in membrane phospholipid unsaturation, induction of unfolded protein response (UPR), and a decrease in the expression of Sirt1 and stearoyl-CoA desaturase-1 (SCD1), catalyzing the conversion of SFA to MUFA. When the SFA supply in the heart overwhelms the cellular capacity to use it for energy, excess exogenous SFA channels to membrane phospholipids, leading to UPR induction, and development of diastolic dysfunction.

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Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation: Comparing Uninterrupted Rivaroxaban and Warfarin (ASCERTAIN)

Kimura T., Kashimura S., Nishiyama T., Katsumata Y., Inagawa K., Ikegami Y., Nishiyama N., Fukumoto K., Tanimoto Y., Aizawa Y., Tanimoto K., Fukuda K., Takatsuki S.

JACC: Clinical Electrophysiology (JACC: Clinical Electrophysiology)  4 ( 12 ) 1598 - 1609 2018.12

ISSN  2405500X

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© 2018 American College of Cardiology Foundation Objectives: This randomized study compared uninterrupted rivaroxaban therapy with warfarin therapy as prophylaxis against catheter ablation (CA)-induced asymptomatic cerebral infarction (ACI) and identified the risk factors of rivaroxaban. Background: The reported incidence of ACI during CA for atrial fibrillation (AF) remains at 10% to 30%, and periprocedural oral anticoagulation could affect this incidence. Methods: Patients with nonvalvular AF undergoing radiofrequency CA were randomly assigned to receive either uninterrupted rivaroxaban or warfarin as periprocedural anticoagulation therapy. CA was performed after at least 1 month of adequate anticoagulation. Cerebral magnetic resonance imaging (MRI) was performed within 2 weeks before and 1 day after CA to detect ACI. Results: A total 132 patients were enrolled; 127 (median: 60.0 years of age; 83.5% males; 64.6% incidence of paroxysmal AF) complied with the study protocol and were analyzed; 64 patients received rivaroxaban, and 63 patients received warfarin. The rates of CA-induced ACI in the rivaroxaban group (15.6% [10 of 64 patients]) were similar to those in the warfarin group (15.9% [10 of 63 patients]; p = 1.000). No thromboembolic events developed; no differences in major or nonmajor bleeding rates were observed between the 2 drug groups (3.1% vs. 1.6%, respectively, or 18.8% vs. 19.0%, respectively). Multiple regression analysis indicated that the presence of deep and subcortical white matter hyperintensity (p = 0.002; odds ratio [OR]: 5.323) and the frequency of cardioversions (p = 0.016; OR: 1.250) were associated with the incidence of ACI. Conclusions: No notable differences were found between the incidence of CA-induced ACI in the rivaroxaban group and that in the warfarin group in this randomized study.

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Sex-dependent phenotypic variability of an SCN5a mutation: Brugada syndrome and sick sinus syndrome

Aizawa Y., Fujisawa T., Katsumata Y., Kohsaka S., Kunitomi A., Ohno S., Sonoda K., Hayashi H., Hojo R., Fukamizu S., Nagase S., Ito S., Nakajima K., Nishiyama T., Kimura T., Kurita Y., Furukawa Y., Takatsuki S., Ogawa S., Nakazato Y., Sumiyoshi M., Kosaki K., Horie M., Fukuda K.

Journal of the American Heart Association (Journal of the American Heart Association)  7 ( 18 )  2018.09

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© 2018 The Authors. Background Brugada syndrome (BS) is known to be 9 times more prevalent in males than females. However, little is known about the development of sick sinus syndrome in female members with familial BS. Methods and Results Familial BS patients and family members, both from our institutions and collaborating sites that specialize in clinical care of BS, participated in this study. We collected information on their clinical and genetic background, along with the inheritance patterns of BS. Detailed information on each case with familial BS is described. A total of 7 families, including 25 BS patients (12 females and 13 males), were included. Seven were probands and 18 were family members. Ten out of the 12 female patients and none of the 13 male patients developed sick sinus syndrome. Sudden death or spontaneous ventricular fibrillation occurred in 7 out of 13 male patients and 2 out of 12 female patients. Conclusions Familial BS existed in which female patients developed sick sinus syndrome but male patients did not. Some of those female patients with sick sinus syndrome had unrecognized BS. Information should be collected not only regarding a family history of sudden death or BS, but also whether a pacemaker was implanted in female members.

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Improvement in the electrocardiograms associated with right ventricular hypertrophy after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension

Nishiyama Takahiko, Takatsuki Seiji, Kawakami Takashi, Katsumata Yoshinori, Kimura Takehiro, Kataoka Masaharu, Tsuruta Hikaru, Itabashi Yuji, Murata Mitsushige, Yuasa Shinsuke, Aizawa Yoshiyasu, Fukuda Keiichi

IJC Heart and Vasculature (IJC Heart and Vasculature)  19   75 - 82 2018.06

ISSN  2352-9067

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<p>Background: Balloon pulmonary angioplasty (BPA) is a treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods and results: In 60 patients with CTEPH, we examined the hemodynamic data before and after BPA. In addition, the sequential ECG findings for right ventricular hypertrophy (RVH) were assessed. The mean pulmonary arterial pressure (mPAP) decreased from 38 ± 11 to 20 ± 4 mm Hg (p &lt; 0.05). The ROC analysis showed that the S waves in V5, R waves in V1 + S waves in V5, S waves in I, and QRS axis were significant predictors of an mPAP ≧ 30 mm Hg (AUC &gt; 0.75, p &lt; 0.01). The predictive values for the mPAP before the BPA were the S and R waves in lead V6, and P waves in lead II (33.417 + 0.078 × P in II − 0.10 × R in V6 + 0.012 × S in V6). The change in the mPAP (ΔmPAP) correlated with the change in the amplitudes of the ECGs: ΔS wave in lead I (R = 0.544, p &lt; 0.001), ΔR in V1 + S in V5 (R = 0.476, p &lt; 0.001), and ΔP wave in II (R = 0.511, p &lt; 0.001). At 6 months of follow-up, the improvement in an R in V1 + S in V5 of ≧10 mm implied a better functional status. Conclusion: BPA therapy reduced the pulmonary arterial pressure in patients with CTEPH and was associated with an improvement in the ECG findings related to RVH.</p>

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Prevalence and clinical characteristics of obstructive- and central-dominant sleep apnea in candidates of catheter ablation for atrial fibrillation in Japan

Kohno Takashi, Kimura Takehiro, Fukunaga Koichi, Yamasawa Wakako, Fujisawa Taishi, Fukuoka Ryoma, Nakajima Kazuaki, Kashimura Shin, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

International Journal of Cardiology (International Journal of Cardiology)  260   99 - 102 2018.06

ISSN  0167-5273

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<p>Introduction: We aimed to study the prevalence and types of sleep apnea (SA) as well as their clinical characteristics in atrial fibrillation (AF) ablation candidates in Japan. Methods: Before catheter ablation, 197 consecutive AF patients (age: 60 ± 9 years, body mass index; 25.0 ± 3.0) were evaluated with portable polygraphy. We compared the clinical characteristics, according to the severity of SA as well as its types, as defined by the presence of obstruction and the mixed vs. central apnea indices. Results: The mean apnea–hypopnea index (AHI) was 17.7 ± 11.9, with 135 AF patients having an AHI ≥10 (68.5%). Patients with an AHI ≥10 had a significantly higher body mass index, plasma brain natriuretic peptide (BNP) level, prevalence of hypertension, and larger left atrial size. Among patients with an AHI ≥10, the incidence of obstructive-dominant SA was 60.9% and that of central-dominant SA was 7.6%. The prevalence of hypertension was significantly higher in obstructive-dominant SA patients (obstructive vs. central: 48.3% vs. 20.0%, P = 0.038). The obstructive apnea index correlated with plasma BNP level and age, but the central and mixed apnea indices did not. Conclusions: The prevalence of SA was common in AF ablation candidates, even without an obesity epidemic, and the SA type was predominantly obstructive. Portable polygraphy was useful for detecting undiagnosed SA patients in AF ablation candidates.</p>

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Response by Fujisawa et al to Letter Regarding Article, "pulmonary Artery Denervation by Determining Targeted Ablation Sites for Treatment of Pulmonary Arterial Hypertension"

Fujisawa Taishi, Kataoka Masaharu, Kawakami Takashi, Isobe Sarasa, Nakajima Kazuaki, Kunitomi Akira, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Murata Mitsushige, Fukuda Keiichi, Takatsuki Seiji

Circulation: Cardiovascular Interventions 11 ( 2 )  2018.02

ISSN  1941-7640

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The Durability of Atrial Fibrillation Ablation Using an Oesophageal Temperature Cut-Off of 38 °C

Kimura Takehiro, Nishiyama Nobuhiro, Negishi Masachika, Nishiyama Ako, Takazawa Takako, Fujisawa Taishi, Nakajima Kazuaki, Kashimura Shin, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

Heart Lung and Circulation (Heart Lung and Circulation)  28 ( 7 ) 1050 - 1058 2018.01

ISSN  1443-9506

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<p>Background: A lower cut-off of the oesophageal temperature (ET) during catheter ablation of atrial fibrillation (AF) should be safer, but its durability may become in question. We evaluated an ET cut-off of 38 °C with an output of 25 W on the posterior wall. Methods: In 636 consecutive patients (age: 60 ± 10 years, male: 542, paroxysmal AF: 405, CHADS₂ score: 0.7 ± 0.9), an ET probe was utilised in 303 patients (259 pulmonary vein isolations [PVIs] and 44 simultaneous isolations of the posterior wall and all PVs box isolations [BOXIs]). When the ET increased to &gt;38 °C, the radiofrequency delivery was switched off and the ablation point was tagged as an “EsoTag” by the CARTO™ system (Biosense Webster, Irvine, CA, USA). We analysed the characteristics of the ablation lesions at the EsoTags with respect to the dormant conduction, gaps in the redo-session, and ablation outcome. Results: EsoTags were identified in 94.6% of the left PVIs and all BOXIs, and dormant conduction at the EsoTags was identified in 12.0% and 6.8%, respectively. In 10,796 ablation points, the ablation at the EsoTags that were associated with dormant conduction had a significantly shorter duration, smaller force-time integral, and smaller Δimpedance. The duration of an ET of &gt;38 °C was significantly and positively correlated with the body mass index and negatively with the left atrial appendage flow velocity. During the redo-sessions in a 10.5 ± 6.0 months of follow-up (PVI: 14.7%, BOXI: 11.4%), reconnections at the EsoTags with dormant conduction were observed only in two patients after the PVI. The AF survival rate did not significantly differ in the presence of dormant conduction at the EsoTags (83.1% vs. 75.0%, p = 0.696). There were no patients hospitalised for gastroparesis. Conclusions: Atrial fibrillation ablation utilising an oesophageal temperature cut-off of 38 °C might be safe and durable.</p>

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Real-time analysis of the heart rate variability during incremental exercise for the detection of the ventilatory threshold

Shiraishi Yasuyuki, Katsumata Yoshinori, Sadahiro Taketaro, Azuma Koichiro, Akita Keitaro, Isobe Sarasa, Yashima Fumiaki, Miyamoto Kazutaka, Nishiyama Takahiko, Tamura Yuichi, Kimura Takehiro, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

Journal of the American Heart Association (Journal of the American Heart Association)  7 ( 1 )  2018.01

ISSN  2047-9980

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<p>Background--It has never been possible to immediately evaluate heart rate variability (HRV) during exercise. We aimed to visualize the real-time changes in the power spectrum of HRV during exercise and to investigate its relationship to the ventilatory threshold (VT). Methods and Results--Thirty healthy subjects (29.1±5.7 years of age) and 35 consecutive patients (59.0±13.2 years of age) with myocardial infarctions underwent cardiopulmonary exercise tests with an RAMP protocol ergometer. The HRV was continuously assessed with power spectral analyses using the maximum entropy method and projected on a screen without delay. During exercise, a significant decrease in the high frequency (HF) was followed by a drastic shift in the power spectrum of the HRV with a periodic augmentation in the low frequency/HF (L/H) and steady low HF. When the HRV threshold (HRVT) was defined as conversion from a predominant high frequency (HF) to a predominant low frequency/HF (L/H), the VO₂ at the HRVT (HRVT-VO₂) was substantially correlated with the VO₂ at the lactate threshold and VT) in the healthy subjects (r=0.853 and 0.921, respectively). The mean difference between each threshold (0.65 mL/kg per minute for lactate threshold and HRVT, 0.53 mL/kg per minute for VT and HRVT) was nonsignificant (P &gt; 0.05). Furthermore, the HRVT-VO₂ was also correlated with the VT-VO₂ in these myocardial infarction patients (r=0.867), and the mean difference was -0.72 mL/kg per minute and was nonsignificant (P &gt; 0.05). Conclusions--A HRV analysis with our method enabled real-time visualization of the changes in the power spectrum during exercise. This can provide additional information for detecting the VT.</p>

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Development of monomorphic ventricular tachycardia in a patient with fever-induced Brugada syndrome

Sato Y., Aizawa Y., Fujisawa T., Ito S., Katano K., Fuse N., Miyabe A., Osada K., Ishihara R., Tosaka A., Tamamura T., Mizumura T., Sugimura Y., Nakajima K., Katsumata Y., Nishiyama T., Kimura T., Furukawa Y., Takatsuki S., Kosaki K., Fukuda K.

