掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Aims

Patients with mitral regurgitation (MR) present with considerable heterogeneity in cardiac damage depending on underlying aetiology, disease progression, and comorbidities. This study aims to capture their cardiopulmonary complexity by employing a machine-learning (ML)-based phenotyping approach.

Methods and results

Data were obtained from 1426 patients undergoing mitral valve transcatheter edge-to-edge repair (MV TEER) for MR. The ML model was developed using 609 patients (derivation cohort) and validated on 817 patients from two external institutions. Phenotyping was based on echocardiographic data, and ML-derived phenotypes were correlated with 5-year outcomes. Unsupervised agglomerative clustering revealed four phenotypes among the derivation cohort: Cluster 1 showed preserved left ventricular ejection fraction (LVEF; 56.5 ± 7.79%) and regular left ventricular end-systolic diameter (LVESD; 35.2 ± 7.52 mm); 5-year survival in Cluster 1, hereinafter serving as a reference, was 60.9%. Cluster 2 presented with preserved LVEF (55.7 ± 7.82%) but showed the largest mitral valve effective regurgitant orifice area (0.623 ± 0.360 cm2) and highest systolic pulmonary artery pressures (68.4 ± 16.2 mmHg); 5-year survival ranged at 43.7% (P-value: 0.032). Cluster 3 was characterized by impaired LVEF (31.0 ± 10.4%) and enlarged LVESD (53.2 ± 10.9 mm); 5-year survival was reduced to 38.3% (P-value: <0.001). The poorest 5-year survival (23.8%; P-value: <0.001) was observed in Cluster 4 with biatrial dilatation (left atrial volume: 312 ± 113 mL; right atrial area: 46.0 ± 8.83 cm2) although LVEF was only slightly reduced (51.5 ± 11.0%). Importantly, the prognostic significance of ML-derived phenotypes was externally confirmed.

Conclusion

ML-enabled phenotyping captures the complexity of extra-mitral valve cardiac damage, which does not necessarily occur in a sequential fashion. This novel phenotyping approach can refine risk stratification in patients undergoing MV TEER in the future.

DOI： 10.1093/ehjci/jead013

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jjcc.2022.10.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Congenital heart disease (CHD) is caused by cardiovascular developmental defects and has a global prevalence of ∼1%. The etiology of CHD is multifactorial and remains generally unknown, despite advances in analytical techniques based on next-generation sequencing (NGS). The aim of our study was to elucidate the multi-genetic origin and pathogenesis of an intriguing familial case with complex CHD. METHODS: We performed an original trio-based gene panel analysis using NGS of the family, including two siblings with CHD of single ventricular phenotype, and their unaffected parents. The pathogenicity of the detected rare variants was investigated in silico, and the functional effects of the variants were confirmed in vitro using luciferase assays. The combinatorial effect of gene alterations of the putative responsible genes was tested in vivo using genetically engineered mutant mice. RESULTS: NGS-based gene panel analyses revealed two heterozygous rare variants in NODAL and in TBX20 common to the siblings and to just one of parents. Both variants were suspected pathogenic in silico, and decreased transcriptional activities of downstream signaling pathways were observed in vitro. The analyses of Nodal and Tbx20 double mutant mice demonstrated that Nodal+/-Tbx20-/- embryos showed more severe defects than Nodal+/+Tbx20-/- embryos during early heart development. The expression of Pitx2, a known downstream target of Nodal, was downregulated in Tbx20-/- mutants. CONCLUSIONS: Two rare variants on NODAL and TBX20 genes detected in this family were considered to be loss-of-function mutations. Our results suggest that NODAL and TBX20 may be complementary for the cardiac development, and a combinatorial loss-of-function of NODAL and TBX20 could be implicated in digenic inherence as the etiology of complex CHD associated with single ventricle defects in this family.

DOI： 10.3389/fcvm.2023.1135141

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.bbrc.2022.09.108

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

Background

<p lang="en">The implementation of advance care planning (ACP) in heart failure management is insufficient. Social isolation (SI) could be a barrier to ACP initiation, albeit the relationship between SI and patients' preference for ACP or end‐of‐life care remains unknown.

</p> Methods and Results

<p lang="en"> We conducted a questionnaire survey, including assessments of SI using the 6‐item Lubben Social Network Scale as well as patients' perspectives on ACP and end‐of‐life care. Of the 160 patients approached by our multidisciplinary heart failure team during admission, 120 patients (75.0%) completed the survey (median age, 73.0 years; men, 74.2%). A Cox proportional hazard model was constructed to elucidate the short‐term (180‐day) prognostic impact of SI. Overall, 28.3% of participants were at high risk for SI (6‐item Lubben Social Network Scale score &lt;12). High‐risk patients had more negative attitudes toward ACP than those without (61.8% versus 80.2%; P =0.035). The actual performance of ACP conversation in patients with and without high risk were 20.6% and 30.2%, respectively. Regarding preference in end‐of‐life care, “Saying what one wants to tell loved ones” (73.5% versus 90.6%; P =0.016) and “Spending enough time with family” (58.8% versus 77.9%; P =0.035) were less important in high‐risk patients. High risk for SI was associated with higher 180‐day risk‐adjusted all‐cause mortality (hazard ratio, 7.89 [95% CI, 1.53–40.75]).

</p> Conclusions

<p lang="en">In hospitalized patients with heart failure, high risk for SI was frequently observed. High‐risk patients were associated with a negative attitude toward ACP, despite higher mortality. Further research is required to establish an ideal approach to provide ACP in socially vulnerable patients.

</p>

DOI： 10.1161/jaha.122.026645

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掲載種別：研究論文（学術雑誌）   出版者・発行元：BMJ  

Objective

A novel artificial intelligence-based phenotyping approach to stratify patients with severe aortic stenosis (AS) prior to transcatheter aortic valve replacement (TAVR) has been proposed, based on echocardiographic and haemodynamic data. This study aimed to analyse the recovery of extra-aortic valve cardiac damage in accordance with this novel stratification system following TAVR.

Methods

The proposed phenotyping approach was previously established employing data from 366 patients with severe AS from a bicentric registry. For this consecutive study, echocardiographic follow-up data, obtained on day 147±75.1 after TAVR, were available from 247 patients (67.5%).

Results

Correction of severe AS by TAVR significantly reduced the proportion of patients suffering from concurrent severe mitral regurgitation (from 9.29% to 3.64%, p value: 0.0015). Moreover, pulmonary artery pressures were ameliorated (estimated systolic pulmonary artery pressure: from 47.2±15.8 to 43.3±15.1 mm Hg, p value: 0.0079). However, right heart dysfunction as well as the proportion of patients with severe tricuspid regurgitation remained unchanged. Clusters with persistent right heart dysfunction ultimately displayed 2-year survival rates of 69.2% (95% CI 56.6% to 84.7%) and 74.6% (95% CI 65.9% to 84.4%), which were significantly lower compared with clusters with little or no persistent cardiopulmonary impairment (88.3% (95% CI 83.3% to 93.5%) and 85.5% (95% CI 77.1% to 94.8%)).

Conclusions

This phenotyping approach preprocedurally identifies patients with severe AS, who will not recover from extra-aortic valve cardiac damage following TAVR and whose survival is therefore significantly reduced. Importantly, not the degree of pulmonary hypertension at initial presentation, but the irreversibility of right heart dysfunction determines prognosis.

DOI： 10.1136/openhrt-2022-002068

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.

DOI： 10.1038/s41467-022-33152-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sleep disorders and sleep duration have attracted considerable attention as potential modifiable risk factors for the development and progression of heart failure (HF). However, whether these sleep behaviors could aggravate the underlying cardiac condition remains ambiguous. We evaluated the associations between the levels of plasma B-type natriuretic peptide (BNP) and sleep-disordered breathing (SDB), sleep quality and quantity, or daytime sleepiness in cardiovascular diseases (CVD) patients. A total of 1717 consecutive patients with CVD [median age, 66 years (55-74 years); female, 27.5%] were enrolled. SDB was screened by nocturnal pulse oximetry; sleep quality and quantity were determined by Pittsburg Sleep Quality Index, and daytime sleepiness was examined by Epworth Sleepiness Scale. The median plasma BNP level was 54.9 pg/ml (23.5-146.4 pg/ml). Multiple regression analyses showed that the BNP level in the highest quintile (BNP > 181.8 pg/ml) was associated with SDB (severe: OR, 5.88; 95% CI 3.17-10.88; moderate: OR, 3.62; 95% CI 2.17-6.02; mild: OR, 2.22: 95% CI 1.42-3.47). There were no significant associations between other sleep parameters and higher BNP levels. The relationship between SDB and BNP levels was unchanged regardless of the previous history of symptomatic HF. SDB was independently associated with the elevated plasma BNP level in patients with a variety of CVD.

DOI： 10.1007/s00380-021-01998-6

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Circulation Society  

DOI： 10.1253/circj.cj-21-0978

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Induced pluripotent stem cells (iPSCs) are terminally differentiated somatic cells that differentiate into various cell types. iPSCs are expected to be used for disease modeling and for developing novel treatments because differentiated cells from iPSCs can recapitulate the cellular pathology of patients with genetic mutations. However, a barrier to using iPSCs for comprehensive drug screening is the difficulty of evaluating their pathophysiology. Recently, the accuracy of image analysis has dramatically improved with the development of artificial intelligence (AI) technology. In the field of cell biology, it has become possible to estimate cell types and states by examining cellular morphology obtained from simple microscopic images. AI can evaluate disease-specific phenotypes of iPS-derived cells from label-free microscopic images; thus, AI can be utilized for disease-specific drug screening using iPSCs. In addition to image analysis, various AI-based methods can be applied to drug development, including phenotype prediction by analyzing genomic data and virtual screening by analyzing structural formulas and protein–protein interactions of compounds. In the future, combining AI methods may rapidly accelerate drug discovery using iPSCs. In this review, we explain the details of AI technology and the application of AI for iPSC-based drug screening.

DOI： 10.3390/ph15050562

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Aims

Hypothesizing that aortic outflow velocity profiles contain more valuable information about aortic valve obstruction and left ventricular contractility than can be captured by the human eye, features of the complex geometry of Doppler tracings from patients with severe aortic stenosis (AS) were extracted by a convolutional neural network (CNN).

Methods and results

After pre-training a CNN (VGG-16) on a large data set (ImageNet data set; 14 million images belonging to 1000 classes), the convolutional part was employed to transform Doppler tracings to 1D arrays. Among 366 eligible patients [age: 79.8 ± 6.77 years; 146 (39.9%) women] with pre-procedural echocardiography and right heart catheterization prior to transcatheter aortic valve replacement (TAVR), good quality Doppler tracings from 101 patients were analysed. The convolutional part of the pre-trained VGG-16 model in conjunction with principal component analysis and k-means clustering distinguished two shapes of aortic outflow velocity profiles. Kaplan–Meier analysis revealed that mortality in patients from Cluster 2 (n = 40, 39.6%) was significantly increased [hazard ratio (HR) for 2-year mortality: 3; 95% confidence interval (CI): 1–8.9]. Apart from reduced cardiac output and mean aortic valve gradient, patients from Cluster 2 were also characterized by signs of pulmonary hypertension, impaired right ventricular function, and right atrial enlargement. After training an extreme gradient boosting algorithm on these 101 patients, validation on the remaining 265 patients confirmed that patients assigned to Cluster 2 show increased mortality (HR for 2-year mortality: 2.6; 95% CI: 1.4–5.1, P-value: 0.004).

Conclusion

Transfer learning enables sophisticated pattern recognition even in clinical data sets of limited size. Importantly, it is the left ventricular compensation capacity in the face of increased afterload, and not so much the actual obstruction of the aortic valve, that determines fate after TAVR.

DOI： 10.1093/ehjdh/ztac004

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その他リンク： https://academic.oup.com/ehjdh/article-pdf/3/2/153/47117014/ztac004.pdf

記述言語：英語  

COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has spread worldwide, resulting in health and economic crises. Vaccination against SARS-CoV-2 infection is considered a valid prevention measure to control this pandemic. There have been reports of cases of myopericarditis following mRNA COVID-19 vaccination. We present a case of a 20-year-old man with recurrent myopericarditis following an initial episode of influenza virus-induced myopericarditis and after a second dose of the mRNA-1273 Moderna COVID-19 vaccine. Careful attention should be paid to patients with a history of myocarditis following COVID-19 vaccination.

DOI： 10.1016/j.cjco.2021.12.002

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.exger.2021.111679

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jcin.2021.12.043

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

DOI： 10.3389/fcell.2021.831304

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Understanding sex differences is critical for improving outcomes in patients with cardiovascular conditions. Sleep and psychological disturbances contribute to the development and progression of cardiovascular diseases, and important sex differences persist in their incidence and association with clinical outcomes. METHODS: Sex-based variation in sleep and psychological disturbances were assessed in consecutive patients with cardiovascular diseases in a single university hospital. The prevalence of insomnia, sleep disordered breathing (SDB), anxiety, and depression was assessed using the Pittsburgh Sleep Quality Index (PSQI), nocturnal pulse oximeter, and the Hospital Anxiety and Depression Scale (HADS). The effect of sex on the prevalence of sleep and psychological disturbances as well as their associations was quantified using multivariate logistic regression models. RESULTS: Among 1,233 patients (mean age 63.6 years, 25% women), women were significantly less likely than men to experience SDB (17.5% vs 31.5%, p < 0.001), but more likely to report an increased burden of insomnia (54.7% vs 43.3%, p = 0.001) and depression (23.9% vs 16.7%, p = 0.004). Insomnia was associated with depression, which was more remarkable among women (p value for interaction: 0.039). SDB was associated with anxiety among women but not men (p value for interaction: 0.003). There was no significant difference in the prevalence of anxiety between women and men. CONCLUSIONS: Among patients with cardiovascular disease, women reported an increased burden of insomnia and depression compared to men. The association between sleep and psychological disturbances may be more pronounced in women, suggesting that cardiologists should increase efforts for identification of such comorbidities and administer corresponding treatment, especially in women.

DOI： 10.1007/s11325-021-02544-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Substantial emotional or physical stress may lead to an imbalance in the brain, resulting in stress cardiomyopathy (SC) and transient left ventricular (LV) apical ballooning. Even though these conditions are severe, their precise underlying mechanisms remain unclear. Appropriate animal models are needed to elucidate the precise mechanisms. In this study, we established a new animal model of epilepsy-induced SC. The SC model showed an increased expression of the acute phase reaction protein, c-Fos, in the paraventricular hypothalamic nucleus (PVN), which is the sympathetic nerve center of the brain. Furthermore, we observed a significant upregulation of neuropeptide Y (NPY) expression in the left stellate ganglion (SG) and cardiac sympathetic nerves. NPY showed neither positive nor negative inotropic and chronotropic effects. On the contrary, NPY could interrupt β-adrenergic signaling in cardiomyocytes when exposure to NPY precedes exposure to noradrenaline. Moreover, its elimination in the left SG via siRNA treatment tended to reduce the incidence of SC. Thus, our results indicated that upstream sympathetic activation induced significant upregulation of NPY in the left SG and cardiac sympathetic nerves, resulting in cardiac dysfunctions like SC.

DOI： 10.3389/fnins.2022.1013712

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>Advances in deep learning technology have enabled complex task solutions. The accuracy of image classification tasks has improved owing to the establishment of convolutional neural networks (CNN). Cellular senescence is a hallmark of ageing and is important for the pathogenesis of ageing-related diseases. Furthermore, it is a potential therapeutic target. Specific molecular markers are used to identify senescent cells. Moreover senescent cells show unique morphology, which can be identified. We develop a successful morphology-based CNN system to identify senescent cells and a quantitative scoring system to evaluate the state of endothelial cells by senescence probability output from pre-trained CNN optimised for the classification of cellular senescence, Deep Learning-Based Senescence Scoring System by Morphology (Deep-SeSMo). Deep-SeSMo correctly evaluates the effects of well-known anti-senescent reagents. We screen for drugs that control cellular senescence using a kinase inhibitor library by Deep-SeSMo-based drug screening and identify four anti-senescent drugs. RNA sequence analysis reveals that these compounds commonly suppress senescent phenotypes through inhibition of the inflammatory response pathway. Thus, morphology-based CNN system can be a powerful tool for anti-senescent drug screening.

DOI： 10.1038/s41467-020-20213-0

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その他リンク： http://www.nature.com/articles/s41467-020-20213-0

記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Early engagement in advance care planning (ACP) is recommended in heart failure (HF) management. We investigated the preferences of patients with HF regarding ACP and end-of-life (EOL) care, including their desired timing of ACP initiation. METHODS AND RESULTS: Data were collected using a 92-item questionnaire survey, which was directly distributed to hospitalized patients by dedicated physicians and nurses in a university hospital setting. One-hundred eighty-seven patients agreed to participate (response rate: 92.6%), and 171 completed the survey [valid response rate: 84.7%; men: 67.3%; median age: 73.0 (63.0-81.0) years]. Logistic regression analyses were conducted to identify the predictors of positive attitudes towards ACP. Most recognized ACP as important for their care (n = 127, 74.3%), 48.1% stated that ACP should be initiated after repeated HF hospitalizations in the past year, and 29.0% preferred ACP to begin during the first or second HF hospitalization. Only 21.7% of patients had previously engaged in ACP conversations during HF management. Positive attitudes towards ACP were associated with lower depressive symptoms [two-item Patient Health Questionnaire; odds ratio (OR): 0.75, 95% confidence interval (CI): 0.61-0.92, P-value: 0.006], marriage (OR: 2.53, 95% CI: 1.25-5.12, P-value: 0.010), and a high educational level (OR: 2.66, 95% CI: 1.28-5.56, P-value: 0.009), but not with severity of HF (represented by Seattle Heart Failure Model risk score). Regarding EOL care, while 'Saying what one wants to tell loved ones' (83.4%), 'Dying a natural death' (81.8%), and 'Being able to stay at one's favorite place' (75.6%) were the three most important factors for patients, preferences for 'Receiving sufficient treatment' (56.5%) and 'Knowing what to expect about future condition' (50.3%) were divergent. CONCLUSIONS: Despite patients' preferences for ACP conversations, there was a discrepancy between preference and engagement in ACP among patients hospitalized for HF. Patients' preferences regarding EOL care may differ; physicians need to consider the appropriate ACP approach to align with patients' care goals.

DOI： 10.1002/ehf2.13578

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.jcin.2021.08.034

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: New-onset atrial tachyarrhythmia (ATA) often develops after atrial septal defect (ASD) closure. Its development raises some potential concerns such as stroke and bleeding complications caused by anticoagulant therapy and limited access to the left atrium for catheter ablation. Although it is essential to identify the risk factors of new-onset ATA, few studies have examined these factors. This study investigated unknown risk factors for the development of new-onset ATA after transcatheter ASD closure in patients without a history of ATA. METHODS: A total of 238 patients without a history of ATA, aged ≥18 years and who underwent transcatheter ASD closure at the current hospital were reviewed. Patient characteristics were compared between the groups with and without new-onset ATA. The factors associated with new-onset ATA were examined using univariate and multivariable analyses. RESULTS: Thirteen (13) (5.5%) patients experienced ATA during follow-up (mean, 21±14 months). Compared with patients without new-onset ATA, patients with new-onset ATA were older (48±18 vs 66±11 years; p<0.001) and had high brain natriuretic peptide (BNP) levels (36±36 vs 177±306 pg/mL; p<0.001). On multivariable analysis, BNP ≥40 pg/mL before ASD closure was associated with new-onset ATA after adjusting for age (OR, 4.91; 95% CI, 1.22-19.8; p=0.025). CONCLUSION: Patients with BNP levels >40 pg/mL before transcatheter ASD closure may have a higher risk of developing new-onset ATA.

