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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