Effects of heart rate and right ventricular pressure on right coronary arterial flow and its systolic versus diastolic distribution in a variety of congenital heart diseases in children.

BACKGROUND AND METHODS: In order to elucidate the underlying adjusting mechanism of human right coronary arterial (RCA) flow to increased right ventricular pressure (RVP) in children, we recorded RCA flow velocity in 24 pediatric cardiac patients at the orifice of its main trunk at the time of heart catheterization using the Doppler guidewire. RESULTS: The ratio of diastolic flow (DF)/total flow (TF), or the proportion of the DF time integral over a total of one cardiac cycle, had a negative correlation with heart rate (HR; r = -0.58, n = 11) in children with normal right ventricular systolic pressure (RVSP; RVSP < 35 mmHg). In contrast, the DF/TF ratio had a good correlation (r = 0.88, n = 24) with RVSP in all patients under study. The ratio of diastolic area (DA)/total area (TA), defined as the ratio of an area encircled by the aortic pressure curve above and the RVP curve below for diastole, over a total of one cardiac cycle, representing the overall effect of both HR and transcoronary pressure difference, also correlated well (r = 0.89, n = 24) with DF/TF. Total volume flow of the RCA also increased (r= 0.76, n = 24) with increases in RVSP, first by an increase in flow velocity through the RCA, during both systole and diastole, then by widening of the RCA lumen at very high pressures. These changes were initially more dependent on diastole with increasing RVSP because: (i) of a more marked augmentation of flow velocity in diastole compared with systole; and then (ii) of a significant decrease in flow velocity in systole at very high pressures. CONCLUSIONS: We clarify how the RCA manages to increase flow through it at different HR as a function of chronic RVP overload in pediatric cardiac patients.

Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney.

BACKGROUND: The cDNA of the multispecific organic anion transporter 1 (OAT1) responsible for the tubular secretion of organic anions was recently isolated. In the current study, we investigated the developmental changes in OAT1 expression in the rat kidney. METHODS: Ontogenic expression of rat OAT1 was investigated by Northern blot, in situ hybridization, Western blot, and immunohistochemical analysis. In addition, para-aminohippurate (PAH) accumulation was measured using fetal, neonatal, and adult rat kidney slices. RESULTS: In Northern blot analysis, OAT1 was detected as early as on embryonic day 18 in the fetal kidney. The expression level of OAT1 mRNA increased remarkably just after birth (postnatal day 0). In situ hybridization revealed OAT1 expression on embryonic day 19. In both the fetal and neonatal kidneys, OAT1 mRNA was localized in a relatively deep region in the cortex. Western blot analysis detected OAT1 protein on embryonic day 20, and the expression level increased after birth. Immunohistochemical analysis did not reveal OAT1 staining in the fetal kidneys. A faint signal of OAT1 protein was detected on postnatal day 0; thereafter, the expression level increased. In the functional study using kidney slices, low but definite probenecid-sensitive PAH accumulation was noted in fetal rat kidney on embryonic day 20. After birth, probenecid-sensitive PAH uptake was increased. CONCLUSIONS: The present study consistently demonstrates the remarkable increase of OAT1 expression after birth, and the immature excretory capacity of the proximal tubules of the neonatal kidney can be attributed, at least in part, to the low expression level of OAT1.

[Relation between serum eosinophil cationic protein (ECP) level and asthma attack in children].

Serum eosinophil cationic protein (sECP) levels were measured in 339 patients with childhood asthma, and the clinical courses of these patients were followed for 57 weeks. While considering the history and characteristics of each patient, we examined the correlation between asthma attack frequency and sECP, blood eosinophil count, and serum total IgE (tIgE) to determine their usefulness in predicting asthma attacks. Among patients with no other allergic diseases, sECP levels in patients who had no asthma attacks two weeks before or after the measurement were significantly lower than those of patients who had attacks during the same four-week period. Among patients who had attacks, those patients with no attack for a year after the measurement were also found to have low sECP levels. Similarly, even among patients with asthma attacks and high sECP levels, there were cases where attacks were well controlled using nebulizer treatments with DSCG or BDP. The incident rate of attacks for patients with other allergic diseases and a low sECP was low. Yet, there was no common trend in patients with high sECP levels. Moreover, this study detected a significant correlation between sECP level and blood eosinophil count as well as between sECP level and serum tIgE. The most significant correlation with asthma attack frequency was sECP level. Thus, sECP level seems to reflect the allergy activity level, especially two weeks prior to and after the measurement. For patients without other allergic diseases, asthma attack prediction during the two weeks period after the measurement of sECP also seems possible. Therefore, periodic measurement of sECP level is useful in objectively monitoring the improvement of symptoms and establishing the treatment plan, including treatment with DSCG or BDP.