DOI： 10.1016/j.hlc.2021.02.018

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記述言語：英語  

DOI： 10.1161/CIRCIMAGING.121.012641

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Heart failure (HF) is a highly prevalent, heterogeneous, and life-threatening condition. Precise prognostic understanding is essential for effective decision making, but little is known about patients' attitudes toward prognostic communication with their physicians. METHODS AND RESULTS: We conducted a questionnaire survey, consisting of patients' prognostic understanding, preferences for information disclosure, and depressive symptoms, among hospitalized patients with HF (92 items in total). Individual 2-year survival rates were calculated using the Seattle Heart Failure Model, and its agreement level with patient self-expectations of 2-year survival were assessed. A total of 113 patients completed the survey (male 65.5%, median age 75.0 years, interquartile range 66.0-81.0 years). Compared with the Seattle Heart Failure Model prediction, patient expectation of 2-year survival was matched only in 27.8% of patients; their agreement level was low (weighted kappa = 0.11). Notably, 50.9% wished to know "more," although 27.7% felt that they did not have an adequate prognostic discussion. Compared with the known prognostic variables (eg, age and HF severity), logistic regression analysis demonstrated that female and less depressive patients were associated with patients' preference for "more" prognostic discussion. CONCLUSIONS: Patients' overall prognostic understanding was suboptimal. The communication process requires further improvement for patients to accurately understand their HF prognosis and be involved in making a better informed decision.

DOI： 10.1016/j.cardfail.2020.10.009

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掲載種別：研究論文（学術雑誌）   出版者・発行元：SAGE Publications  

Instrumental activities of daily living (IADL) are significantly related to quality of life and mortality among individuals with heart disease. However, few reports have examined IADL in persons with chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to clarify factors related to IADL in persons with CTEPH. This retrospective, observational study enrolled 163 persons with CTEPH (mean ± standard deviation age = 65 ± 13 years; 68% female) admitted to the Department of Cardiology at Keio University Hospital between January 2015 and July 2019. The Frenchay Activities Index (FAI) was used to assess IADL. Age, sex, body mass index, World Health Organization functional class (WHO-FC), cardiac function (mean pulmonary arterial pressure, mean right atrial pressure, pulmonary capillary wedge pressure, and cardiac index), pulmonary function (percentage vital capacity, percentage forced expiratory volume in 1 s, diffusion capacity of carbon monoxide (DLCO)/alveolar volume (VA)), physical function (knee extension strength and walking speed), and 6-min walking distance (6MWD) were assessed. Multiple regression analysis was performed to identify factors significantly associated with FAI. Mean FAI was 25 ± 8. Univariate analysis showed that sex, WHO-FC, DLCO/VA, walking speed, and 6MWD were correlated with FAI. Multiple regression analysis showed that 6MWD (sβ = 0.338, 95% CI 0.014–0.034, p &lt; .001), sex (sβ = 0.268, 95% CI 2.238–7.165, p &lt; .001), and DLCO/VA (sβ = 0.257, 95% CI 1.011–3.528, p &lt; .001) were significantly correlated with FAI ( R² = 0.261). IADL were associated with exercise tolerance, sex, and DLCO/VA in persons with CTEPH. In the future, more details of IADL are expected to be clarified by analyzing individual components of IADL and investigating social background characteristics, including living environment.

DOI： 10.1177/14799731211046634

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その他リンク： http://journals.sagepub.com/doi/full-xml/10.1177/14799731211046634

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Thyroid hormones (THs) are synthesized in the thyroid gland, and they circulate in the blood to regulate cells, tissues, and organs in the body. In particular, they exert several effects on the cardiovascular system. It is well known that THs raise the heart rate and cardiac contractility, improve the systolic and diastolic function of the heart, and decrease systemic vascular resistance. In the past 30 years, some researchers have studied the molecular pathways that mediate the role of TH in the cardiovascular system, to better understand its mechanisms of action. Two types of mechanisms, which are genomic and non-genomic pathways, underlie the effects of THs on cardiomyocytes. In this review, we summarize the current knowledge of the action of THs in the cardiac function, the clinical manifestation and parameters of their hemodynamics, and treatment principles for patients with hyperthyroid- or hypothyroid-associated heart disease. We also describe the cardiovascular drugs that induce thyroid dysfunction and explain the mechanism underlying the thyroid toxicity of amiodarone, which is considered the most effective antiarrhythmic agent. Finally, we discuss the recent reports on the involvement of thyroid hormones in the regulation of myocardial regeneration and metabolism in the adult heart.

DOI： 10.3389/fphys.2021.606931

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Depression and anxiety are common mental health problems that are strongly associated with sleep disturbances, according to community-based researches. However, this association has not been investigated among patients admitted for cardiovascular diseases (CVDs). We examined the prevalence of depression and anxiety in inpatients with various CVDs and their association with sleep disturbances. MATERIALS AND METHODS: This cross-sectional study included 1294 patients hospitalized for CVDs in a Japanese university hospital were evaluated for their mental status using the Hospital Anxiety and Depression Scale (HADS), for sleep-disordered breathing (SDB) using pulse oximetry, and for sleep quality using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Patient characteristics were as below: mean age, 63.9±14.7 years; 25.7% female. Overall, 18.9% had depression (HADS-depression≥8) and 17.1% had anxiety (HADS-anxiety≥8). The presence of depression was associated with female sex, older age, higher plasma brain natriuretic peptide level, lower estimated glomerular filtration rate, and the prevalence of heart failure. Overall, 46.5% patients were categorized as having a poor sleep quality (PSQI>5), and 28.5% patients had SDB (3% oxygen desaturation index>15). Although depression and anxiety were not associated with SDB, they were independently associated with poor sleep quality (OR = 3.09, 95% CI 2.19-4.36; OR = 3.93, 95% CI 2.71-5.69, respectively). CONCLUSIONS: Depression and anxiety were not uncommon in patients with CVDs. Poor sleep quality could be an important risk factor linked to psychological disturbances.

DOI： 10.1371/journal.pone.0244484

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Frequent nightmares can pose a serious clinical problem, especially in association with sleep and psychological disturbances, in the general population. However, this association has not been investigated in inpatients with cardiovascular (CV) diseases. Furthermore, whether CV medications could induce iatrogenic nightmares remains unknown. In a cross-sectional designed study, we evaluated the prevalence and determinants of frequent nightmares and its association with sleep and psychological disturbances among hospitalized CV patients. METHODS AND RESULTS: A total of 1233 patients (mean age, 64 ± 15 years; 25.1% female) hospitalized for various CV diseases in a single university hospital were enrolled. We assessed nightmares and sleep characteristics using the Pittsburgh Sleep Quality Index (PSQI), sleep-disordered breathing (SDB) using nocturnal pulse oximetry, and psychological disturbances using Hospital Anxiety and Depression Scale (HADS). Overall, 14.8% and 3.6% of the patients had at least one nightmare per month and per week (frequent nightmares), respectively. In this cohort, 45.9% had insomnia (modified PSQI > 5), 28.0% had SDB (3% oxygen desaturation index > 15), 18.5% had depression (HADS-depression ≥ 8), and 16.9% had anxiety (HADS-anxiety ≥ 8). Frequent nightmares were not associated with CV medications and SDB but were associated with depression [odds ratio (OR) = 4.61, 95% confidence interval (CI) = 2.03-10.48], anxiety (OR = 5.32, 95% CI = 2.36-12.01), and insomnia (OR = 7.15, 95% CI = 2.41-21.22). CONCLUSIONS: Frequent nightmares were not uncommon in patients hospitalized for CV diseases. Although the cause-effect relationship is unclear, frequent nightmares were associated with psychological disturbances and insomnia, but not iatrogenic factors, among hospitalized CV patients. Cardiologists should be more conscientious to nightmare complaints with respect to screening for psychological disturbances and insomnia.

DOI： 10.1093/eurjcn/zvaa016

PubMed

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記述言語：英語  

Infected aortic aneurysm (IAA) is a rare, life-threatening disease with rapid progression and a high mortality rate. An 84-year-old man developed IAA caused by urosepsis owing to extended-spectrum β-lactamase-producing Escherichia coli infection. Considering surgical risk and perioperative mortality, the patient underwent computed tomography-guided percutaneous abscess drainage and continuous irrigation with optimal antibiotic therapy. We controlled his systemic inflammation without surgery; thus, he was discharged. Six months later, we confirmed that the abscess had almost disappeared in the follow-up computed tomography scan. Percutaneous abscess drainage and irrigation may be an effective therapeutic option for surgical high-risk patients with IAA.

DOI： 10.1016/j.cjco.2020.08.008

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記述言語：英語  

Thrombosis, especially venous thromboembolism, is a complication often associated with COVID-19. However, there have been relatively few reports of arterial thrombosis. Here, we describe a case of non-severe COVID-19 in a patient with dilated cardiomyopathy. After admission, symptoms, laboratory data, and imaging findings improved, but D-dimer levels gradually increased. Contrast computed tomography (CT) and echocardiography revealed a left ventricular thrombus. Anti-coagulant treatment diminished the thrombus, and the patient recovered and was discharged. Although a left ventricular thrombus is a rare COVID-19 complication, performing appropriate diagnostic tests could improve COVID-19 mortality in patients with dilated cardiomyopathy.

DOI： 10.1016/j.cjco.2020.09.014

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Heart failure (HF) is a risk factor for adverse post-procedural outcome after revascularization; however, it is unclear how left ventricular systolic dysfunction (LVSD) and clinical HF symptoms affect percutaneous coronary intervention (PCI) outcomes. We investigated the characteristics and long-term outcomes of patients with clinical HF or LVSD after PCI. METHODS: This was a Japanese multicenter registry study of adult patients receiving PCI. Among 4689 consecutive patients who underwent PCI at 15 hospitals from January 2009 to December 2012, we analyzed 2634 (56.2%) with documented left ventricular ejection fraction (LVEF). They were divided into four groups based on clinical HF (symptoms or HF hospitalization) and LVEF [≥35% and <35% (HF due to LVSD)]. The primary outcome was major adverse cardiovascular events (MACE), comprising all-cause death, acute coronary syndrome, HF hospitalization, performance of coronary artery bypass grafting, and stroke within 2 years after the initial PCI. RESULTS: Our findings revealed 354 patients (13.4%) with HF (clinical HF, n = 173, 48.9%; LVSD, n = 132, 37.3%; both, n = 49; 13.8%). The incidence of MACE was higher in patients with clinical HF or LVSD, and was largely due to higher non-cardiac death and HF hospitalization. After adjustment, clinical HF (hazard ratio 2.16, 95% confidence interval; 1.49-3.14) and lower LVEF (per 10%, hazard ratio 0.89, 95% confidence interval; 0.81-0.99) were independently associated with higher MACE risk. CONCLUSIONS: Clinical HF and LVSD were independently associated with adverse long-term clinical outcomes, particularly with non-cardiac death and HF readmission, in patients treated with PCI.

DOI： 10.1016/j.jjcc.2020.06.014

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Supercentenarians (those aged ≥110 years) are approaching the current human longevity limit by preventing or surviving major illness. Identifying specific biomarkers conducive to exceptional survival might provide insights into counter-regulatory mechanisms against aging-related disease. Here, we report associations between cardiovascular disease-related biomarkers and survival to the highest ages using a unique dataset of 1,427 oldest individuals from three longitudinal cohort studies, including 36 supercentenarians, 572 semi-supercentenarians (105-109 years), 288 centenarians (100-104 years), and 531 very old people (85-99 years). During follow-up, 1,000 participants (70.1%) died. Overall, N-terminal pro-B-type natriuretic peptide (NT-proBNP), interleukin-6, cystatin C and cholinesterase are associated with all-cause mortality independent of traditional cardiovascular risk factors and plasma albumin. Of these, low NT-proBNP levels are statistically associated with a survival advantage to supercentenarian age. Only low albumin is associated with high mortality across age groups. These findings expand our knowledge on the biology of human longevity.

DOI： 10.1038/s41467-020-17636-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.cjca.2020.03.052

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This observational study aimed to examine the extent of early invasive strategy (EIS) utilization in patients with non-ST elevation acute coronary syndrome (NSTE-ACS) according to the National Cardiovascular Data Registry (NCDR) CathPCI risk score, and its association with clinical outcomes. Using a prospective multicenter Japanese registry, 2968 patients with NSTE-ACS undergoing percutaneous coronary intervention within 72 hours of hospital arrival were analyzed. Multivariable logistic regression analyses were performed to determine predictors of EIS utilization. Additionally, adverse outcomes were compared between patients treated with and without EIS. Overall, 82.1% of the cohort (n = 2436) were treated with EIS, and the median NCDR CathPCI risk score was 22 (interquartile range: 14-32) with an expected 0.3-0.6% in-hospital mortality. Advanced age, peripheral artery disease, chronic kidney disease or patients without elevation of cardiac biomarkers were less likely to be treated with EIS. EIS utilization was not associated with a risk of in-hospital mortality; yet, it was associated with an increased risk of acute kidney injury (AKI) (adjusted odds ratio: 1.42; 95% confidence interval: 1.02-2.01) regardless of patients' in-hospital mortality risk. Broader use of EIS utilization comes at the cost of increased AKI development risk; thus, the pre-procedural risk-benefit profile of EIS should be reassessed appropriately in patients with lower mortality risk.

DOI： 10.3390/jcm9041106

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記述言語：英語  

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.

DOI： 10.1016/j.cjca.2020.03.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Skeletal muscle comprises 30-40% of the weight of a healthy human body and is required for voluntary movements in humans. Mature skeletal muscle is formed by multinuclear cells, which are called myofibers. Formation of myofibers depends on the proliferation, differentiation, and fusion of muscle progenitor cells during development and after injury. Muscle progenitor cells are derived from muscle satellite (stem) cells (MuSCs), which reside on the surface of the myofiber but beneath the basement membrane. MuSCs play a central role in postnatal maintenance, growth, repair, and regeneration of skeletal muscle. In sedentary adult muscle, MuSCs are mitotically quiescent, but are promptly activated in response to muscle injury. Physiological and chronological aging induces MuSC aging, leading to an impaired regenerative capability. Importantly, in pathological situations, repetitive muscle injury induces early impairment of MuSCs due to stem cell aging and leads to early impairment of regeneration ability. In this review, we discuss (1) the role of MuSCs in muscle regeneration, (2) stem cell aging under physiological and pathological conditions, and (3) prospects related to clinical applications of controlling MuSCs.

DOI： 10.3390/ijms21051830

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1016/j.healun.2019.08.022

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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掲載種別：研究論文（学術雑誌）  

© The Author(s) 2020. Noonan syndrome is known to have various cardiovascular defects, which include pulmonary artery stenosis. Pulmonary artery stenosis is characterized by obstruction of pulmonary artery blood flow that can cause elevated pulmonary artery pressure and ventilation-perfusion inequality, which can cause dyspnea on exertion and eventually, heart failure. Although the etiology of pulmonary artery stenosis related to congenital diseases is still unknown, balloon pulmonary angioplasty has being reported to be effective to selected patients with Alagille and Williams syndromes, but not from Noonan syndrome despite of modest prevalence of pulmonary artery stenosis. Here, we report the first Noonan syndrome patient with pulmonary artery stenosis who underwent successful balloon pulmonary angioplasty. The strategy used in balloon pulmonary angioplasty was planned with careful morphologic evaluation by computed tomographic angiography, and performed with scoring balloons in a graded approach with multiple sessions. After balloon pulmonary angioplasty, we confirmed maintained dilation of lesions and symptom alleviation, suggesting that balloon pulmonary angioplasty can be performed safely on pulmonary artery stenosis in a Noonan syndrome patient.

DOI： 10.1177/2045894020954310

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.2302/kjm.2018-0004-OA

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(公財)日本心臓財団  

症例は84歳女性。2011年に閉塞性肥大型心筋症(HOCM)を偶発的に指摘され近医通院を開始した。その後2016年8月頃より労作時胸痛が出現し増悪傾向を認め、同年11月に当院循環器内科を紹介受診した。経胸壁心エコーにて最大圧較差119mmHgの左室潤出路狭窄を認め、シベンゾリン、ビソプロロール導入後も改善に乏しく、2017年1月に経皮的中隔心筋焼灼術(PTSMA)を施行した。心室中隔基部を灌流する合計4本の中隔枝に対しアルコール焼灼を施行し、術中にエコー上で最大圧較差19mmHgまで軽減を確認した。術後は症状も消失したため問題なく退院となったが、2ヵ月後の2017年3月頃より労作時胸痛が再燃し、心エコーで最大圧較差96mmHgと流出路狭窄の再増悪を認め、PTSMA再施行目的に同年4月に入院となった。冠動脈造影では初回治療時にアルコール焼灼した4本の中隔枝のうち最も近位部の枝に再灌流を認め、同枝に対し再度アルコール焼灼を施行した。術後心エコーで最大圧較差15mmHgまで改善を認め、症状も消失し、1年半後の現在も再燃なく経過している。今回、初回PTSMA施行後の遠隔期に有症候性の流出路狭窄が再燃し、2回目のPTSMAで治療し得た閉塞性肥大型心筋症の1例を経験したので文献的考察を交えて報告する。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00679&link_issn=&doc_id=20191018140013&doc_link_id=10.11281%2Fshinzo.51.1072&url=https%3A%2F%2Fdoi.org%2F10.11281%2Fshinzo.51.1072&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

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.

DOI： 10.1007/s00380-019-01378-1

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記述言語：日本語   出版者・発行元：(一社)日本補体学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.hrtlng.2018.08.010

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記述言語：英語  

DOI： 10.1161/CIRCRESAHA.119.314678

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: There is no consensus on the length of hospital stay (LOHS) and post-interventional management after balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). We examined temporal trends with respect to LOHS and requirement for intensive care for BPA and their relationship with the incidence of BPA-related complications. METHODS: From November 2012 to September 2017, a total of 123 consecutive patients with CTEPH who underwent BPA were enrolled (age: 66.0 [54.0 to 74.0], World Health Organization [WHO] functional class II/III/IV; 27/88/8). Patients were divided for analysis into 3 groups according to the date of their first BPA: early-, middle-, and late-phase groups. RESULTS: Mean pulmonary arterial pressure decreased from 36.0 (29.0 to 45.0) to 20.0 (16.0 to 22.0) mm Hg after BPA (P < 0.001). The LOHS was 41.0 (31.0 to 54.0) days in total including all sessions and 6.6 (6.0 to 7.9) days/session. Despite no significant differences in age, baseline hemodynamics, and laboratory data among the 3 groups, there was a significant reduction in LOHS (7.9 [7.0 to 9.5], 6.5 [6.1 to 7.3], 6.0 [5.3 to 6.5] days/session, P < 0.001) and use of intensive/high care unit (100%, 93%, 46%, P < 0.001). The reduction in LOHS and intensive/high care unit use did not affect the occurrence of BPA-related complications. CONCLUSIONS: Increasing experience with BPA was associated with a reduction in LOHS and the use of intensive/high care unit, but no change was noted in the rate of BPA-related complications. These findings suggest that the reduction in both LOHS and use of the intensive care unit for BPA is feasible and does not jeopardize the safety of the procedure.