Journal of Arrhythmia (Journal of Arrhythmia)  34 ( 4 ) 465 - 468 2018

ISSN  18804276

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© 2018 The Authors. A 50-year-old woman visited the emergency department with a high fever due to pneumonia. Incessant monomorphic ventricular tachycardia occurred and was terminated by intravenous lidocaine. Her ECG during sinus rhythm demonstrated ST segment elevation suggestive of Brugada syndrome (BS). An intensive examination could not detect any structural disease, and typical coved-type ST elevation was unmasked by a pilsicainide injection leading to a diagnosis of BS. An ICD was implanted for secondary prevention of ventricular arrhythmia. The patient has been free from any recurrences of arrhythmia for 3 years.

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IL (interleukin)-10-STAT3-galectin-3 axis is essential for osteopontin-producing reparative macrophage polarization after myocardial infarction

Shirakawa K., Endo J., Kataoka M., Katsumata Y., Yoshida N., Yamamoto T., Isobe S., Moriyama H., Goto S., Kitakata H., Hiraide T., Fukuda K., Sano M.

Circulation (Circulation)  138 ( 18 ) 2021 - 2035 2018

ISSN  00097322

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© 2018 American Heart Association, Inc. BACKGROUND: Both osteopontin (OPN) and galectin-3 have been implicated in phagocytic clearance of dead cells and reparative fibrosis during wound healing. CD206+ macrophages are involved in tissue repair through phagocytosis and fibrosis after myocardial infarction (MI). However, the relationship among OPN, galectin-3, and macrophage polarization in the context of MI remains unclear. METHODS: The time course of Spp1 (encoding OPN) expression in the heart after MI showed a strong activation of Spp1 on day 3 after MI. To identify where in the body and in which cells the transcriptional activity of Spp1 increased after MI, we analyzed EGFP (enhanced green fluorescent protein)-Spp1 knockin reporter mice on day 3 after MI. RESULTS: The transcriptional activity of Spp1 increased only in CD206+ macrophages in the infarct myocardium, and most of CD206+ macrophages have strong transcriptional activation of Spp1 after MI. The temporal expression pattern of Lgal3 (encoding galectin-3) in cardiac macrophages after MI was similar to that of Spp1, and OPN is almost exclusively produced by galectin-3hiCD206+ macrophages. Although both interleukin (IL)-4 and IL-10 were reported to promote CD206+ macrophage-mediated cardiac repair after MI, IL-10- but not IL-4-stimulated CD11b+Ly6G− cells could differentiate into OPN-producing galectin-3hiCD206+ macrophages and showed enhanced phagocytic ability. Inhibition of STAT3 tyrosine phosphorylation suppressed IL-10-induced expression of intracellular galectin-3 and transcriptional activation of Spp1. Knockdown of galectin-3 suppressed their ability to differentiate into OPN-producing cells, but not STAT3 activation. The tyrosine phosphorylation of STAT3 and the appearance rate of galectin-3hiCD206+ cells on cardiac CD11b+Ly6G− cells in Spp1 knockout mice were the same as those in wild-type mice. Spp1 knockout mice showed vulnerability to developing post-MI left ventricular chamber dilatation and the terminal deoxynucleo-tidyltransferase 2'-Deoxyuridine-5'-triphosphate nick-end labeling (TUNEL)-positive cells in the infarcted myocardium after MI remained higher in number in Spp1 knockout mice than in wild-type mice. CONCLUSIONS: OPN is almost exclusively produced by galectin-3hiCD206+ macrophages, which specifically appear in the infarct myocardium after MI. The IL-10-STAT3-galectin-3 axis is essential for OPN-producing reparative macrophage polarization after myocardial infarction, and these macrophages contribute to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results suggest that galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling OPN levels.

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Pulmonary Artery Denervation by Determining Targeted Ablation Sites for Treatment of Pulmonary Arterial Hypertension

Fujisawa Taishi, Kataoka Masaharu, Kawakami Takashi, Isobe Sarasa, Nakajima Kazuaki, Kunitomi Akira, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Murata Mitsushige, Fukuda Keiichi, Takatsuki Seiji

Circulation: Cardiovascular Interventions 10 ( 10 )  2017.10

ISSN  1941-7640

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Negative legacy of obesity

Shirakawa Kohsuke, Endo Jin, Katsumata Yoshinori, Yamamoto Tsunehisa, Kataoka Masaharu, Isobe Sarasa, Yoshida Naohiro, Fukuda Keiichi, Sano Motoaki

PLoS One 12 ( 10 )  2017.10

ISSN  1932-6203

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<p>Obesity promotes excessive inflammation, which is associated with senescence-like changes in visceral adipose tissue (VAT) and the development of type 2 diabetes (T2DM) and cardiovascular diseases. We have reported that a unique population of CD44^hi CD62L^lo CD4⁺ T cells that constitutively express PD-1 and CD153 exhibit cellular senescence and cause VAT inflammation by producing large amounts of osteopontin. Weight loss improves glycemic control and reduces cardiovascular disease risk factors, but its long-term effects on cardiovascular events and longevity in obese individuals with T2DM are somewhat disappointing and not well understood. High-fat diet (HFD)-fed obese mice were subjected to weight reduction through a switch to a control diet. They lost body weight and visceral fat mass, reaching the same levels as lean mice fed a control diet. However, the VAT of weight reduction mice exhibited denser infiltration of macrophages, which formed more crown-like structures compared to the VAT of obese mice kept on the HFD. Mechanistically, CD153⁺ PD-1⁺ CD4⁺ T cells are long-lived and not easily eliminated, even after weight reduction. Their continued presence maintains a self-sustaining chronic inflammatory loop via production of large amounts of osteopontin. Thus, we concluded that T-cell senescence is essentially a negative legacy effect of obesity.</p>

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A subtype of idiopathic ventricular fibrillation and its relevance to catheter ablation and genetic variants

Nishiyama Takahiko, Aizawa Yoshiyasu, Ito Shogo, Katsumata Yoshinori, Kimura Takehiro, Takatsuki Seiji

HeartRhythm Case Reports 3 ( 5 ) 271 - 275 2017.05

ISSN  2214-0271

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The absence of a left atrial appendage in a patient with paroxysmal atrial fibrillation with a persistent left superior vena cava

Katsumata Yoshinori, Kashimura Shin, Nishiyama Takahiko, Kimura Takehiro, Takatsuki Seiji

European Heart Journal Cardiovascular Imaging 18 ( 3 ) 374 2017.03

ISSN  2047-2404

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An RyR2 mutation found in a family with a short-coupled variant of torsade de pointes

Kimura Mai, Fujisawa Taishi, Aizawa Yoshiyasu, Matsuhashi Noritaka, Ito Shogo, Nakajima Kazuaki, Kashimura Shin, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Yuasa Shinsuke, Takatsuki Seiji, Kosaki Kenjiro, Fukuda Keiichi

International Journal of Cardiology 227   367 - 369 2017.01

ISSN  0167-5273

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Effect of Compliance to Updated AHA/ACC Performance and Quality Measures Among Patients With Atrial Fibrillation on Outcome (from Japanese Multicenter Registry)

Inohara Taku, Kimura Takehiro, Ueda Ikuko, Ikemura Nobuhiro, Tanimoto Kojiro, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Nishiyama Takahiko, Katsumata Yoshinori, Fukuda Keiichi, Takatsuki Seiji, Kohsaka Shun

American Journal of Cardiology  2017

ISSN  0002-9149

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<p>Performance measures (PMs) are used to accelerate translation of scientific evidence into clinical practice. However, it remains unknown how they are applied in the real world and whether the compliance to these metrics will lead to improved patient's outcome in atrial fibrillation (AF). Within the Japanese multicenter AF registry (n = 1,874), adherence of the AF PMs (based on 2016 American Heart Association/American College of Cardiology criteria) and its association with quality of life scaling and clinical outcomes was evaluated. The patient was deemed "adherent" when all applicable components of the PMs for outpatient settings (CHA₂DS₂-VASc risk score documentation [PM-4], anticoagulation prescribed [PM-5], and monthly international normalized ratio (INR) for warfarin treatment [PM-6]) were satisfied. The Atrial Fibrillation Effect on Quality of Life (AFEQT) questionnaire was assessed at baseline and 1 year. About a half of patients (46.1%) were adherent to the AF PMs. PMs were more frequently achieved in patients managed with rhythm control compared with rate control. The achievement rate for each component was 53.9% for PM-4, 85.6% for PM-5, and 90.3% for PM-6, respectively. Although AFEQT global scores at baseline were similar (median 79.2 [interquartile ranges 66.7 to 88.5] vs 77.1 [64.8 to 88.0], p = 0.227), AFEQT global scores at 1-year follow-up were significantly greater in adherence group than those in nonadherence group (89.2 [78.5 to 96.6] vs 86.7 [76.7 to 95.0], p = 0.021). This tendency was consistent regardless of therapeutic strategies. There remains an important opportunity to improve the quality of care in patients with AF. Adherence to the AF PMs might lead to the improvement of patient's quality of life.</p>

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The effects of hydrogen gas inhalation on adverse left ventricular remodeling after percutaneous coronary intervention for ST-elevated myocardial infarction

Katsumata Yoshinori, Sano Fumiya, Abe Takayuki, Tamura Tomoyoshi, Fujisawa Taishi, Shiraishi Yasuyuki, Kohsaka Shun, Ueda Ikuko, Homma Koichiro, Suzuki Masaru, Okuda Shigeo, Maekawa Yuichiro, Kobayashi Eiji, Hori Shingo, Sasaki Junichi, Fukuda Keiichi, Sano Motoaki

Circulation Journal 81 ( 7 ) 940 - 947 2017

ISSN  1346-9843

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<p>Background: Hydrogen gas inhalation (HI) reduced infarct size and mitigated adverse left ventricular (LV) remodeling in a rat model of acute myocardial infarction (AMI). We designed a prospective, open-label, rater-blinded clinical pilot study in patients experiencing ST-elevated MI (STEMI). Methods and Results: The 20 patients with an initial diagnosis of STEMI were assigned to either an HI group (1.3% H2 with 26% oxygen) or a control group (26% oxygen). There were no HI-related severe adverse events. In the full analysis set, the cardiac salvage index as evaluated using cardiac magnetic resonance imaging at 7 days after primary percutaneous coronary intervention (PCI), showed no significant between-group difference (HI: 50.0±24.3%; control: 60.1±20.1%; P=0.43). However, the improvement from day 7 in the HI group was numerically greater than that in the control group in some of the surrogate outcomes at 6-month follow-up, including the LV stroke volume index (HI: 9.2±7.1 mL/m²; control: -1.4±7.2 mL/m²; P=0.03) and the LV ejection fraction (HI: 11.0%±9.3%; control: 1.7%±8.3%; P=0.11). Conclusions: The first clinical study has shown that HI during PCI is feasible and safe and may also promote LV reverse remodeling at 6 months after STEMI. The study was not powered to test efficacy and a further large-scale trial is warranted. (Clinical trials registration: UMIN00006825).</p>

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Puncture of the Closed Coronary Sinus Ostium in a Patient With Coronary Sinus Atresia

Nakajima Kazuaki, Fujisawa Taishi, Kashimura Shin, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Aizawa Yoshiyasu, Takatsuki Seiji

JACC: Clinical Electrophysiology  2016.12

ISSN  2405-500X

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Obesity accelerates T cell senescence in murine visceral adipose tissue

Shirakawa Kohsuke, Yan Xiaoxiang, Shinmura Ken, Endo Jin, Kataoka Masaharu, Katsumata Yoshinori, Yamamoto Tsunehisa, Anzai Atsushi, Isobe Sarasa, Yoshida Naohiro, Itoh Hiroshi, Manabe Ichiro, Sekai Miho, Hamazaki Yoko, Fukuda Keiichi, Minato Nagahiro, Sano Motoaki

Journal of Clinical Investigation 126 ( 12 ) 4626 - 4639 2016.12

ISSN  0021-9738

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<p>Chronic inflammation in visceral adipose tissue (VAT) precipitates the development of cardiometabolic disorders. Although changes in T cell function associated with visceral obesity are thought to affect chronic VAT inflammation, the specific features of these changes remain elusive. Here, we have determined that a high-fat diet (HFD) caused a preferential increase and accumulation of CD44^hiCD62LloCD4⁺ T cells that constitutively express PD-1 and CD153 in a B cell-dependent manner in VAT. These cells possessed characteristics of cellular senescence and showed a strong activation of Spp1 (encoding osteopontin [OPN]) in VAT. Upon T cell receptor stimulation, these T cells also produced large amounts of OPN in a PD-1-resistant manner in vitro. The features of CD153⁺PD-1⁺CD44hiCD4⁺ T cells were highly reminiscent of senescence-associated CD4⁺ T cells that normally increase with age. Adoptive transfer of CD153⁺PD-1⁺CD44hiCD4⁺ T cells from HFD-fed WT, but not Spp1-deficient, mice into the VAT of lean mice fed a normal diet recapitulated the essential features of VAT inflammation and insulin resistance. Our results demonstrate that a distinct CD153⁺PD-1⁺CD44hiCD4⁺ T cell population that accumulates in the VAT of HFD-fed obese mice causes VAT inflammation by producing large amounts of OPN. This finding suggests a link between visceral adiposity and immune aging.</p>

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Visualization of in vivo metabolic flows reveals accelerated utilization of glucose and lactate in penumbra of ischemic heart

Sugiura Yuki, Katsumata Yoshinori, Sano Motoaki, Honda Kurara, Kajimura Mayumi, Fukuda Keiichi, Suematsu Makoto

