Japan National Cardiovascular Center Research Institute

Osaka, Japan

Japan National Cardiovascular Center Research Institute

Osaka, Japan
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BACKGROUND—: The genotype-phenotype correlation of SCN5A mutations as a predictor of cardiac events in Brugada syndrome remains controversial. We aimed to establish a registry limited to probands, with a long follow-up period, so that the genotype-phenotype correlation of SCN5A mutations in Brugada syndrome can be examined without patient selection bias. METHODS—: This multicenter registry enrolled 415 probands (n=403; men, 97%; age, 46±14 years) diagnosed with Brugada syndrome whose SCN5A gene was analyzed for mutations. RESULTS—: During a mean follow-up period of 72 months, the overall cardiac event rate was 2.5%/year. Compared with probands without mutations (SCN5A (-), n=355), probands with SCN5A mutations (SCN5A(+), n=60) experienced their first cardiac event at a younger age (34 vs. 42 years, P=0.013), had a higher positive rate of late potentials (89% vs. 73%, P=0.016), exhibited longer P-wave, PQ, and QRS durations, and had a higher rate of cardiac events (P=0.017 by log-rank). Multivariate analysis indicated that only SCN5A mutation and history of aborted cardiac arrest were significant predictors of cardiac events (SCN5A(+) vs. SCN5A(-): hazard ratio, 2.0 and P=0.045; history of aborted cardiac arrest vs. no such history: hazard ratio, 6.5 and P<0.001). CONCLUSIONS—: Brugada syndrome patients with SCN5A mutations exhibit more conduction abnormalities on electrocardiogram and have higher risk for cardiac events. © 2017 by the American College of Cardiology Foundation and the American Heart Association, Inc.


Morooka N.,Japan National Cardiovascular Center Research Institute
Circulation Research | Year: 2017

RATIONALE:: Lymphatic vasculature constitutes a second vascular system, essential for immune surveillance and tissue fluid homeostasis. Maturation of the hierarchical vascular structure, with a highly branched network of capillaries and ducts, is crucial for its function. Environmental cues mediate the remodeling process, but the mechanism that underlies this process is largely unknown. OBJECTIVE:: Polydom (also called Svep1) is an extracellular matrix protein identified as a high-affinity ligand for integrin α9β1. However, its physiological function is unclear. Here, we investigated the role of Polydom in lymphatic development. METHODS AND RESULTS:: We generated Polydom-deficient mice. Polydom mice showed severe edema and died immediately after birth because of respiratory failure. We found that, although a primitive lymphatic plexus was formed, it failed to undergo remodeling in Polydom embryos, including sprouting of new capillaries and formation of collecting lymphatic vessels. Impaired lymphatic development was also observed after knockdown/knockout of polydom in zebrafish. Polydom was deposited around lymphatic vessels, but secreted from surrounding mesenchymal cells. Expression of Foxc2, a transcription factor involved in lymphatic remodeling, was decreased in Polydom mice. Polydom bound to the lymphangiogenic factor Angiopoietin-2, which was found to upregulate Foxc2 expression in cultured lymphatic endothelial cells. Expressions of Tie1/Tie2 receptors for Angiopoietins were also decreased in Polydom mice. CONCLUSIONS:: Polydom affects remodeling of lymphatic vessels in both mouse and zebrafish. Polydom deposited around lymphatic vessels seems to ensure Foxc2 upregulation in lymphatic endothelial cells, possibly via the Angiopoietin-2 and Tie1/Tie2 receptor system. © 2017 American Heart Association, Inc.


Kise K.,Osaka University | Kinugasa-Katayama Y.,Osaka University | Kinugasa-Katayama Y.,Japan National Cardiovascular Center Research Institute | Takakura N.,Osaka University
Advanced Drug Delivery Reviews | Year: 2016

Tumor tissues consist of heterogeneous cancer cells including cancer stem cells (CSCs) that can terminally differentiate into cancer cells. Tissue-specific stem cells in normal organs maintain their stemness in a specific microenvironment, the stem cell niche; several studies have suggested that there are specific microenvironments that maintain CSCs in an immature phenotype. Cell types in a CSC niche vary from fibroblasts, to endothelial cells, immune cells, and so on; these non-cancer cells have been suggested to change their original features in the normal tissue/organ and to acquire a phenotype that protects CSCs from anticancer therapies. Therefore, to kill CSCs, we need to understand the cellular and molecular mechanisms involved in the maintenance of the immature phenotype of CSC. s and in drug resistance. © 2015 Elsevier B.V.


