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Yamamoto K.,Tottori University | Origasa H.,University of Toyama | Hori M.,Japan National Cardiovascular Center Research Institute
European Journal of Heart Failure | Year: 2013

Aims: The therapeutic strategy for heart failure with preserved ejection fraction (HFPEF) has not been established. The Japanese Diastolic Heart Failure Study (J-DHF) is a multicentre, prospective, randomized, open, blinded-endpoint trial, designed to assess the effects of carvedilol in HFPEF patients.Methods and resultsA total of 245 patients with heart failure and ejection fraction >40% were randomly assigned into those treated with (carvedilol group, n = 120) and without carvedilol (control group, n = 125). The primary outcome is a composite of cardiovascular death and unplanned hospitalization for heart failure. During a median follow-up of 3.2 years, the primary endpoint occurred in 29 patients in the carvedilol group and in 34 patients in the control group [adjusted hazard ratio (HR) 0.902, 95% confidence interval (CI) 0.546-1.488, P = 0.6854]. Another major composite endpoint, cardiovascular death and unplanned hospitalization for any cardiovascular causes, occurred in 38 patients of the carvedilol group and 52 patients of the control group (HR 0.768, 95% CI 0.504-1.169; P = 0.2178). The target dose of carvedilol was 20 mg/day, but the median prescribed dose was 7.5 mg/day. In the patients treated with standard doses (carvedilol >7.5 mg/day, n = 58), this composite outcome was significantly less than in the controls (HR 0.539, 95% CI 0.303-0.959; P = 0.0356), whereas it was comparable with the controls in the patients treated with carvedilol ≤7.5 mg/day (n = 62, HR 1.070, 95% CI 0.650-1.763; P = 0.7893).ConclusionsCarvedilol did not improve prognosis of HFPEF patients overall; however, the standard dose, not the low dose, prescription might be effective. This may facilitate further investigation.UMIN number: C000000318. © 2012 The Author.


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.


Sotomi Y.,Japan National Cardiovascular Center Research Institute
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology | Year: 2013

Although several prognostic factors for atrial fibrillation (AF) recurrence after catheter ablation (CA) have been reported, predictors of very late recurrence (VLR; initial recurrence >12 months after ablation) remain unidentified. This study investigated clinical variables predictive of VLR after CA for AF. This retrospective single-centre cohort study evaluated data from 1016 consecutive drug-refractory AF patients who underwent single CA for AF from July 2004 to May 2010. After excluding 324 patients with a short follow-up period (<1 year) and 300 patients with recurrence within a year of CA, 392 patients were included. Study subjects were divided into two groups on the basis of VLR presence. Preoperative clinical variables were evaluated as predictors of VLR using the Cox proportional hazards model. The annual rate of VLR was 7.6% after single CA. Univariate analysis revealed that hypertension [hazard ratio (HR) 1.77, 95% confidence interval (CI) 0.93-3.37, P = 0.08], obesity (HR 1.84, 95% CI 0.98-3.45, P = 0.06), long-standing persistent AF (HR 2.35, 95% CI 1.08-5.11, P = 0.03), and abnormally high preoperative C-reactive protein (CRP) levels >0.5 mg/dL (HR 4.28, 95% CI 2.03-9.03, P < 0.0001) were associated with VLR. In the multivariate model, only abnormally high preoperative CRP level was an independent predictor of VLR (HR 4.9, 95% CI 2.3-10.7, P < 0.0001). Even after a year without AF, VLR occurred annually in 7.6% cases. Continued vigilance for VLR after CA is clinically desirable, especially for patients with abnormally high preoperative CRP levels.


Kobayashi J.,Japan National Cardiovascular Center Research Institute
Vascular Health and Risk Management | Year: 2011

Although porcine aortic valves or pericardial tissue mounted on a stent have made implantation techniques easier, these valves sacrifice orifice area and increase stress at the attachment of the stent, which causes primary tissue failure. Optimizing hemodynamics to prevent patient-prosthetic mismatch and improve durability, stentless bioprostheses use was revived in the early 1990s. The purpose of this review is to provide a current overview of stentless valves in the aortic position. Retrospective and prospective randomized controlled studies showed similar operative mortality and morbidity in stented and stentless aortic valve replacement (AVR), though stentless AVR required longer cross-clamp and cardiopulmonary bypass time. Several cohort studies showed improved survival after stentless AVR, probably due to better hemodynamic performance and earlier left ventricular (LV) mass regression compared with stented AVR. However, there was a bias of operation age and nonrandomization. A randomized trial supported an improved 8-year survival of patients with the Freestyle or Toronto valves compared with Carpentier-Edwards porcine valves. On the contrary, another randomized study did not show improved clinical outcomes up to 12 years. Freedom from reoperation at 12 years in Toronto stentless porcine valves ranged from 69% to 75%, which is much lower than for Carpentier-Edwards Perimount valves. Cusp tear with consequent aortic regurgitation was the most common cause of structural valve deterioration. Cryolife O'Brien valves also have shorter durability compared with stent valves. Actuarial freedom from reoperation was 44% at 10 years. Early prosthetic valve failure was also reported in patients who underwent root replacement with Shelhigh stentless composite grafts. There was no level I or IIa evidence of more effective orifice area, mean pressure gradient, LV mass regression, surgical risk, durability, and late outcomes in stentless bioprostheses. There is no general recommendation to prefer stentless bioprostheses in all patients. For new-generation pericardial stentless valves, follow-up over 15 years is necessary to compare the excellent results of stented valves such as the Carpentier- Edwards Perimount and Hancock II valves. © 2011 Kobayashi, publisher and licensee Dove Medical Press Ltd.


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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