Scientific Reports 6 2016.09

ISSN  2045-2322

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<p>Acute ischemia produces dynamic changes in labile metabolites. To capture snapshots of such acute metabolic changes, we utilized focused microwave treatment to fix metabolic flow in vivo in hearts of mice 10 min after ligation of the left anterior descending artery. The left ventricle was subdivided into short-Axis serial slices and the metabolites were analyzed by capillary electrophoresis mass spectrometry and matrix-Assisted laser desorption/ionization imaging mass spectrometry. These techniques allowed us to determine the fate of exogenously administered 13 C 6-glucose and 13 C 3-lactate. The penumbra regions, which are adjacent to the ischemic core, exhibited the greatest adenine nucleotide energy charge and an adenosine overflow extending from the ischemic core, which can cause ischemic hyperemia. Imaging analysis of metabolic pathway flows revealed that the penumbra executes accelerated glucose oxidation, with remaining lactate utilization for tricarboxylic acid cycle for energy compensation, suggesting unexpected metabolic interplays of the penumbra with the ischemic core and normoxic regions.</p>

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A Novel SCN5A Mutation Found in a Familial Case of Long QT Syndrome Complicated by Severe Left Ventricular Dysfunction

Kimura Mai, Kohno Takashi, Aizawa Yoshiyasu, Inohara Taku, Shiraishi Yasuyuki, Katsumata Yoshinori, Egashira Toru, Fukushima Hiroyuki, Kosaki Kenjiro, Fukuda Keiichi

Canadian Journal of Cardiology  2016.08

ISSN  0828-282X

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<p>A 16-year-old boy with long QT syndrome type 3 (LQT3) was admitted for decompensated heart failure resulting from dilated cardiomyopathy (DCM). His brother was also diagnosed with LQT3 and DCM. A comprehensive genetic analysis identified a novel . SCN5A missense mutation-p.Q371E-in these 2 affected living family members. It might be important to suspect the coexistence of DCM and LQT3 (which is rare according to previous articles) in cases with this novel . SCN5A missense mutation.</p>

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Assessment of atrial fibrillation ablation outcomes with clinic ECG, monthly 24-h Holter ECG, and twice-daily telemonitoring ECG

Kimura Takehiro, Aizawa Yoshiyasu, Kurata Naomi, Nakajima Kazuaki, Kashimura Shin, Kunitomi Akira, Nishiyama Takahiko, Katsumata Yoshinori, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Fukuda Keiichi, Takatsuki Seiji

Heart and Vessels    1 - 9 2016.07

ISSN  0910-8327

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<p>Differences in the methodologies for evaluating atrial fibrillation (AF) ablation outcomes should be evaluated. In the present study, we compared the AF ablation outcomes among periodic clinic electrocardiography (ECG), 24-h Holter ECG, and telemonitoring ECG to evaluate the differences among these methods. In addition, we evaluated the AF-free survival rate for each method with different durations of the blanking period. A total of 30 AF patients were followed up for 6 months after initial catheter ablation, with clinic ECG on every clinic visit, monthly 24-h Holter ECG, and telemonitoring ECG twice daily and upon symptoms. AF relapse was defined as AF or atrial tachycardia detected with any of the methods. Two patients dropped out of the study, and 28 patients were followed up for 8.8 ± 2.7 months. Patients underwent 3.6 ± 0.8 clinic ECG, 5.1 ± 0.8 Holter ECG, and 273 ± 68 telemonitoring ECG examinations. During the first, second, third, fourth, fifth, and sixth months of follow-up, Holter ECG detected relapses in 11.1, 8.3, 11.5, 15.4, 4.2, and 4.8 % of patients and telemonitoring ECG detected relapses in 32.1, 25.0, 25.0, 17.9, 28.6, and 17.9 % of patients, respectively. When no duration was set for the blanking period, the AF-free survival rate was significantly lower with telemonitoring ECG (46.4 %) than with Holter ECG (78.6 %, P = 0.013) or clinic ECG (85.7 %, P = 0.002). In addition, when the duration of the blanking period was set to 3 months, the AF-free survival rate was significantly lower with telemonitoring ECG than with clinic ECG (92.9 vs. 71.4 %, P = 0.041). The AF ablation outcomes with twice-daily telemonitoring ECG might differ from those with clinic ECG when the duration of the blanking period is 0–3 months. A follow-up based solely on clinic ECG might underestimate AF recurrence.</p>

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Comparison of circadian, weekly, and seasonal variations of electrical storms and single events of ventricular fibrillation in patients with Brugada syndrome

Aizawa Yoshiyasu, Takatsuki Seiji, Kaneko Yoshiaki, Noda Takashi, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Niwano Shinichi, Kurita Takashi, Mitsuhashi Takeshi, Kamakura Shiro, Shimizu Akihiko, Horie Minoru, Aizawa Yoshifusa, Fukuda Keiichi

IJC Heart and Vasculature 11   104 - 110 2016.06

ISSN  2352-9067

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<p>In patients with Brugada syndrome (BS), VF occurred predominantly during the nocturnal period. Some patients also developed ESs. In addition to the circadian rhythm, patients showed weekly and seasonal patterns. The patients with ESs had peak episodes of VF on Saturday and in the winter and spring, while episodes of VF in patients with single VF events occurred most often on Monday with smaller seasonal variation. Except for age, there was no difference in the clinical or ECG characteristics between the patients with ESs and those with single VF episodes.</p>

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Cardiac sirt1 mediates the cardioprotective effect of caloric restriction by suppressing local complement system activation after ischemia-reperfusion

Yamamoto Tsunehisa, Tamaki Kayoko, Shirakawa Kohsuke, Ito Kentaro, Yan Xiaoxiang, Katsumata Yoshinori, Anzai Atsushi, Matsuhashi Tomohiro, Endo Jin, Inaba Takaaki, Tsubota Kazuo, Sano Motoaki, Fukuda Keiichi, Shinmura Ken

American Journal of Physiology - Heart and Circulatory Physiology 310 ( 8 ) H1003 - H1014 2016.04

ISSN  0363-6135

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<p>Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia- reperfusion injury. Am J Physiol Heart Circ Physiol 308: H894– H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM-Sirt1^-/-) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (-40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM-Sirt1^-/- mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM-Sirt1^-/- mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout (C3^-/-) mice treated with CR was similar to that in the ad libitum-fed C3^-/- mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.</p>

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Electrical superior vena cava isolation using photodynamic therapy in a canine model

Kimura Takehiro, Takatsuki Seiji, Miyoshi Shunichiro, Takahashi Mei, Ogawa Emiyu, Nakajima Kazuaki, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Arai Tsunenori, Fukuda Keiichi

Europace 18 ( 2 ) 294 - 300 2016.02

ISSN  1099-5129

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<p>Aims With the new era of multi-tip radiofrequency or balloon ablation catheters replacing the point-to-point ablation strategy, we aimed to determine the feasibility of a ring-laser catheter ablation technology to electrically isolate the superior vena cava (SVC) by exploring the advantages of the limitless catheter tip size possibly with the photodynamic therapy (PDT)-mediated ablation. Methods and results We developed a first-generation prototype of a circular-laser-mapping catheter by fitting a 7 cm plastic optical fibre onto a circular variable-loop Lasso™ mapping catheter. Following SVC venography, both the laser catheter and another ring catheter for monitoring the SVC potentials were placed at the SVC. After the systemic infusion of a photosensitizer (talaporfin sodium), we initiated the irradiation with an output of 1 W in three canines and 0.3 W in four. The creation of electrical isolation as well as occurrence of phrenic nerve injury, sinus node injury, and SVC stenosis were evaluated before, immediately after, and 1 month after the procedure. A PDT-mediated SVC isolation was successfully performed in all seven canines. The isolation was completed with a laser irradiation of 70.4 ± 71.4 J/cm under 30.9 ± 5.0 μg/mL of a photosensitizer without any sinus node injury, phrenic nerve palsy, or SVC stenosis in both the acute and chronic evaluations. The minimum isolation time of 270 s was not correlated with the laser input power or the photosensitizer concentration. Conclusion The electrical SVC isolation was successfully and instantly achieved using the PDT laser-ring catheter without any complications.</p>

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Diagnostic accuracy of commercially available automated external defibrillators

Nishiyama Takahiko, Nishiyama Ako, Negishi Masachika, Kashimura Shin, Katsumata Yoshinori, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Mitamura Hideo, Fukuda Keiichi, Takatsuki Seiji

Journal of the American Heart Association 4 ( 12 )  2015.12

ISSN  2047-9980

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<p>Background-Although automated external defibrillators (AEDs) have contributed to a better survival of out-of-hospital cardiac arrests, there have been reports of their malfunctioning. We investigated the diagnostic accuracy of commercially available AEDs using surface ECGs of ventricular fibrillation (VF), ventricular tachycardia (VT), and supraventricular tachycardia (SVT). Methods and Results-ECGs(VF 31, VT 48, SVT 97) were stored during electrophysiological studies and transmitted to 4 AEDs, the LifePak CR Plus (CR Plus), HeartStart FR3 (FR3), and CardioLife AED-2150 (CL2150) and -9231 (CL9231), through the pad electrode cables. For VF, the CL2150 and CL9231 advised shocks in all cases, and the CR Plus and FR3 advised shocks in all but one VF case. For VTs faster than 180 bpm, the ratios for advising shocks were 79%, 36%, 89%, and 96% for the CR Plus, FR3, CL2150, and CL9231, respectively. The FR3 and CR Plus did not advise shocks for narrow QRS SVTs, whereas the CL9231 tended to treat high-rate tachycardias faster than 180 bpm even with narrow QRS complexes. The characteristics of the shock advice for the FR3 differed from that for the CL9231 (kappa coefficient [κ]=0.479, P &lt; 0.001), and the CR Plus and CL2150 had characteristics somewhere between the 2 former AEDs (κ=0.818, P &lt; 0.001). Conclusions-Commercially available AEDs diagnosed VF almost always correctly. For VT and SVT diagnoses, a discrepancy was evident among the 4 investigated AEDs. The differences in the arrhythmia diagnosis algorithms for differentiating SVT from VT were thought to account for these differences.</p>

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Predictive factors of lead failure in patients implanted with cardiac devices

Aizawa Yoshiyasu, Negishi Masachika, Kashimura Shin, Nakajima Kazuaki, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Kohsaka Shun, Takatsuki Seiji, Fukuda Keiichi

International Journal of Cardiology 199   277 - 281 2015.09

ISSN  0167-5273

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<p>Introduction Lead failures (LFs) are one of the most common complications in patients implanted with cardiovascular implantable electronic devices. LFs often cause serious secondary complications such as inappropriate ICD shocks or asystole. This study aimed to identify the clinical factors associated with the occurrence of LFs. Methods A total of 735 consecutive device implantations (mean age 67 ± 15 years, males 64%) performed at a single university hospital setting from 1997 to 2014 were included. The implanted devices consisted of 421 pacemakers, 250 implantable cardioverter defibrillators (ICD), 9 cardiac resynchronization therapy pacemakers (CRT-P), and 55 CRT defibrillators (CRT-D). The primary endpoint was the development of an LF. Results During a mean duration of 5.8 ± 4.3 years, 38 LFs developed in 31 patients (mean age 56 ± 14 years). LFs included 32 ICD (7 Sprint Fidelis, 2 Riata), and 6 pacing leads. Nine patients received inappropriate ICD shocks and 1 had syncope due to an LF. All patients underwent lead reinsertions with device replacements. Eight patients required opposite site implantations due to venous occlusions. The predictive factors of LFs were the age, male sex, taller body length, ICD vs. pacemaker, lesser lead number, extra-thoracic puncture of the axillary vein vs. a cut-down of the cephalic vein, use of recalled leads and patients with idiopathic ventricular fibrillation (IVF) and Brugada syndrome (BrS). Conclusion LFs occurred mainly with ICD leads. A lesser age, the puncture method, lead model, and diagnosis of IVF/BrS were associated with the development of LFs.</p>

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Predictive factors of lead failure in patients implanted with cardiac devices

Aizawa Yoshiyasu, Negishi Masachika, Kashimura Shin, Nakajima Kazuaki, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Kohsaka Shun, Takatsuki Seiji, Fukuda Keiichi

International Journal of Cardiology 199   277 - 281 2015.09

ISSN  0167-5273

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<p>Introduction Lead failures (LFs) are one of the most common complications in patients implanted with cardiovascular implantable electronic devices. LFs often cause serious secondary complications such as inappropriate ICD shocks or asystole. This study aimed to identify the clinical factors associated with the occurrence of LFs. Methods A total of 735 consecutive device implantations (mean age 67 ± 15 years, males 64%) performed at a single university hospital setting from 1997 to 2014 were included. The implanted devices consisted of 421 pacemakers, 250 implantable cardioverter defibrillators (ICD), 9 cardiac resynchronization therapy pacemakers (CRT-P), and 55 CRT defibrillators (CRT-D). The primary endpoint was the development of an LF. Results During a mean duration of 5.8 ± 4.3 years, 38 LFs developed in 31 patients (mean age 56 ± 14 years). LFs included 32 ICD (7 Sprint Fidelis, 2 Riata), and 6 pacing leads. Nine patients received inappropriate ICD shocks and 1 had syncope due to an LF. All patients underwent lead reinsertions with device replacements. Eight patients required opposite site implantations due to venous occlusions. The predictive factors of LFs were the age, male sex, taller body length, ICD vs. pacemaker, lesser lead number, extra-thoracic puncture of the axillary vein vs. a cut-down of the cephalic vein, use of recalled leads and patients with idiopathic ventricular fibrillation (IVF) and Brugada syndrome (BrS). Conclusion LFs occurred mainly with ICD leads. A lesser age, the puncture method, lead model, and diagnosis of IVF/BrS were associated with the development of LFs.</p>

