Pulmonary Arterial Pressure Management Based on Oral Medicine for Pediatric Living Donor Liver Transplant With Portopulmonary Hypertension.

Pediatric living donor liver transplantation (LDLT) in patients with advanced portopulmonary hypertension (PoPH) is associated with poor prognoses. Recently, novel oral medications, including endothelin receptor antagonists (ERAs), phosphodiesterase 5 (PDE5) inhibitors, and oral prostacyclin (PGI2) have been used to treat PoPH. Pediatric patients with PoPH who underwent LDLT from 2006 to 2016 were enrolled. Oral pulmonary hypertension (PH) medication was administered to control pulmonary arterial pressure (PAP). Four patients had PoPH. Their ages ranged from 6 to 16 years, and their original diseases were biliary atresia (n = 2), portal vein obstruction (n = 1), and intrahepatic portal systemic shunt (n = 1). For preoperative management, 2 patients received continuous intravenous PGI2 and 2 oral medications (an ERA alone or an ERA and a PDE5 inhibitor), and 2 received only oral drugs (an ERA and a PDE5 inhibitor). One patient managed only with intravenous PGI2 died. In the remaining 3 cases, intravenous PGI2 or NO was discontinued before the end of the first postoperative week. Postoperative medications were oral PGI2 alone (n = 1), an ERA alone (n = 1), or the combination of an ERA and a PDE5 inhibitor (n = 1). An ERA was the first-line therapy, and a PDE5 inhibitor was added if there was no effect. New oral PH medications were effective and safe for use in pediatric patients following LDLT. In particular, these new oral drugs prevent the need for central catheter access to infuse PGI2.

Analysis of public discourse on heart transplantation in Japan using social network service data.

The clarification of public concerns regarding heart transplantation is important for improving low organ donation rates in Japan. In the present study, we used the Twitter data of 4986 tweets (between August 2015 and January 2016) and 1429 tweets (between April 2016 and May 2016) to analyze public discourse on heart transplantation in Japan and identify the reasons for low organ donation rates. We manually categorized all tweets relevant to heart transplantation into nine categories and counted the number of tweets in each category per month. During the study period, the most popular category of tweets was related to the media, followed by money (tweets questioning or even criticizing the high price of fundraising goals to go overseas for heart transplantations), while some tweets were misconceptions. We also conducted a sentiment analysis, which revealed that the most popular negative tweets were related to money, while the most positive tweets were related to reports on the favorable outcomes of recipients. Our results suggest that listening to concerns, providing correct information (particularly for some misconceptions), and emphasizing the outcomes of recipients will facilitate an increase in the number of people contemplating heart transplantation and organ donation.

Brain natriuretic peptide as a hormonal marker of ventricular diastolic dysfunction in children with Kawasaki disease.

Although an increased level of serum brain natriuretic peptide (BNP) has been reported in children in the acute phase of Kawasaki disease (KD), no precise relation was documented between the serum BNP level and left ventricular (LV) systolic function. We hypothesized that the increased BNP levels may be explained by diastolic abnormalities in those with KD. We prospectively studied 25 patients in the acute phase of KD. Patients with abnormal systolic function were excluded. Pediatric cardiologists making the assessment of LV diastolic function were blinded to the BNP levels. Doppler interrogation was applied to measure LV inflow velocities, which were transformed to z scores using control measurements obtained from 83 healthy subjects. In the patients, the BNP levels ranged from 2.0 to 450.0 pg/ml, with a mean of 54.0 +/- 102.8 pg/ml. Six patients with abnormal velocities (> 2 SD in z score) showed significantly higher levels of BNP (152 +/- 173 pg/ml) than those in the remaining patients (p < 0.01). The BNP levels correlated positively with diastolic atrial velocity in z score (r = 0.51, p < 0.05), and negatively with diastolic early velocity to atrial velocity ratio in z score (r = -0.75, p < 0.01). This study suggests that LV diastolic dysfunction may occur in some children in the acute phase of KD, causing an increased level of BNP.