Pulmonary arterial compliance in children with atrial and ventricular septal defect.

Previous studies have documented the normal values of pulmonary arterial compliance (Cp) in animals and adult humans. In the past, variations in Cp and its measurement in children with septal defects has been unknown. In the present study, we found the Windkessel model, which uses compliance and resistance as parameters, to be a useful tool in understanding Cp in pediatric patients. Calculations of Cp were based on the pulmonary arterial diastolic pressure waveform as an exponential function of time. First, Cp was estimated by studying pressure tracings of the main pulmonary artery (MPA) obtained from both routine cardiac catheterization and pressure measured by a catheter-tip manometer, which was performed during a catheterization study of seven children with various congenital heart diseases. Second, 124 children with atrial and ventricular septal defects aged between 45 days and 12 years were studied using the data obtained from routine catheterization. Hemodynamic data were used to calculate pulmonary vascular resistance (Rp), pulmonary arterial time constant (Tp) and Cp. A strong correlation (r = 0.954) was found in the Cp value estimated by data obtained from routine catheterization and from the catheter-tip manometer study. The present study shows an estimated mean (SEM) Cp in normal children of 1.53 (0.17) ml/mmHg per m2. The estimated mean (SEM) Cp was 1.91 (0.10) and 1.70 (0.11) ml/mmHg per m2 in children with atrial septal defect (ASD) and ventricular septal defect (VSD), respectively. It was found that Cp was significantly (P = 0.04) higher in female patients with a VSD. Also, a significantly low Cp (0.95 +/- 0.06 ml/mmHg per m2) was observed in patients with a VSD and pulmonary hypertension (VSDPH). In conclusion, Cp was calculated by the exponential decay portion of the MPA diastolic pressure waveform. A normal Cp value was observed in ASD and VSD patients and a significantly low Cp was observed in children with a VSDPH. Cp was higher in female VSD patients than in male VSD patients.

Subcellular localization of glucocorticoid receptor protein in the human kidney glomerulus.

BACKGROUND: The detailed mechanisms of glucocorticoid action in idiopathic nephrotic syndrome and progressive glomerulonephritides have not been clearly elucidated. The pharmacological actions of glucocorticoids are mediated by their binding to an intracellular protein, the glucocorticoid receptor (GR). The determination of GR localization in normal glomerular cells is essential to elucidate the mechanisms of glucocorticoid action in various glomerular diseases. METHODS: We carried out an immunoblot examination using antihuman GR-specific antibody and homogenates of isolated normal human glomeruli and mesangial cells in culture. Immunohistochemical examinations were also performed on normal human kidney specimens at light and electron microscopic levels. The nuclear translocation of GRs elicited by ligand binding was further investigated by confocal laser-scanning microscopic inspection of freshly isolated glomeruli and mesangial cells cultured with dexamethasone. RESULTS: An immunoblot examination demonstrated the presence of a 94 kDa protein, a molecular weight consistent with that of GRs, in the homogenates of glomeruli and cultured mesangial cells. By light microscopic examination, GRs were strongly detected in the nucleus and moderately in the cytoplasm of all glomerular cells, parietal and visceral epithelial cells, endothelial cells, and mesangial cells. By electron microscopic examination, the nuclear GRs of all glomerular cells were found to be diffusely distributed in the euchromatin. Additionally, the immunofluorescence intensities of nuclear GRs in isolated glomeruli and mesangial cells in culture became more intense by the addition of dexamethasone. CONCLUSIONS: Our findings suggest that all subsets of human glomerular cells definitely express the GR protein, which potentially undergoes translocation by glucocorticoids.