DOI： 10.1016/j.cjca.2018.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem cells (iPSC) are one the most prominent innovations of medical research in the last few decades. iPSCs can be easily generated from human somatic cells and have several potential uses in regenerative medicine, disease modeling, drug screening, and precision medicine. However, further innovation is still required to realize their full potential. Machine learning is an algorithm that learns from large datasets for pattern formation and classification. Deep learning, a form of machine learning, uses a multilayered neural network that mimics human neural circuit structure. Deep neural networks can automatically extract features from an image, although classical machine learning methods still require feature extraction by a human expert. Deep learning technology has developed recently; in particular, the accuracy of an image classification task by using a convolutional neural network (CNN) has exceeded that of humans since 2015. CNN is now used to address several tasks including medical issues. We believe that CNN would also have a great impact on the research of stem cell biology. iPSCs are utilized after their differentiation to specific cells, which are characterized by molecular techniques such as immunostaining or lineage tracing. Each cell shows a characteristic morphology; thus, a morphology-based identification system of cell type by CNN would be an alternative technique. The development of CNN enables the automation of identifying cell types from phase contrast microscope images without molecular labeling, which will be applied to several researches and medical science. Image classification is a strong field among deep learning tasks, and several medical tasks will be solved by deep learning-based programs in the future.

DOI： 10.1186/s41232-019-0103-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Periprocedural stroke is a rare but life-threatening complication of percutaneous coronary intervention (PCI). Transradial intervention (TRI) is more beneficial than transfemoral intervention for periprocedural bleeding and acute kidney injuries, but its effect on periprocedural stroke has not been fully investigated. Our study aimed to assess risk predictors of periprocedural stroke according to PCI access site. METHODS AND RESULTS: Between 2008 and 2016, 17 966 patients undergoing PCI were registered in a prospective multicenter database. Periprocedural stroke was defined as loss of neurological function caused by an ischemic or hemorrhagic event with residual symptoms lasting at least 24 hours after onset. Periprocedural stroke was observed in 42 patients (0.3%). Stroke patients were older and had a higher incidence of chronic kidney disease, peripheral artery disease, and acute coronary syndrome but were less likely to undergo TRI. Multivariable logistic regression analysis revealed TRI (odds ratio; 0.33; 95% CI, 0.16-0.71; P=0.004) was significantly associated with a lower occurrence of periprocedural stroke. Finally, propensity score-matching analysis showed that TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention (0.1% versus 0.4%; P=0.014). According to our sensitivity analysis, this finding was robust to the presence of an unmeasured confounder in almost all plausible scenarios. CONCLUSIONS: TRI was associated with a reduced risk of periprocedural stroke compared with transfemoral intervention. Increased TRI use may reduce overall PCI complications and should be recommended as the optimal access site for both urgent/emergent and elective PCIs.

DOI： 10.1161/CIRCINTERVENTIONS.118.006761

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Excessive daytime sleepiness (EDS) is a significant public health concern, with sleep-disordered breathing (SDB) being a common cause. However, their precise relationship in patients with cardiovascular disease (CVD) is unclear. Furthermore, whether comorbid psychological disorders could contribute to EDS remains unknown. We aimed to assess the prevalence of EDS and its related factors, including SDB and depression, in patients with CVD.Methods and Results:We analyzed data from 1,571 patients admitted for various CVDs in a single university hospital (median age, 67 [56-76] years; 29.6% women). We assessed EDS using the Japanese version of the Epworth Sleepiness Scale (ESS; median 6.0 [4.0-9.0]). The presence of EDS (ESS >10, n=297 [18.9%]) did not differ between patients with and without SDB, which was screened with nocturnal pulse oximetry. In contrast, the patients with EDS had higher depression scores (Hospital Anxiety and Depression Scale subscore for depression [HADS-D] and Patient Healthcare Questionnaire [PHQ]-9). The depression scores, measured by HADS-D (odds ratio [OR] 1.14; 95% confidence interval [CI], 1.07-1.22) and PHQ-9 (OR, 1.14; 95% CI, 1.07-1.20) were independent determinants of EDS. These relationships among EDS, SDB, and depression were consistent among the subgroups with cardiovascular comorbidities. CONCLUSIONS: The presence of EDS is associated with depressive symptoms, but not with SDB, in patients with CVD, suggesting that these patients should be thoroughly assessed for psychological disturbances.

DOI： 10.1253/circj.CJ-17-1395

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Deep learning technology is rapidly advancing and is now used to solve complex problems. Here, we used deep learning in convolutional neural networks to establish an automated method to identify endothelial cells derived from induced pluripotent stem cells (iPSCs), without the need for immunostaining or lineage tracing. Networks were trained to predict whether phase-contrast images contain endothelial cells based on morphology only. Predictions were validated by comparison to immunofluorescence staining for CD31, a marker of endothelial cells. Method parameters were then automatically and iteratively optimized to increase prediction accuracy. We found that prediction accuracy was correlated with network depth and pixel size of images to be analyzed. Finally, K-fold cross-validation confirmed that optimized convolutional neural networks can identify endothelial cells with high performance, based only on morphology.

DOI： 10.1016/j.stemcr.2018.04.007

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 < 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 > 0.75, p < 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 < 0.001), ΔR in V1 + S in V5 (R = 0.476, p < 0.001), and ΔP wave in II (R = 0.511, p < 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.

DOI： 10.1016/j.ijcha.2018.05.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. The gene-body regions (GBRs) of some cardiomyocyte (CM)-specific genes are long and highly hypomethylated in CMs. To explore the cell-type specificities of epigenetic patterns and functions, multiple epigenetic modifications of GBRs were compared among CMs, liver cells and embryonic stem cells (ESCs). RESULTS: We found that most genes show a moderately negative correlation between transcript levels and gene lengths. As CM-specific genes are generally longer than other cell-type-specific genes, we hypothesized that the gene-body epigenetic features of CMs may support the transcriptional regulation of CM-specific genes. We found gene-body DNA hypomethylation in a CM-specific gene subset co-localized with rare gene-body marks, including RNA polymerase II (Pol II) and p300. Interestingly, 5-hydroxymethylcytosine (5hmC) within the gene body marked cell-type-specific genes at neonatal stages and active gene-body histone mark H3K36 trimethylation declined and overlapped with cell-type-specific gene-body DNA hypomethylation and selective Pol II/p300 accumulation in adulthood. Different combinations of gene-body epigenetic modifications were also observed with genome-wide scale cell-type specificity, revealing the occurrence of dynamic epigenetic rearrangements in GBRs across different cell types. CONCLUSIONS: As 5hmC enrichment proceeded to hypomethylated GBRs, we considered that hypomethylation may not represent a static state but rather an equilibrium state of turnover due to the balance between local methylation linked to transcription and Tet oxidative modification causing demethylation. Accordingly, we conclude that demethylation in CMs can be a used to establish such cell-type-specific epigenetic domains in relation to liver cells. The establishment of cell-type-specific epigenetic control may also change genomic contexts of evolution and may contribute to the development of cell-type-specific transcriptional coordination.

DOI： 10.1186/s12864-018-4752-4

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There is a growing interest in the optimizing care of acute coronary syndrome (ACS) in young patients, largely owing to their potential for longer life expectancy. Herein, we aimed to investigate the clinical characteristics and outcome of young ACS patients (e.g. under 60 year old) from a Japanese multicenter percutaneous coronary intervention (PCI) registry (KiCS-PCI). KiCS-PCI registered consecutive ACS patients from 15 institutions, and 1560 (24.0%) out of 6499 ACS-related PCI involved patients aged <60 years. In this group, prevalence of dyslipidemia, smoking and family history of premature coronary artery disease (CAD) was higher, while the other classical risk factors were lower when compared to the old patients. After adjustment for known confounders, presentation with cardiogenic shock (CS) before PCI (OR 32.57, 95% CI 12.06-87.97), culprit lesion of LMT (OR 7.53, 95% CI 1.26-44.98), multi-vessel disease (OR 3.82, 95% CI 1.37-10.63) and higher body mass index (OR 1.12, 95% CI 1.00-1.24) showed association with higher in-hospital mortality in young patients. Multi-vessel disease (OR 4.1, 95% CI 1.9-8.9) and chronic kidney disease (OR 3.56, 95% CI 2.26-5.68) were associated with CS presentation. CS presentation was inversely associated with classical risk factors such as hypertension (OR 0.61, 95% CI 0.38-0.96), family history of CAD (OR 0.49, 95% CI 0.25-0.96), and dyslipidemia (OR 0.45, 95% CI 0.29-0.71) and culprit lesion of RCA (OR 0.60, 95% CI 0.37-0.94). Overall, ACS in the younger population was observed frequently, accounting for a quarter of ACS-related PCI. CS was a harbinger for in-hospital mortality in these patients.

DOI： 10.1007/s12928-017-0471-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: To assess patient perspectives on secondary lifestyle modification and knowledge of 'heart attack' after percutaneous coronary intervention (PCI) for coronary artery disease (CAD). DESIGN: Observational cross-sectional study. SETTING: A single university-based hospital centre in Japan. PARTICIPANTS: In total, 236 consecutive patients with CAD who underwent PCI completed a questionnaire (age, 67.4±10.1 years; women, 14.8%; elective PCI, 75.4%). The survey questionnaire included questions related to confidence levels about (1) lifestyle modification at the time of discharge and (2) appropriate recognition of heart attack symptoms and reactions to these symptoms on a four-point Likert scale (1=not confident to 4=completely confident). PRIMARY OUTCOME MEASURE: The primary outcome assessed was the patients' confidence level regarding lifestyle modification and the recognition of heart attack symptoms. RESULTS: Overall, patients had a high level of confidence (confident or completely confident,>75%) about smoking cessation, alcohol restriction and medication adherence. However, they had a relatively low level of confidence (<50%) about the maintenance of blood pressure control, healthy diet, body weight and routine exercise (≥3 times/week). After adjustment, male sex (OR 3.61, 95% CI 1.11 to 11.8) and lower educational level (OR 3.25; 95% CI 1.70 to 6.23) were identified as factors associated with lower confidence levels. In terms of confidence in the recognition of heart attack, almost all respondents answered 'yes' to the item 'I should go to the hospital as soon as possible when I have a heart attack'; however, only 28% of the responders were confident in their ability to distinguish between heart attack symptoms and other conditions. CONCLUSIONS: There were substantial disparities in the confidence levels associated with lifestyle modification and recognition/response to heart attack. These gaps need to be studied further and disseminated to improve cardiovascular care.

DOI： 10.1136/bmjopen-2017-019119

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1161/CIRCHEARTFAILURE.117.004764

PubMed

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Objectives: To evaluate whether repeated brain natriuretic peptide (BNP) measurements after percutaneous transluminal septal myocardial ablation (PTSMA) provide prognostic information regarding the response to PTSMA in patients with drug-refractory hypertrophic obstructive cardiomyopathy (HOCM). Background: Plasma BNP levels are associated with clinical outcomes in patients with HOCM. However, the prognostic value of plasma BNP level changes before and after PTSMA remains unclear. Methods: We measured the plasma BNP levels serially before and after PTSMA, and evaluated the relationship between the changes in plasma BNP levels and clinical improvement in 47 patients. The patients were assigned to two groups based on the reduction in the New York Heart Association class ≥1 (good responder) or <1 (poor responder) before and after PTSMA. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status. Results: The plasma BNP levels gradually decreased after PTSMA, although the levels plateaued 3 months until 12 months after PTSMA. Although the plasma BNP levels and resting left ventricular outflow tract peak pressure gradient before PTSMA were comparable between the groups, the ratio of the BNP levels before and after PTSMA in the good responder group was significantly lower than that in the poor responder group (0.43 (range, 0.24-0.68) vs 0.78 (range, 0.62-0.93), p=0.002). The KCCQ score changes in the good responder group were significantly higher than those in the poor responder group. Conclusions: The plasma BNP level ratio was associated with long-term clinical improvement of heart failure after PTSMA for drug-refractory HOCM.

DOI： 10.1136/openhrt-2018-000786

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Despite the ever-increasing complexity of percutaneous coronary intervention (PCI), the incidence, predictors, and in-hospital outcomes of catheter-induced coronary artery dissection (CICAD) is not well defined. In addition, there are little data on whether persistent coronary flow impairment after CICAD will affect clinical outcomes. We evaluated 17,225 patients from 15 participating hospitals within the Japanese PCI registry from January 2008 to March 2016. Associations between CICAD and in-hospital adverse cardiovascular events were evaluated using multivariate logistic regression. Outcomes of patients with CICAD with or without postprocedural flow impairment (TIMI flow ≤ 2 or 3, respectively) were analyzed. The population was predominantly male (79.4%; mean age, 68.2 ± 11.0 years); 35.6% underwent PCI for complex lesions (eg. chronic total occlusion or a bifurcation lesion.). CICAD occurred in 185 (1.1%), and its incidence gradually decreased (p < 0.001 for trend); postprocedural flow impairment was observed in 43 (23.2%). Female sex, complex PCI, and target lesion in proximal vessel were independent predictors (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.53-3.10; OR, 2.19; 95% CI, 1.58-3.04; and OR, 1.55; 95% CI, 1.06-2.28, respectively). CICAD was associated with an increased risk of in-hospital adverse events (composite of new-onset cardiogenic shock and new-onset heart failure) regardless of postprocedural flow impairment (OR, 10.9; 95% CI, 5.30-22.6 and OR, 2.27; 95% CI, 1.20-4.27, respectively for flow-impaired and flow-recovered CICAD). In conclusion, CICAD occurred in roughly 1% of PCI cases; female sex, complex PCI, and proximal lesion were its independent risk factors. CICAD was associated with adverse in-hospital cardiovascular events regardless of final flow status. Our data implied that the appropriate selection of PCI was necessary for women with complex lesions.

DOI： 10.1371/journal.pone.0204333

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Percutaneous coronary intervention (PCI) is widely used; however, factors of high-cost care after PCI have not been thoroughly investigated. We sought to evaluate the in-hospital costs related to PCI and identify predictors of high costs. METHODS: We extracted 2,354 consecutive PCI cases (1,243 acute cases, 52.8%) from 3 Japanese cardiovascular centers from 2011 to 2015. In-hospital complications were predefined under consensus definitions (eg, acute kidney injury [AKI]). We extracted the facility cost data for each patient's resource under the universal Japanese insurance system. We classified the patients into total cost quartiles and identified predictors for the highest quartile ("high-cost" group). In addition, incremental costs for procedure-related complications were calculated. RESULTS: During the study period, a total of 401 cases (17.0%) experienced procedure-related complications. The in-hospital acute and elective PCI costs per case were US $14,840 (interquartile range [IQR] 11,370-20,070) and US $11,030 (IQR 8929-14,670), respectively. After adjusting for baseline differences, any of the procedure-related complications remained an independent predictor of high costs (acute: odds ratio 1.66, 95% CIs 1.13-2.43; elective: odds ratio 3.73, 95% CIs 1.96-7.11). Notably, incremental costs were mainly attributed to AKI, which accounted for 37.5% of all incremental costs; it increased by US $9,840 for each AKI event, and the total cost increase reached US $2,588,035. CONCLUSIONS: Procedure-related complications, particularly postprocedural AKI, were associated with higher costs in PCI. Further studies are required to evaluate prospectively whether the preventive strategy with a personalized risk stratification for AKI could save costs.

DOI： 10.1016/j.ahj.2017.08.008

PubMed

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語  

The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3. ES cells containing a triple knockout in the DNA methyltransferases Dnmt1, Dnmt3a, and Dnmt3b showed correlation between the fluctuation of Pou5f1, Zfp42, and Nanog gene expression. We suggest that an epigenetic barrier is key to preventing the propagation of fluctuating pluripotency gene expression in ES cells.

DOI： 10.1002/1873-3468.12791

PubMed

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Door-to-balloon (DTB) time ≤90 min is an important quality indicator in the management of ST-elevation myocardial infarction (STEMI), but a considerable number of patients still do not meet this goal, particularly in countries outside the USA and Europe.Methods and Results:We analyzed 2,428 STEMI patients who underwent primary PCI ≤12 h of symptom onset who were registered in an ongoing prospective multicenter database (JCD-KiCS registry), between 2008 and 2013. We analyzed both the time trend in DTB time within this cohort in the registry, and independent predictors of delayed DTB time >90 min. Median DTB time was 90 min (IQR, 68-115 min) during the study period and there were no significant changes with year. Predictors for delay in DTB time included peripheral artery disease, prior revascularization, off-hour arrival, age >75 years, heart failure at arrival, and use of IABP or VA-ECMO. Notably, high-volume PCI-capable institutions (PCI ≥200/year) were more adept at achieving shorter DTB time compared with low-volume institutions (PCI <200/year). CONCLUSIONS: Half of the present STEMI patients did not achieve DTB time ≤90 min. Targeting the elderly and patients with multiple comorbidities, and PCI performed in off-hours may aid in its improvement.

DOI： 10.1253/circj.CJ-16-0905

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD.

DOI： 10.1038/srep44312

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Andersen-Tawil syndrome (ATS) is a rare inherited channelopathy. The cardiac phenotype in ATS is typified by a prominent U wave and ventricular arrhythmia. An effective treatment for this disease remains to be established. We reprogrammed somatic cells from three ATS patients to generate induced pluripotent stem cells (iPSCs). Multi-electrode arrays (MEAs) were used to record extracellular electrograms of iPSC-derived cardiomyocytes, revealing strong arrhythmic events in the ATS-iPSC-derived cardiomyocytes. Ca2+ imaging of cells loaded with the Ca2+ indicator Fluo-4 enabled us to examine intracellular Ca2+ handling properties, and we found a significantly higher incidence of irregular Ca2+ release in the ATS-iPSC-derived cardiomyocytes than in control-iPSC-derived cardiomyocytes. Drug testing using ATS-iPSC-derived cardiomyocytes further revealed that antiarrhythmic agent, flecainide, but not the sodium channel blocker, pilsicainide, significantly suppressed these irregular Ca2+ release and arrhythmic events, suggesting that flecainide's effect in these cardiac cells was not via sodium channels blocking. A reverse-mode Na+/Ca2+exchanger (NCX) inhibitor, KB-R7943, was also found to suppress the irregular Ca2+ release, and whole-cell voltage clamping of isolated guinea-pig cardiac ventricular myocytes confirmed that flecainide could directly affect the NCX current (INCX). ATS-iPSC-derived cardiomyocytes recapitulate abnormal electrophysiological phenotypes and flecainide suppresses the arrhythmic events through the modulation of INCX.