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Optimal conditions for cardiac catheter ablation using photodynamic therapy

Kimura Takehiro, Takatsuki Seiji, Miyoshi Shunichiro, Takahashi Mei, Ogawa Emiyu, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Arai Tsunenori, Fukuda Keiichi

Europace 17 ( 8 ) 1309 - 1315 2015.06

ISSN  1099-5129

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<p>Aims Photodynamic therapy (PDT) is based on non-thermal injury mediated by singlet oxygen species and is used clinically in cancer therapy. In our continuing efforts to apply this technology to cardiac catheter ablation, we clarified the optimal condition for creating PDT-mediated lesions using a laser catheter. Methods and results In a total of 35 canines, we applied a laser directly to the epicardium of the beating heart during open-chest surgery at 15 min after administration of a photosensitizer, talaporfin sodium. We evaluated the lesion size (depth and width) using hematoxylin-eosin staining under varying conditions as follows: laser output (5, 10, 20 W/cm&lt;sup&gt;2&lt;/sup&gt;), irradiation time (0-60 s), photosensitizer concentration (0, 2.5, 5 mg/kg), blood oxygen concentration (103.5 ± 2.1 vs. 548.0 ± 18.4 torr), and contact force applied during irradiations (low: &lt;20 g, high: &gt;20 g). A laser irradiation at 20 W/cm&lt;sup&gt;2&lt;/sup&gt; for 60 s under 5 mg/kg (29 μg/mL) of photosensitizer induced a lesion 8.7 ± 0.8 mm deep and 5.2 ± 0.2 mm wide. The lesion size was thus positively correlated to the laser power, irradiation time, and photosensitizer concentration, and was independent of the applied contact force and oxygen concentration. In addition, the concentration of the photosensitizer strongly correlated with the changes in the pulse oximetry data and fluorescence of the backscattering laser, suggesting that a clinically appropriate condition could be estimated in real time. Conclusion Photodynamic therapy-mediated cardiac lesions might be controllable by regulating the photosensitizer concentration, laser output, and irradiation time.</p>

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Optimal conditions for cardiac catheter ablation using photodynamic therapy

Kimura Takehiro, Takatsuki Seiji, Miyoshi Shunichiro, Takahashi Mei, Ogawa Emiyu, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Arai Tsunenori, Fukuda Keiichi

Europace 17 ( 8 ) 1309 - 1315 2015.06

ISSN  1099-5129

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<p>Aims Photodynamic therapy (PDT) is based on non-thermal injury mediated by singlet oxygen species and is used clinically in cancer therapy. In our continuing efforts to apply this technology to cardiac catheter ablation, we clarified the optimal condition for creating PDT-mediated lesions using a laser catheter. Methods and results In a total of 35 canines, we applied a laser directly to the epicardium of the beating heart during open-chest surgery at 15 min after administration of a photosensitizer, talaporfin sodium. We evaluated the lesion size (depth and width) using hematoxylin-eosin staining under varying conditions as follows: laser output (5, 10, 20 W/cm&lt;sup&gt;2&lt;/sup&gt;), irradiation time (0-60 s), photosensitizer concentration (0, 2.5, 5 mg/kg), blood oxygen concentration (103.5 ± 2.1 vs. 548.0 ± 18.4 torr), and contact force applied during irradiations (low: &lt;20 g, high: &gt;20 g). A laser irradiation at 20 W/cm&lt;sup&gt;2&lt;/sup&gt; for 60 s under 5 mg/kg (29 μg/mL) of photosensitizer induced a lesion 8.7 ± 0.8 mm deep and 5.2 ± 0.2 mm wide. The lesion size was thus positively correlated to the laser power, irradiation time, and photosensitizer concentration, and was independent of the applied contact force and oxygen concentration. In addition, the concentration of the photosensitizer strongly correlated with the changes in the pulse oximetry data and fluorescence of the backscattering laser, suggesting that a clinically appropriate condition could be estimated in real time. Conclusion Photodynamic therapy-mediated cardiac lesions might be controllable by regulating the photosensitizer concentration, laser output, and irradiation time.</p>

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A cost-utility analysis for catheter ablation of atrial fibrillation in combination with warfarin and dabigatran based on the CHADS₂ score in Japan

Kimura Takehiro, Igarashi Ataru, Ikeda Shunya, Nakajima Kazuaki, Kashimura Shin, Kunitomi Akira, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

Journal of Cardiology  2015.06

ISSN  0914-5087

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<p>Background: We aimed to clarify the cost-effectiveness of an expensive combination therapy for atrial fibrillation (AF) using both catheter ablation and dabigatran compared with warfarin at each CHADS₂ score for patients in Japan. Methods: A Markov model was constructed to analyze costs and quality-adjusted life years associated with AF therapeutic options with a time horizon of 10 years. The target population was 60-year-old patients with paroxysmal AF. The indication for anticoagulation was determined according to the Japanese guideline. Anticoagulation-related data were derived from the RE-LY study and the AF recurrence rate was set at 2.7% per month during the first 12 months and at 0.40% per month afterwards. Stroke risk was determined according to AF recurrence, anticoagulation, and CHADS₂ score. The risks for stroke recurrence and stroke death were also considered. Costs were calculated from the healthcare payer's perspective, and only direct medical costs were included. Results: Warfarin was the most preferred option for patients with a CHADS₂ score of 0 from a health economics aspect. Ablation under warfarin was preferred for a CHADS₂ score of 1-3, while ablation under dabigatran was preferred for a CHADS₂ score ≥4. The quality of life score for AF had the largest impact on the incremental cost-effectiveness ratios in the analysis between the anticoagulation arm and the anticoagulation+ablation arm for a CHADS₂ score of 2. Within the range of the Japanese willingness-to-pay threshold (¥5,000,000), the ablation+warfarin arm became the best option with its probability of 81.7% for a CHADS₂ score of 2; the dabigatran+ablation arm was the most preferred option with its probability of 56.1% for a CHADS₂ score of 4. Conclusions: Ablation under dabigatran therapy is an expensive therapeutic option, but it might benefit patients with a low quality of life and a high CHADS₂ score.</p>

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Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart

Matsuhashi Tomohiro, Hishiki Takako, Zhou Heping, Ono Tomohiko, Kaneda Ruri, Iso Tatsuya, Yamaguchi Aiko, Endo Jin, Katsumata Yoshinori, Atsushi Anzai, Yamamoto Tsunehisa, Shirakawa Kohsuke, Yan Xiaoxiang, Shinmura Ken, Suematsu Makoto, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 82   116 - 124 2015.05

ISSN  0022-2828

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<p>Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. &lt;sup&gt;13&lt;/sup&gt;C&lt;inf&gt;6&lt;/inf&gt;-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.</p>

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Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart

Matsuhashi Tomohiro, Hishiki Takako, Zhou Heping, Ono Tomohiko, Kaneda Ruri, Iso Tatsuya, Yamaguchi Aiko, Endo Jin, Katsumata Yoshinori, Atsushi Anzai, Yamamoto Tsunehisa, Shirakawa Kohsuke, Yan Xiaoxiang, Shinmura Ken, Suematsu Makoto, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 82   116 - 124 2015.05

ISSN  0022-2828

　View Summary

<p>Dichloroacetate (DCA) promotes pyruvate entry into the Krebs cycle by inhibiting pyruvate dehydrogenase (PDH) kinase and thereby maintaining PDH in the active dephosphorylated state. DCA has recently gained attention as a potential metabolic-targeting therapy for heart failure but the molecular basis of the therapeutic effect of DCA in the heart remains a mystery. Once-daily oral administration of DCA alleviates pressure overload-induced left ventricular remodeling. We examined changes in the metabolic fate of pyruvate carbon (derived from glucose) entering the Krebs cycle by metabolic interventions of DCA. &lt;sup&gt;13&lt;/sup&gt;C&lt;inf&gt;6&lt;/inf&gt;-glucose pathway tracing analysis revealed that instead of being completely oxidized in the mitochondria for ATP production, DCA-mediated PDH dephosphorylation results in an increased acetyl-CoA pool both in control and pressure-overloaded hearts. DCA induces hyperacetylation of histone H3K9 and H4 in a dose-dependent manner in parallel to the dephosphorylation of PDH in cultured cardiomyocytes. DCA administration increases histone H3K9 acetylation in in vivo mouse heart. Interestingly, DCA-dependent histone acetylation was associated with an up-regulation of 2.3% of genes (545 out of 23,474 examined). Gene ontology analysis revealed that these genes are highly enriched in transcription-related categories. This evidence suggests that sustained activation of PDH by DCA results in an overproduction of acetyl-CoA, which exceeds oxidation in the Krebs cycle and results in histone acetylation. We propose that DCA-mediated PDH activation has the potential to induce epigenetic remodeling in the heart, which, at least in part, forms the molecular basis for the therapeutic effect of DCA in the heart.</p>

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Visualization of the left atrial appendage by phased-array intracardiac echocardiography from the pulmonary artery in patients with atrial fibrillation

Nishiyama Takahiko, Katsumata Yoshinori, Inagawa Kohei, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Aizawa Yoshiyasu, Tanimoto Kojiro, Fukuda Keiichi, Takatsuki Seiji

Europace 17 ( 4 ) 546 - 551 2015.04

ISSN  1099-5129

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<p>Aims The left atrial appendage (LAA) represents the major source of cardiac thrombus formation in patients with atrial fibrillation (AF). Phased-array intracardiac echocardiography (ICE) has become available and frequently used during catheter ablation of AF. We attempted to study the feasibility of using ICE for the visualization and evaluation of the LAA from the pulmonary artery (PA) in patients with AF. Methods and Results Eighty patients with AF undergoing catheter ablation (70 males, 57.5 ± 9.1 years) were included. Transoesophageal echocardiography was performed on the prior day before the catheter ablation, and ICE was performed just before the transseptal puncture during the catheter ablation. The ICE catheter was advanced up into the PA from the femoral vein, where the LAA was clearly and entirely visualized by manipulating the ICE catheter. We compared the degree of spontaneous echo contrast, and the correlation was obtained between the ICE and TEE (κ = 0.534, P &lt; 0.001). Furthermore, the LAA flow velocity (LAA emptying and filling velocities) measured by ICE had a good correlation to that measured by TEE (R = 0.872, P &lt; 0.01 and R = 0.753, P &lt; 0.01, respectively). No patients developed any complications. Conclusion The utilization of ICE in the PA is feasible for the observation and evaluation of the LAA.</p>

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Visualization of the left atrial appendage by phased-array intracardiac echocardiography from the pulmonary artery in patients with atrial fibrillation

Nishiyama Takahiko, Katsumata Yoshinori, Inagawa Kohei, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Aizawa Yoshiyasu, Tanimoto Kojiro, Fukuda Keiichi, Takatsuki Seiji

Europace 17 ( 4 ) 546 - 551 2015.04

ISSN  1099-5129

　View Summary

<p>Aims The left atrial appendage (LAA) represents the major source of cardiac thrombus formation in patients with atrial fibrillation (AF). Phased-array intracardiac echocardiography (ICE) has become available and frequently used during catheter ablation of AF. We attempted to study the feasibility of using ICE for the visualization and evaluation of the LAA from the pulmonary artery (PA) in patients with AF. Methods and Results Eighty patients with AF undergoing catheter ablation (70 males, 57.5 ± 9.1 years) were included. Transoesophageal echocardiography was performed on the prior day before the catheter ablation, and ICE was performed just before the transseptal puncture during the catheter ablation. The ICE catheter was advanced up into the PA from the femoral vein, where the LAA was clearly and entirely visualized by manipulating the ICE catheter. We compared the degree of spontaneous echo contrast, and the correlation was obtained between the ICE and TEE (κ = 0.534, P &lt; 0.001). Furthermore, the LAA flow velocity (LAA emptying and filling velocities) measured by ICE had a good correlation to that measured by TEE (R = 0.872, P &lt; 0.01 and R = 0.753, P &lt; 0.01, respectively). No patients developed any complications. Conclusion The utilization of ICE in the PA is feasible for the observation and evaluation of the LAA.</p>

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Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

Anzai Atsushi, Shimoda Masayuki, Endo Jin, Kohno Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Yamamoto Tsunehisa, Ito Kentaro, Yan Xiaoxiang, Shirakawa Kosuke, Shimizu-Hirota Ryoko, Yamada Yoshitake, Ueha Satoshi, Shinmura Ken, Okada Yasunori, Fukuda Keiichi, Sano Motoaki

Circulation Research 116 ( 4 ) 612 - 623 2015.02

ISSN  0009-7330

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<p>Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.</p>

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Adventitial CXCL1/G-CSF expression in response to acute aortic dissection triggers local neutrophil recruitment and activation leading to aortic rupture

Anzai Atsushi, Shimoda Masayuki, Endo Jin, Kohno Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Yamamoto Tsunehisa, Ito Kentaro, Yan Xiaoxiang, Shirakawa Kosuke, Shimizu-Hirota Ryoko, Yamada Yoshitake, Ueha Satoshi, Shinmura Ken, Okada Yasunori, Fukuda Keiichi, Sano Motoaki

Circulation Research 116 ( 4 ) 612 - 623 2015.02

ISSN  0009-7330

　View Summary

<p>Rationale: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. Objective: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. Methods and Results: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. Conclusions: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.</p>

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Risk factors for early replacement of cardiovascular implantable electronic devices

Aizawa Yoshiyasu, Kunitomi Akira, Nakajima Kazuaki, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Kohsaka Shun, Takatsuki Seiji, Fukuda Keiichi