Bidirectional cavopulmonary shunt with right ventricular outflow patency: the impact of pulsatility on pulmonary endothelial function.

OBJECTIVE: Although in vitro studies have suggested the importance of flow pulsatility in endothelial function, few reports have focused on pulmonary endothelial function under decreased pulsatile flow after a bidirectional cavopulmonary shunt with or without an additional pulmonary flow source. The purpose of the present study was to assess the pulmonary endothelial function after bidirectional cavopulmonary shunt. METHODS AND RESULTS: Pulmonary vasodilating response was evaluated in 10 patients 0.4 to 7.0 years (median 1.6 years) after bidirectional cavopulmonary shunt who were provided an additional flow source by retaining the pulmonary outflow tract and in 8 control subjects. Average pulmonary flow velocity was measured with a Doppler flow wire placed in the segmental lower lobe pulmonary artery during incremental infusion of acetylcholine (10(-8), 10(-7), 10(-6), and 10(-5) mol/L) and then of nitroglycerin (0.5 and 1.0 microg. kg(-1). min(-1)) after recovery. In the control subjects, a dose-dependent increase in flow velocity was observed in response to acetylcholine (maximum increase was 155% +/- 17% of baseline) and to nitroglycerin (maximum increase was 151% +/- 20% of baseline). In contrast, patients showed a significantly impaired response to acetylcholine (maximum increase was 124% +/- 17% of baseline; P <.01 vs control), whereas the response to nitroglycerin was preserved (138% +/- 12% of baseline; P =.09 vs control). In addition, the maximum response to acetylcholine correlated significantly with the pulmonary pulse pressure (r = 0.89, P <.01) and with the pulmonary flow pulsatility (r = 0.88, P <.01). CONCLUSIONS: These results clearly suggest that patients after bidirectional cavopulmonary shunt show pulmonary endothelial functional attenuation and, of more importance, that decreased pulsatility of cavopulmonary flow is mainly responsible for this endothelial abnormality.

Pulmonary hypertension associated with postoperative biliary atresia: report of two cases.

The authors report on 2 patients with biliary atresia in whom pulmonary hypertension (PH) developed in the long-term follow-up after hepatoportoenterostomy. Both had portal hypertension and had undergone distal splenorenal shunt. Dyspnea developed around 14 to 15 years of age. Cardiac catheterization showed pulmonary artery pressure (PAP) of 99/37 (58) and 67/32 (48) mm Hg, respectively, which did not respond to vasodilators. One patient suffered from respiratory tract infection followed by right heart failure and subsequent death at 20 years of age. Postmortum histological findings exhibited severe thickening of the pulmonary artery wall. PH may grow insidiously even after successful hepatoportoenterostomy. Careful monitoring of PAP and hemodynamic response of PAP to vasodilators is essential for evaluating the reversibility of PH and making treatment decisions.

Selectin on activated platelets enhances neutrophil endothelial adherence in myocardial reperfusion injury.

OBJECTIVES: The glycoprotein P-selectin is an adhesion molecule that is rapidly expressed on the surface of platelets and endothelium during the inflammatory process. P-selectin on endothelium has been reported to play an important role in reperfusion injury. However, little is known regarding P-selectin on platelets in contributing to the pathophysiology of myocardial reperfusion injury. In this study, we hypothesized that P-selectin on platelets may enhance neutrophil endothelial adherence and this may play a role in neutrophil-mediated reperfusion injury. METHODS: Endothelial cells, cardiomyocytes, platelets and neutrophils were isolated from adult rats. Endothelial cells and cardiomyocytes were cultivated in a co-culture system. After exposure to hypoxia and reoxygenation, neutrophil adherence and migration were examined. RESULTS: After exposure to 6 h of hypoxia, endothelial cells co-incubated with platelets showed significantly greater neutrophil adherence (63.1 +/- 4.0%) and migration (78.2 +/- 6.7%) than endothelial cells alone (adhesion: 44.2 +/- 2.8%, migration: 57.9 +/- 4.9%). These increases were significantly inhibited (adhesion: 42.1 +/- 3.5%, migration: 65.5 +/- 3.8%) by an anti-P-selectin monoclonal antibody. Moreover, the superoxide-anion production was significantly elevated when activated platelets were added to neutrophils. This enhanced production was also inhibited by anti-P-selectin antibody. CONCLUSION: The presence of activated platelets enhanced neutrophil adhesion and migration process after hypoxia reoxygenation. This process may occur following platelet-neutrophil interactions via P-selectin and subsequent neutrophil activation.