DOI： 10.1016/j.bbrep.2017.01.002

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ijcard.2016.11.052

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sleep-disordered breathing (SDB) or short sleep duration and coronary artery disease (CAD) are related, yet, the prevalence of SDB and short sleep duration as well as their mechanism remain unknown. Enhanced vascular inflammation is also implicated as one of the pathophysiologic mechanisms in CAD. The aims of this study were to evaluate the prevalence of patients with SDB and short sleep duration, and to examine their relationship with serum C-reactive protein (CRP) level in CAD patients. METHODS AND RESULTS: We evaluated 161 CAD patients who underwent percutaneous coronary intervention, using nocturnal pulse oximetry, a non-invasive screening method for nocturnal intermittent hypoxia. Based on three percent oxygen desaturation index (3% ODI), the patients were divided into nocturnal intermittent hypoxia (3% ODI ≥ 15; n = 45) and control groups (3% ODI < 15, n = 116). The nocturnal intermittent hypoxia group had higher body mass index and serum CRP level compared with the control group. Short sleep duration (<6 h, n = 45) was also associated with increased CRP level compared with the control group (≥6 h, n = 116). In multiple regression analysis, nocturnal intermittent hypoxia (β = 0.332, 95% confidence interval [CI] 0.102-0.562, P = 0.005) and short sleep duration (β = 0.311, 95% CI 0.097-0.526, P = 0.005) were both independent determinants for log serum CRP level. CONCLUSIONS: Nocturnal intermittent hypoxia and short sleep duration were independently associated with elevated serum CRP level in CAD patients, suggesting that both SDB and sleep shortage are associated with enhanced inflammation in CAD patients. SDB and sleep duration may be important modifiable factors in the clinical management of patients with CAD.

DOI： 10.1016/j.sleep.2016.09.012

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Long QT Syndrome (LQTS) is well characterized inheritable, life threatening disease, and often related to large pedigrees of family history. The present study established induced pluripotent stem cell (iPSC) from the patients with LQTS, and investigated whether the LQTS patient-derived iPSCs can be utilized for disease characterization, and drug response. We reprogrammed patient somatic cells, differentiated cardiomyocytes and examined electrophysiological properties. Genotype analysis showed the heterozygote mutation in KCNQ1 gene, 1893delC, indicating that this patient was type 1 LQTS. Drug response examination using multielectrode analysis (MEA) revealed the LQTS-iPSC-derived cardiomyocytes revealed IKs disturbance, but not IKr. Electrophysiological recording confirmed 1893delC has a dominant negative role in IKs channel function by trafficking defect. Isoproterenol induced ventricular tachycardia-like arrhythmia. This study provides the evidences that iPSCs can be utilized for characterization, drug response, and diagnosis for patients with LQTS to conduct medical therapies. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.PL

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

SCN5A is abundant in heart and has a major role in INa. Loss-of-function mutation in SCN5A results in Brugada syndrome (BrS), which causes sudden death in adults. It remains unclear why disease phenotype does not manifest in the young even though mutated SCN5A is expressed in the young. The aim of the present study is to elucidate the timing of the disease manifestation in BrS. A gain-of-function mutation in SCN5A also results in Long QT syndrome type 3 (LQTS3), leading to sudden death in the young. Induced pluripotent stem cells (iPSCs) were generated from a patient with a mixed phenotype of LQTS3 and BrS with the E1784K SCN5A mutation. Here we show that electrophysiological analysis revealed that LQTS3/BrS iPSC-derived cardiomyocytes recapitulate the phenotype of LQTS3 but not BrS. Each β-subunit of the sodium channel is differentially expressed in embryonic and adult hearts. SCN3B is highly expressed in embryonic hearts and iPSC-derived cardiomyocytes. A heterologous expression system revealed that INa of mutated SCN5A is decreased and SCN3B augmented INa of mutated SCN5A. Knockdown of SCN3B in LQTS3/BrS iPSC-derived cardiomyocytes successfully unmasked the phenotype of BrS. Isogenic control of LQTS3/BrS (corrected-LQTS3/BrS) iPSC-derived cardiomyocytes gained the normal electrophysiological properties.

DOI： 10.1038/srep34198

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Besides its potent plasma cholesterol-lowering activity, statin treatment has several other important effects, including lowering high-sensitive C-reactive protein (hs-CRP), levels, and stabilizing risk factors of atherosclerosis, thereby reducing the risk of cardiovascular events. Our aim in this study was to identify how intensive statin therapy can affect plasma levels of inflammatory markers over the long term. METHODS AND RESULTS: We used a prospective, randomized, open blinded-endpoint design. A total of 30 patients with stable coronary artery disease treated with everolimus-eluting stent implantation were randomized to receive rosuvastatin 2.5 (standard therapy group) or 10 mg (intensive therapy group) for 12 months. Plasma levels of hs-CRP, pentraxin-3, monocyte chemoattractant protein-1, and CXC chemokine ligand 4 were measured after a percutaneous coronary intervention, at 1, 3, 6, 9, and 12 months. Levels of LDL cholesterol (LDL-C) and HDL cholesterol were also measured. We investigated short-term and long-term clinical outcomes. After 12 months of therapy, the intensive therapy group had lower levels of LDL-C than the standard therapy group. Plasma levels of hs-CRP largely fluctuated in the standard therapy group, whereas they were stable in the intensive therapy group during the follow-up period. There were no significant differences in serum pentraxin-3, monocyte chemoattractant protein-1, and CXC chemokine ligand 4 levels, or in the incidence of any clinical adverse events, between the standard and the intensive therapy groups. CONCLUSION: Intensive rosuvastatin therapy stabilizes hs-CRP levels, but not chemokine levels, besides lowering LDL-C levels. Thus, this therapy may inhibit the progression of atherosclerosis by stably inhibiting the inflammatory cascade.

DOI： 10.1097/MCA.0000000000000375

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記述言語：日本語   出版者・発行元：(公財)日本心臓財団  

動脈管開存(PDA)に対する経カテーテル的閉鎖術には、大きく分けて2種類のデバイスを用いた治療法が行われている。従来より標準的治療法として行われてきたコイル閉鎖術とAMPLAZERTM Duct Occluder(ADO;St.Jude Medical、St.Paul、MN、USA)を用いた閉鎖術である。アンプラッツァー閉鎖術は、その安全性と有用性が評価され、世界的に広く普及してきたが、成人PDA症に対するコイル閉鎖術とアンプラッツァー閉鎖術を比較検討した報告は少ない。そこで、今回われわれは、成人PDAに対するコイル閉鎖術とアンプラッツァー閉鎖術の有効性、安全性についての比較検討を行った。対象は、経カテーテル的閉鎖術を施行した成人PDA患者連続24症例(コイル群11例、アンプラッツァー群13例)。その結果、PDAに対する経カテーテル的閉鎖術は、コイル群、アンプラッツァー群ともに高い成功率(91%vs100%、p=ns)が得られたが、コイル群で残存シャントに関連した溶血を2例に認め、また2例に永続的な残存シャントを認めた。一方、アンプラッツァー群では、全例で完全閉鎖が得られ、溶血をはじめとした合併症は認めなかった。以上より、成人PDAに対する経カテーテル的閉鎖術はいずれの治療法も高い成功率と安全性が得られたが、わが国でもADOが使用可能となった現在では、最小動脈管径が2mm以上のPDAに対しては、ADOを用いたアンプラッツァー閉鎖術が第一選択になり得ると考えられた。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00679&link_issn=&doc_id=20160822330004&doc_link_id=%2Fah2sinzd%2F2016%2F004808%2F007%2F0913-0920%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fah2sinzd%2F2016%2F004808%2F007%2F0913-0920%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   掲載種別：研究論文（学術雑誌）  

PubMed

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Embryonic stem cells (ESCs) are a hallmark of ideal pluripotent stem cells. Epigenetic reprogramming of induced pluripotent stem cells (iPSCs) has not been fully accomplished. iPSC generation is similar to somatic cell nuclear transfer (SCNT) in oocytes, and this procedure can be used to generate ESCs (SCNT-ESCs), which suggests the contribution of oocyte-specific constituents. Here, we show that the mammalian oocyte-specific linker histone H1foo has beneficial effects on iPSC generation. Induction of H1foo with Oct4, Sox2, and Klf4 significantly enhanced the efficiency of iPSC generation. H1foo promoted in vitro differentiation characteristics with low heterogeneity in iPSCs. H1foo enhanced the generation of germline-competent chimeric mice from iPSCs in a manner similar to that for ESCs. These findings indicate that H1foo contributes to the generation of higher-quality iPSCs.

DOI： 10.1016/j.stemcr.2016.04.015

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Introduction: Long QT syndrome type 1 (LQT1) is caused by mutations in KCNQ1 coding slowly-activating delayed-rectifier K+ channels. We identified the novel missense mutation M437V of KCNQ1 in a LQT1 patient. Here, we employed iPS cell (iPSC)-derived cardiomyocytes to investigate electrophysiological properties of the mutant channel and LQT1 cardiomyocytes. Methods: To generate iPSCs from the patient and a healthy subject, peripheral blood T cells were reprogrammed by Sendai virus vector encoding human OCT3/4, SOX2, KLF4, and c-MYC. Cardiomyocytes were prepared from iPSCs and human embryonic stem cells using a cytokine-based two-step differentiation method and were subjected to patch clamp experiments. Results: LQT1 iPSC-derived cardiomyocytes exhibited prolongation of action potential duration (APD), which was due to a reduction of the KCNQ1-mediated current IKs; Na+, Ca2+ and other K+ channel currents were comparable. When expressed in HEK293 and COS7 cells, the mutant KCNQ1 was normally expressed in the plasma membrane but generated smaller currents than the wild type. Isoproterenol significantly prolonged APDs of LQT1 cardiomyocytes, while shortening those of healthy ones. A mathematical model for IKs-reduced human ventricular myocytes reproduced APD prolongation and generation of early afterdepolarizations (EADs) under β-adrenergic stimulation. Conclusions: QT prolongation of the LQT1 patient with the mutation M437V of KCNQ1 was caused by IKs reduction, which may render the patient vulnerable to generation of EADs and arrhythmias.

DOI： 10.1016/j.reth.2015.12.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Human pluripotent stem cells (hPSCs) are uniquely dependent on aerobic glycolysis to generate ATP. However, the importance of oxidative phosphorylation (OXPHOS) has not been elucidated. Detailed amino acid profiling has revealed that glutamine is indispensable for the survival of hPSCs. Under glucose- and glutamine-depleted conditions, hPSCs quickly died due to the loss of ATP. Metabolome analyses showed that hPSCs oxidized pyruvate poorly and that glutamine was the main energy source for OXPHOS. hPSCs were unable to utilize pyruvate-derived citrate due to negligible expression of aconitase 2 (ACO2) and isocitrate dehydrogenase 2/3 (IDH2/3) and high expression of ATP-citrate lyase. Cardiomyocytes with mature mitochondria were not able to survive without glucose and glutamine, although they were able to use lactate to synthesize pyruvate and glutamate. This distinguishing feature of hPSC metabolism allows preparation of clinical-grade cell sources free of undifferentiated hPSCs, which prevents tumor formation during stem cell therapy.

DOI： 10.1016/j.cmet.2016.03.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcin.2015.12.016

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcin.2015.09.025

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記述言語：英語  

DOI： 10.1016/j.ijcard.2015.08.145

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Japan  

Recently, induced pluripotent stem cells (iPSCs) have attracted attention as a novel tool for the modeling of disease because of their potential to reveal new insights that have not been elucidated using animal models. Since iPSC generation was first reported, there have been many efforts to improve the method of generating iPSCs for clinical applications. To date, many methods for iPSC generation have been reported. Each has advantages and disadvantages for the modeling of disease, and thus the most appropriate method differs depending on the intended use of the iPSCs. Additionally, as the study of disease modeling with human iPSCs has progressed, the need to remove uncertainties due to variations in iPSCs cell lines has increasingly focused researchers’ attention on attaining experimental accuracy. Recognition of these uncertainties is important for the advancement of disease modeling studies with iPSCs.

DOI： 10.1007/978-4-431-55966-5_1

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Springer Japan  

Innovation in stem cell biology has greatly impacted on medical researches. The generation of induced pluripotent stem cell (iPSC) established the novel concept not only in regenerative medicine but also disease modelling. There are several reports that disease-specific iPSC-derived cells have recapitulated cellular phenotypes of wide varieties of diseases. The disease-specific iPSCs are utilised to understand unknown pathogenesis by in vitro examination of disease-specific iPSC-derived cells. It is also shown that disease-specific iPSC-derived cells can be applied to high throughput screening for new drugs. Early reports about disease modelling using iPSCs focused on various types of cardiac arrhythmia because it is difficult to model human arrhythmia in animal models such as a genetically engineered mouse and it is relatively clear to show the phenotypes of cardiac arrhythmia in iPSC-derived cardiomyocyte such as abnormal electrophysiological activities. In this chapter, we focus on the conceptual and practical issues about cardiac arrhythmia modelling using disease-specific iPSCs and discuss the future directions.

DOI： 10.1007/978-4-431-55966-5_4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Despite significant advances in medical treatment, cardiovascular disease is still a major cause of morbidity and mortality in advanced countries. To improve the outcome, the further promotion of basic cardiovascular science has a pivotal role for the developing novel therapeutic approach. However, due to the inaccessibility of human heart tissue, we couldn't obtain the sufficient amount of patient's heart tissues. The discovery of human-induced pluripotent stem cells (iPSCs) is highly expected to provide the breakthrough to this obstruction. Through the patient-specific iPSCs-derived cardiomyocytes, we could analyze the patient-specific heart diseases directly and repetitively. Herein we introduce the outline of creation for cardiac disease modeling using patient-specific iPSCs. Within several topics, we present the actual representative methodologies throughout the process from the derivation of cardiomyocytes to those of functional analysis.

DOI： 10.1007/7651_2014_165

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: In patients with hypertrophic obstructive cardiomyopathy (HOCM), left atrial (LA) volume measurement is very important to provide prognostic information. Recent studies demonstrated that multidetector CT (MDCT) is useful to assess the changes in LA volume. Our aim was to examine the utility of a follow-up cardiac MDCT for long-term evaluation of the effect of percutaneous transluminal septal myocardial ablation (PTSMA) on LA volume. METHODS: We studied a consecutive cohort of 20 patients with drug-refractory symptomatic HOCM after PTSMA. We evaluated LA volume analyses with cardiac MDCT on patients who underwent PTSMA as compared to echocardiography. RESULTS: Before PTSMA, 75% of all patients had heart failure-associated symptoms in the New York Heart Association functional class III/IV. All patients experienced relief from heart failure-associated symptoms after PTSMA. Cardiac MDCT showed significant reduction in the index of maximum LA volume during follow-up compared to before PTSMA in the same way as in echocardiography (93.6±34.1 mL/m(2) vs 82.6±35.3 mL/m(2), p=0.035). A Bland-Altman plot showed small mean differences and limits of agreement in the measurements of the index of maximum LA volume before and after PTSMA between echocardiography and MDCT. CONCLUSIONS: The follow-up cardiac MDCT was a useful tool to evaluate the effectiveness of PTSMA on reduction of LA volume. Cardiac MDCT might provide comparable measurements of the LA volume in patients with drug-refractory symptomatic HOCM before and after PTSMA compared to echocardiography.

DOI： 10.1136/openhrt-2015-000359

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, iPSCs have attracted attention as a new source of cells for regenerative therapies. Although the initial method for generating iPSCs relied on dermal fibroblasts obtained by invasive biopsy and retroviral genomic insertion of transgenes, there have been many efforts to avoid these disadvantages. Human peripheral T cells are a unique cell source for generating iPSCs. iPSCs derived from T cells contain rearrangements of the T cell receptor (TCR) genes and are a source of antigen-specific T cells. Additionally, T cell receptor rearrangement in the genome has the potential to label individual cell lines and distinguish between transplanted and donor cells. For safe clinical application of iPSCs, it is important to minimize the risk of exposing newly generated iPSCs to harmful agents. Although fetal bovine serum and feeder cells have been essential for pluripotent stem cell culture, it is preferable to remove them from the culture system to reduce the risk of unpredictable pathogenicity. To address this, we have established a protocol for generating iPSCs from human peripheral T cells using Sendai virus to reduce the risk of exposing iPSCs to undefined pathogens. Although handling Sendai virus requires equipment with the appropriate biosafety level, Sendai virus infects activated T cells without genome insertion, yet with high efficiency. In this protocol, we demonstrate the generation of iPSCs from human peripheral T cells in feeder-free conditions using a combination of activated T cell culture and Sendai virus.

DOI： 10.3791/53225

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記述言語：英語  

DOI： 10.1016/j.ijcard.2015.06.036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcin.2015.05.029

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The precise assemblage of several types of cardiac precursors controls heart organogenesis. The cardiac precursors show dynamic movement during early development and then form the complicated heart structure. However, cardiomyocyte movements inside the newly organized mammalian heart remain unclear. We previously established the method of ex vivo time-lapse imaging of the murine heart to study cardiomyocyte behavior by using the Fucci (fluorescent ubiquitination-based cell cycle indicator) system, which can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei in living cardiomyocytes as red, green, and yellow, respectively. Global analysis of gene expression in Fucci green positive ventricular cardiomyocytes confirmed that cell cycle regulatory genes expressed in G1/S, S, G2/M, and M phase transitions were upregulated. Interestingly, pathway analysis revealed that many genes related to the cell cycle were significantly upregulated in the Fucci green positive ventricular cardiomyocytes, while only a small number of genes related to cell motility were upregulated. Time-lapse imaging showed that murine proliferating cardiomyocytes did not exhibit dynamic movement inside the heart, but stayed on site after entering the cell cycle.

DOI： 10.1016/j.bbrc.2015.07.036

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The generation of induced pluripotent stem cells (iPSCs) has opened up a new scientific frontier in medicine. This technology has made it possible to obtain pluripotent stem cells from individuals with genetic disorders. Because iPSCs carry the identical genetic anomalies related to those disorders, iPSCs are an ideal platform for medical research. The pathophysiological cellular phenotypes of genetically heritable heart diseases such as arrhythmias and cardiomyopathies, have been modeled on cell culture dishes using disease-specific iPSC-derived cardiomyocytes. These model systems can potentially provide new insights into disease mechanisms and drug discoveries. This review focuses on recent progress in cardiovascular disease modeling using iPSCs, and discusses problems and future perspectives concerning their use.

