著者

Toshinao Takahashi Toshio Nagai Masato Kanda Mei-Lan Liu Naomichi Kondo Atsuhiko T Naito Takehiko Ogura Haruaki Nakaya Jong-Kook Lee Issei Komuro Yoshio Kobayashi

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.79, no.12, pp.2703-2712, 2015-11-25 (Released:2015-11-25)

参考文献数

42

被引用文献数

7 17

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Background:Adipose tissue is one of the sources of mesenchymal stem cells, which have the potential to differentiate into various types of cells, including myocytes. Whether brown adipose tissue (BAT)-derived cells might differentiate into the cardiac pacemaking-conducting cells, and have the potential to regenerate the cardiac conduction system (CCS), is investigated in this study.Methods and Results:BAT was isolated from the interscapular area of mice and enzymatically digested before culture. Round or fusiform cells showed spontaneous beating at 4–7 days after culturing of BAT-derived cells. Reverse transcriptase-polymerase chain reaction analysis and immunocytochemical analysis revealed that BAT-derived cells expressed several cardiomyocytes, the CCS and pacemaker (PM) cell marker genes and proteins. Patch-clamp techniques revealed that spontaneous electrical activity and the shape of the action potential showed properties of cardiac PM cells. Next, a complete atrioventricular (AV) block was created in mice and green fluorescent protein-positive (GFP (+)) BAT-derived cells were injected intramyocardially around the AV node. At 1 week after transplantation, 50% of BAT-derived cells injected mice showed a sinus rhythm or a 2:1 AV block. Immunohistochemical analysis revealed that injected GFP (+) cells were engrafted and some GFP (+) cells co-expressed several cardiac PM cell marker proteins.Conclusions:BAT-derived cells differentiate into the CCS and PM-like cells in vitro and in vivo, and may become a useful cell source for arrhythmia therapy. (Circ J 2015; 79: 2703–2712)

著者

Kyohei Marume Seiji Takashio Toshiyuki Nagai Kenichi Tsujita Yoshihiko Saito Tsutomu Yoshikawa Toshihisa Anzai

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-18-0639, (Released:2018-11-09)

参考文献数

50

被引用文献数

22

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Background:Statins might be associated with improved survival in patients with heart failure with preserved ejection fraction (HFpEF). The effect of statins in HFpEF without coronary artery disease (CAD), however, remains unclear.Methods and Results:From the JASPER registry, a multicenter, observational, prospective cohort with Japanese patients aged ≥20 years requiring hospitalization with acute HF and LVEF ≥50%, 414 patients without CAD were selected for outcome analysis. Based on prescription of statins at admission, we divided patients into the statin group (n=81) or no statin group (n=333). We followed them for 25 months. The association between statin use and primary (all-cause mortality) and secondary (non-cardiac death, cardiac death, or rehospitalization for HF) endpoints was assessed in the entire cohort and in a propensity score-matched cohort. In the propensity score-matched cohort, 3-year mortality was lower in the statin group (HR, 0.21; 95% CI: 0.06–0.72; P=0.014). The statin group had a significantly lower incidence of non-cardiac death (P=0.028) and rehospitalization for HF (P<0.001), but not cardiac death (P=0.593). The beneficial effect of statins on mortality did not have any significant interaction with cholesterol level or HF severity.Conclusions:Statin use has a beneficial effect on mortality in HFpEF without CAD. The present findings should be tested in an adequately powered randomized clinical trial.

著者

Toshiyuki Niki Tetsuzo Wakatsuki Koji Yamaguchi Yoshio Taketani Hiroyasu Oeduka Kenya Kusunose Takayuki Ise Takashi Iwase Hirotsugu Yamada Takeshi Soeki Masataka Sata

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.80, no.2, pp.450-460, 2016-01-25 (Released:2016-01-25)

参考文献数

53

被引用文献数

22 67

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Background:The effects of eicosapentaenoic acid (EPA) on coronary artery disease have been previously reported; however, those of the addition of EPA to strong statins on coronary plaque components and local inflammatory cytokines are not known.Methods and Results:A total of 95 patients who had been treated with strong statin for at least 6 months were randomized into 2 groups: an EPA group (additional treatment with EPA at 1,800 mg/day, n=48) or a control group (no additional treatment, n=47), for 6 months. The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment. We also measured plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein.A significant reduction in lipid volume (18.5±1.3 to 15.0±1.5 mm3, P=0.007) and a significant increase in fibrous volume (22.9±0.8 to 25.6±1.1 mm3, P=0.01) were observed in IB-IVUS image analyses in the EPA group, but no significant changes in the plaque components in the control group. CS levels of pentraxin 3 and monocyte chemoattractant protein-1 were lower after than before treatment with EPA (3.3±2.1 to 2.6±1.2 ng/ml, 120.4±26.2 to 110.2±26.8 pg/ml, P=0.015 and P=0.008, respectively); however, there were no significant changes in those inflammatory cytokines between pre- and post-treatment in the control group.Conclusions:The addition of EPA was associated with reduced lipid volume in coronary plaques and decreased inflammatory cytokines. (Circ J 2016; 80: 450–460)