Regional left ventricular motion during early filling phase in patients with right ventricular pressure overload.

Global left ventricular (LV) diastolic function has been reported to be disturbed under conditions of right ventricular pressure overload (RVPO). However, from the standpoint of regional wall motion, only a little information related to the mechanism of LV diastolic dysfunction is available. Eight patients with RVPO and 7 healthy volunteers were investigated using tagged cine magnetic resonance imaging. Regional diastolic fraction (RDF) was determined in 4 segments (anterior, lateral, inferior, and septal) in the mid-ventricular short axis section and in 2 segments (septal and lateral) in the 4-chamber section. A heterogeneity index was obtained from the RDFs of the short axis section. In the RVPO group, in both short axis and 4-chamber sections, the RDF of the septal segment was depressed, and it showed an inverse correlation with the right-to-left ventricular systolic pressure (RV/LV) ratio (r = -0.74, p < 0.05) in the short axis section. In the 4-chamber section, the RDF was lower in the septal segment than in the lateral segment (p < 0.05). The heterogeneity index in the RVPO group was greater than that in the control group (p < 0.01). The index correlated positively with the RV/LV ratio (r = 0.77, p < 0.05). The altered regional diastolic motion results in increased heterogeneity in regional diastolic motion.

Hybrid artificial lung with interleukin-10 and endothelial constitutive nitric oxide synthase gene-transfected endothelial cells attenuates inflammatory reactions induced by cardiopulmonary bypass.

BACKGROUND: Recently, the research on hybrid artificial organs such as heart, liver, and kidney has been reported to yield new possibilities for clinical use. However, there have been few reports on the practical use of a hybrid artificial lung, primarily due to difficulties in the concept for its application and techniques for cell attachment. In this study, we investigated the possibility for developing a novel strategy: a hybrid artificial lung with constitutive nitric oxide synthase (NOS) and interleukin (IL)-10 gene-transfected endothelial cells to attenuate inflammatory reactions induced by cardiopulmonary bypass. METHODS AND RESULTS: First, we performed an in vitro study to confirm the efficacy of our gene transfection into endothelial cells. Constitutive nitric oxide synthase and IL-10 cDNA were transfected into endothelial cells according to the hemagglutinating virus of Japan-liposome method. Levels of nitric oxide released from the endothelial constitutive NOS (ecNOS)-transfected endothelial cells were significantly higher than those of control cells (24 hours after the stimulation by lipopolysaccharide: 284.5 +/- 54.0 versus 95.7 +/- 27.9 mumol/L, P = 0.0001). On the other hand, IL-8 levels in the transfected endothelial cells were significantly lower than those in the control group (48 hours after stimulation by tumor necrosis factor-alpha: 3.1 +/- 2.4 versus 62.1 +/- 1.3 ng/mL, P = 0.0002), and IL-10 was detected in the transfected group but not in the control group. Next, we performed an in vivo study to evaluate the possibility of developing a hybrid artificial lung. One-hour partial cardiopulmonary bypass with this lung was established in rats undergoing femorofemoral bypass. Artificial lungs with no cells (group C; n = 5), that were coated with untreated endothelial cells (group E; n = 5), or that were coated with ecNOS and IL-10 gene-transfected endothelial cells (group T; n = 3) were used. At 45 minutes after the initiation of cardiopulmonary bypass, group T showed higher nitric oxide levels than groups C and E (T versus C versus E: 75.2 +/- 6.8 versus 67.2 +/- 4.3 versus 68.6 +/- 5.2 mumol/L, P = NS). The serum IL-8 levels just after cardiopulmonary bypass in group T were significantly lower than those in group C (1728 +/- 282 versus 4275 +/- 145 pg/mL, P = 0.0151). The Pao2 levels in group T just after weaning from cardiopulmonary bypass were significantly higher than those in group C (271.3 +/- 41.7 versus 136.6 +/- 12.3 mm Hg, P = 0.0362). CONCLUSIONS: These results demonstrate that a hybrid artificial lung with IL-10 and ecNOS gene-transfected endothelial cells inhibited IL-8 release and increased nitric oxide production. This suggests the possibility of developing a hybrid artificial lung capable of preserving native lung function by attenuating cardiopulmonary bypass-induced inflammatory reactions via inhibition of IL-8 release and enhanced nitric oxide production.