DOI： 10.3390/ijms160818894

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記述言語：英語  

DOI： 10.1038/ncomms8295

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記述言語：英語  

DOI： 10.1016/j.ijcard.2015.02.054

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Duchenne muscular dystrophy (DMD) is a chronic and life-threatening disease that is initially supported by muscle regeneration but eventually shows satellite cell exhaustion and muscular dysfunction. The life-long maintenance of skeletal muscle homoeostasis requires the satellite stem cell pool to be preserved. Asymmetric cell division plays a pivotal role in the maintenance of the satellite cell pool. Here we show that granulocyte colony-stimulating factor receptor (G-CSFR) is asymmetrically expressed in activated satellite cells. G-CSF positively affects the satellite cell population during multiple stages of differentiation in ex vivo cultured fibres. G-CSF could be important in developing an effective therapy for DMD based on its potential to modulate the supply of multiple stages of regenerated myocytes. This study shows that the G-CSF-G-CSFR axis is fundamentally important for long-term muscle regeneration, functional maintenance and lifespan extension in mouse models of DMD with varying severities.

DOI： 10.1038/ncomms7745

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The proportion of elderly acute coronary syndrome (ACS) patients who receive optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) and whether OMT affects their long-term outcomes remain unclear. We retrospectively investigated 405 ACS patients who underwent stent implantation between 2005 and 2009, and compared the outcomes between patients <80 years of age vs. ≥80 years of age. The prescription rate of the recommended medical agents for ACS in both groups during hospitalization and 2 years after admission was also retrieved. Among the enrolled study population, 75 patients (19%) were aged ≥80 years. These elderly patients had a higher 2-year mortality compared with patients aged <80 years group. The prescription rate of beta-blockers, angiotensin-blocking drugs, and statins tended to be lower in patients aged ≥80 years than in those aged <80 years. Furthermore, among patients ≥80 years of age, those who received OMT had better clinical outcome of 2-year mortality compared to those without OMT. Elderly patients with ACS treated by PCI are at substantially higher risk of adverse events than younger patients. However, they are less likely to receive OMT. PCI with OMT might improve the clinical outcomes of elderly ACS patients.

DOI： 10.1007/s00380-014-0474-y

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記述言語：英語  

DOI： 10.1016/j.ijcard.2014.12.078

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with β-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients.

DOI： 10.1074/jbc.M114.593384

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

There exist circadian patterns in the occurrence of sudden cardiac death. The suprachiasmatic nuclei is the 'master clock' in mammalian bodies. Furthermore, several circadian genes have been successfully isolated in basic studies and a huge variety of key players form the human circadian rhythm. Obvious circadian patterns are present in the occurrence of critical events, but those characteristics differ greatly according to each disease. In this review we summarized the current understanding of the basic mechanism and association with specific cardiovascular diseases that demonstrate a circadian onset of fatal events. We also summarized the recent deep understanding of sleep-disordered breathing. The close relationship between sleep-disordered breathing and cardiovascular diseases may provide us with the possibility of a novel intervention against sudden cardiac death.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mitochondrial diseases are heterogeneous disorders, caused by mitochondrial dysfunction. Mitochondria are not regulated solely by nuclear genomic DNA but by mitochondrial DNA. It is difficult to develop effective therapies for mitochondrial disease because of the lack of mitochondrial disease models. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major mitochondrial diseases. The aim of this study was to generate MELAS-specific induced pluripotent stem cells (iPSCs) and to demonstrate that MELAS-iPSCs can be models for mitochondrial disease. We successfully established iPSCs from the primary MELAS-fibroblasts carrying 77.7% of m.3243A>G heteroplasmy. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.

DOI： 10.1016/j.fob.2015.03.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cardiac regenerative therapy with human pluripotent stem cells (hPSCs), such as human embryonic stem cells and induced pluripotent stem cells, has been hampered by the lack of efficient strategies for expanding functional cardiomyocytes (CMs) to clinically relevant numbers. The development of the massive suspension culture system (MSCS) has shed light on this critical issue, although it remains unclear how hPSCs could differentiate into functional CMs using a MSCS. The proliferative rate of differentiating hPSCs in the MSCS was equivalent to that in suspension cultures using nonadherent culture dishes, although the MSCS provided more homogeneous embryoid bodies (EBs), eventually reducing apoptosis. However, pluripotent markers such as Oct3/4 and Tra-1-60 were still expressed in EBs 2 weeks after differentiation, even in the MSCS. The remaining undifferentiated stem cells in such cultures could retain a strong potential for teratoma formation, which is the worst scenario for clinical applications of hPSC-derived CMs. The metabolic purification of CMs in glucose-depleted and lactate-enriched medium successfully eliminated the residual undifferentiated stem cells, resulting in a refined hPSC-derived CM population. In colony formation assays, no Tra-1-60-positive colonies appeared after purification. The nonpurified CMs in the MSCS produced teratomas at a rate of 60%. However, purified CMs never induced teratomas, and enriched CMs showed proper electrophysiological properties and calcium transients. Overall, the combination of a MSCS and metabolic selection is a highly effective and practical approach to purify and enrich massive numbers of functional CMs and provides an essential technique for cardiac regenerative therapy with hPSC-derived CMs.

DOI： 10.5966/sctm.2014-0072

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Despite the accumulating genetic and molecular investigations into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help to elucidate these disease mechanisms; however, cardiomyocytes from patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) potentially hold much promise for deciphering the pathogenesis of HCM. The purpose of this study is to elucidate the interactions between genetic backgrounds and environmental factors involved in the disease progression of HCM. METHODS AND RESULTS: We generated iPSCs from 3 patients with HCM and 3 healthy control subjects, and cardiomyocytes were differentiated. The HCM pathological phenotypes were characterized based on morphological properties and high-speed video imaging. The differences between control and HCM iPSC-derived cardiomyocytes were mild under baseline conditions in pathological features. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. Interestingly, endothelin-1 strongly induced pathological phenotypes such as cardiomyocyte hypertrophy and intracellular myofibrillar disarray in the HCM iPSC-derived cardiomyocytes. We then reproduced these phenotypes in neonatal cardiomyocytes from the heterozygous Mybpc3-targeted knock in mice. High-speed video imaging with motion vector prediction depicted physiological contractile dynamics in the iPSC-derived cardiomyocytes, which revealed that self-beating HCM iPSC-derived single cardiomyocytes stimulated by endothelin-1 showed variable contractile directions. CONCLUSIONS: Interactions between the patient's genetic backgrounds and the environmental factor endothelin-1 promote the HCM pathological phenotype and contractile variability in the HCM iPSC-derived cardiomyocytes.

DOI： 10.1161/JAHA.114.001263

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記述言語：英語  

DOI： 10.1016/j.ijcard.2014.07.211

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mammalian cardiomyocytes withdraw from the cell cycle shortly after birth, although it remains unclear how cardiomyocyte cell cycles behave during development. Compared to conventional immunohistochemistry in static observation, time-lapse imaging can reveal comprehensive data in hard-to-understand biological phenomenon. However, there are no reports of an established protocol of successful time-lapse imaging in mammalian heart. Thus, it is valuable to establish a time-lapse imaging system to enable the observation of cell cycle dynamics in living murine cardiomyocytes. This study sought to establish time-lapse imaging of murine heart to study cardiomyocyte cell cycle behavior. The Fucci (fluorescent ubiquitination-based cell cycle indicator) system can effectively label individual G1, S/G2/M, and G1/S-transition phase nuclei red, green and yellow, respectively, in living mammalian cells, and could therefore be useful to visualize the real-time cell cycle transitions in living murine heart. To establish a similar system for time-lapse imaging of murine heart, we first developed an ex vivo culture system, with the culture conditions determined in terms of sample state, serum concentration, and oxygen concentration. The optimal condition (slice culture, oxygen concentration 20%, serum concentration 10%) successfully mimicked physiological cardiomyocyte proliferation in vivo. Time-lapse imaging of cardiac slices from E11.5, E14.5, E18.5, and P1 Fucci-expressing transgenic mice revealed an elongated S/G2/M phase in cardiomyocytes during development. Our time-lapse imaging of murine heart revealed a gradual elongation of the S/G2/M phase during development in living cardiomyocytes.

DOI： 10.1016/j.yjmcc.2014.03.020

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記述言語：英語  

DOI： 10.1016/j.ijcard.2014.04.032

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jcin.2013.08.020

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DOI： 10.1016/j.ijcard.2014.03.057

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

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 PGD(2) biosynthesis. We examined a downstream mechanism of cardioprotection elicited by PGD(2) biosynthesis. Acute PGD(2) treatment did not protect hearts against I/R injury. We then speculated that PGD(2) and its metabolite 15-deoxy-Δ12,14-PGJ(2) 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 PGD(2) receptors (ie, DP1 and DP2) in the heart but abundant expression of PGF(2α) receptor (FP), which binds PGF(2α) and PGD(2) with equal affinity. Glucocorticoids also failed to induce the expression of L-PGDS-dependent Nrf2 target genes in FP-knockout hearts. PGD(2) acted through its metabolite 15-deoxy-Δ12,14-PGJ(2) 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, PGD(2) 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 PGD(2) (15-deoxy-Δ12,14-PGJ(2)) as another mechanism by which glucocorticoids induce cardioprotection.

DOI： 10.1161/HYPERTENSIONAHA.113.01639

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Transradial cardiac catheterization (TRCC) has unique technical challenges such as access difficulty related to anatomical variations and/or radial artery (RA) spasm. We sought to evaluate the incidence of anatomical variations of the RA and whether they would affect RA spasm and procedural achievement of TRCC. A total of 744 consecutive patients who underwent TRCC were analyzed by routine radial arteriography. Anatomical variations were defined as abnormal origin of the RA and/or radioulnar loop and/or tortuous configuration. RA spasm was defined as >75 % stenosis at first radial arteriography. Overall, anatomical variations were noted in 68 patients (9.1 %), including 39 cases of abnormal origin (5.2 %), 11 cases of radioulnar loop (1.5 %), and 42 cases of tortuous configuration (5.6 %). Transradial procedures failed in 26 patients (3.5 %), and more frequently in patients with anatomical variation than in those with normal anatomy (23.5 % vs 1.5 %, P < 0.001). Importantly, on multivariate analysis the presence of anatomical variation was a distinct predictor of transradial procedure failure (odds ratio (OR) 17.80; 95 % CI 7.55-43.73; P < 0.001). RA spasm was observed in 83 patients (11.2 %), and more frequently in patients with anatomical variation than in those with normal anatomy (35.3 % vs 8.7 %, P < 0.001). Anatomical variation (OR 4.74; 95 % CI 2.61-8.47; P < 0.001) and female gender (OR 2.23; 95 % CI 1.01-4.73; P = 0.041) were distinct predictors of RA spasm. Anatomical variations were observed in 9.1 % of the patients, and strongly correlated with RA spasm and procedural achievement of TRCC.

DOI： 10.1007/s00380-013-0324-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

DOI： 10.1371/journal.pone.0112900

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記述言語：英語  

DOI： 10.1016/j.ijcard.2013.12.045

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem cells (iPSCs) have been proposed as novel cell sources for genetic disease models and revolutionary clinical therapies. Accordingly, human iPSC-derived cardiomyocytes are potential cell sources for cardiomyocyte transplantation therapy. We previously developed a novel generation method for human peripheral T cell-derived iPSCs (TiPSCs) that uses a minimally invasive approach to obtain patient cells. However, it remained unknown whether TiPSCs with genomic rearrangements in the T cell receptor (TCR) gene could differentiate into functional cardiomyocyte in vitro. To address this issue, we investigated the morphology, gene expression pattern, and electrophysiological properties of TiPSC-derived cardiomyocytes differentiated by floating culture. RT-PCR analysis and immunohistochemistry showed that the TiPSC-derived cardiomyocytes properly express cardiomyocyte markers and ion channels, and show the typical cardiomyocyte morphology. Multiple electrode arrays with application of ion channel inhibitors also revealed normal electrophysiological responses in the TiPSC-derived cardiomyocytes in terms of beating rate and the field potential waveform. In this report, we showed that TiPSCs successfully differentiated into cardiomyocytes with morphology, gene expression patterns, and electrophysiological features typical of native cardiomyocytes. TiPSCs-derived cardiomyocytes obtained from patients by a minimally invasive technique could therefore become disease models for understanding the mechanisms of cardiac disease and cell sources for revolutionary cardiomyocyte therapies.

DOI： 10.1371/journal.pone.0085645

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recently, induced pluripotent stem cells (iPSCs) were established as promising cell sources for revolutionary regenerative therapies. The initial culture system used for iPSC generation needed fetal calf serum in the culture medium and mouse embryonic fibroblast as a feeder layer, both of which could possibly transfer unknown exogenous antigens and pathogens into the iPSC population. Therefore, the development of culture systems designed to minimize such potential risks has become increasingly vital for future applications of iPSCs for clinical use. On another front, although donor cell types for generating iPSCs are wide-ranging, T cells have attracted attention as unique cell sources for iPSCs generation because T cell-derived iPSCs (TiPSCs) have a unique monoclonal T cell receptor genomic rearrangement that enables their differentiation into antigen-specific T cells, which can be applied to novel immunotherapies. In the present study, we generated transgene-free human TiPSCs using a combination of activated human T cells and Sendai virus under defined culture conditions. These TiPSCs expressed pluripotent markers by quantitative PCR and immunostaining, had a normal karyotype, and were capable of differentiating into cells from all three germ layers. This method of TiPSCs generation is more suitable for the therapeutic application of iPSC technology because it lowers the risks associated with the presence of undefined, animal-derived feeder cells and serum. Therefore this work will lead to establishment of safer iPSCs and extended clinical application.

DOI： 10.1371/journal.pone.0097397

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記述言語：英語   掲載種別：論文集(書籍)内論文   出版者・発行元：Humana Press Inc.  

To bring the notion of cardiac regenerative medicine to fruition, researchers have tried to determine which stem cells, embryonic stem (ES) cells or somatic stem cells, are most suitable. Thus far, there is no clear indication which is better, because both have their own advantages and disadvantages. In 2006, murine induced pluripotent stem (iPS) cells were first established. Since then, basic research into the properties of iPS cells has continued apace. Originally, human iPS cells were generated from dermal fibroblasts by retrovirus-mediated gene transfer. Although this technique is sophisticated and easy to perform, the skin biopsy is accompanied by some bleeding and pain, and there may be some damage to the host genome because of retrovirus-mediated transgene integration. However, methods of producing iPS cells have improved steadily. For clinical application in the cardiovascular field, efficient methods that produce pluripotent stem cells that can differentiate into cardiomyocytes need to be developed. Existing methods for ES cells can be applied to iPS cells to obtain cardiomyocyte differentiation. In addition, existing purification methods can be used to obtain pure cardiomyocytes from a population of mixed cells. These techniques have themselves been the subject of extensive research, and continued advances are now making the clinical application of pluripotent stem cells a reality. We are at the forefront of medical innovations in the cardiovascular field based on the use of pluripotent stem cells.

DOI： 10.1007/978-1-62703-417-3_10

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A looped brachiocephalic trunk may cause transradial coronary angiography (TRA) failure with a right radial approach. The prevalences of aortic aneurysm (AA) and a looped brachiocephalic trunk are closely related to increased age. OBJECTIVE: The aim of this study was to clarify the relationship between AA and a looped brachiocephalic trunk. PATIENTS AND METHODS: A total of 1306 consecutive patients who underwent TRA through the right radial artery at Keio University Hospital between January 2007 and December 2011 were examined retrospectively. A looped brachiocephalic trunk was defined as the presence of a full 360° loop in the 45° left anterior oblique view requiring a change in the access site to the left radial or femoral artery. RESULTS: Of the 1306 patients who underwent TRA at Keio University Hospital between January 2007 and December 2011, 137 had AA. The patients were divided into two groups: patients with a looped brachiocephalic trunk and those without it. Patients in the looped brachiocephalic group were older and had a higher BMI. The prevalence of hypertension was higher in the looped brachiocephalic trunk group. Creatinine clearance was lower in patients with a looped brachiocephalic trunk than in those without a looped brachiocephalic trunk. Multivariate analysis showed that AA was an independent predictor of a looped brachiocephalic trunk. CONCLUSION: AA is a predictor of a looped brachiocephalic trunk that should be considered in patients undergoing TRA.

DOI： 10.1097/MCA.0b013e3283650254

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00380-013-0364-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Periprocedural myocardial infarction (pMI) is an important complication associated with percutaneous coronary intervention (PCI). However, data on the frequency of biomarker testing and the incidence of pMI remain unclear. Using the multicenter Japan Cardiovascular Database, we identified 2182 patients who underwent PCI without preprocedural cardiac biomarker elevation (silent ischemia, stable angina, or unstable angina without biomarker elevation) from September 2008 to August 2011. Of these, 550 patients (25.2 %) underwent cardiac biomarker testing within 6-24 h after PCI. The incidence of pMI was 2.7 % among all identified patients and 7.5 % among those who underwent cardiac marker testing. Of note, cardiac biomarker testing was performed more frequently than no testing in patients with a higher risk profile such as unstable angina (32.7 vs 24.7 %, P < 0.001), higher symptom scaling (28.2 vs 22.5 %, P = 0.008), urgent or emergent procedures (19.3 vs 15.0 %, P = 0.022 or 4.2 vs 1.0 %, P < 0.001, respectively), and type C lesion (31.3 vs 25.2 %, P = 0.006). Presentation with silent ischemia (odds ratio = 1.51, 95 % confidence interval (CI) 1.16-1.97) and nonemergent PCIs (odds ratio = 3.45, 95 % CI 1.79-6.67) were associated with no postprocedural cardiac biomarker testing. The real-world multicenter PCI registry in Japan revealed an incidence of 2.7 % for pMI; however, cardiac biomarkers were assessed in only 25.2 % of patients after PCI. The results suggest an underuse of postprocedural biomarker testing and room for procedural quality improvement, particularly in cases of silent ischemia and nonemergent cases.

DOI： 10.1007/s00380-012-0314-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Transcatheter closure of secundum atrial septal defect (ASD) has been widely performed as a less invasive alternative to surgery with zero mortality so far in Japan. In the US and Europe, intracardiac echocardiography (ICE) has replaced transesophageal echocardiography (TEE) as a primary imaging tool during percutaneous ASD closure. However, the experience of ICE in ASD closure is limited in Japan. Consecutive 51 patients underwent percutaneous ASD closure with ICE guidance. Clinical results were compared to those of 41 patients who underwent ASD closure with TEE guidance. Pediatric patients and patients with multiple ASDs who were expected to need multiple devices were excluded. Success rate was similar in both groups (ICE 96.1 %, TEE 92.7 %). Catheterization laboratory time was significantly shortened with ICE than with TEE (131 vs. 155 min, p = 0.0003). There were no complications related to the use of ICE. ICE-guided ASD closure is feasible in most adult patients. ICE is superior to TEE in shortening catheterization laboratory time and eliminating general anesthesia, and can potentially replace TEE as the primary image guide during percutaneous ASD closure.

DOI： 10.1007/s12928-013-0187-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG.