International Journal of Cardiology 178   99 - 101 2015.01

ISSN  0167-5273

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Risk factors for early replacement of cardiovascular implantable electronic devices

Aizawa Yoshiyasu, Kunitomi Akira, Nakajima Kazuaki, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Kohsaka Shun, Takatsuki Seiji, Fukuda Keiichi

International Journal of Cardiology 178   99 - 101 2015.01

ISSN  0167-5273

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Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury

Shinmura Ken, Tamaki Kayoko, Ito Kentaro, Yan Xiaoxiang, Yamamoto Tsunehisa, Katsumata Yoshinori, Matsuhashi Tomohiro, Sano Motoaki, Fukuda Keiichi, Suematsu Makoto, Ishii Isao

American Journal of Physiology - Heart and Circulatory Physiology 308 ( 8 ) H894 - H903 2015

ISSN  0363-6135

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<p>Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with N&lt;sup&gt;G&lt;/sup&gt;-nitro-L-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS&lt;sup&gt;−/−&lt;/sup&gt;) mice to either 3-mo ad libitum (AL) feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice. eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice. In eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS&lt;sup&gt;−/−&lt;/sup&gt;mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.</p>

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Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury

Shinmura Ken, Tamaki Kayoko, Ito Kentaro, Yan Xiaoxiang, Yamamoto Tsunehisa, Katsumata Yoshinori, Matsuhashi Tomohiro, Sano Motoaki, Fukuda Keiichi, Suematsu Makoto, Ishii Isao

American Journal of Physiology - Heart and Circulatory Physiology 308 ( 8 ) H894 - H903 2015

ISSN  0363-6135

　View Summary

<p>Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with N&lt;sup&gt;G&lt;/sup&gt;-nitro-L-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS&lt;sup&gt;−/−&lt;/sup&gt;) mice to either 3-mo ad libitum (AL) feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice. eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice. In eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS&lt;sup&gt;−/−&lt;/sup&gt;mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS&lt;sup&gt;−/−&lt;/sup&gt; mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.</p>

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Operator-blinded contact force monitoring during pulmonary vein isolation using conventional and steerable sheaths

Kimura Takehiro, Takatsuki Seiji, Oishi Ako, Negishi Masachika, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi

International Journal of Cardiology 177 ( 3 ) 970 - 976 2014.12

ISSN  0167-5273

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<p>Background We performed contact force (CF) monitoring during pulmonary vein (PV) isolation to evaluate CF according to sheath type, catheter position, and inadequate ablation.</p><p>Methods Thirty consecutive patients (paroxysmal atrial fibrillation, 23; CHADS₂ score, 0.5 ± 0.7; age, 56 ± 10 years) who underwent PV isolation using a CF-sensing catheter were included. Data for operator-blinded CF, impedance, and duration of the "first touch" (first round of ablation in each PV) was collected. We compared the CF, maximum CF, force-time integral, average impedance, and impedance drop (Δ impedance) between different sheaths (Swartz™ vs. Agilis™) in 12 different catheter positions, and in inadequate first touches requiring additional ablation.</p><p>Results A total of 1283 ablation points (Swartz™, 620 points; Agilis™, 663 points) were evaluated. The average CF was significantly higher in the Agilis™ group (17.8 ± 13.0 g) than the Swartz™ group (15.0 ± 12.4 g; P &lt; 0.001), especially in the anterior, inferior-anterior, and inferior-posterior sections of the right PV, and the top of the roof, and calina of the left PV. The Δ impedance showed a mildly significant negative relationship with the average CF (r = - 0.206; P &lt; 0.001) and with the force-time integral (r = - 0.279; P &lt; 0.001). Compared to first touches, the average CF and Δ impedance were significantly smaller in inadequate first touches in the Swartz™ group, but not in the Agilis™ group.</p><p>Conclusions CF for PV isolation was significantly different depending on the position of the catheter and the type of sheath.</p>

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Operator-blinded contact force monitoring during pulmonary vein isolation using conventional and steerable sheaths

Kimura Takehiro, Takatsuki Seiji, Oishi Ako, Negishi Masachika, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi

International Journal of Cardiology 177 ( 3 ) 970 - 976 2014.12

ISSN  0167-5273

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<p>Background We performed contact force (CF) monitoring during pulmonary vein (PV) isolation to evaluate CF according to sheath type, catheter position, and inadequate ablation.</p><p>Methods Thirty consecutive patients (paroxysmal atrial fibrillation, 23; CHADS₂ score, 0.5 ± 0.7; age, 56 ± 10 years) who underwent PV isolation using a CF-sensing catheter were included. Data for operator-blinded CF, impedance, and duration of the "first touch" (first round of ablation in each PV) was collected. We compared the CF, maximum CF, force-time integral, average impedance, and impedance drop (Δ impedance) between different sheaths (Swartz™ vs. Agilis™) in 12 different catheter positions, and in inadequate first touches requiring additional ablation.</p><p>Results A total of 1283 ablation points (Swartz™, 620 points; Agilis™, 663 points) were evaluated. The average CF was significantly higher in the Agilis™ group (17.8 ± 13.0 g) than the Swartz™ group (15.0 ± 12.4 g; P &lt; 0.001), especially in the anterior, inferior-anterior, and inferior-posterior sections of the right PV, and the top of the roof, and calina of the left PV. The Δ impedance showed a mildly significant negative relationship with the average CF (r = - 0.206; P &lt; 0.001) and with the force-time integral (r = - 0.279; P &lt; 0.001). Compared to first touches, the average CF and Δ impedance were significantly smaller in inadequate first touches in the Swartz™ group, but not in the Agilis™ group.</p><p>Conclusions CF for PV isolation was significantly different depending on the position of the catheter and the type of sheath.</p>

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Pericardial endoscopy-guided left atrial appendage ligation

Kimura Takehiro, Takatsuki Seiji, Miyoshi Shunichiro, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Jinzaki Masahiro, Fukuda Keiichi

Circulation: Cardiovascular Interventions 7 ( 6 ) 844 - 850 2014.12

ISSN  1941-7640

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<p>Background-Approaches for closing the left atrial appendage (LAA) have been developed for stroke prevention. However, the prevailing maneuvers require an open-chest surgery, intravascular access, or transseptal puncture. We evaluated the feasibility and safety of pericardial endoscopy-guided LAA ligation in a canine model. Methods and Results-We used a total of 8 canines and computed tomography was performed before the procedures. After a double percutaneous pericardiocentesis, a transurethral rigid endoscope was inserted into the pericardial space. The ENDOLOOP ligature was advanced to the ostium of the LAA by counter pulling the tip of the LAA with forceps. After confirming the positioning guided by transesophageal echocardiography, the ligature was securely tightened. Acute success was evaluated by transesophageal echocardiography and chronic success was evaluated by blood testing, computed tomography, and transesophageal echocardiography. The LAA ligation was safely achieved in all canines without major complications. One month after the ligation, the ligated LAA was replaced by fibrotic tissue, and both the transesophageal echocardiography and computed tomographic images revealed no residual shunt. There was only a localized adhesion of the pericardium, where the original LAA was located, without the need for antibiotic or steroid administration. The postprocedural internal surface of the ligated LAA was smooth by virtue of intimal growth. Blood tests showed a slight elevation of the inflammatory markers, but this normalized spontaneously. Conclusions-Pericardial endoscopy-guided LAA ligation could provide an alternative, minimally invasive, and feasible solution for LAA closure that does not require vascular access or a transseptal puncture.</p>

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Pericardial endoscopy-guided left atrial appendage ligation

Kimura Takehiro, Takatsuki Seiji, Miyoshi Shunichiro, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Jinzaki Masahiro, Fukuda Keiichi

Circulation: Cardiovascular Interventions 7 ( 6 ) 844 - 850 2014.12

ISSN  1941-7640

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<p>Background-Approaches for closing the left atrial appendage (LAA) have been developed for stroke prevention. However, the prevailing maneuvers require an open-chest surgery, intravascular access, or transseptal puncture. We evaluated the feasibility and safety of pericardial endoscopy-guided LAA ligation in a canine model. Methods and Results-We used a total of 8 canines and computed tomography was performed before the procedures. After a double percutaneous pericardiocentesis, a transurethral rigid endoscope was inserted into the pericardial space. The ENDOLOOP ligature was advanced to the ostium of the LAA by counter pulling the tip of the LAA with forceps. After confirming the positioning guided by transesophageal echocardiography, the ligature was securely tightened. Acute success was evaluated by transesophageal echocardiography and chronic success was evaluated by blood testing, computed tomography, and transesophageal echocardiography. The LAA ligation was safely achieved in all canines without major complications. One month after the ligation, the ligated LAA was replaced by fibrotic tissue, and both the transesophageal echocardiography and computed tomographic images revealed no residual shunt. There was only a localized adhesion of the pericardium, where the original LAA was located, without the need for antibiotic or steroid administration. The postprocedural internal surface of the ligated LAA was smooth by virtue of intimal growth. Blood tests showed a slight elevation of the inflammatory markers, but this normalized spontaneously. Conclusions-Pericardial endoscopy-guided LAA ligation could provide an alternative, minimally invasive, and feasible solution for LAA closure that does not require vascular access or a transseptal puncture.</p>

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Effect of Nocturnal Intermittent Hypoxia on Left Atrial Appendage Flow Velocity in Atrial Fibrillation

Kimura Takehiro, Kohno Takashi, Nakajima Kazuaki, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

Canadian Journal of Cardiology  2014.10

ISSN  0828-282X

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<p>Background: The mechanism underlying the associations of sleep-disordered breathing (SDB) with stroke and atrial fibrillation (AF) is not well established. We explored the relationship between nocturnal intermittent hypoxia, a marker of SDB, and left atrial (LA)/LA appendage (LAA) function among AF patients. Methods: We evaluated 134 consecutive AF candidates for catheter ablation (age, 59.6 ± 9.4 years; body mass index [BMI], 24.8 ± 3.2; Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc) score, 1.2 ± 1.1, paroxysmal AF, n= 83) using nocturnal pulse oximetry, a noninvasive screening method for nocturnal intermittent hypoxia. Based on 3% oxygen desaturation index (3% ODI), patients were divided into nocturnal intermittent hypoxia (3% ODI &gt; 15; n= 32) and control groups (3% ODI ≤ 15; n= 102). Results: The nocturnal intermittent hypoxia group demonstrated significantly higher weight, BMI, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS&lt;inf&gt;2&lt;/inf&gt;) and CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc scores, serum hemoglobin A1c and plasma brain natriuretic peptide levels, LA size, and prevalence of hypertension, vascular disease, and sick sinus syndrome. Echocardiographically, nocturnal intermittent hypoxia was associated with a higher grade of spontaneous echo contrast and low LAA flow velocity. Multiple regression analysis adjusted for type of AF, CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc score, BMI, plasma brain natriuretic peptide level, LA size, and rhythm on echocardiography revealed that 3% ODI was a factor independently associated with LAA flow velocity (β=-0.184; 95% confidence interval,-0.818 to-0.006). Conclusions: Nocturnal intermittent hypoxia was an independent determinant for low LAA flow velocity in patients with AF, suggesting that the connection between SDB and LAA function might underlie the association of AF with stroke.</p>

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Effect of Nocturnal Intermittent Hypoxia on Left Atrial Appendage Flow Velocity in Atrial Fibrillation

Kimura Takehiro, Kohno Takashi, Nakajima Kazuaki, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi, Takatsuki Seiji

Canadian Journal of Cardiology  2014.10

ISSN  0828-282X

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<p>Background: The mechanism underlying the associations of sleep-disordered breathing (SDB) with stroke and atrial fibrillation (AF) is not well established. We explored the relationship between nocturnal intermittent hypoxia, a marker of SDB, and left atrial (LA)/LA appendage (LAA) function among AF patients. Methods: We evaluated 134 consecutive AF candidates for catheter ablation (age, 59.6 ± 9.4 years; body mass index [BMI], 24.8 ± 3.2; Congestive Heart Failure, Hypertension, Age (≥75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc) score, 1.2 ± 1.1, paroxysmal AF, n= 83) using nocturnal pulse oximetry, a noninvasive screening method for nocturnal intermittent hypoxia. Based on 3% oxygen desaturation index (3% ODI), patients were divided into nocturnal intermittent hypoxia (3% ODI &gt; 15; n= 32) and control groups (3% ODI ≤ 15; n= 102). Results: The nocturnal intermittent hypoxia group demonstrated significantly higher weight, BMI, Congestive Heart Failure, Hypertension, Age, Diabetes, Stroke/Transient Ischemic Attack (CHADS&lt;inf&gt;2&lt;/inf&gt;) and CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc scores, serum hemoglobin A1c and plasma brain natriuretic peptide levels, LA size, and prevalence of hypertension, vascular disease, and sick sinus syndrome. Echocardiographically, nocturnal intermittent hypoxia was associated with a higher grade of spontaneous echo contrast and low LAA flow velocity. Multiple regression analysis adjusted for type of AF, CHA&lt;inf&gt;2&lt;/inf&gt;DS&lt;inf&gt;2&lt;/inf&gt;-VASc score, BMI, plasma brain natriuretic peptide level, LA size, and rhythm on echocardiography revealed that 3% ODI was a factor independently associated with LAA flow velocity (β=-0.184; 95% confidence interval,-0.818 to-0.006). Conclusions: Nocturnal intermittent hypoxia was an independent determinant for low LAA flow velocity in patients with AF, suggesting that the connection between SDB and LAA function might underlie the association of AF with stroke.</p>