The increase of memory T cell subsets in children with idiopathic nephrotic syndrome.

Two-color and three-color flow cytometry was carried out to determine whether the memory T cells (CD45RO+ T cells) play a major role in lymphocyte dysfunction of 26 children with idiopathic nephrotic syndrome (INS). The INS patients were divided into three groups: (1) 10 patients who were not receiving glucocorticoid hormone (GCH) and were suffering from acute nephrotic state were referred to as N1; (2) 8 patients who were in remission maintained by GCH therapy alone were referred to as N2; (3) 8 patients who were free of GCH therapy for at least 4 months were referred to as N3. Group N1 demonstrated a significant increase in the percentage of CD45RO+CD4+ T cells and CD45RO+CD8+ T cells (p < 0.05) compared with 11 controls, and these subsets were noted to have a tendency to decrease to control levels in groups N2 and N3. Furthermore, interleukin-2 receptor-alpha expressed subsets in CD45RO+CD4+ T cells (CD45RO+CD4+CD25+ T cells) were also increased only in group N1 (p < 0.02). A similar tendency of absolute counts was observed in these subsets. These results suggest that activated memory T cells reflect lymphocyte dysfunction at initial onset or relapse in INS children.

Dependence of canine right coronary arterial flow upon heart rate and right ventricular pressure.

There is a paucity of knowledge regarding right coronary pulsatile hemodynamics when the right ventricle is under hemodynamic overload as is often the case in pediatric patients with congenital cardiac anomalies. To elucidate the exact mechanisms for the right coronary artery (RCA) to cope with the overload, we studied nine open-chest adult Beagles and analyzed the flow signals of the RCA in relation to independently varied heart rate (pacing) and right ventricular pressure (pulmonary artery banding). Both increased heart rate and right ventricular pressure increased the total volume flow of the RCA. The diastolic over total flow ratio (D/T), however, enlarged on increasing right ventricular pressures while it declined on increasing heart rates. Our data confirmed, as well, that increased flow of RCA on rising heart rate was provided mainly by an increase in systolic phase, while the increase on augmented right ventricular pressure was provided by the increase in diastolic phase. The RCA manages to deliver blood to the right ventricular musculature in two different ways in response to increasing heart rate and right ventricular pressure.

[Hamilton's operation in Bland-White-Garland syndrome].

A 14-year-old boy, who had been treated medically for mitral regurgitation, underwent cardiac catheterization which revealed not only mitral regurgitation but also anomalous origin of the left coronary artery from the pulmonary artery. Thus he was diagnosed as Bland-White-Garland syndrome which was repaired by Hamilton's operation. Under cardiopulmonary bypass, the pulmonary trunk was opened longitudinally. After aorto-pulmonary window (A-P window) was created, a heterogenous pericardial baffle was attached to the posterior wall of the pulmonary trunk connecting A-P window and the ostium of left coronary artery. Thereafter the pulmonary trunk was enlarged with a patch of the same material. He did well postoperatively. Postoperative angiogram demonstrated satisfactory reconstruction of two-coronary-artery system.

Two-dimensional pulsed Doppler echocardiographic technique for estimating pulmonary to systemic blood flow ratio in children with atrial septal defect and patent ductus arteriosus.