DOI： 10.1093/hmg/ddt210

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記述言語：英語  

DOI： 10.1016/j.yjmcc.2013.05.008

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Heart disease remains a leading cause of death worldwide. Owing to the limited regenerative capacity of heart tissue, cardiac regenerative therapy has emerged as an attractive approach. Direct reprogramming of human cardiac fibroblasts (HCFs) into cardiomyocytes may hold great potential for this purpose. We reported previously that induced cardiomyocyte-like cells (iCMs) can be directly generated from mouse cardiac fibroblasts in vitro and vivo by transduction of three transcription factors: Gata4, Mef2c, and Tbx5, collectively termed GMT. In the present study, we sought to determine whether human fibroblasts also could be converted to iCMs by defined factors. Our initial finding that GMT was not sufficient for cardiac induction in HCFs prompted us to screen for additional factors to promote cardiac reprogramming by analyzing multiple cardiac-specific gene induction with quantitative RT-PCR. The addition of Mesp1 and Myocd to GMT up-regulated a broader spectrum of cardiac genes in HCFs more efficiently compared with GMT alone. The HCFs and human dermal fibroblasts transduced with GMT, Mesp1, and Myocd (GMTMM) changed the cell morphology from a spindle shape to a rod-like or polygonal shape, expressed multiple cardiac-specific proteins, increased a broad range of cardiac genes and concomitantly suppressed fibroblast genes, and exhibited spontaneous Ca(2+) oscillations. Moreover, the cells matured to exhibit action potentials and contract synchronously in coculture with murine cardiomyocytes. A 5-ethynyl-2'-deoxyuridine assay revealed that the iCMs thus generated do not pass through a mitotic cell state. These findings demonstrate that human fibroblasts can be directly converted to iCMs by defined factors, which may facilitate future applications in regenerative medicine.

DOI： 10.1073/pnas.1304053110

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記述言語：日本語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The long QT syndrome type 2 (LQT2) is inheritable life threatening arrhythmic disorder and one of the most common genetic variants in long QT syndrome. There are some indications for treatment of the patients with LQT2 but it is impossible to completely prevent fatal arrhythmia. To develop novel therapy for the patients with LQT2, it has been desired to generate diseasespecific and patient-specific disease model. Human induced pluripotent stem (iPS) cells are somatic cell-derived pluripotent stem cells with infinite proliferation ability and multipotency. Patient-specific iPS cells can be derived from patient somatic cells, have all genomic information encoded in patient's genome including mutation and all SNPs, and can be ideal disease models of the patients. To generate disease model for LQT2 by iPS cells, we should firstly generate iPS cells from the patient with LQT2 and confirm the genomic mutation in iPS cells. In this study, we showed the successful generation of iPS cells from a patient with KCNH2 G603D mutation. The patient specific iPS cells properly expressed stem cell markers, such as NANOG and OCT3/4. We also confirmed that the KCNH2 G603D (G1808A) mutation was taken over in patient specific iPS cells. These patient-specific iPS cells may contribute to the future analysis for disease pathogenesis and drug innovation.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Heart disease remains a major cause of death despite advances in medical technology. Heart-regenerative therapy that uses pluripotent stem cells (PSCs) is a potentially promising strategy for patients with heart disease, but the inability to generate highly purified cardiomyocytes in sufficient quantities has been a barrier to realizing this potential. Here, we report a nongenetic method for mass-producing cardiomyocytes from mouse and human PSC derivatives that is based on the marked biochemical differences in glucose and lactate metabolism between cardiomyocytes and noncardiomyocytes, including undifferentiated cells. We cultured PSC derivatives with glucose-depleted culture medium containing abundant lactate and found that only cardiomyocytes survived. Using this approach, we obtained cardiomyocytes of up to 99% purity that did not form tumors after transplantation. We believe that our technological method broadens the range of potential applications for purified PSC-derived cardiomyocytes and could facilitate progress toward PSC-based cardiac regenerative therapy.

DOI： 10.1016/j.stem.2012.09.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Apical ballooning syndrome (ABS) is uniquely characterized by the acute onset of transient extensive kinesis of the apical and mid portions of the left ventricle without significant epicardial coronary artery stenosis, accompanied by chest symptoms and electrocardiogram changes similar to those of acute coronary syndrome. We report a case of ABS with severe coronary artery stenosis presenting as acute coronary syndrome after emotional stress. ABS should be considered a cause of left ventricular wall motion abnormalities even if a coronary arteriogram shows severe coronary artery stenosis.

DOI： 10.1007/s00380-012-0242-9

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記述言語：英語   出版者・発行元：JAPANESE PHARMACOLOGICAL SOC  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem cell (iPSC) technology has great potential to establish novel therapeutic approaches in regenerative medicine and disease analysis. Although cell therapy using iPSC-derived cells still has many hurdles to overcome before clinical applications, disease analysis using patient-specific iPSCs may be of practical use in the near future. There are several reports that patient-specific iPSC-derived cells have recapitulated the apparent cellular phenotypes of a wide variety of diseases. Moreover, some studies revealed that it could be possible to discover effective new drugs and to clarify disease pathogenesis by examination of patient-specific iPSC-derived cells in vitro. We have recently reported that iPSCs can be a diagnostic tool in a patient with a novel mutation. For definitive diagnosis in a patient with long QT syndrome who had an uncharacterized genetic mutation, we succeeded in clarifying the patient's cellular electrophysiologic characteristics and the molecular mechanism underlying the disease phenotype through the multifaceted analyses of patient-specific iPSC-derived cardiomyocytes. In this review, we focus on the conceptual and practical issues in disease modeling using patient-specific iPSCs and discuss future directions in this research field.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Patient-specific induced pluripotent stem (iPS) cells can be generated by introducing transcription factors that are highly expressed in embryonic stem (ES) cells into somatic cells. This opens up new possibilities for cell transplantation-based regenerative medicine by overcoming the ethical issues and immunological problems associated with ES cells. Despite the development of various methods for the generation of iPS cells that have resulted in increased efficiency, safety, and general versatility, it remains unknown which types of iPS cells are suitable for clinical use. Therefore, the aims of the present study were to assess (1) the differentiation potential, time course, and efficiency of different types of iPS cell lines to differentiate into cardiomyocytes in vitro and (2) the properties of the iPS cell-derived cardiomyocytes. We found that high-quality iPS cells exhibited better cardiomyocyte differentiation in terms of the time course and efficiency of differentiation than low-quality iPS cells, which hardly ever differentiated into cardiomyocytes. Because of the different properties of the various iPS cell lines such as cardiac differentiation efficiency and potential safety hazards, newly established iPS cell lines must be characterized prior to their use in cardiac regenerative medicine.

DOI： 10.1155/2013/659739

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記述言語：英語   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MicroRNAs (miRNAs) play a pivotal role during embryonic development and are required for proper organogenesis, including hematopoiesis. Recent studies suggest that, in the early mesoderm, there is an interaction between the hematopoietic and cardiac lineages. However, whether miRNAs can affect other lineages remains unknown. Therefore, we investigated whether hematopoietic miR-142-3p modulated the mesoderm formation. We report that knockdown (KD) of miR-142-3p, a hematopoietic-specific miRNA, in zebrafish resulted in loss of hematopoiesis during embryonic development. Intriguingly, we observed abnormal cardiac phenotypes and insufficiency of somitegenesis in KD-morphants. In the early developmental stage, a tiny heart, contractile dysfunction in the ventricle, cardiac arrhythmia (e.g. a 2:1 ratio of atrial:ventricular beating), and bradycardia were consistently observed. Histological examination revealed severe hypoplasia of the ventricle and disrupted muscle alignment. To determine the mechanism, we performed DNA microarray analysis. The results revealed that the expression of several mesodermal genes essential for the formation of cardiac and somatic mesoderm, such as no tail, T-box gene 16, mesoderm posterior a, one eye pinhead, and rho-associated, coiled-coil containing protein kinase (Rock2a), were increased in miR-142-3p KD-morphants. The luciferase reporter assay revealed that miR-142-3p repressed luciferase activity on the Rock2a 3'-UTR. The findings of the present study indicate that miR-142-3p plays a critical role in hematopoiesis, cardiogenesis, and somitegenesis in the early stage of mesoderm formation via regulation of Rock2a.

DOI： 10.1016/j.bbrc.2012.07.148

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Long QT syndrome (LQTS) is an inheritable and life-threatening disease; however, it is often difficult to determine disease characteristics in sporadic cases with novel mutations, and more precise analysis is necessary for the successful development of evidence-based clinical therapies. This study thus sought to better characterize ion channel cardiac disorders using induced pluripotent stem cells (iPSCs). METHODS AND RESULTS: We reprogrammed somatic cells from a patient with sporadic LQTS and from controls, and differentiated them into cardiomyocytes through embryoid body (EB) formation. Electrophysiological analysis of the LQTS-iPSC-derived EBs using a multi-electrode array (MEA) system revealed a markedly prolonged field potential duration (FPD). The IKr blocker E4031 significantly prolonged FPD in control- and LQTS-iPSC-derived EBs and induced frequent severe arrhythmia only in LQTS-iPSC-derived EBs. The IKs blocker chromanol 293B did not prolong FPD in the LQTS-iPSC-derived EBs, but significantly prolonged FPD in the control EBs, suggesting the involvement of IKs disturbance in the patient. Patch-clamp analysis and immunostaining confirmed a dominant-negative role for 1893delC in IKs channels due to a trafficking deficiency in iPSC-derived cardiomyocytes and human embryonic kidney (HEK) cells. CONCLUSIONS: This study demonstrated that iPSCs could be useful to characterize LQTS disease as well as drug responses in the LQTS patient with a novel mutation. Such analyses may in turn lead to future progress in personalized medicine.

DOI： 10.1093/cvr/cvs206

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We describe an 85-year-old woman with severe aortic stenosis, who also had severe coronary artery disease. She suffered from dyspnea on exertion and frequent syncope. Echocardiography revealed an immobile and heavily calcified aortic valve, and coronary angiography revealed two-vessel disease including chronic total occlusion. Open-heart surgery was refused and she was referred to our department. She underwent percutaneous coronary intervention (PCI) for the right coronary artery and left anterior descending artery. Following PCI, percutaneous balloon aortic valvuloplasty (BAV) was performed on the same day. We chose balloons of 15 × 60 mm, 18 × 60 mm, and 20 × 60 mm, respectively. Improvement in the mean aortic valve pressure gradient (PG) and calculated aortic valve area (mean PG 48-23 mmHg, 0.8-1.2 cm(2), respectively) was observed after the final balloon dilatation. No significant complications occurred. The combination of BAV with PCI may be a useful treatment for relief of the associated symptoms of severe aortic stenosis and coronary artery disease, though it does not improve the long-term prognosis.

DOI： 10.1007/s00380-011-0208-3

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記述言語：日本語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We herein describe a 57-year-old man with coronary-pulmonary artery fistulas that had abnormal connections between the left common carotid artery and the left internal mammary artery. The patient was treated with percutaneous coil embolization using antegrade (via the coronary artery) and retrograde (via the pulmonary artery) approaches. Coronary artery fistulas have diverse anatomical variations, and it is important to thoroughly evaluate the anatomy before beginning any mode of treatment, surgical or endovascular. In the case reported herein, multislice computed tomography played a pivotal role in the preprocedure evaluation.

DOI： 10.1007/s00380-011-0172-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

A conus artery is sometimes a good collateral source for the left anterior descending coronary artery and the right coronary artery (RCA). In some cases, the conus artery arises independently of the RCA from a separate orifice, which is called an isolated conus artery. The conus artery is often missed by angiography for RCA if a catheter is deeply engaged. This case report describes a percutaneous coronary intervention of chronic total occlusion of the proximal RCA with good collateral circulation from an isolated conus artery by super-selective ipsilateral injection via the artery.

DOI： 10.1007/s00380-011-0170-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The prevalence of success of percutaneous coronary interventions (PCIs) of chronic total occlusions (CTOs) remains relatively low. We determined the effect of preoperative multidetector computed tomography coronary angiography (CTCA) in PCIs of CTOs. METHODS: The study population was 100 consecutive patients who underwent PCIs of CTOs from January 2005 to December 2007 at Keio University School of Medicine. They were divided into two groups according to the absence (non-CT group, n=60) or presence (CT group, n=40) of preoperative CTCA. The effect of preoperative CTCA was assessed in the prevalence of success of the procedure, prevalence of complications, irradiation time, and the dose of contrast agents. RESULTS: The prevalence of procedural success was similar in both groups (non-CT group vs CT group 80.0% vs 77.5%, p=0.76). Irradiation time and the dose of contrast agents were also similar between these groups. The prevalence of complications was significantly reduced in the CT group (23.3% vs 7.5%, p=0.039), especially coronary perforations, which required treatment only in the non-CT group (10.0% vs 0.0%, p=0.039). Multiple logistic regression analysis revealed that use of a rotablator (odds ratio [OR]: 4.40, 95% confidence interval [CI]: 1.19-16.27, p=0.027) and absence of preoperative CTCA (OR: 4.26, 95% CI: 1.04-17.49, p=0.044) were independent determinants of complications. CONCLUSION: Preoperative CTCA does not affect the prevalence of procedural success, irradiation time and the dose of contrast agents, but may be useful to reduce the prevalence of complications during PCIs of CTOs.

DOI： 10.1016/j.ijcard.2010.10.026

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem cells (iPSCs) have become important cell sources for genetic disease models, and they have the potential to be cell sources for future clinical therapies. However, invasive tissue sampling reduces the number of candidates who consent to donate cells for iPSC generation. In addition, integrated transgenes can potentially insert at inappropriate points in the genome, and in turn have a direct oncogenic effect. Technical modifications using a combination of activated T cells and a temperature-sensitive mutant of Sendai virus (SeV) can avoid invasive tissue sampling and residual transgene issues in generating iPSCs. Such advances may increase the number of consenting patients for cell donations. Here we present a detailed protocol for the generation of iPSCs from a small amount of human peripheral blood using a combination of activated T cells and mutant SeV encoding human OCT3/4, SOX2, KLF4 and c-MYC; T cell-derived iPSCs can be generated within 1 month of blood sampling.

DOI： 10.1038/nprot.2012.015

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記述言語：英語   出版者・発行元：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0735-1097(12)61002-X

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyocyte differentiation from ES cells. Therefore, we investigated when and how Wnt2 acts in cardiogenesis during ES cell differentiation. Wnt2 was strongly expressed in the early developing murine heart. We applied this embryonic Wnt2 expression pattern to ES cell differentiation, to elucidate Wnt2 function in cardiomyocyte differentiation. Wnt2 knockdown revealed that intrinsic Wnt2 was essential for efficient cardiomyocyte differentiation from ES cells. Moreover, exogenous Wnt2 increased cardiomyocyte differentiation from ES cells. Interestingly, the effects on cardiogenesis of intrinsic Wnt2 knockdown and exogenous Wnt2 addition were temporally restricted. During cardiomyocyte differentiation from ES cells, Wnt2 didn't activate canonical Wnt pathway but utilizes JNK/AP-1 pathway which is required for cardiomyocyte differentiation from ES cells. Therefore we conclude that Wnt2 plays strong positive stage-specific role in cardiogenesis through non-canonical Wnt pathway in murine ES cells.

DOI： 10.1016/j.yjmcc.2011.11.010

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記述言語：英語   出版者・発行元：日本成人先天性心疾患学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Takotsubo cardiomyopathy (TC) mimics myocardial infarction and is well defined and known to not only Japan but also western countries. However, whether or not there are differences in the characteristics of TC between Japan and USA remains unknown. PATIENTS: Data for patients who had undergone urgent left heart catheterization for suspected acute coronary syndrome were retrospectively retrieved from Keio University School of Medicine (KUSM) database in Japan and Lahey Clinic Medical Center (LCMC) database in USA between 2002 and 2007. RESULTS: During the study period, 626 coronary angiographies were performed in KUSM and 1,880 coronary angiographies were performed in LCMC. Twelve patients in Japan and 34 patients in USA met the inclusion criteria. Mean age of patients in Japan was 75 years where 92% were women, compared to 67 years and 94% women in USA. Although the prevalence of hypertension, dyslipidemia and diabetes mellitus were similar between Japan and USA, there was a trend towards fewer patients in Japan displaying a history of coronary revascularization. Surprisingly, a family history of premature coronary artery disease (CAD) was present in 21% of USA patients, whereas no patients were present in Japan. There were no differences in the incidence of readmission for heart failure, cardiac death and TC recurrence during the follow-up period. CONCLUSION: Patients with TC in Japan have fewer prior overt CAD and fewer family history of premature CAD, but no significant differences were found in the long-term prognosis and the recurrence rate between patients in Japan and USA.

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Since skin is the most superficial organ, skin aging is a complex process resulting from not only intrinsic factors (passage of time and genetic factors) but also extrinsic factors (UV irradiation and environmental pollutants). Important reasons for skin aging, such as wrinkling, sagging, and laxity, are a decreased number of fibroblasts and decreased synthesis of extracellular proteins in the dermis, as well as increased degradation of the collagenous matrix from UV irradiation and other environmental stresses. Fulvic acid is derived from humic substances, which are formed naturally during the decay of plant and animal residues. Fulvic acid has been shown to have chelating activity, to act as buffer solution, to have antimicrobial activity in vitro and to have an effect in treatment of eczema in vivo. We investigated the effect of fulvic acid on fibroblasts and matrix metalloproteinases (MMPs), which are responsible for degradation of collagen. Normal adult fibroblasts and calcein-AM were used in a cell viability study, and FITC-labeled collagen was used to evaluate MMP activity and inhibitory effect of fulvic acid. A concentration of 1% fulvic acid increased cell viability by 26.1% when compared with a control, and 5% fulvic acid did not show any cytotoxicity. In the presence of 0.25 units of MMP-8, the inhibition of collagen degradation was 47% in 1% fulvic acid (P &lt
0.01) and 61% in 5% fulvic acid (P &lt
0.01), and in the presence of 0.5 units of MMP-8, the inhibition of collagen degradation was 23% in 1% fulvic acid (P &lt
0.01) and 56% in 5% fulvic acid (P &lt
0.01). Our study suggests the possibility of an anti-aging effect of fulvic acid due to an increase in fibroblast viability and a prevention of collagen degradation.

DOI： 10.2336/nishinihonhifu.74.427

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The number of percutaneous coronary interventions (PCI) performed for octogenarians with acute coronary syndrome (ACS) continue to increase. The short- and long-term outcomes of intravascular ultrasound (IVUS)-guided PCI with drug-eluting stents (DES) or bare metal stents (BMS) for ACS in octogenarians, however, remain largely unknown. We analyzed clinical outcomes of octogenarians undergoing IVUS-guided PCI for ACS with either DES or BMS. During the study period, a total of 776 patients with ACS underwent IVUS-guided PCI and 75 of them were octogenarians. In-hospital mortality tended to be lower in the DES group than in the BMS group. Between 6 months and 1 year of follow up, treatment with DES compared with BMS tended to result in fewer target lesion revascularizations. Major adverse cardiac events were similar between patients receiving DES and BMS. In octogenarians with ACS treated with IVUS-guided PCI, DES appears as safe as BMS, providing similar short- and long-term outcomes.