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Evaluation of differences in automated QT/QTc measurements between Fukuda Denshi and Nihon Koden systems

Sano Motoaki, Aizawa Yoshiyasu, Katsumata Yoshinori, Nishiyama Nobuhiro, Takatsuki Seiji, Kamitsuji Shigeo, Kamatani Naoyuki, Fukuda Keiichi

PLoS One 9 ( 9 )  2014.09

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<p>Background: Automatic measurement becomes a preference, and indeed a necessity, when analyzing 1000 s of ECGs in the setting of either drug-inducing QT prolongation screening or genome-wide association studies of QT interval. The problem is that individual manufacturers apply different computerized algorithms to measure QT interval. We conducted a comparative study to assess the outcomes with different automated measurements of QT interval between ECG machine manufacturers and validated the related heart rate correction methods.</p><p>Methods and Results: Herein, we directly compared these different commercial systems using 10,529 Fukuda Denshi ECGs and 72,754 Nihon Kohden ECGs taken in healthy Japanese volunteers. Log-transformed data revealed an equal optimal heart rate correction formula of QT interval for Fukuda Denshi and Nihon Kohden, in the form of QTc = QT/RR-^0.347. However, with the raw data, the optimal heart rate correction formula of QT interval was in the form of QTc = QT+0.1566(1- RR) for Fukuda Denshi and QTc = QT+0.1526(1-RR) for Nihon Kohden. After optimization of heart rate correction of QT interval by the linear regression model using either log-transformed data or raw data, QTc interval was ,10 ms longer in Nihon Kohden ECGs than in those recorded on Fukuda Denshi machines. Indeed, regression analysis revealed that differences in the ECG machine used had up to a two-fold larger impact on QT variation than gender difference. Such an impact is likely to be of considerable importance when ECGs for a given individual are recorded on different machines in the setting of multi-institutional joint research.</p><p>Conclusions: We recommend that ECG machines of the same manufacturer should be used to measure QT and RR intervals in the setting of multi-institutional joint research. It is desirable to unify the computer algorithm for automatic QT and RR measurements from an ECG.</p>

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Evaluation of differences in automated QT/QTc measurements between Fukuda Denshi and Nihon Koden systems

Sano Motoaki, Aizawa Yoshiyasu, Katsumata Yoshinori, Nishiyama Nobuhiro, Takatsuki Seiji, Kamitsuji Shigeo, Kamatani Naoyuki, Fukuda Keiichi

PLoS ONE 9 ( 9 )  2014.09

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<p>Background: Automatic measurement becomes a preference, and indeed a necessity, when analyzing 1000 s of ECGs in the setting of either drug-inducing QT prolongation screening or genome-wide association studies of QT interval. The problem is that individual manufacturers apply different computerized algorithms to measure QT interval. We conducted a comparative study to assess the outcomes with different automated measurements of QT interval between ECG machine manufacturers and validated the related heart rate correction methods.</p><p>Methods and Results: Herein, we directly compared these different commercial systems using 10,529 Fukuda Denshi ECGs and 72,754 Nihon Kohden ECGs taken in healthy Japanese volunteers. Log-transformed data revealed an equal optimal heart rate correction formula of QT interval for Fukuda Denshi and Nihon Kohden, in the form of QTc = QT/RR-^0.347. However, with the raw data, the optimal heart rate correction formula of QT interval was in the form of QTc = QT+0.1566(1- RR) for Fukuda Denshi and QTc = QT+0.1526(1-RR) for Nihon Kohden. After optimization of heart rate correction of QT interval by the linear regression model using either log-transformed data or raw data, QTc interval was ,10 ms longer in Nihon Kohden ECGs than in those recorded on Fukuda Denshi machines. Indeed, regression analysis revealed that differences in the ECG machine used had up to a two-fold larger impact on QT variation than gender difference. Such an impact is likely to be of considerable importance when ECGs for a given individual are recorded on different machines in the setting of multi-institutional joint research.</p><p>Conclusions: We recommend that ECG machines of the same manufacturer should be used to measure QT and RR intervals in the setting of multi-institutional joint research. It is desirable to unify the computer algorithm for automatic QT and RR measurements from an ECG.</p>

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Thoracic impedance as a therapeutic marker of acute decompensated heart failure

Aizawa Yoshiyasu, Takatsuki Seiji, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Tanimoto Kojiro, Fukuda Yukiko, Sato Toshiaki, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 174 ( 3 ) 840 - 842 2014.07

ISSN  0167-5273

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Thoracic impedance as a therapeutic marker of acute decompensated heart failure

Aizawa Yoshiyasu, Takatsuki Seiji, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Tanimoto Kojiro, Fukuda Yukiko, Sato Toshiaki, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 174 ( 3 ) 840 - 842 2014.07

ISSN  0167-5273

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Clinical characteristics of atrial fibrillation detected by implanted devices and its association with ICD therapy

Aizawa Yoshiyasu, Takatsuki Seiji, Negishi Masachika, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Tanimoto Kojiro, Kohsaka Shun, Sano Motoaki, Fukuda Keiichi

International Journal of Cardiology 172 ( 3 )  2014.04

ISSN  0167-5273

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Clinical characteristics of atrial fibrillation detected by implanted devices and its association with ICD therapy

Aizawa Yoshiyasu, Takatsuki Seiji, Negishi Masachika, Kashimura Shin, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Tanimoto Yoko, Tanimoto Kojiro, Kohsaka Shun, Sano Motoaki, Fukuda Keiichi

International Journal of Cardiology 172 ( 3 )  2014.04

ISSN  0167-5273

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Lung natural killer cells play a major counter-regulatory role in pulmonary vascular hyperpermeability after myocardial infarction

Yan Xiaoxiang, Hegab Ahmed E., Endo Jin, Anzai Atsushi, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Kentaro, Yamamoto Tsunehisa, Betsuyaku Tomoko, Shinmura Ken, Shen Weifeng, Vivier Eric, Fukuda Keiichi, Sano Motoaki

Circulation Research 114 ( 4 ) 637 - 649 2014.02

ISSN  0009-7330

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<p>RATIONALE:: Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. OBJECTIVE:: We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. METHODS AND RESULTS:: Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1β-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. CONCLUSIONS:: This study is the first to identify a critical role for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after myocardial infarction.</p>

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Lung natural killer cells play a major counter-regulatory role in pulmonary vascular hyperpermeability after myocardial infarction

Yan Xiaoxiang, Hegab Ahmed E., Endo Jin, Anzai Atsushi, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Kentaro, Yamamoto Tsunehisa, Betsuyaku Tomoko, Shinmura Ken, Shen Weifeng, Vivier Eric, Fukuda Keiichi, Sano Motoaki

Circulation Research 114 ( 4 ) 637 - 649 2014.02

ISSN  0009-7330

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<p>RATIONALE:: Natural killer (NK) cells are lymphocytes of the innate immune system that play specialized and niche-specific roles in distinct organs. OBJECTIVE:: We investigated the possible function of NK cells in the pathogenesis of congestive heart failure after myocardial infarction. METHODS AND RESULTS:: Depletion of NK cells from mice had little effect on cytokine expression (tumor necrosis factor-α, interleukin [IL]-6, and IL-1β), neutrophil and macrophage infiltration into infarcted myocardium, or left ventricular remodeling after myocardial infarction. However, these mice exhibited severe respiratory distress associated with protein-rich, high-permeability alveolar edema accompanied by neutrophil infiltration. In addition, there were 20-fold more NK cells in the mouse lungs than in heart, and these cells were accumulated around the vasculature. CD107a-positive and interferon-γ-positive cell populations were unchanged, whereas IL-10-positive populations increased. Adoptive transfer of NK cells from wild-type mice, but not from IL-10 knockout mice, into the NK cell-depleted mice rescued the respiratory phenotype. IL-1β-mediated dextran leakage from a lung endothelial cell monolayer was also blocked by coculture with NK cells from wild-type mice but not from IL-10 knockout mice. CONCLUSIONS:: This study is the first to identify a critical role for lung NK cells in protecting lung from the development of cardiogenic pulmonary edema after myocardial infarction. © 2014 American Heart Association, Inc.</p>

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Endogenous prostaglandin D₂ and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2

Katsumata Yoshinori, Shinmura Ken, Sugiura Yuki, Tohyama Shugo, Matsuhashi Tomohiro, Ito Hideyuki, Yan Xiaoxiang, Ito Kentaro, Yuasa Shinsuke, Ieda Masaki, Urade Yoshihiro, Suematsu Makoto, Fukuda Keiichi, Sano Motoaki

Hypertension 63 ( 1 ) 80 - 87 2014.01

ISSN  0194-911X

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<p>We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia-reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)-derived PGD2 biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD2 biosynthesis. Acute PGD2 treatment did not protect hearts against I/R injury. We then speculated that PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2-like 2 (Nrf2) target genes in the heart in an L-PGDS-dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD2 receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF2α receptor (FP), which binds PGF2α and PGD2 with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD2 acted through its metabolite 15-deoxy-Δ12,14-PGJ2 in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD2 protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD2 (15-deoxy-Δ12,14- PGJ2) as another mechanism by which glucocorticoids induce cardioprotection. © 2013 American Heart Association, Inc.</p>

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Endogenous prostaglandin D₂ and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2

Katsumata Yoshinori, Shinmura Ken, Sugiura Yuki, Tohyama Shugo, Matsuhashi Tomohiro, Ito Hideyuki, Yan Xiaoxiang, Ito Kentaro, Yuasa Shinsuke, Ieda Masaki, Urade Yoshihiro, Suematsu Makoto, Fukuda Keiichi, Sano Motoaki

Hypertension 63 ( 1 ) 80 - 87 2014.01

ISSN  0194-911X

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<p>We recently demonstrated that glucocorticoids markedly upregulate the expression of cyclooxygenase-2 in cardiomyocytes and protect hearts from ischemia-reperfusion (I/R) injury by activating lipocalin-type prostaglandin D (PGD) synthase (L-PGDS)-derived PGD2 biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD2 biosynthesis. Acute PGD2 treatment did not protect hearts against I/R injury. We then speculated that PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 activate gene expression networks to mediate the glucocorticoid-mediated cardioprotection. Using an unbiased approach, we identified that glucocorticoids induce a number of well-known erythroid-derived 2-like 2 (Nrf2) target genes in the heart in an L-PGDS-dependent manner and that the cardioprotective effect of glucocorticoids against I/R injury was not seen in Nrf2-knockout hearts. We showed relatively low expression of PGD2 receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF2α receptor (FP), which binds PGF2α and PGD2 with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD2 acted through its metabolite 15-deoxy-Δ12,14-PGJ2 in the heart as evidenced by the glucocorticoid-mediated activation of peroxisome proliferator-activated receptor-γ. In turn, glucocorticoids failed to induce the expression of L-PGDS-dependent Nrf2 target genes in hearts pretreated with peroxisome proliferator-activated receptor-γ antagonist GW9662, and glucocorticoid-mediated cardioprotection against I/R injury was compromised in FP-knockout mice and GW9662-treated mice. In conclusion, PGD2 protects heart against I/R injury by activating Nrf2 predominantly via FP receptor. In addition, we propose activation of peroxisome proliferator-activated receptor-γ by the dehydrated metabolite of PGD2 (15-deoxy-Δ12,14- PGJ2) as another mechanism by which glucocorticoids induce cardioprotection.</p>

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Serum Inflammation Markers Predicting Successful Initial Catheter Ablation for Atrial Fibrillation

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Fukuda Keiichi

Heart Lung and Circulation 23 ( 7 ) 636 - 643 2014

ISSN  1443-9506

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<p>Background: We investigated various serum inflammatory markers to predict ablation responders who have no atrial fibrillation (AF) relapse after the initial ablation. Methods: Forty-four consecutive AF patients (age: 59 ± 8 years, paroxysmal: 31, CHADS₂: 1.1 ± 1.1) who underwent an initial pulmonary vein isolation were investigated. Various serum inflammatory markers, such as adiponectin, ANP, BNP, 1CTP, F1+2, hs-CRP, IL-6, intact P1NP, MDA-LDL, MMP-2, TGF-β, TIMP-2, and TNF-α, were evaluated prior to ablation. AF relapse was defined as AF documented in telemonitoring electrocardiograms twice a day during 9.7 ± 2.4 months of follow-up with three months of a blanking-period. Results: A total of 29 patients (paroxysmal: 21) maintained sinus rhythm after the initial catheter ablation. These ablation responders had significantly lower MMP-2 (Sinus vs. Relapsed: 748 ± 132.7 vs. 841.2 ± 152.4 ng/mL, P=0.042) and TNF-α (1.1 ± 0.4 vs. 1.8 ± 1.7 pg/mL, P=0.046) levels prior to ablation. A BNP-adjusted Cox multivariate regression analysis revealed that the independent predictive factor for AF recurrence was high MMP-2 levels (&gt;766 ng/mL) accompanied by high TNF-α levels (&gt;1.2 pg/mL). Conclusions: The levels of MMP-2 and TNF-α might be useful for predicting initial AF catheter ablation responders. © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).</p>

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Thrombus Formation in the Left Atrial Appendage During Catheter Ablation for Atrial Fibrillation Under Sufficient Heparinization

Kimura Takehiro, Takatsuki Seiji, Tanimoto Kojiro, Katsumata Yoshinori, Nishiyama Takahiko, Inagawa Kohei, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi

Canadian Journal of Cardiology 30 ( 4 )  2014

ISSN  0828-282X

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Narrow QRS tachycardia

Aizawa Y., Takatsuki S., Inagawa K., Katsumata Y., Nishiyama T., Kimura T., Nishiyama N., Sato Y., Fukumoto K., Tanimoto Y., Tanimoto K., Fukuda K.