著者

Yoichiro Otaki Tetsu Watanabe Tsuneo Konta Masafumi Watanabe Shouichi Fujimoto Yuji Sato Koichi Asahi Kunihiro Yamagata Kazuhiko Tsuruya Ichiei Narita Masato Kasahara Yugo Shibagaki Kunitoshi Iseki Toshiki Moriyama Masahide Kondo Tsuyoshi Watanabe

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.11, pp.2776-2782, 2018-10-25 (Released:2018-10-25)

参考文献数

28

被引用文献数

13

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Background: Aortic artery disease (AAD), such as aortic dissection or aortic aneurysm rupture, is fatal, with an extremely high mortality. Because of its low incidence, the risk for the development of AAD has not yet been elucidated. Hypertension (HT) is an established risk factor for cardiovascular disease, but there has been no prospective study on the effect of HT on AAD-related mortality. Methods and Results: We used a nationwide database of 276,197 subjects (aged 40–75 years) who participated in the annual “Specific Health Check and Guidance in Japan” from 2008 to 2010. There were 80 AAD-related deaths during the follow-up period of 1,049,549 person-years. On multivariate Cox proportional hazard regression, HT was an independent risk factor for AAD-related death in apparently healthy subjects. On receiver operating characteristics curve analysis for AAD-related death, abnormal systolic and diastolic blood pressure (SBP and DBP) were 130 mmHg and 82 mmHg, respectively. The prediction capacity was significantly improved by the addition of SBP to confounding risk factors. Notably, further improvement of the C index was observed by addition of DBP to the model with SBP. Conclusions: This is the first report to prospectively show that HT is a risk factor for AAD-related death. Both SBP and DBP are of critical importance in the primary prevention of AAD-related death in apparently healthy subjects.

著者

Masahide Harada Masayuki Koshikawa Yuji Motoike Tomohide Ichikawa Kunihiko Sugimoto Eiichi Watanabe Yukio Ozaki

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.11, pp.2715-2721, 2018-10-25 (Released:2018-10-25)

参考文献数

27

被引用文献数

19

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Background: In atrial fibrillation (AF) patients, the effect of direct oral anticoagulant (DOACs) therapy on the incidence of left atrial appendage thrombus (LAT) remains poorly investigated. This study examined the prevalence and risk factors of LAT in AF patients on DOACs undergoing catheter ablation, and sought an anticoagulation strategy for LAT. Methods and Results: In 407 AF patients on DOACs, transesophageal echocardiography (TEE) was performed 1 day before ablation. If patients had LAT, initial DOACs were switched to dabigatran (300 mg) or warfarin based on their renal function; TEE was repeated after treatment for ≥4 weeks. LAT was detected in 18 patients (4.4%). The prevalence of persistent AF and low-dose treatment/inappropriate dose reduction of DOACs, CHADS2/CHA2DS2-VASc scores, serum N-terminal pro-brain natriuretic peptide levels, and LA dimension/LA volume index significantly increased in patients with LAT vs. those without LAT. AF rhythm on TEE and spontaneous echo contrast also increased in patients with LAT; LA appendage flow velocity decreased. In the multivariate analysis, persistent AF and inappropriately reduced DOAC dose were risk factors for LAT. On repeat TEE, LAT had disappeared in 13 of 16 patients treated with dabigatran and in 2 of 2 patients treated with warfarin. Conclusions: DOACs still carry a finite risk of LAT in AF patients. Inappropriately reduced DOAC dose should be avoided to minimize the thromboembolic risk. Regular-dose dabigatran may have therapeutic efficacy against LAT.