A two-dimensional pulsed Doppler echocardiographic method was evaluated for quantifying the pulmonary (Qp) to systemic (Qs) blood flow ratio. Twenty six patients were studied, 15 with atrial septal defect (ASD) and 11 with patent ductus arteriosus (PDA). An apical four-chamber view was used to measure the maximal Doppler flow velocities in the right and left ventricular inflow regions (RVIR and LVIR) and the maximal diameters of the tricuspid and mitral anuli at diastole. The two-dimensional pulsed Doppler pulmonary to systemic blood flow ratio (Qp/Qs) estimation involved calculating the area of the Doppler flow velocity signal along the time scale multiplied by the diameter of either the tricuspid or mitral anulus as measured on the apical four-chamber view. In ASD patients, Qp was measured at RVIR and Qs at LVIR. In PDA patients, Qp was calculated at LVIR and Qs at RVIR. Twenty-six healthy children comprised the control group. The areas of the Doppler flow velocity signals along the time scales of RVIR and LVIR were also quantified and the diameters of the tricuspid and mitral anuli were measured. In the control group, the linear correlation of the trans-mitral M(d)*M(a) to trans-tricuspid T(d)*T(a) value was r = 0.909, n = 26. The correlations between Doppler Qp/Qs ratio estimates and those obtained at cardiac catheterization were r = 0.902, n = 15 in ASD and r = 0.967, n = 11 in PDA. These results suggest a clinical application of this Doppler echocardiographic method in the noninvasive estimation of the cardiac shunt in ASD and PDA.

Evaluation and comparison of the axis of the interventricular septum by two-dimensional echocardiography among the patients with congenital heart disease (ASD, VSD, PDA, PS, TOF) and the normal subjects.

A two-dimensional echocardiographic method was applied to determine the axis of interventricular septum (IVS) in the horizontal plane. This study comprised 19 subjects with ASD, 15 subjects with VSD(I), 20 subjects with VSD(II), 13 subjects with PDA, 16 subjects with PS, 15 subjects with TOF and 99 normal children. Parasternal left ventricular short axis view was taken, and the IVS was recorded by using the polaroid prints. The axis of the IVS in the horizontal plane was measured from the recorded polaroid prints. The value of the angularity of IVS (IVS-A) expressed as means +/- one standard deviation (mean +/- 1S.D.) is 52.0 +/- 13.7 degrees in ASD, 42.2 +/- 9.7 degrees in VSD(I), 43.7 +/- 9.1 degrees in VSD(II), 41.6 +/- 11.4 degrees in PDA, 38.6 +/- 10.9 degrees in PS, 61.0 +/- 8.5 degrees in TOF and 40.1 +/- 8.2 degrees in normal controls. There was no significant difference among VSD(I), VSD(II), PDA, PS and normal controls but a highly significant difference was noted in ASD and TOF as compared to other groups. The correlation coefficient of the IVS-A with (1) the Qp/Qs ratio, (2) the magnitude of shunt (%), (3) the right ventricular pressure and (4) the hematocrits were evaluated among the patient groups. The IVS-A of ASD and VSD(II) had a good correlation with the shunt flow (r = 0.921 and 0.88 respectively) and/or the Qp/Qs ratio (r = 0.782 and 0.955 respectively); while that of VSD(I), PDA, and PS had a good correlation with the right ventricular pressure (r = 0.956, 0.953, 0.842 respectively) and that of TOF was mostly concerned with the hematocrits (r = 0.911). Besides, the IVS-A in each severe CHD subgroup was significantly (p less than 0.005 or a better value) higher than the normal control group. Thus an alternative method was validated for evaluating the severity of congenital heart disease by using a noninvasive two-dimensional echocardiographic technique.

Km mutant of acid alpha-glucosidase in a case of cardiomyopathy without signs of skeletal muscle involvement.

A male patient is reported with a mutation of acid alpha-glucosidase causing an altered Km toward natural substrates. Cardiac arrhythmia was found at 12 years of age, and he died of heart failure at 15 years. No skeletal muscle involvement was observed either clinically or histologically. Acid alpha-glucosidase activity in fibroblasts was moderately low (43% of the control mean) with normal Km for 4-methylumbelliferyl alpha-D-glucoside. The hydrolysis of glycogen was markedly decreased (14% of the control mean), and the Km for maltose was increased 4-fold and for glycogen 5-fold. The biosynthesis and the posttranslational processing of the mutant enzyme appeared normal, but the total amount of the enzyme was lower than normal. This mutant enzyme comigrated with normal acid alpha-glucosidase on starch gel electrophoresis, and not with the rare isozyme, acid alpha-glucosidase 2. A possible role of this mutant enzyme in the pathogenesis of this disease and the relationship to glycogenesis II are discussed.