Herz 39 ( 2 ) 276 - 278 2014

ISSN  0340-9937

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Narrow QRS tachycardia

Aizawa Y., Takatsuki S., Inagawa K., Katsumata Y., Nishiyama T., Kimura T., Nishiyama N., Sato Y., Fukumoto K., Tanimoto Y., Tanimoto K., Fukuda K.

Herz 39 ( 2 ) 276 - 278 2014

ISSN  0340-9937

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Serum Inflammation Markers Predicting Successful Initial Catheter Ablation for Atrial Fibrillation

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Fukuda Keiichi

Heart Lung and Circulation 23 ( 7 ) 636 - 643 2014

ISSN  1443-9506

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<p>Background: We investigated various serum inflammatory markers to predict ablation responders who have no atrial fibrillation (AF) relapse after the initial ablation. Methods: Forty-four consecutive AF patients (age: 59 ± 8 years, paroxysmal: 31, CHADS₂: 1.1 ± 1.1) who underwent an initial pulmonary vein isolation were investigated. Various serum inflammatory markers, such as adiponectin, ANP, BNP, 1CTP, F1+2, hs-CRP, IL-6, intact P1NP, MDA-LDL, MMP-2, TGF-β, TIMP-2, and TNF-α, were evaluated prior to ablation. AF relapse was defined as AF documented in telemonitoring electrocardiograms twice a day during 9.7 ± 2.4 months of follow-up with three months of a blanking-period. Results: A total of 29 patients (paroxysmal: 21) maintained sinus rhythm after the initial catheter ablation. These ablation responders had significantly lower MMP-2 (Sinus vs. Relapsed: 748 ± 132.7 vs. 841.2 ± 152.4 ng/mL, P=0.042) and TNF-α (1.1 ± 0.4 vs. 1.8 ± 1.7 pg/mL, P=0.046) levels prior to ablation. A BNP-adjusted Cox multivariate regression analysis revealed that the independent predictive factor for AF recurrence was high MMP-2 levels (&gt;766 ng/mL) accompanied by high TNF-α levels (&gt;1.2 pg/mL). Conclusions: The levels of MMP-2 and TNF-α might be useful for predicting initial AF catheter ablation responders.</p>

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Thrombus Formation in the Left Atrial Appendage During Catheter Ablation for Atrial Fibrillation Under Sufficient Heparinization

Kimura Takehiro, Takatsuki Seiji, Tanimoto Kojiro, Katsumata Yoshinori, Nishiyama Takahiko, Inagawa Kohei, Nishiyama Nobuhiro, Tanimoto Yoko, Aizawa Yoshiyasu, Fukuda Keiichi

Canadian Journal of Cardiology 30 ( 4 )  2014

ISSN  0828-282X

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Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation

Aizawa Yoshiyasu, Yamakawa Hiroyuki, Takatsuki Seiji, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Mitamura Hideo, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 168 ( 5 ) 5083 - 5085 2013.10

ISSN  0167-5273

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Efficacy and safety of bepridil for prevention of ICD shocks in patients with Brugada syndrome and idiopathic ventricular fibrillation

Aizawa Yoshiyasu, Yamakawa Hiroyuki, Takatsuki Seiji, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Mitamura Hideo, Ogawa Satoshi, Fukuda Keiichi

International Journal of Cardiology 168 ( 5 ) 5083 - 5085 2013.10

ISSN  0167-5273

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Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Yan Xiaoxiang, Anzai Atsushi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Kentaro, Endo Jin, Yamamoto Tsunehisa, Takeshima Akiko, Shinmura Ken, Shen Weifeng, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 62   24 - 35 2013.09

ISSN  0022-2828

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<p>Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M₁ and M₂ macrophages, respectively, based on surface-marker expression. M₁ macrophages dominated at 1-3days post-MI, whereas M₂ macrophages represented the predominant macrophage subset after 5days. The M₂ macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M₁ macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4⁺ T cells, whereas Th2 and Th17 cells were minor populations. CD8⁺ T cells, γδT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies.</p>

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Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction

Yan Xiaoxiang, Anzai Atsushi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Kentaro, Endo Jin, Yamamoto Tsunehisa, Takeshima Akiko, Shinmura Ken, Shen Weifeng, Fukuda Keiichi, Sano Motoaki

Journal of Molecular and Cellular Cardiology 62   24 - 35 2013.09

ISSN  0022-2828

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<p>Acute myocardial infarction (MI) causes sterile inflammation, which is characterized by recruitment and activation of innate and adaptive immune system cells. Here we delineate the temporal dynamics of immune cell accumulation following MI by flow cytometry. Neutrophils increased immediately to a peak at 3days post-MI. Macrophages were numerically the predominant cells infiltrating the infarcted myocardium, increasing in number over the first week post-MI. Macrophages are functionally heterogeneous, whereby the first responders exhibit high expression levels of proinflammatory mediators, while the late responders express high levels of the anti-inflammatory cytokine IL-10; these macrophages can be classified into M₁ and M₂ macrophages, respectively, based on surface-marker expression. M₁ macrophages dominated at 1-3days post-MI, whereas M₂ macrophages represented the predominant macrophage subset after 5days. The M₂ macrophages expressed high levels of reparative genes in addition to proinflammatory genes to the same levels as in M₁ macrophages. The predominant subset of dendritic cells (DCs) was myeloid DC, which peaked in number on day 7. Th1 and regulatory T cells were the predominant subsets of CD4⁺ T cells, whereas Th2 and Th17 cells were minor populations. CD8⁺ T cells, γδT cells, B cells, natural killer (NK) cells and NKT cells peaked on day 7 post-MI. Timely reperfusion reduced the total number of leukocytes accumulated in the post-MI period, shifting the peak of innate immune response towards earlier and blunting the wave of adaptive immune response. In conclusion, these results provide important knowledge necessary for developing successful immunomodulatory therapies. © 2013 Elsevier Ltd.</p>

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Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Jinzaki Masahiro, Fukuda Keiichi

Heart Rhythm 10 ( 6 ) 921 - 925 2013.06

ISSN  1547-5271

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<p>BACKGROUND Strokes develop even in patients with low CHADS₂ scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS₂ scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-"cactus," "cauliflower," "chicken wing," and "windsock"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS₂ score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA₂DS₂-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a "cauliflower" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA ₂DS₂-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS₂ scores.</p>

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Anatomical characteristics of the left atrial appendage in cardiogenic stroke with low CHADS2 scores

Kimura Takehiro, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Nishiyama Nobuhiro, Fukumoto Kotaro, Aizawa Yoshiyasu, Tanimoto Yoko, Tanimoto Kojiro, Jinzaki Masahiro, Fukuda Keiichi

Heart Rhythm 10 ( 6 ) 921 - 925 2013.06

ISSN  1547-5271

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<p>BACKGROUND Strokes develop even in patients with low CHADS₂ scores, and the left atrial appendage (LAA) is the embolic source 90% of the time. We focused on the LAA morphology as a new predictor of strokes. OBJECTIVE To clarify the anatomical characteristics of the LAA for risk stratification of strokes in patients with nonvalvular atrial fibrillation (AF) who have low CHADS₂ scores. METHODS Among 80 patients who underwent catheter ablation of AF with contrast-enhanced computed tomography, the LAA characteristics were compared between 30 patients with histories of strokes and 50 age-matched controls. The LAA anatomy was classified into 4 types-"cactus," "cauliflower," "chicken wing," and "windsock"- discriminated by the computed tomography measurements of the length, angle, and number of lobes of the LAA. RESULTS The average CHADS₂ score did not differ significantly between patients with stroke and controls (0.8 ± 0.8 vs 0.6 ± 0.7; P = .277). Eight (26.7%) patients with stroke had CHA₂DS₂-VASc scores of 0. The left atrial size, LAA flow velocity, left ventricular function, and serum brain natriuretic peptide level were also unable to predict strokes. However, a "cauliflower" LAA, defined as a main lobe of less than 4 cm long without forked lobes, was significantly more common in patients with stroke (odds ratio 3.857; 95% confidence interval 1.482-10.037; P = .005). The CHA ₂DS₂-VASc score-adjusted logistic regression analysis revealed the cauliflower LAA as an independent predictor of a stroke (odds ratio 3.355; 95% confidence interval 1.243-9.055; P = .017). CONCLUSIONS The LAA anatomy might be useful for predicting strokes in patients with nonvalvular AF who have low CHADS₂ scores. © 2013 Heart Rhythm Society. All rights reserved.</p>

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Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block

Aizawa Yoshiyasu, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Ogawa Satoshi, Fukuda Keiichi

International Heart Journal 54 ( 4 ) 240 - 242 2013

ISSN  1349-2365

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<p>A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fbrilla-tion (VF) had occurred during breakfast and was defbrillated by an automated external defbrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these benefcial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF.</p>

Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block

Aizawa Yoshiyasu, Takatsuki Seiji, Inagawa Kohei, Katsumata Yoshinori, Nishiyama Takahiko, Kimura Takehiro, Nishiyama Nobuhiro, Fukumoto Kotaro, Tanimoto Yoko, Tanimoto Kojiro, Ogawa Satoshi, Fukuda Keiichi

International heart journal 54 ( 4 ) 240 - 242 2013

ISSN  1349-2365

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<p>A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fbrilla-tion (VF) had occurred during breakfast and was defbrillated by an automated external defbrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these benefcial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF.</p>

PGD ₂-CRTH2 pathway promotes tubulointerstitial fibrosis

Ito Hideyuki, Yan Xiaoxiang, Nagata Nanae, Aritake Kosuke, Katsumata Yoshinori, Matsuhashi Tomohiro, Nakamura Masataka, Hirai Hiroyuki, Urade Yoshihiro, Asano Koichiro, Kubo Masato, Utsunomiya Yasunori, Hosoya Tatsuo, Fukuda Keiichi, Sano Motoaki

Journal of the American Society of Nephrology 23 ( 11 ) 1797 - 1809 2012.10

ISSN  1046-6673

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<p>Urinary excretion of lipocalin-type PGD ₂ synthase (L-PGDS), which converts PG H ₂ to PGD ₂, increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD ₂ contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD ₂ might be a strategy to slow the progression of renal fibrosis in CKD.</p>

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PGD ₂-CRTH2 pathway promotes tubulointerstitial fibrosis

Ito Hideyuki, Yan Xiaoxiang, Nagata Nanae, Aritake Kosuke, Katsumata Yoshinori, Matsuhashi Tomohiro, Nakamura Masataka, Hirai Hiroyuki, Urade Yoshihiro, Asano Koichiro, Kubo Masato, Utsunomiya Yasunori, Hosoya Tatsuo, Fukuda Keiichi, Sano Motoaki

Journal of the American Society of Nephrology 23 ( 11 ) 1797 - 1809 2012.10

ISSN  1046-6673

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<p>Urinary excretion of lipocalin-type PGD ₂ synthase (L-PGDS), which converts PG H ₂ to PGD ₂, increases in early diabetic nephropathy. In addition, L-PGDS expression in the tubular epithelium increases in adriamycin-induced nephropathy, suggesting that locally produced L-PGDS may promote the development of CKD. In this study, we found that L-PGDS-derived PGD ₂ contributes to the progression of renal fibrosis via CRTH2-mediated activation of Th2 lymphocytes. In a mouse model, the tubular epithelium synthesized L-PGDS de novo after unilateral ureteral obstruction (UUO). L-PGDS-knockout mice and CRTH2-knockout mice both exhibited less renal fibrosis, reduced infiltration of Th2 lymphocytes into the cortex, and decreased production of the Th2 cytokines IL-4 and IL-13. Furthermore, oral administration of a CRTH2 antagonist, beginning 3 days after UUO, suppressed the progression of renal fibrosis. Ablation of IL-4 and IL-13 also ameliorated renal fibrosis in the UUO kidney. Taken together, these data suggest that blocking the activation of CRTH2 by PGD ₂ might be a strategy to slow the progression of renal fibrosis in CKD. Copyright © 2012 by the American Society of Nephrology.</p>

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Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5

Inagawa Kohei, Miyamoto Kazutaka, Yamakawa Hiroyuki, Muraoka Naoto, Sadahiro Taketaro, Umei Tomohiko, Wada Rie, Katsumata Yoshinori, Kaneda Ruri, Nakade Koji, Kurihara Chitose, Obata Yuichi, Miyake Koichi, Fukuda Keiichi, Ieda Masaki

Circulation Research 111 ( 9 ) 1147 - 1156 2012.10

ISSN  0009-7330

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<p>RATIONALE: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. OBJECTIVE: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. METHODS AND RESULTS: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into α-myosin heavy chain (αMHC)-GFP transgenic mouse hearts induced the expression of αMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric α-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes. CONCLUSIONS: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts.</p>

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Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5

Inagawa Kohei, Miyamoto Kazutaka, Yamakawa Hiroyuki, Muraoka Naoto, Sadahiro Taketaro, Umei Tomohiko, Wada Rie, Katsumata Yoshinori, Kaneda Ruri, Nakade Koji, Kurihara Chitose, Obata Yuichi, Miyake Koichi, Fukuda Keiichi, Ieda Masaki

Circulation Research 111 ( 9 ) 1147 - 1156 2012.10

ISSN  0009-7330

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<p>RATIONALE: After myocardial infarction (MI), massive cell death in the myocardium initiates fibrosis and scar formation, leading to heart failure. We recently found that a combination of 3 cardiac transcription factors, Gata4, Mef2c, and Tbx5 (GMT), reprograms fibroblasts directly into functional cardiomyocytes in vitro. OBJECTIVE: To investigate whether viral gene transfer of GMT into infarcted hearts induces cardiomyocyte generation. METHODS AND RESULTS: Coronary artery ligation was used to generate MI in the mouse. In vitro transduction of GMT retrovirus converted cardiac fibroblasts from the infarct region into cardiomyocyte-like cells with cardiac-specific gene expression and sarcomeric structures. Injection of the green fluorescent protein (GFP) retrovirus into mouse hearts, immediately after MI, infected only proliferating noncardiomyocytes, mainly fibroblasts, in the infarct region. The GFP expression diminished after 2 weeks in immunocompetent mice but remained stable for 3 months in immunosuppressed mice, in which cardiac induction did not occur. In contrast, injection of GMT retrovirus into α-myosin heavy chain (αMHC)-GFP transgenic mouse hearts induced the expression of αMHC-GFP, a marker of cardiomyocytes, in 3% of virus-infected cells after 1 week. A pooled GMT injection into the immunosuppressed mouse hearts induced cardiac marker expression in retrovirus-infected cells within 2 weeks, although few cells showed striated muscle structures. To transduce GMT efficiently in vivo, we generated a polycistronic retrovirus expressing GMT separated by 2A "self-cleaving" peptides (3F2A). The 3F2A-induced cardiomyocyte-like cells in fibrotic tissue expressed sarcomeric α-actinin and cardiac troponin T and had clear cross striations. Quantitative RT-PCR also demonstrated that FACS-sorted 3F2A-transduced cells expressed cardiac-specific genes. CONCLUSIONS: GMT gene transfer induced cardiomyocyte-like cells in infarcted hearts. © 2012 American Heart Association, Inc.</p>

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Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

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<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

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Deleterious effect of the IL-23/IL-17A axis and γδT cells on left ventricular remodeling after myocardial infarction.