著者

Hyukchan Kwon Kiwoong Kim Yong-Ho Lee Jin-Mok Kim Kwon Kyu Yu Namsik Chung Young-Guk Ko

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.74, no.7, pp.1424-1430, 2010 (Released:2010-06-25)

参考文献数

25

被引用文献数

14 25

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Background: Accurate identification of patients with acute coronary syndrome (ACS) is often difficult especially when an electrocardiogram (ECG) does not show typical elevation of ST segment. The aim of the present study was therefore to evaluate the efficacy of magnetocardiography (MCG) for diagnosis of ACS in patients with acute chest pain presenting without ST segment elevation. Methods and Results: In the present retrospective study 364 patients with the suspected ACS without ST segment elevation were selected. Significant coronary artery disease (CAD) was defined as a stenosis ≥50% in at least one of 16 segments of the 3 major coronary arteries and their branches. The MCG recordings were obtained at resting state using a 64-channel MCG system in a magnetically shielded room. The patients were classified on the basis of the probability distribution. The presence of significant CAD was identified with a sensitivity of 84.0% and a specificity of 85.0%, compared to 44.7% and 89.8% on ECG. In the subgroup of patients without specific findings on ECG or biomarker test, MCG had a sensitivity of 73.5% and a specificity of 82.3%. Conclusions: MCG was acceptably sensitive and specific in identifying patients with ACS even in the absence of specific findings on ECG and positive biomarker tests. Thus, MCG seems beneficial for the early triage of patients with acute chest pain.  (Circ J 2010; 74: 1424 - 1430)

著者

Kentaro Jujo Nobuhisa Hagiwara

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.11, pp.2705-2706, 2018-10-25 (Released:2018-10-25)

参考文献数

15

著者

Yukina Hirata Hirotsugu Yamada Masataka Sata

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2475-2476, 2018-09-25 (Released:2018-09-25)

参考文献数

12

被引用文献数

7

著者

Noboru Fujino Kenshi Hayashi Kenji Sakata Akihiro Nomura Masa-aki Kawashiri

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.11, pp.2699-2700, 2018-10-25 (Released:2018-10-25)

参考文献数

12

被引用文献数

1

著者

Satoshi Suda Yuki Sakamoto Seiji Okubo Junya Aoki Takashi Shimoyama Takuya Kanamaru Kentaro Suzuki Akihito Kutsuna Noriko Matsumoto Chikako Nito Yasuhiro Nishiyama Masahiro Mishina Kazumi Kimura

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2647-2654, 2018-09-25 (Released:2018-09-25)

参考文献数

22

被引用文献数

1 6

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Background: This study investigated changes in anticoagulant use, treatment, and functional outcomes in acute ischemic stroke (AIS) patients with non-valvular atrial fibrillation (NVAF) over a 6-year period. Methods and Results: Patients with AIS and NVAF admitted to our department from April 2011 to March 2017 were analyzed retrospectively. Patients were divided into 3 groups based on the time of the initial visit (Periods 1–3, corresponding to April 2011–March 2013, April 2013–March 2015, and April 2015–March 2017, respectively). Associations between prescribed medication prior to event and stroke severity, reperfusion therapy, and outcomes were assessed. There was no significant change in the rate of insufficient warfarin and inappropriately lowered doses of direct oral anticoagulant (DOAC) treatment over time. The number of patients receiving prior DOAC treatment increased, but neurological severity on admission was milder than in the other 2 groups. The rate of reperfusion therapy increased from 19.9% (Period 1) to 42.7% (Period 3) for moderate-to-severe stroke patients. Multivariate logistic regression analysis revealed that reperfusion therapy was independently positively associated with good functional outcomes, but negatively associated with mortality (odds ratios [95% confidence intervals] 7.14 [3.34–15.29] and 0.13 [0.008–0.69], respectively). Conclusions: Inappropriate anticoagulant use for stroke patients with NVAF did not decrease over time. An increase in reperfusion therapy was a strong factor in improved functional outcomes and mortality.

著者

Satoshi Kodera Hiroyuki Morita Arihiro Kiyosue Jiro Ando Tomoyuki Takura Issei Komuro

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2602-2608, 2018-09-25 (Released:2018-09-25)

参考文献数

39

被引用文献数

2 12

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Background: The addition of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to statin therapy reduces the rate of cardiovascular events. This study examined the cost-effectiveness of PCSK9 inhibitor+statin compared with standard therapy (statin monotherapy) in the treatment of triple-vessel coronary artery disease (CAD) in Japan. Methods and Results: A Markov model was applied to assess the costs and benefits associated with PCSK9 inhibitor+statin over a projected 30-year period from the perspective of a public healthcare payer in Japan. The incremental cost-effectiveness ratio (ICER), expressed as the quality-adjusted life-years (QALYs), was estimated. The effects on survival and numbers of events were based on the FOURIER trial and the CREDO Kyoto registry. The ICER of PCSK9 inhibitor+statin over standard therapy was 13.5 million (95% confidence interval 7.6–23.5 million) Japanese Yen (JPY) per QALY gained for triple-vessel CAD. The probability of the cost-effectiveness of PCSK9 inhibitor+statin vs. standard therapy was 0.0008% at a cost-effectiveness threshold of 5 million JPY. In patients with poorly controlled familial hypercholesterolemia (FH) with triple-vessel CAD, the ICER was 3.4 million JPY per QALY gained. Conclusions: PCSK9 inhibitor plus statin did not show good cost-effectiveness for triple-vessel CAD; however, it showed good cost-effectiveness for patients with triple-vessel CAD and poorly controlled FH in Japan.