Regional ventricular systolic abnormalities caused by a rudimentary chamber in patients with univentricular hearts.

Previous studies have demonstrated that regional wall motion abnormalities are common in univentricular hearts; however, the mechanism of this abnormality and its relation to hemodynamics remain unclear. The aim of this study was to document and analyze the etiology of regional wall motion abnormality and its relation to hemodynamics in univentricular hearts. Sixteen patients (age 11+/-6 years) were examined. A tagged cine magnetic resonance imaging method that superimposes "tags" on myocardium was used to assess regional systolic motion. The tags were traced from end-diastole to end-systole, and the percent regional shortening fraction was calculated as the shortening ratio. The tags were positioned on 6 segments. Normal ranges for wall motion were established from 10 normal volunteers. An asynchrony index was calculated as the SD divided by the mean regional shortening fraction to quantify asynchronous regional motion. Hemodynamic parameters were also obtained by cardiac catheterization. In patients, regional shortening fraction was significantly lower in segments adjacent to the rudimentary chamber compared with normal values in both circumferential and longitudinal directions (p <0.05 and p <0.01, respectively). The asynchrony index was much greater in patients than in controls (62+/-25 vs 27+/-10, p <0.01). The index correlated with rudimentary chamber volume and the rudimentary/main chamber volume ratio (r = 0.58, r = 0.79, respectively). Furthermore, the index correlated with end-diastolic pressure (r = 0.82). The rudimentary chamber may play an important role in causing asynchronous regional motion, and this motion may contribute to ventricular diastolic dysfunction.

Pulmonary disease models induced by in vivo hemagglutinating virus of Japan liposome-mediated endothelin-1 gene transfer.

Overproduction and overexpression of endothelin-1 (ET-1) have been reported to contribute to the pathophysiology of pulmonary diseases, including pulmonary fibrosis, obliterative bronchiolitis, and primary pulmonary hypertension. To determine whether ET-1 contributes to the pathogenesis of pulmonary disease, we locally overexpressed ET-1 using an in vivo UV-inactivated hemagglutinating virus of Japan (HVJ) liposome-mediated gene transfer system. Plasmid DNA of ET-1 (pME18fc preproET-1) and high mobility group 1 (HMG1) protein were co-encapsulated in liposomes. Then the plasmid DNA and liposome complexes were introduced into the lung via the trachea in Wistar rats, using HVJ-mediated membrane fusion. Control animals received instillation of HVJ liposome with an empty cassette. Two weeks after in vivo transfection of the preproET-1 gene, hyperplastic connective tissue plaques were seen in the alveolar duct and small conducting airways, indicating histologically distinctive obliterative bronchiolitis. No histopathologic changes were seen in the control animals. These results suggested that local overexpression of ET-1 may play an important role in the pathogenesis of obliterative bronchiolitis.