Kitamura S.,Japan National Cardiovascular Center Research Institute
Circulation Journal | Year: 2011

The internal thoracic artery (ITA) has become the gold standard graft material for modern coronary artery bypass grafting (CABG) because of its excellent long-term patency. The use of ITA grafts has also prolonged the postoperative survival of patients when applied to the left anterior descending artery or used bilaterally as 2 grafts for the left coronary system. Moreover, recent large-scale randomized clinical trials comparing the survival rates between CABG and percutaneous coronary intervention (PCI) with stents have shown that CABG is more effective for improving the survival of patients with severe coronary artery disease and/or in those with diabetes mellitus. The fundamental principle underlying these clinical benefits of CABG is the excellent endothelial function of the ITA, which provides physiological and metabolic effects that are beneficial not only for the graft itself, but also for the recipient coronary system. The production of nitric oxide and prostanoids by the ITA endothelium and their beneficial effects on the downstream coronary artery should therefore be taken into consideration when debating the merits of CABG vs. PCI.


Kokubo Y.,Japan National Cardiovascular Center Research Institute
Current Opinion in Neurology | Year: 2012

Purpose of review: Recently, many guidelines have given new evidence on the risk factors for stroke. In this review, I refer to the most important guidelines for primary prevention of stroke and hypertension, especially focused on diet and physical activity. Recent findings: The health behavior recommendations in recent guidelines for the primary prevention of stroke are virtually identical, and the same recommendations appear in the recent guidelines for the management of hypertension, especially with respect to diet and physical activity. The recommended health behaviors consist of weight reduction, reduction of salt intake, increase in fruit and vegetable intake, decrease in saturated and total fat intake (increase in fish intake), physical activity, and moderation of alcohol consumption. Fruits and vegetables have high levels of potassium, antioxidants, phytochemicals, and dietary fiber, and thus are also considered preventive of cardiovascular disease and its risk factors. It was found that individuals with many of these health behaviors have been shown to have a lowered risk of stroke. Summary: The health behaviors, especially those related to diet and physical activity, appearing in recent guidelines for the management of hypertension are also important for the primary prevention of stroke, and appear in recent stroke guidelines. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Ogo T.,Japan National Cardiovascular Center Research Institute
Current Opinion in Pulmonary Medicine | Year: 2015

Purpose of review Chronic thromboembolic pulmonary hypertension (CTEPH), especially when severe in patients unsuited for pulmonary endarterectomy, has a poor prognosis. Balloon pulmonary angioplasty (BPA) is a new catheterbased alternative treatment option for patients with inoperable CTEPH. BPA has not been widely accepted, however, primarily because of possible fatal complications, although effects described in 2001 were encouraging. Recent studies about BPA from Japan and Norway are promising. However, this emerging catheter-based intervention is still considered to be experimental because of a number of concerns and unanswered questions. This review describes the recent progress in BPA at the dawn of a new CTEPH treatment era. Recent findings Recent studies about BPA show consistently beneficial effects in haemodynamics, symptoms, 6-minute walking distance, and biomarkers. Exercise capacity and right ventricular function are also improved by BPA. However, this new technique still has potentially fatal complications, including reperfusion oedema and pulmonary artery perforation, even in recent studies. There remain a number of concerns and unanswered questions about BPA, including indications, best procedural approach, and long-term outcomes. Summary Recent advances in BPA for inoperable CTEPH are promising. Further investigation by multidisciplinary CTEPH teams is mandatory before BPA's role in CTEPH treatment strategies is determined. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Shimizu W.,Japan National Cardiovascular Center Research Institute | Horie M.,Shiga University of Medical Science
Circulation Research | Year: 2011

Since 1995, when a potassium channel gene, hERG (human ether-à-go- go-related gene), now referred to as KCNH2, encoding the rapid component of cardiac delayed rectifier potassium channels was identified as being responsible for type 2 congenital long-QT syndrome, a number of potassium channel genes have been shown to cause different types of inherited cardiac arrhythmia syndromes. These include congenital long-QT syndrome, short-QT syndrome, Brugada syndrome, early repolarization syndrome, and familial atrial fibrillation. Genotype-phenotype correlations have been investigated in some inherited arrhythmia syndromes, and as a result, gene-specific risk stratification and gene-specific therapy and management have become available, particularly for patients with congenital long-QT syndrome. In this review article, the molecular structure and function of potassium channels, the clinical phenotype due to potassium channel gene mutations, including genotype-phenotype correlations, and the diverse mechanisms underlying the potassium channel gene-related diseases will be discussed. © 2011 American Heart Association, Inc.