著者

Hideki Ishii Toyoaki Murohara

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2481-2482, 2018-09-25 (Released:2018-09-25)

参考文献数

11

著者

Hiroyuki Tsutsui Shin-ichi Momomura Yoshihiko Saito Hiroshi Ito Kazuhiro Yamamoto Tomomi Ohishi Naoko Okino Toshihito Kitamura Weinong Guo

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2575-2583, 2018-09-25 (Released:2018-09-25)

参考文献数

17

被引用文献数

1 15

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Background: The objective of the present analyses was to describe the baseline characteristics and treatment of the Japanese patients with HFrEF in THE PARALLEL-HF study. Methods and Results: Key demographic, clinical and laboratory findings, along with treatment, were reported and compared with patients enrolled in the PARADIGM-HF trial and other contemporary randomized clinical trials and registries of Japanese patients with HFrEF. In addition, the MAGGIC and EMPHASIS-HF risk scores were calculated. A total of 225 Japanese patients were randomized in PARALLEL-HF with a mean age of 67.9 years and the majority of the patients being male (85.8%) and in NYHA Class II (93.8%). Key baseline characteristics in PARALLEL-HF were generally comparable with PARADIGM-HF, and other contemporary clinical trials and registries of Japanese HFrEF patients. Patients enrolled in PARALLEL-HF were well treated with conventional evidence-based therapy at baseline (angiotensin-converting enzyme inhibitor inhibitor/angiotensin receptor blocker, 62.7%/37.3%; β-blockers, 94.7%; mineralocorticoid receptor antagonist, 59.1%). Despite the evidence-based treatment and most patients being in NYHA Class II, these patients had a low LVEF (mean 28.1%) and were at high risk of cardiovascular mortality and morbidity as assessed by the MAGGIC and EMPHASIS-HF risk scores. Conclusions: Overall, the patients in PARALLEL-HF were largely representative of contemporary ambulatory patients with HFrEF who are well treated with evidence-based therapies. PARALLEL-HF will determine whether sacubitril/valsartan provides similar improvements in clinical outcomes in Japanese HFrEF patients as observed in the PARADIGM-HF study.

著者

Takashi Kunihara

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2472-2474, 2018-09-25 (Released:2018-09-25)

参考文献数

15

著者

Keiko Hatazawa Hidekazu Tanaka Akiko Nonaka Hiroki Takada Fumitaka Soga Yutaka Hatani Hiroki Matsuzoe Hiroyuki Shimoura Junichi Ooka Hiroyuki Sano Yasuhide Mochizuki Kensuke Matsumoto Ken-ichi Hirata

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2566-2574, 2018-09-25 (Released:2018-09-25)

参考文献数

27

被引用文献数

1 28

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Background: Our aim was to investigate the baseline clinical and echocardiographic parameters for predicting left ventricular (LV) dysfunction after anthracycline chemotherapy and heart failure (HF) hospitalization in a single cancer disease. Methods and Results: We studied 73 patients with malignant lymphoma and preserved LV ejection fraction (LVEF). Echocardiography was performed before and after anthracycline chemotherapy. Global longitudinal strain (GLS) was determined from 3 standard apical views. LV dysfunction after anthracycline chemotherapy was defined according to the current definition of cancer therapeutics-related cardiac dysfunction. Long-term (50-month) unfavorable outcome was prespecified as hospitalization for HF. A total of 10 patients had LV dysfunction after anthracycline chemotherapy. Multivariate logistic regression analysis showed that baseline GLS was the only independent predictor of this dysfunction. Receiver-operating characteristic curve analysis identified the optimal GLS cutoff for predicting LV dysfunction after anthracycline chemotherapy as ≤19% (P=0.008). Furthermore, the Kaplan-Meier curve indicated that fewer patients with GLS >19% were hospitalized for HF than among those with GLS ≤19% (log-rank P=0.02). For sequential logistic models, a model based on baseline clinical variables (χ2=2.9) was improved by the addition of baseline LVEF (χ2=9.0; P=0.01), and further improved by the addition of baseline GLS (χ2=13.1, P=0.04). Conclusions: Watchful observation or early therapeutic intervention with established cardioprotective medications may be necessary for patients with malignant lymphoma and preserved LVEF but with abnormal GLS.