Yan Xiaoxiang, Shichita Takashi, Katsumata Yoshinori, Matsuhashi Tomohiro, Ito Hideyuki, Ito Kentaro, Anzai Atsushi, Endo Jin, Tamura Yuichi, Kimura Kensuke, Fujita Jun, Shinmura Ken, Shen Weifeng, Yoshimura Akihiko, Fukuda Keiichi, Sano Motoaki

Journal of the American Heart Association 1 ( 5 )  2012.10

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<p>Left ventricular (LV) remodeling leads to chronic heart failure and is a main determinant of morbidity and mortality after myocardial infarction (MI). At the present time, therapeutic options to prevent LV remodeling are limited. We created a large MI by permanent ligation of the coronary artery and identified a potential link between the interleukin (IL)-23/IL-17A axis and γδT cells that affects late-stage LV remodeling after MI. Despite the finsinf that infarct size 24 hours after surgery was similar to that in wild-type mice, a deficiency in IL-23, IL-17A, or γδT cells improved survival after 7 days, limiting infarct expansion and fibrosis in noninfarcted myocardium and alleviating LV dilatation and systolic dysfunction on day 28 post-MI. M(1) macrophages and neutrophils were the major cellular source of IL-23, whereas &gt;90% of IL-17A-producing T cells in infarcted heart were CD4(-) TCRγδ(+) (γδT) cells. Toll-like receptor signaling and IL-1β worked in concert with IL-23 to drive expansion and IL-17A production in cardiac γδT cells, whereas the sphingosine-1-phosphate receptor and CCL20/CCR6 signaling pathways mediated γδT cell recruitment into infarcted heart. IL-17A was not involved in the acute inflammatory response, but it functioned specifically in the late remodeling stages by promoting sustained infiltration of neutrophils and macrophages, stimulating macrophages to produce proinflammatory cytokines, aggravating cardiomyocyte death, and enhancing fibroblast proliferation and profibrotic gene expression. The IL-23/IL-17A immune axis and γδT cells are potentially promising therapeutic targets after MI to prevent progression to end-stage dilated cardiomyopathy.</p>

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Biphasic time course of the changes in aldosterone biosynthesis under high-salt conditions in dahl salt-sensitive rats

Morizane Shintaro, Mitani Fumiko, Ozawa Kae, Ito Kentaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Hideyuki, Yan Xiaoxiang, Shinmura Ken, Nishiyama Akira, Honma Seijiro, Suzuki Takeshi, Funder John W., Fukuda Keiichi, Sano Motoaki

Arteriosclerosis, Thrombosis, and Vascular Biology 32 ( 5 ) 1194 - 1203 2012.05

ISSN  1079-5642

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<p>Objective-: The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt. Methods And Results-: Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-: Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone.</p>

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Biphasic time course of the changes in aldosterone biosynthesis under high-salt conditions in dahl salt-sensitive rats

Morizane Shintaro, Mitani Fumiko, Ozawa Kae, Ito Kentaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Ito Hideyuki, Yan Xiaoxiang, Shinmura Ken, Nishiyama Akira, Honma Seijiro, Suzuki Takeshi, Funder John W., Fukuda Keiichi, Sano Motoaki

Arteriosclerosis, Thrombosis, and Vascular Biology 32 ( 5 ) 1194 - 1203 2012.05

ISSN  1079-5642

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<p>Objective-: The comorbidity of excess salt and elevated plasma aldosterone has deleterious effects in cardiovascular disease. We evaluated the mechanisms behind the paradoxical increase in aldosterone biosynthesis in relation to dietary intake of salt. Methods And Results-: Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were fed a high-salt diet, and plasma and tissue levels of aldosterone in the adrenal gland and heart were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry. In Dahl-S rats, we found that the delayed and paradoxical increase in aldosterone biosynthesis after the initial and appropriate response to high salt. The late rise in aldosterone biosynthesis was accompanied by upregulation of CYP11B2 expression in the zona glomerulosa and increased adrenal angiotensin II levels and renin-angiotensin system components. It preceded the appearance of left ventricular systolic dysfunction and renal insufficiency. Blockade of angiotensin AT1 receptors reversed the paradoxical increase in aldosterone biosynthesis. In contrast, Dahl-R rats maintained the initial suppression of aldosterone biosynthesis. Aldosterone levels in the heart closely paralleled those in the plasma and adrenal gland and disappeared after bilateral adrenalectomy. Conclusion-: Chronic salt overload in Dahl-S rats stimulates aberrant aldosterone production via activation of the local renin-angiotensin system in the adrenal gland, thereby creating the comorbidity of excess salt and elevated plasma aldosterone. © 2012 American Heart Association, Inc.</p>

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Frequent long-distance flyer's undesirable mileage

Katsumata Yoshinori, Kimura Kensuke, Sano Motoaki, Kudo Mikihiko, Arai Takahide, Ohno Yohei, Tamura Yuichi, Tsuruta Hikaru, Murata Mitsushige, Yozu Ryohei, Fukuda Keiichi

Journal of Thrombosis and Thrombolysis 33 ( 3 ) 296 - 298 2012.04

ISSN  0929-5305

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Frequent long-distance flyer's undesirable mileage

Katsumata Yoshinori, Kimura Kensuke, Sano Motoaki, Kudo Mikihiko, Arai Takahide, Ohno Yohei, Tamura Yuichi, Tsuruta Hikaru, Murata Mitsushige, Yozu Ryohei, Fukuda Keiichi

Journal of Thrombosis and Thrombolysis 33 ( 3 ) 296 - 298 2012.04

ISSN  0929-5305

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Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain

Shinmura Ken, Tamaki Kayoko, Sano Motoaki, Nakashima-Kamimura Naomi, Wolf Alexander M., Amo Taku, Ohta Shigeo, Katsumata Yoshinori, Fukuda Keiichi, Ishiwata Kyoko, Suematsu Makoto, Adachi Takeshi

Circulation Research 109 ( 4 ) 396 - 406 2011.08

ISSN  0009-7330

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<p>Rationale: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. Objective: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Methods and Results: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H2O2 production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose Resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose Resveratrol. Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion.</p>

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Caloric restriction primes mitochondria for ischemic stress by deacetylating specific mitochondrial proteins of the electron transport chain

Shinmura Ken, Tamaki Kayoko, Sano Motoaki, Nakashima-Kamimura Naomi, Wolf Alexander M., Amo Taku, Ohta Shigeo, Katsumata Yoshinori, Fukuda Keiichi, Ishiwata Kyoko, Suematsu Makoto, Adachi Takeshi

Circulation Research 109 ( 4 ) 396 - 406 2011.08

ISSN  0009-7330

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<p>Rationale: Caloric restriction (CR) confers cardioprotection against ischemia/reperfusion injury. However, the exact mechanism(s) underlying CR-induced cardioprotection remain(s) unknown. Recent evidence indicates that Sirtuins, NAD-dependent deacetylases, regulate various favorable aspects of the CR response. Thus, we hypothesized that deacetylation of specific mitochondrial proteins during CR preserves mitochondrial function and attenuates production of reactive oxygen species during ischemia/reperfusion. Objective: The objectives of the present study were (1) to investigate the effect of CR on mitochondrial function and mitochondrial proteome and (2) to investigate what molecular mechanisms mediate CR-induced cardioprotection. Methods and Results: Male 26-week-old Fischer344 rats were randomly divided into ad libitum-fed and CR (40% reduction) groups for 6 months. No change was observed in basal mitochondrial function, but CR preserved postischemic mitochondrial respiration and attenuated postischemic mitochondrial H2O2 production. CR decreased the level of acetylated mitochondrial proteins that were associated with enhanced Sirtuin activity in the mitochondrial fraction. We confirmed a significant decrease in the acetylated forms of NDUFS1 and cytochrome bc1 complex Rieske subunit in the CR heart. Low-dose Resveratrol treatment mimicked the effect of CR on deacetylating them and attenuated reactive oxygen species production during anoxia/reoxygenation in cultured cardiomyocytes without changing the expression levels of manganese superoxide dismutase. Treatment with nicotinamide completely abrogated the effect of low-dose Resveratrol. Conclusions: These results strongly suggest that CR primes mitochondria for stress resistance by deacetylating specific mitochondrial proteins of the electron transport chain. Targeted deacetylation of NDUFS1 and/or Rieske subunit might have potential as a novel therapeutic approach for cardioprotection against ischemia/reperfusion. © 2011 American Heart Association, Inc.</p>

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4-Hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway

Zhang Yan, Sano Motoaki, Shinmura Ken, Tamaki Kayoko, Katsumata Yoshinori, Matsuhashi Tomohiro, Morizane Shintaro, Ito Hideyuki, Hishiki Takako, Endo Jin, Zhou Heping, Yuasa Shinsuke, Kaneda Ruri, Suematsu Makoto, Fukuda Keiichi

Journal of Molecular and Cellular Cardiology 49 ( 4 ) 576 - 586 2010.10

ISSN  0022-2828

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<p>Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of α,β-unsaturated aldehydes, such as 4-hydroxy-2-nonenal (4-HNE). There is compelling evidence that high concentrations of aldehydes are responsible for much of the damage elicited by cardiac ischemia-reperfusion injury, while sublethal concentrations of aldehydes stimulate stress resistance pathways, to achieve cardioprotection. We investigated the mechanism of cardioprotection mediated by 4-HNE. For cultured cardiomyocytes, 4-HNE was cytotoxic at higher concentrations (≥20μM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5μM) of 4-HNE primed cardiomyocytes to become resistant to cytotoxic concentrations of 4-HNE. 4-HNE induced nuclear translocation of transcription factor NF-E2-related factor 2 (Nrf2), and enhanced the expression of γ-glutamylcysteine ligase (GCL) and the core subunit of the Xc^- high-affinity cystine transporter (xCT), thereby increasing 1.45-fold the intracellular GSH levels. Cardiomyocytes treated with either Nrf2-specific siRNA or the GCL inhibitor l-buthionine sulfoximine (BSO) were less tolerant to 4-HNE. Moreover, the cardioprotective effect of 4-HNE pretreatment against subsequent glucose-free anoxia followed by reoxygenation was completely abolished in these cells. Intravenous administration of 4-HNE (4mg/kg) activated Nrf2 in the heart and increased the intramyocardial GSH content, and consequently improved the functional recovery of the left ventricle following ischemia-reperfusion in Langendorff-perfused hearts. This cardioprotective effect of 4-HNE was not observed for Nrf2-knockout mice. In summary, 4-HNE activates Nrf2-mediated gene expression and stimulates GSH biosynthesis, thereby conferring on cardiomyocytes protection against ischemia-reperfusion injury.</p>

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Metabolic remodeling induced by mitochondrial aldehyde stress stimulates tolerance to oxidative stress in the heart

Endo Jin, Sano Motoaki, Katayama Takaharu, Hishiki Takako, Shinmura Ken, Morizane Shintaro, Matsuhashi Tomohiro, Katsumata Yoshinori, Zhang Yan, Ito Hideyuki, Nagahata Yoshiko, Marchitti Satori, Nishimaki Kiyomi, Wolf Alexander Martin, Nakanishi Hiroki, Hattori Fumiyuki, Vasiliou Vasilis, Adachi Takeshi, Ohsawa Ikuroh, Taguchi Ryo, Hirabayashi Yoshio, Ohta Shigeo, Suematsu Makoto, Ogawa Satoshi, Fukuda Keiichi

Circulation Research 105 ( 11 ) 1118 - 1127 2009.11

ISSN  0009-7330

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<p>RATIONALE:: Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease. OBJECTIVE:: We investigated how the heart compensates for the accelerated accumulation of aldehydes. METHODS AND RESULTS:: Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2α phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.) CONCLUSIONS:: The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.</p>

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