DOI： 10.1177/0003319711403733

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This unit describes a protocol for the generation of induced pluripotent stem (iPS) cells from human peripheral circulating T cells. Initially, human dermal fibroblasts and retroviral vectors were used to generate human iPS cells. Invasive approaches, such as skin biopsy, and genomic insertion of transgenes into the host genome are not appropriate for routine clinical application. Peripheral circulating T cells are readily available from blood samples of patients and healthy volunteers. For the efficient generation of human iPS cells, efficient introduction of the transgene into host cells is necessary. Using a combination of activated T cell culture and Sendai virus allows for the easy and efficient introduction of transgenes into activated T cells and the generation of human iPS cells without genomic integration of extrinsic genes. The T cell-derived iPS (TiPS) cells exhibit monoclonal T cell receptor (TCR) rearrangement in their genome, a hallmark of mature terminally differentiated T cells.

DOI： 10.1002/9780470151808.sc04a03s18

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

After skeletal muscle injury, neutrophils, monocytes, and macrophages infiltrate the damaged area; this is followed by rapid proliferation of myoblasts derived from muscle stem cells (also called satellite cells). Although it is known that inflammation triggers skeletal muscle regeneration, the underlying molecular mechanisms remain incompletely understood. In this study, we show that granulocyte colony-stimulating factor (G-CSF) receptor (G-CSFR) is expressed in developing somites. G-CSFR and G-CSF were expressed in myoblasts of mouse embryos during the midgestational stage but not in mature myocytes. Furthermore, G-CSFR was specifically but transiently expressed in regenerating myocytes present in injured adult mouse skeletal muscle. Neutralization of endogenous G-CSF with a blocking antibody impaired the regeneration process, whereas exogenous G-CSF supported muscle regeneration by promoting the proliferation of regenerating myoblasts. Furthermore, muscle regeneration was markedly impaired in G-CSFR-knockout mice. These findings indicate that G-CSF is crucial for skeletal myocyte development and regeneration and demonstrate the importance of inflammation-mediated induction of muscle regeneration.

DOI： 10.1084/jem.20101059

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: We recently demonstrated that primitive neural crest-derived (NC) cells migrate from the cardiac neural crest during embryonic development and remain in the heart as dormant stem cells, with the capacity to differentiate into various cell types, including cardiomyocytes. Here, we examined the migration and differentiation potential of these cells on myocardial infarction (MI). METHODS AND RESULTS: We obtained double-transgenic mice by crossing protein-0 promoter-Cre mice with Floxed-enhanced green fluorescent protein mice, in which the NC cells express enhanced green fluorescent protein. In the neonatal heart, NC stem cells (NCSCs) were localized predominantly in the outflow tract, but they were also distributed in a gradient from base to apex throughout the ventricular myocardium. Time-lapse video analysis revealed that the NCSCs were migratory. Some NCSCs persisted in the adult heart. On MI, NCSCs accumulated at the ischemic border zone area (BZA), which expresses monocyte chemoattractant protein-1 (MCP-1). Ex vivo cell migration assays demonstrated that MCP-1 induced NCSC migration and that this chemotactic effect was significantly depressed by an anti-MCP-1 antibody. Small NC cardiomyocytes first appeared in the BZA 2 weeks post-MI and gradually increased in number thereafter. CONCLUSIONS: These results suggested that NCSCs migrate into the BZA via MCP-1/CCR2 signaling and contribute to the provision of cardiomyocytes for cardiac regeneration after MI.

DOI： 10.1161/ATVBAHA.110.214726

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mouse embryonic fibroblasts (MEFs) are the most commonly used feeder cells for pluripotent stem cells. However, autogeneic feeder (AF) cells have several advantages such as no xenogeneic risks and reduced costs. In this report, we demonstrate that common marmoset embryonic stem (cmES) cells can be maintained on common marmoset AF (cmAF) cells. These cmES cells were maintained on cmAF cells for 6 months, retaining their morphology, normal karyotype, and expression patterns for the pluripotent markers Oct-3/4, Nanog, SSEA-3, SSEA-4, TRA-1-60, and TRA-1-81, as well as their ability to differentiate into cardiac and neural cells. Antibody array analysis revealed equivalent protein expression profiles between cmES cells maintained on cmAF cells and MEFs. In addition, similarly prepared human embryonic stem (hES) and induced pluripotent stem (hiPS) cell-derived AF cells supported the growth of and maintained the morphology and pluripotent marker expressions of hES and hiPS cells, respectively. DNA microarray analysis revealed that these hES and hiPS cells had mRNA expression profiles similar to those of hES and hiPS cells maintained on MEFs, respectively. Taken together, these findings imply that AF cells can replace MEFs in the routine maintenance of primate pluripotent stem cells.

DOI： 10.1016/j.scr.2010.09.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem (iPS) cells are generated by reprogramming human somatic cells through the forced expression of several embryonic stem (ES) cell-specific transcription factors. The potential of iPS cells is having a significant impact on regenerative medicine, with the promise of infinite self-renewal, differentiation into multiple cell types, and no problems concerning ethics or immunological rejection. Human iPS cells are currently generated by transgene introduction principally through viral vectors, which integrate into host genomes, although the associated risk of tumorigenesis is driving research into nonintegration methods. Techniques for pluripotent stem cell differentiation and purification to yield cardiomyocytes are also advancing constantly. Although there remain some unsolved problems, cardiomyocyte transplantation may be a reality in the future. After those problems will be solved, applications of human iPS cells in human cardiovascular regenerative medicine will be envisaged for the future. Furthermore, iPS cell technology has generated new human disease models using disease-specific cells. This paper summarizes the progress of iPS cell technology in cardiovascular research.

DOI： 10.4061/2011/348960

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The ras-related small G-protein Rad was originally identified from skeletal muscle of patients with type 2 diabetes mellitus. We have recently reported that Rad plays a critical role in generating arrhythmias. The study was aimed to elucidate the role of Rad in intracellular calcium homeostasis. Methods and Reslts: We developed the transgenic mice that overexpress S105N mutant Rad driven by α-myosin heavy chain promoter. We mesure intracellular Ca concentration ([Ca2+]I) from isolated cardiomyocytes by confocal microscopy. The amplitude of [Ca2+]I transient was significantly increased in S105N-Rad-TG cardiomyocytes, compared with littermate. Furthermore, the Ca2+ sparks and the spontaneous Ca2+ waves occurred with greater frequency in S105N-Rad-TG cells, implicating the enhanced activity of SERCA. We recorded L-type calcium currents (ICa-L) and action potentials (APs) from isolated cardiomyocytes using whole cell patch-clamp technique. The peak ICa-L was dramatically larger in the S105N-Rad-TG cells than in littermate. Early afterdepolarization (EAD) and delayed afterdepolarization (DAD) were frequently observed in S105N-Rad-TG. Then, the phosphorylation of RYR2 at Ser2809 and PKA was significantly enhanced in S105N-Rad-TG by Western blot. Conclusions: Our results provided the first evidence that Rad might regulate RYR2 activity possibly via downstream of PKA signaling pathway. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.OP32_5

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The possibility of modeling human diseases has been a potential in regenerative medicine. Disease modeling especially using human induced pluripotent stem (hiPS) cell is highly applicable for the novel approaches to analyze genetic cardiovascular diseases. Although the inherited fatal arrhythmogenic diseases including long QT syndrome (LQTs) have been characterized by their clinical as well as genomic phenotypes, further investigations for elucidation of pathogenesis and development of tailor-maid therapy are highly desired. We generated hiPS cells from healthy volunteers or patients with LQTs by transfecting 4 reprogmming genes such as Oct3/4, Sox2, Klf4, and c-Myc. Stable iPS colonies were screened by immunostaining and RT-PCR of the various stem cell markers, and cardiac differentiation of hiPS cells were made by formation of embryoid bodies. Molecular characterization of hiPS-derived cardiomyocytes was investigated, and action potential was recorded using conventional microelectrode technique. Furthermore, drug sensitivity test was also performed by multi-electrode array systems. HiPS-derived cardiomyocytes of normal volunteers showed the similar characteristics to native cardiomyocytes on expression of cardiac specific-marker genes and electrophysiologic phenotypes. Notably, LQTs model using patient-specific iPS-derived cardiomyocytes showed the characteristic LQTs phenotype, comparing to healthy control, implicating that disease modeling using hiPS cells may play a crucial role for arrhythmia researches including disease mechanisms as well as development of new therapies. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.SY15_5

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記述言語：日本語   出版者・発行元：The Japanese Society of Electrocardiology  

心臓電気生理・不整脈の研究は，従来ヒト以外の生物種の心筋細胞を用いるか，ヒトイオンチャネル遺伝子を心筋以外の細胞株に異所性に発現させて行われてきたが，これらの方法はヒト心筋細胞とは異なる環境下での検討であるということが課題として指摘されていた．ヒトiPS細胞から分化誘導した心筋細胞の樹立により，この問題の克服が期待されている．今回，ヒトiPS細胞から分化誘導した心筋細胞の電気生理学的特性を検討した．ヒト心筋型イオンチャネルmRNAの発現，ヒト心筋型イオン電流記録，自律神経応答，イオンチャネルブロッカーの作用などが確認された．ヒトiPS細胞から分化誘導した心筋様細胞は心筋細胞に近い特性が獲得されているが，結節型，心房筋型，心室筋型が混在すると考えられた．

DOI： 10.5105/jse.31.325

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その他リンク： http://search.jamas.or.jp/link/ui/2011331786

記述言語：英語   出版者・発行元：The Japanese Society of Inflammation and Regeneration  

Pluripotent stem (iPS) cells are a very promising cell source for models of human genetic diseases and revolutionary new therapies. Successful reprogramming of human blood cells has been reported and is likely to advance the clinical application of iPS cells. In terms of a patient's own somatic cells, generating iPS cells from peripheral blood cells has advantages for clinical applications because these cells are an easily accessible cell source. Of the human peripheral blood cells, T cells can be readily cultured in vitro and proliferate rapidly. Furthermore, only a small amount of peripheral blood is needed to generate iPS cells from T cells, thus increasing the number of patients in whom the technique can be used. iPS cells that contain T-cell receptor (TCR) rearrangements in their genome also have the potential to be traceable markers when establishing novel transplantation therapies. The present review summarizes recent progress in the methods used to generate iPS cells and the future potential of human T cell-derived iPS cells.

DOI： 10.2492/inflammregen.31.393

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記述言語：日本語   出版者・発行元：Japan Heart Foundation  

DOI： 10.11281/shinzo.43.10

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その他リンク： http://search.jamas.or.jp/link/ui/2011136804

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Reactive oxygen species (ROS) attack polyunsaturated fatty acids of the membrane and trigger lipid peroxidation, which results in the generation of alpha,beta-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 (>or=20 microM) but had no appreciable cytotoxicity at lower concentrations. Notably, a sublethal concentration (5muM) 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 gamma-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 (4 mg/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.

DOI： 10.1016/j.yjmcc.2010.05.011

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.stem.2010.06.003

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

RATIONALE: The transcriptional networks guiding heart development remain poorly understood, despite the identification of several essential cardiac transcription factors. OBJECTIVE: To isolate novel cardiac transcription factors, we performed gene chip analysis and found that Zac1, a zinc finger-type transcription factor, was strongly expressed in the developing heart. This study was designed to investigate the molecular and functional role of Zac1 as a cardiac transcription factor. METHODS AND RESULTS: Zac1 was strongly expressed in the heart from cardiac crescent stages and in the looping heart showed a chamber-restricted pattern. Zac1 stimulated luciferase reporter constructs driven by ANF, BNP, or alphaMHC promoters. Strong functional synergy was seen between Zac1 and Nkx2-5 on the ANF promoter, which carries adjacent Zac1 and Nkx2-5 DNA-binding sites. Zac1 directly associated with the ANF promoter in vitro and in vivo, and Zac1 and Nkx2-5 physically associated through zinc fingers 5 and 6 in Zac1, and the homeodomain in Nkx2-5. Zac1 is a maternally imprinted gene and is the first such gene found to be involved in heart development. Homozygous and paternally derived heterozygous mice carrying an interruption in the Zac1 locus showed decreased levels of chamber and myofilament genes, increased apoptotic cells, partially penetrant lethality and morphological defects including atrial and ventricular septal defects, and thin ventricular walls. CONCLUSIONS: Zac1 plays an essential role in the cardiac gene regulatory network. Our data provide a potential mechanistic link between Zac1 in cardiogenesis and congenital heart disease manifestations associated with genetic or epigenetic defects in an imprinted gene network.

DOI： 10.1161/CIRCRESAHA.109.214130

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

During a screen for humoral factors that promote cardiomyocyte differentiation from embryonic stem cells (ESCs), we found marked elevation of granulocyte colony-stimulating factor receptor (G-CSFR) mRNA in developing cardiomyocytes. We confirmed that both G-CSFR and G-CSF were specifically expressed in embryonic mouse heart at the midgestational stage, and expression levels were maintained throughout embryogenesis. Intrauterine G-CSF administration induced embryonic cardiomyocyte proliferation and caused hyperplasia. In contrast, approximately 50% of csf3r(-/-) mice died during late embryogenesis because of the thinning of atrioventricular walls. ESC-derived developing cardiomyocytes also strongly expressed G-CSFR. When extrinsic G-CSF was administered to the ESC- and human iPSC-derived cardiomyocytes, it markedly augmented their proliferation. Moreover, G-CSF-neutralizing antibody inhibited their proliferation. These findings indicated that G-CSF is critically involved in cardiomyocyte proliferation during development, and may be used to boost the yield of cardiomyocytes from ESCs for their potential application to regenerative medicine.

DOI： 10.1016/j.stem.2010.01.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Several applications of pluripotent stem cell (PSC)-derived cardiomyocytes require elimination of undifferentiated cells. A major limitation for cardiomyocyte purification is the lack of easy and specific cell marking techniques. We found that a fluorescent dye that labels mitochondria, tetramethylrhodamine methyl ester perchlorate, could be used to selectively mark embryonic and neonatal rat cardiomyocytes, as well as mouse, marmoset and human PSC-derived cardiomyocytes, and that the cells could subsequently be enriched (>99% purity) by fluorescence-activated cell sorting. Purified cardiomyocytes transplanted into testes did not induce teratoma formation. Moreover, aggregate formation of PSC-derived cardiomyocytes through homophilic cell-cell adhesion improved their survival in the immunodeficient mouse heart. Our approaches will aid in the future success of using PSC-derived cardiomyocytes for basic and clinical applications.

DOI： 10.1038/nmeth.1403

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Cardiomyocytes have been induced from various pluripotent cells, such as embryonic stem cells and myeloid stem cells; however, the generation of cardiac tissues beyond two-dimensional cell-sheets has not been reported. Creating higher order, three-dimensional structures that are unique to heart is the long-awaited next step in realizing cardiac regenerative medicine. We have previously shown that cardiomyocytes can be induced in vitro from undifferentiated cells (animal caps) excised from Xenopus embryos. Cardiomyocytes were induced by first dissociating the animal caps and then reaggregating them following treatment with activin. Here, we describe an interesting method for creating a complete ectopic heart in vivo, involving the introduction of in vitro-created tissue during early embryogenesis. Thus, animal cap reaggregates were transplanted into the abdomen of late-neurula-stage embryos, resulting in two-chambered hearts being formed. The dual-heart larvae matured into adult animals with transplanted hearts intact. Involvement of transplanted hearts in systemic circulation was demonstrated. Moreover, the ectopic hearts possessed higher order structures such as atrium and ventricle, and were morphologically, histologically, and electrophysiologically identical to original hearts. This system should facilitate the study of heart organogenesis and may promote a shift from tissue to organ engineering for clinical applications.

DOI： 10.1387/ijdb.093036mk

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Myocardial cell sheets (MCS) are a potentially valuable tool for tissue engineering aimed at heart regeneration. Several methods have recently been established for the fabrication of MCS. However, the lack of a sufficient blood supply has inhibited functional recovery of the MCS. To address this challenge, we combined MCS transplantation with omentopexy (OP), which utilizes omental tissue as a surgical flap. Rats were divided into five groups: sham, myocardial infarction (MI), MCS transplantation, OP, and MCS+OP. Histologic analysis revealed that MCS+OP drastically reversed MI-induced cardiac remodeling. Echocardiography revealed that MCS increased cardiac function, while OP had a synergistic beneficial effect with MCS transplantation. Immunofluorescence imaging showed that OP increased the survival of transplanted cardiomyocytes, and increased the blood supply through enhancement of angiogenesis and migration of small arteries into the MCS. Taken together, we concluded that OP is a promising strategy for the enhancement of graft function in MCS transplantation.

DOI： 10.1016/j.bbrc.2009.07.024

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The lethal ventricular arrhythmia Torsade de pointes (TdP) is the most common reason for the withdrawal or restricted use of many cardiovascular and non-cardiovascular drugs. The lack of an in vitro model to detect pro-arrhythmic effects on human heart cells hinders the development of new drugs. We hypothesized that recently established human induced pluripotent stem (hiPS) cells could be used in an in vitro drug screening model. In this study, hiPS cells were driven to differentiate into functional cardiomyocytes, which expressed cardiac markers including Nkx2.5, GATA4, and atrial natriuretic peptide. The hiPS-derived cardiomyocytes (hiPS-CMs) were analyzed using a multi electrode assay. The application of ion channel inhibitors resulted in dose-dependent changes to the field potential waveform, and these changes were identical to those induced in the native cardiomyocytes. This study shows that hiPS-CMs represent a promising in vitro model for cardiac electrophysiologic studies and drug screening.

DOI： 10.1016/j.bbrc.2009.05.073

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Lipocalin-type prostaglandin D synthase (L-PGDS), which was originally identified as an enzyme responsible for PGD2 biosynthesis in the brain, is highly expressed in the myocardium, including in cardiomyocytes. However, the factors that control expression of the gene encoding L-PGDS and the pathophysiologic role of L-PGDS in cardiomyocytes are poorly understood. In the present study, we demonstrate that glucocorticoids, which act as repressors of prostaglandin biosynthesis in most cell types, upregulated the expression of L-PGDS together with cytosolic calcium-dependent phospholipase A2 and COX2 via the glucocorticoid receptor (GR) in rat cardiomyocytes. Accordingly, PGD2 was the most prominently induced prostaglandin in vivo in mouse hearts and in vitro in cultured rat cardiomyocytes after exposure to GR-selective agonists. In isolated Langendorff-perfused mouse hearts, dexamethasone alleviated ischemia/reperfusion injury. This cardioprotective effect was completely abrogated by either pharmacologic inhibition of COX2 or disruption of the gene encoding L-PGDS. In in vivo ischemia/reperfusion experiments, dexamethasone reduced infarct size in wild-type mice. This cardioprotective effect of dexamethasone was markedly reduced in L-PGDS-deficient mice. In cultured rat cardiomyocytes, PGD2 protected against cell death induced by anoxia/reoxygenation via the D-type prostanoid receptor and the ERK1/2-mediated pathway. Taken together, these results suggest what we believe to be a novel interaction between glucocorticoid-GR signaling and the cardiomyocyte survival pathway mediated by the arachidonic acid cascade.