Hosoda H.,Japan National Cardiovascular Center Research Institute
Methods in enzymology | Year: 2012

Octanoyl modification of ghrelin is rapidly hydrolyzed to des-acyl ghrelin in blood samples. Owing to the increased interest in ghrelin measurement, a standardized method of sample collection is required. This chapter investigates the effect of a variety of anticoagulants and storage conditions on ghrelin stability. Experiment 1 evaluates the effects of anticoagulants on ghrelin measurements. Experiment 2 evaluates the effect of plasma pH on ghrelin stability. Experiment 3 evaluates the mechanisms of degradation of the active form of ghrelin in plasma. Experiment 4 investigates the kinetics of ghrelin following intravenous injection of rat ghrelin. In whole blood and plasma, octanoylated ghrelin is highly unstable. The collection of blood samples with EDTA-aprotinin under cooled conditions was appropriate to maintain ghrelin stability. Acidification of plasma to pH 3-4 and storage at 4°C maintained ghrelin stability. The degradation of ghrelin was shown to be due to the hydrolysis to des-acyl ghrelin. After intravenous administration to rats, plasma ghrelin levels rapidly decreased with a half-life of 8 min. The results showed that the ghrelin values measured in human blood samples were markedly affected by the conditions of collection and storage, the pH, and the RIA method in measurement. Measuring the ghrelin values of the active form is useful for studying plasma ghrelin changes over short time periods. As ghrelin is highly unstable, it is necessary to standardize the preparation of samples to ensure reliable ghrelin measurements. Copyright © 2012 Elsevier Inc. All rights reserved.


Shirai M.,Japan National Cardiovascular Center Research Institute
Circulation research | Year: 2013

Synchrotron radiation (SR) is increasingly being used for micro-level and nano-level functional imaging in in vivo animal experiments. This review focuses on the methodology that enables repeated and regional assessment of vessel internal diameter and flow in the resistance vessels of different organ systems. In particular, SR absorption microangiography approaches offer unique opportunities for real-time in vivo vascular imaging in small animals, even during dynamic motion of the heart and lungs. We also describe recent progress in the translation of multiple phase-contrast imaging techniques from ex vivo to in vivo small-animal studies. Furthermore, we also review the utility of SR for multiple pinpoint (dimensions 0.2×0.2 mm) assessments of myocardial function at the cross-bridge level in different regions of the heart using small-angle X-ray scattering, resulting from increases in SR flux at modern facilities. Finally, we present cases for the use of complementary SR approaches to study cardiovascular function, particularly the pathological changes associated with disease using small-animal models.


Toyoda K.,Japan National Cardiovascular Center Research Institute | Ninomiya T.,Kyushu University
The Lancet Neurology | Year: 2014

Chronic kidney disease, defined as a reduced glomerular filtration rate or increased urinary albumin excretion, is recognised as a rapidly growing global health burden, and increasing evidence suggests that it contributes to the risk and severity of cerebrovascular diseases. In particular, chronic kidney disease is an established risk factor for stroke and is also strongly associated with subclinical cerebrovascular abnormalities and cognitive impairment, partly because it shares several traditional and non-traditional risk factors, and sometimes uraemia-related and dialysis-related factors, with cerebrovascular diseases. The effect of chronic kidney disease on incident stroke differs among regions and races and is greater in Asian than in non-Asian people. Chronic kidney disease seems to be predictive of severe neurological deficits and poor vital and functional outcomes after both ischaemic and haemorrhagic strokes, which is partly due to the limitations of pharmacotherapies, including limited use and effects of novel oral anticoagulants, other antithrombotic treatments, and reperfusion treatment for hyperacute ischaemic stroke. In view of the strong two-way association between stroke and kidney disease, the pathophysiological interactions between the brain and kidney should be the subject of intensive study. © 2014 Elsevier Ltd.

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