Left ventricular regional systolic motion in patients with right ventricular pressure overload.

Left ventricular regional systolic motion was investigated in patients with right ventricular pressure overload and 10 controls using tagged cine magnetic resonance imaging. The regional shortening fraction was determined in four segments (septal, lateral, inferior, and anterior) on the short-axis image. An asynchrony index, nonhomogeneity of regional shortening, was calculated. Septal shortening in these patients was depressed, and showed an inverse correlation with the right-to-left ventricular peak pressure ratio (r=-0.80, P<0.01). Lateral shortening was greater in the patients than in the controls (P<0.01). The asynchrony index was significantly greater in the patients than in the controls (P<0.01), and correlated with the right-to-left systolic pressure ratio (r=0.64, P=0.02) and the left ventricular end-diastolic pressure (r=0.79, P<0.01). The altered distribution of regional circumferential shortening results in an increased heterogeneity of regional systolic motion. These findings may have important implications for the assessment of ventricular function in patients with right ventricular pressure overload.

Quantitative, non-invasive assessment of ventricular septal defect shunt flow by measuring proximal isovelocity surface area on colour Doppler mapping.

OBJECTIVE: To determine whether the proximal isovelocity surface area (PISA) method could be applied to estimate the magnitude of ventricular septal defect (VSD) shunt flow. DESIGN: Prospective analysis of clinical, echocardiographic, and angiographic data. SETTING: University hospital. PATIENTS: 14 children with VSD. METHODS: Colour Doppler images of VSD shunt flow were obtained in parasternal long axis view, four chamber view or both, adjusted to provide the best imaging of flow. The VSD shunt flow rate and shunt volume were calculated as follows: shunt flow rate (SFR) = 2 pi r2 V/BSA in ml/s/m2; shunt volume = SFR x shunt duration time. The shunt volume, shunt fraction, and pulmonary to systemic flow ratio (Qp:Qs) were confirmed by cardiac catheterisation. RESULTS: There was a correlation between shunt variables determined by PISA and those by catheterisation, including shunt volume (r = 0.78, P = 0.001) and shunt fraction (r = 0.74, P = 0.003). Qp:Qs was also significantly correlated with SFR (r = 0.79, P = 0.0007). The SFR was significantly different between the four patients with Qp:Qs < 2.0 (mean (SD) 54 (33) ml/s/m2) and the 10 patients with Qp:Qs > 2.0 (186 (69) ml/s/m2) (P = 0.004). CONCLUSIONS: These data suggest that the PISA method is a reliable non-invasive investigation for the quantitative assessment of VSD shunt flow and provides important information for decisions regarding surgical repair.

Accelerated ventricular rhythm in the newborn.

Accelerated ventricular rhythm was observed in two newborn infants. Neither of them had any causative clinical symptoms for the ventricular arrhythmia. The arrhythmia disappeared when the infants were 18 days and 45 days old, respectively. Arrhythmia was noted in the fetal period, especially in case 1.

A case of pigmentary type of orthochromatic leukodystrophy with early onset and globoid cells.

We report herein a sporadic case of the pigmentary type of orthochromatic leukodystrophy with early onset and very rapid clinical course. The patient's development was normal until 2 years old, when he experienced visual disturbance. Rapid deterioration resulted in death 1.5 years after the onset. Metachromatic leukodystrophy, globoid cell leukodystrophy and adrenoleukodystrophy were excluded by biochemical assays. Autopsy findings were compatible with the diagnosis of the pigmentary type of orthochromatic leukodystrophy. However, there were unique findings of severe neuronal loss and the collection of globoid-like cells in the interface of the gray matter and the white matter. Immunohistochemical staining of myelin basic protein, proteolipid protein and galactocerebroside demonstrated that these myelin constituents were equally preserved in the posterior column, while absent in the lateral and anterior columns of the spinal cord.