DOI： 10.1172/JCI37413

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Induced pluripotent stem (iPS) cells have recently been established by transfecting mouse and human fibroblasts with the transcription factors Oct3/4, Sox2, Klf4 and c-Myc, known to be expressed at high levels in embryonic stem (ES) cells. These cells have great potential in regenerative medicine as they have the capacity to differentiate into all three germ layer-derived cells and are syngeneic. The differentiation of ES cells into cardiomyocytes mimics the early processes involved in heart development. Recent studies describe the contribution of various growth factors and corresponding inhibitors to heart development during embryogenesis. Bone morphogenetic proteins, Wnt protein and Notch signals play critical roles in heart development in a context- and time-dependent manner. Consistent with ES cells, the exposure of iPS cells to such growth factors is hypothesized to augment differentiation into cardiomyocytes. The combination of iPS cells and appropriate developmental signal information has the potential for providing the foundations for future regenerative medicine.

DOI： 10.1586/14779072.6.6.803

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Common marmoset monkeys have recently attracted much attention as a primate research model, and are preferred to rhesus and cynomolgus monkeys due to their small bodies, easy handling and efficient breeding. We recently reported the establishment of common marmoset embryonic stem cell (CMESC) lines that could differentiate into three germ layers. Here, we report that our CMESC can also differentiate into cardiomyocytes and investigated their characteristics. After induction, FOG-2 was expressed, followed by GATA4 and Tbx20, then Nkx2.5 and Tbx5. Spontaneous beating could be detected at days 12-15. Immunofluorescent staining and ultrastructural analyses revealed that they possessed characteristics typical of functional cardiomyocytes. They showed sinus node-like action potentials, and the beating rate was augmented by isoproterenol stimulation. The BrdU incorporation assay revealed that CMESC-derived cardiomyocytes retained a high proliferative potential for up to 24 weeks. We believe that CMESC-derived cardiomyocytes will advance preclinical studies in cardiovascular regenerative medicine.

DOI： 10.1016/j.bbrc.2008.02.141

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Severe heart failure is associated with damage to the myocardium that is irreversible with current medical therapies. Recent experimental and clinical studies, however, have opened the possibility of solving many of the associated problems, making this an exciting and tangible goal. There are many potential cell sources for regenerative cardiac medicine, including bone marrow stem cells, endothelial progenitor cells, skeletal myocytes, adult cardiac stem cells, and embryonic stem (ES) cells. Although ES cells are highly proliferative and suitable for mass production, they are not autologous, and an efficient protocol is yet to be established to ensure selective cardiomyocyte induction. Recent studies have successfully established inducible pluripotent stem (iPS) cells from mouse and human fibroblasts by the gene transfer of 4 transcription factors that are strongly expressed in ES cells: Oct3/4, Sox2, Klf4 and c-Myc. iPS cells can differentiate into all 3 germ layer-derived cells and are syngeneic, indicating that they can become an ideal cell source for regenerative medicine. Despite these successes, the accumulating evidence from fields as diverse as developmental biology, stem cell biology and tissue engineering must be integrated to achieve the full potential of cardiac regenerative medicine.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The administration of granulocyte colony-stimulating factor (G-CSF) after myocardial infarction (MI) improves cardiac function and survival rates in mice. It was also reported recently that bone marrow (BM)-derived c-kit(+) cells or macrophages in the infarcted heart are associated with improvement of cardiac remodeling and function. These observations prompted us to examine whether BM-derived hematopoietic cells mobilized by G-CSF administration after MI play a beneficial role in the infarct region. A single hematopoietic stem cell from green fluorescent protein (GFP)-transgenic mice was used to reconstitute hematopoiesis in each experimental mouse. MI was then induced, and the mice received G-CSF for 10 days. In the acute phase, a number of GFP(+) cells showing the elongated morphology were found in the infarcted area. Most of these cells were positive for vimentin and alpha-smooth muscle actin but negative for CD45, indicating that they were myofibroblasts. The number of these cells was markedly enhanced by G-CSF administration, and the enhanced myofibroblast-rich repair was considered to lead to improvements of cardiac remodeling, function, and survival rate. Next, G-CSF-mobilized monocytes were harvested from the peripheral blood of GFP-transgenic mice and injected intravenously into the infarcted mice. Following this procedure, GFP(+) myofibroblasts were observed in the infarcted myocardium. These results indicate that cardiac myofibroblasts are hematopoietic in origin and could arise from monocytes/macrophages. MI leads to the recruitment of monocytes, which differentiate into myofibroblasts in the infarct region. Administration of G-CSF promotes this recruitment and enhances cardiac protection.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. METHODS AND RESULTS: Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein-transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein-expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted <0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and alpha-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and alpha-smooth muscle actin. CONCLUSIONS: We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts.

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeting of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha. Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Disorders of L-type Ca2+ channels can cause severe cardiac arrhythmias. A subclass of small GTP-binding proteins, the RGK family, regulates L-type Ca2+ current (I(Ca,L)) in heterologous expression systems. Among these proteins, Rad (Ras associated with diabetes) is highly expressed in the heart, although its role in the heart remains unknown. Here we show that overexpression of dominant negative mutant Rad (S105N) led to an increase in I(Ca,L) and action potential prolongation via upregulation of L-type Ca2+ channel expression in the plasma membrane of guinea pig ventricular cardiomyocytes. To verify the in vivo physiological role of Rad in the heart, a mouse model of cardiac-specific Rad suppression was created by overexpressing S105N Rad, using the alpha-myosin heavy chain promoter. Microelectrode studies revealed that action potential duration was significantly prolonged with visible identification of a small plateau phase in S105N Rad transgenic mice, when compared with wild-type littermate mice. Telemetric electrocardiograms on unrestrained mice revealed that S105N Rad transgenic mice had significant QT prolongation and diverse arrhythmias such as sinus node dysfunction, atrioventricular block, and ventricular extrasystoles, whereas no arrhythmias were observed in wild-type mice. Furthermore, administration of epinephrine induced frequent ventricular extrasystoles and ventricular tachycardia in S105N Rad transgenic mice. This study provides novel evidence that the suppression of Rad activity in the heart can induce ventricular tachycardia, suggesting that the Rad-associated signaling pathway may play a role in arrhythmogenesis in diverse cardiac diseases.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Embryonic stem (ES) cells cultured on gelatin-coated plates or feeder layers form tight aggregated colonies by the E-cadherin-mediated cell-cell adhesions. Here we show that murine ES cells do not make cell-cell contacts or form colonies when cultured on the plate coated with a fusion protein of E-cadherin and IgG Fc domain. The cells in culture retain all ES cell features including pluripotency to differentiate into cells of all three germ layers and germ-line transmission after extended culture. Furthermore, they show a higher proliferative ability, lower dependency on LIF, and higher transfection efficiency than colony-forming conditions. Our results suggest that aggregated colony formation might inhibit diffusion of soluble factors and increase cell-cell communication, which may result in a heterogeneous environment within and between surrounding cells of the colony. This method should enable more efficient and scalable culture of ES cells, an important step towards the clinical application of these cells.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The avascularity of cardiac valves is abrogated in several valvular heart diseases (VHDs). This study investigated the molecular mechanisms underlying valvular avascularity and its correlation with VHD. Chondromodulin-I, an antiangiogenic factor isolated from cartilage, is abundantly expressed in cardiac valves. Gene targeting of chondromodulin-I resulted in enhanced Vegf-A expression, angiogenesis, lipid deposition and calcification in the cardiac valves of aged mice. Echocardiography showed aortic valve thickening, calcification and turbulent flow, indicative of early changes in aortic stenosis. Conditioned medium obtained from cultured valvular interstitial cells strongly inhibited tube formation and mobilization of endothelial cells and induced their apoptosis; these effects were partially inhibited by chondromodulin-I small interfering RNA. In human VHD, including cases associated with infective endocarditis, rheumatic heart disease and atherosclerosis, VEGF-A expression, neovascularization and calcification were observed in areas of chondromodulin-I downregulation. These findings provide evidence that chondromodulin-I has a pivotal role in maintaining valvular normal function by preventing angiogenesis that may lead to VHD.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The realization of regenerative cardiac medicine depends on the availability of cardiomyocytes in sufficient numbers for transplantation of cardiac tissue and the accompanying blood vessels. Embryonic stem (ES) cells, bone marrow (BM) stem cells, and tissue-derived stem cells are all potential cell sources. Although ES cells are highly proliferative and suitable for mass production, an efficient protocol is yet to be established to ensure selective cardiomyocyte induction using these cells. Recent advances in developmental biology have clarified the involvement of critical factors in cardiomyocyte differentiation, including bone morphogenic protein and Wnt signaling proteins, and such factors have the potential to improve the efficiency of stem cell induction. Initial studies of the intracoronary administration of BM mononuclear cells after myocardial infarction has yielded promising results; however, intensive investigation of the underlying molecular mechanisms at play as well as double-blinded clinical trials will be necessary to establish the extent of both migration of the BM stem cells into the damaged cardiac tissue and their differentiation into cardiomyocytes. Several types of cardiac tissue stem cells have also been reported, but an accurate and extensive comparison of these cells with regard to their characteristics and multipotency remains to be done. An integrative study involving developmental biology, stem cell biology, and tissue engineering is required to achieve the full potential of cardiac regeneration.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Autologous skeletal muscle cell (SM) transplantation into the in vivo heart sometimes induces serious arrhythmias. The purpose of this study was to investigate the electrophysiology of cardiomyocyte (CM) and SM in direct contact and to study the mechanism underlying the cause of arrhythmia using the recently developed cell sheet engineering technique. METHODS: Primary cultured rat neonatal SM and CM were prepared, and cell sheets were fabricated using temperature-responsive culture dishes. The action potential was recorded by a conventional microelectrode. Intracellular calcium concentration and optical mapping image of the action potential were recorded using Fluo-3 and di-4-ANEPPS, respectively. A video motion-detecting system was used for the detection of arrhythmias. RESULTS: SM myotubes occasionally displayed automaticity. SM sheets did not display synchronized contraction, but instead groups of myotubes contracted independently. The action potential of SM, induced by artificial pacing, did not expand to the entire sheet but was limited within a restricted, small area around the electrode, and it was unfeasible to generate an electrical connection or propagate an action potential between CM and SM sheets. SM sheets, in which some of the myotubes displayed automaticity, caused fibrillation-like contraction in the co-cultured CM sheets, and this arrhythmia was specifically blocked by the stretch-activated channel blocker GsMTx-4. CONCLUSIONS: These findings show that SM sheets do not contract synchronously or generate functional syncytia with the surrounding CM sheets and that stretch-induced arrhythmias due to spontaneous contraction of SM may occur in the CM sheet.

PubMed

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記述言語：英語  

Embryonic stem (ES) cells are a promising source of cardiomyocytes, but clinical application of ES cells has been hindered by the lack of reliable selective differentiation methods. Differentiation into any lineage is partly dependent on the regulatory mechanisms of normal early development. Although several signals, including bone morphogenetic protein (BMP), Wnt and FGF, are involved in heart development, scarce evidence is available about the exact signals that mediate cardiomyocyte differentiation. While investigating the involvement of BMP signaling in early heart formation in the mouse, we found that the BMP antagonist Noggin is transiently but strongly expressed in the heart-forming region during gastrulation and acts at the level of induction of mesendoderm to establish conditions conducive to cardiogenesis. We applied this finding to develop an effective protocol for obtaining cardiomyocytes from mouse ES cells by inhibition of BMP signaling.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

We developed a novel simple method for making functional myocardial cell sheets that may be used as transplants. Polymerized human fibrin-coated dishes were prepared with fibrinogen monomers mixed with thrombin. Neonatal rat cardiomyocytes cultured on these dishes formed myocardial cell sheets within 4 days. These cell sheets were easily dissociated intact from the polymerized fibrin layer, because the fibrin had been digested by intrinsic protease. Two overlaid myocardial cell sheets exhibited synchronized spontaneous beating and captured artificial pacing. Optical mapping confirmed that the conduction of the action potential between two partially overlaid myocardial cell sheets was established, and the action potential propagated across the junction without any delay. Transplanted three-layered myocardial cell sheets exhibited strong spontaneous beating and showed well-differentiated striations and an increase in cell size. This simple method of cell sheet engineering may also be applicable for various other cell types.

PubMed

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記述言語：日本語   出版者・発行元：(一社)日本脈管学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Dividing cardiomyocytes are observed in autopsied human hearts following recent myocardial infarction, however there is a lack of information in the literature on the division of these cells. In this study we used a rat model to investigate how and when adult mammalian cardiomyocytes proliferate by cell division after myocardial infarction. Myocardial infarction was induced in Wistar rats by ligation of the left coronary artery. The rats were sacrificed periodically up to 28 days following induced myocardial infarction, and the hearts subjected to microscopic investigation. Cardiomyocytes entering the cell cycle were assayed by observation of nuclear morphology and measuring expression of Ki-67, a proliferating cell marker. Ki-67 positive cardiomyocytes and dividing nuclei were observed initially after 1 day. After 2 days dividing cells gradually increased in number at the ischemic border zone, reaching a peak increase of 1.12% after 3 days, then gradually decreasing in number. Dividing nuclei increased at the ischemic border zone after 3 days, peaked by 0.14% at day 5, and then decreased. In contrast, Ki-67 positive cells and dividing nuclei were limited in number in the non-ischemic area throughout all experiments. In conclusion, mitogenic cardiomyocytes are present in the adult rat heart following myocardial infarction, but were spatially and temporally restricted.

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Gastrointestinal involvement is often seen in patients with systemic lupus erythematosus (SLE). All parts of the gastrointestinal tract may be affected. However, rectal involvement at onset is rare. We describe here a case of SLE in which rectal ulcers due to vasculitis occurred as the initial manifestation of the disease without involvement of any other organ. The ulcers worsened, along with the appearance of lupus nephritis 5 years later. When steroid therapy was initiated, there was rapid clinical and radiographic improvement. Our case suggests that rectal ulcer is a rare but important complication of SLE and can represent the initial and sole clinical manifestation of the disease.

Scopus

PubMed

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

近年の人工知能(AI)の進歩は著しく,さまざまな分野では社会実装されている.これまでの基礎研究におけるAIの利用は,網羅的遺伝子発現解析におけるクラスタリングやゲノム解析などに用いられてきた.AIによる画像認識は顔認識や自動運転など日常生活に広く取り入れられているが,基礎研究においてはあまり用いられてこなかった.基礎研究においては細胞を用いたさまざまな研究がなされており,細胞の種類,形体や状態は主に免疫染色を用いて顕微鏡により観察されている.一方,位相差顕微鏡によっても細胞の特徴を描出することは可能であるが,免疫染色などを用いないと人間が詳細な情報を得ることは困難である.しかし機械学習を用いることにより,位相差顕微鏡画像から多能性幹細胞に由来する分化細胞の種類を自動認識することや,病的細胞の自動判別系を確立することが可能である.これらの技術は今後ますます発展していくことが想定され,AIを用いることで循環器基礎研究も飛躍的に発展していくことが期待される.(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00060&link_issn=&doc_id=20221228010027&doc_link_id=issn%3D0039-2359%26volume%3D283%26issue%3D14%26spage%3D1359&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D283%26issue%3D14%26spage%3D1359&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(公財)日本心臓財団  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：日本語   出版者・発行元：日本心脈管作動物質学会  

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記述言語：日本語   出版者・発行元：(一社)日本老年医学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(公財)大和証券ヘルス財団  

心臓線維芽細胞に発現する転写因子c-Mycの心臓における役割を、single cell解析に基づいて調べ、心臓線維芽細胞が心不全の治療標的となり得るか検証した。心不全時に特異的に出現する心臓線維芽細胞集団を見つけ、その細胞集団ではc-Mycが特徴的に発現していることを見出した。さらに、その線維芽細胞においてc-Mycは心不全の進行に寄与していることが示唆された。一方、c-Mycを心臓線維芽細胞で過剰発現させ、その遺伝子発現を網羅的に解析したところ、その細胞自体は炎症や線維化に関連した遺伝子の発現が低下しており、心不全の進行を抑制する働きが予想された。これらのことから、in vivoではc-Myc陽性心不全特異的心臓線維芽細胞は別の細胞と相互作用することにより、心不全の進行に寄与しているという仮説が立てられた。

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語   出版者・発行元：(有)科学評論社  

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記述言語：日本語   出版者・発行元：(一社)日本成人先天性心疾患学会  

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記述言語：日本語   出版者・発行元：日本内科学会-関東地方会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：日本筋学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：日本語   出版者・発行元：(一社)日本補体学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

DOI： 10.1016/S0735-1097(18)30711-3

Web of Science

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記述言語：日本語   出版者・発行元：(NPO)日本医工学治療学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：英語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語   出版者・発行元：(一社)日本循環器学会  

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記述言語：日本語  

DOI： 10.2169/naika.105.1287

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：英語   出版者・発行元：(一社)日本心血管インターベンション治療学会  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

Web of Science

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：最新医学社  

CiNii Article

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その他リンク： http://search.jamas.or.jp/link/ui/2013318779

記述言語：日本語   出版者・発行元：医歯薬出版  

CiNii Article

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その他リンク： http://search.jamas.or.jp/link/ui/2013226911

記述言語：日本語   出版者・発行元：メディカ出版  

CiNii Article

CiNii Books

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その他リンク： http://search.jamas.or.jp/link/ui/2013172459

記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：医学書院  

CiNii Article

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J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：日本語   出版者・発行元：医学書院  

DOI： 10.11477/mf.1408101965

CiNii Article

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J-GLOBAL

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：日本語   出版者・発行元：学研メディカル秀潤社  

CiNii Article

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(一社)日本不整脈心電学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   掲載種別：書評論文，書評，文献紹介等  

The bone morphogenetic protein (BMP) family is the largest subfamily of the transforming growth factor-beta (TGF-β) superfamily. Some BMPs are expressed before cardioblast formation and throughout the late stages of heart development. BMPs have crucial roles in a broad range of biological events, including cellular proliferation, differentiation, migration and apoptosis during organ development. At least six BMPs (BMP2, 4, 5, 6, 7 and 10) are expressed in the heart, where they have both independent and redundant functions. Experiments on genetically modified mice have demonstrated the importance of BMP signaling for heart morphogenesis after the mid-gestation stage. Interestingly, BMPs play a dual role in heart development. Precise regulation of BMP inhibition and BMP stimulation is required for proper heart development during the early stage of cardiomyocyte differentiation. Knowledge of embryogenesis is frequently used in studies of stem cell biology. Through the application of BMP signal regulation in cardiac development, many systems for the differentiation of embryonic stem (ES) cells into cardiomyocytes are developed. These results reveal the crucial role of temporal and spatial regulation of BMPs and BMP antagonists in heart development. © 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ddstr.2008.12.001

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD  

DOI： 10.1016/j.yjmcc.2008.09.697

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：ELSEVIER SCIENCE INC  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：日本ヒト細胞学会  

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記述言語：日本語   出版者・発行元：日本ヒト細胞学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：LIPPINCOTT WILLIAMS & WILKINS  

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記述言語：日本語   出版者・発行元：(一社)日本心臓病学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：日本語   出版者・発行元：(一社)日本脈管学会  

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記述言語：英語   出版者・発行元：社団法人日本循環器学会  

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記述言語：日本語   出版者・発行元：日本炎症・再生医学会  

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