著者

Tomoya Yamashita Tomohiro Hayashi Tokiko Tabata Ken-ichi Hirata

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.10, pp.2470-2471, 2018-09-25 (Released:2018-09-25)

参考文献数

8

被引用文献数

3

著者

Kimiko Yamamoto Joji Ando

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.82, no.11, pp.2691-2698, 2018-10-25 (Released:2018-10-25)

参考文献数

59

被引用文献数

26

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Vascular endothelial cells (ECs) maintain circulatory system homeostasis by changing their functions in response to changes in hemodynamic forces, including shear stress and stretching. However, it is unclear how ECs sense changes in shear stress and stretching and transduce these changes into intracellular biochemical signals. The plasma membranes of ECs have recently been shown to respond to shear stress and stretching differently by rapidly changing their lipid order, fluidity, and cholesterol content. Such changes in the membranes’ physical properties trigger the activation of membrane receptors and cell responses specific to each type of force. Artificial lipid-bilayer membranes show similar changes in lipid order in response to shear stress and stretching, indicating that they are physical phenomena rather than biological reactions. These findings suggest that the plasma membranes of ECs act as mechanosensors; in response to mechanical forces, they first alter their physical properties, modifying the conformation and function of membrane proteins, which then activates downstream signaling pathways. This new appreciation of plasma membranes as mechanosensors could help to explain the distinctive features of mechanotransduction in ECs involving shear stress and stretching, which activate a variety of membrane proteins and multiple signal transduction pathways almost simultaneously.

著者

JCS Joint Working Group

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.74, no.11, pp.2479-2500, 2010 (Released:2010-10-25)

参考文献数

174

被引用文献数

88 113

著者

Kenya Kusunose Yuichiro Okushi Hirotsugu Yamada Susumu Nishio Yuta Torii Yukina Hirata Yoshihito Saijo Takayuki Ise Koji Yamaguchi Shusuke Yagi Takeshi Soeki Tetsuzo Wakatsuki Masataka Sata

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-18-0017, (Released:2018-04-28)

参考文献数

28

被引用文献数

1 17

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Background:High prevalence of frailty and of diastolic dysfunction (DD) in heart failure and high mortality in frail adults have been noted. We characterized frailty by quantifying differences on echocardiography, and assessed the added prognostic utility of frailty and DD grade in an elderly population.Methods and Results:One hundred and ninety-one patients ≥65 years who had at least 1 cardiovascular risk factor were prospectively recruited for clinically indicated echocardiography at the present institute. Weight loss, exhaustion, and deficits in physical activity, gait speed, and handgrip strength were used to categorize patients as frail (≥3 features), intermediately frail (1 or 2 features), or non-frail (0 features). DD grade ≥2 was defined as severe. Frailty was associated with larger left atrial volume, smaller stroke volume, and worse DD grade after adjustment for age. In a period of 14 months, 29 patients (15%) had cardiovascular events. The addition of frailty score and severe DD significantly improved the prognostic power of a model containing male gender (model 1, male gender, χ2=6.4; model 2, model 1 plus frailty score, χ2=16.7, P=0.004; model 3, model 2 plus severe DD, χ2=25.5, P=0.015).Conclusions:Both frailty and DD grade were significantly associated with future cardiovascular events in an elderly population with preserved ejection fraction and ≥1 risk factor of cardiovascular disease.

著者

Dominic P. Del Re

出版者

The Japanese Circulation Society

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

vol.80, no.7, pp.1504-1510, 2016-06-24 (Released:2016-06-24)

参考文献数

93

被引用文献数

2 12

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Initially identified inDrosophila melanogaster, the Hippo signaling pathway regulates organ size through modulation of cell proliferation, survival and differentiation. This pathway is evolutionarily conserved and canonical signaling involves a kinase cascade that phosphorylates and inhibits the downstream effector Yes-associated protein (YAP). Recent research has demonstrated a fundamental role of Hippo signaling in cardiac development, homeostasis, injury and regeneration, and remains the subject of intense investigation. However, 2 prominent members of this pathway, RASSF1A and Mst1, have been shown to influence heart function and stress responses through YAP-independent mechanisms. This review summarizes non-canonical targets of RASSF1A and Mst1 and discusses their role in the context of cardiac hypertrophy, autophagy, apoptosis and function. (Circ J 2016; 80: 1504–1510)