Publications (22) View all
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Article: Public access defibrillation improved the outcome after out-of-hospital cardiac arrest in school-age children: a nationwide, population-based, Utstein registry study in Japan.
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ABSTRACT: AIMS: The purpose of this study was to determine whether implementation of public access defibrillation (PAD) improves the outcome after out-of-hospital cardiac arrest (OHCA) in school-age children at national level.METHODS AND RESULTS: We conducted a prospective, nationwide, population-based Japanese Utstein registry study of consecutive OHCA cases in elementary and middle school children (7-15 years of age) who had a bystander-witnessed arrest of presumed cardiac origin during 2005-09 and received pre-hospital resuscitation by emergency responders. The primary endpoint was a favourable neurological outcome 1 month after an arrest. Among 230 eligible patients enrolled, 128 had ventricular fibrillation (VF) as an initial rhythm. Among these 128 patients, 29 (23%) children received a first shock by a bystander. Among these 29 patients, the proportion of the favourable neurological outcome after OHCA was 55%. During the study period, the proportion of patients initially shocked by a bystander among eligible patients increased from 2 to 21% (P = 0.002 for trend). The proportion of patients with a favourable neurological outcome after OHCA increased from 12 to 36% overall (P = 0.006). The collapse to defibrillation time was shorter in bystander-initiated defibrillation when compared with defibrillation by emergency responders (3.3 ± 3.7 vs. 12.9 ± 5.8 min, P < 0.001), and was independently associated with a favourable neurological outcome after OHCA [P = 0.03, odds ratio (OR) per 1 min increase, 0.90 (95% confidence interval 0.82-0.99)]. A non-family member's witness was independently associated with VF as the initial rhythm [P < 0.001, OR 4.03 (2.08-7.80)].CONCLUSION: Implementation of PAD improved the outcome after OHCA in school-age children at national level in Japan.Europace 04/2013; · 1.98 Impact Factor -
Article: Chronic Effects of Pulmonary Artery Stenosis on Hemodynamic and Structural Development of the Lungs.
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ABSTRACT: Pulmonary artery (PA) stenosis is a difficult obstructive defect to manage as clinicians cannot know a priori which obstructions to treat and when. Prognosis of PA stenosis and its chronic effects on lung development are poorly understood. This study aimed to characterize the hemodynamic and structural effects of PA stenosis during development. Fourteen male Sprague-Dawley rats underwent left pulmonary artery (LPA) banding at age 21 days and thirteen underwent sham-operation. Hemodynamic and structural impacts were studied longitudinally at 20, 36, 52, 100 and 160 days. Chronic LPA banding resulted in a significant reduction in LPA flow (p<0.0001) and size of both proximal LPA (p<0.0001) and distal LPA (p<0.01), as well as a significant increase in flow and size of the right pulmonary artery (p<0.05) throughout development. Flows and sizes adapted such that normal levels of wall shear were restored after banding. At 160 days, LPA banding resulted in a significant decrease in left lung volume and an increase in right lung volume but no significant differences in total lung volume. There was an elevation of proximal LPA pressure as well as right ventricular hypertrophy in the banded animals. The banded lung exhibited arterial disorganization, loss of vessels and enlargement of its bronchial arteries, while the contralateral lung showed signs of vascular pathology. There are consequences on development of both lungs in the presence of an LPA stenosis at young age. These results suggest that early intervention may be necessary to optimize left lung growth and minimize right lung vascular pathology.AJP Lung Cellular and Molecular Physiology 10/2012; · 3.66 Impact Factor -
Article: Loss of Adenomatous Poliposis Coli-α3 Integrin Interaction Promotes Endothelial Apoptosis in Mice and Humans.
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ABSTRACT: Rationale: Pulmonary hypertension (PH) is characterized by progressive elevation in pulmonary pressure and loss of small pulmonary arteries. As bone morphogenetic proteins (BMPs) promote pulmonary angiogenesis by recruiting the Wnt/β-catenin pathway, we proposed that βcatenin activation could reduce loss and/or induce regeneration of small PAs and attenuate PH. Objective: This study aims to establish the role of β-catenin in protecting the pulmonary endothelium and stimulating compensatory angiogenesis following injury. Methods and Results: To assess the impact of β-catenin activation on chronic hypoxia-induced PH, we used the adenomatous polyposis coli (Apc(Min/+)) mouse, where reduced APC causes constitutive β-catenin elevation. Surprisingly, hypoxic Apc(Min/+) mice displayed greater PH and small PA loss compared to control C57Bl6J (C57) littermates. Pulmonary artery endothelial cells (PAECs) isolated from Apc(Min/+) demonstrated reduced survival and angiogenic responses along with a profound reduction in adhesion to laminin. The mechanism involved failure of APC to interact with the cytoplasmic domain of the α3 integrin, to stabilize focal adhesions and activate integrin-linked kinase (ILK-1) and pAkt. We found that PAECs from lungs of patients with idiopathic PH have reduced APC expression, decreased adhesion to laminin and impaired vascular tube formation. These defects were corrected in the cultured cells by transfection of APC. Conclusions: We show that APC is integral to PAEC adhesion and survival and is reduced in PAECs from PH patient lungs. The data suggest that decreased APC may be a cause of increased risk or severity of PH in genetically susceptible individuals.Circulation Research 09/2012; · 9.49 Impact Factor -
Article: Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions.
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ABSTRACT: Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastase-specific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease.American Journal Of Pathology 09/2011; 179(3):1560-72. · 4.89 Impact Factor -
Article: Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival.
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ABSTRACT: Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARγ and β-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARγ/β-catenin-dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARγ in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction.The Journal of clinical investigation 08/2011; 121(9):3735-46. · 15.39 Impact Factor
