Catalytic Chemoselective Conjugate Addition of Amino Alcohols to α,ß-Unsaturated Ester: Hydroxy Group over Amino Group and Conjugate Addition over Transesterification.

A highly chemoselective conjugate addition of amino alcohols to α,ß-unsaturated ester using a soft Lewis acid/hard Brønsted base cooperative catalyst was developed. This catalysis achieved chemoselective addition of a hydroxy group over an amino group. Moreover, soft metal alkoxide generation enabled chemoselective soft conjugate addition over hard transesterification. Various amino alcohols, including unprecedented cyclic ß-amino alcohol, were applicable to the present catalysis.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Long-term administration of beraprost sodium for pulmonary arterial hypertension associated with congenital heart disease.

Pulmonary arterial hypertension (PAH) is often associated with congenital heart disease (CHD). Acute administration of beraprost reduces pulmonary vascular resistance in patients with idiopathic PAH and PAH associated with CHD; however, little is known about whether or not long-term treatment with oral beraprost benefits these patients. We report the case of a patient suffering from severe PAH associated with large patent ductus arteriosus (PDA), who was considered to be ineligible for PDA closure using a conventional treatment strategy. Eventually, long-term administration of oral beraprost ameliorated the degree of PAH and the patient subsequently underwent successful closure of the PDA.

Noninvasive estimation of left ventricular end-diastolic pressure using tissue Doppler imaging combined with pulsed-wave Doppler echocardiography in patients with ventricular septal defects: a comparison with the plasma levels of the B-type natriuretic Peptide.

BACKGROUND: There are limited data regarding whether the ratio of the peak transmitral flow velocity during early diastole (E) to the peak mitral annular velocity during early diastole (Ea) obtained by tissue Doppler imaging (TDI) and the plasma levels of the B-type natriuretic peptide (BNP) are useful for evaluating the left ventricular end-diastolic pressure (LVEDP) in children with ventricular septal defects (VSD). We investigated the validity of noninvasive estimation of the LVEDP in VSD infants. METHODS: We studied 48 patients (mean age, 9 +/- 6 months). Using pulsed-wave Doppler echocardiography and TDI, E and Ea were measured to calculate the E/Ea ratio. The LVEDP and the ratio of pulmonary to systemic blood flow (Qp/Qs) were determined invasively. RESULTS: There were significant positive correlations between E and both the LVEDP value and the Qp/Qs ratio. In contrast, Ea showed significant negative correlations with the LVEDP value and Qp/Qs ratio. The E/Ea ratio correlated significantly with the LVEDP value and Qp/Qs ratio. The plasma BNP levels correlated significantly with the Qp/Qs ratio, although they did not show a significant correlation with the LVEDP. An E/Ea ratio of >9.8 indicated patients with a LVEDP of >10 mmHg with a sensitivity of 92% and specificity of 80%. CONCLUSION: TDI combined with pulsed-wave Doppler echocardiography predicted the LVEDP of VSD infants, whereas the plasma BNP value did not have a significant association with the LVEDP.

Paradoxical relationship between B-type natriuretic peptide and pulmonary vascular resistance in patients with ventricular septal defect and concomitant severe pulmonary hypertension.

B-type natriuretic peptide (BNP) reflects volume overload on left ventricle and pulmonary hypertension (PH) in patients with ventricular septal defect (VSD). Pulmonary vascular resistance (PVR) has been reported to correlate positively with BNP in VSD patients with various degrees of PH. We aimed to investigate the relationship between PVR and BNP in VSD patients with severe PH. We examined 24 subjects with VSD concomitant severe PH aged from 2 months to 17 years (median: 4 months). The ratio of pulmonary to systemic pressure (Pp/Ps), the ratio of pulmonary to systemic flow (Qp/Qs), the ratio of pulmonary to systemic resistance (Rp/Rs), and PVR were determined by cardiac catheterization. PVR and Rp/Rs ranged from 1.6 to 15.5 (mean: 5.7 +/- 3.9) Wood unit . m(2) and 0.1 to 0.8 (mean: 0.4 +/- 0.2), respectively. BNP ranged from 5.5 to 69 (mean: 31 +/- 19) pg/ml. Negative correlations were observed between BNP and PVR (r = -0.56, p = 0.004) and BNP and Rp/Rs (r = -0.51, p = 0.01). BNP was significantly lower (<10 pg/ml) in VSD patients with Eisenmenger physiology as compared with the others (p = 0.003). We should draw attention to evaluate BNP values in VSD patients with severe PH.

Using transthoracic Doppler echocardiography to diagnose reduced coronary flow velocity reserve in the posterior descending coronary artery in children with elevated right ventricular pressure.

BACKGROUND: Advances in transthoracic Doppler echocardiography enable noninvasive measurements of coronary flow velocity and coronary flow velocity reserve (CFVR) in the posterior descending coronary artery (PD). METHODS AND RESULTS: To evaluate CFVR in the PD of children with elevated right ventricular (RV) pressure, 19 children with RV pressure overload and 13 age-matched controls with normal RV pressure were studied using transthoracic Doppler echocardiography. Average peak flow velocity (APV) was measured at rest and in hyperemic conditions (intravenous administration of adenosine of 0.16 mg.kg(-1).min(-1)). Compared with controls, the PD CFVR was significantly reduced in the patients with elevated RV pressure (1.87+/-0.42 vs 2.49+/-0.55, p<0.01) because their mean baseline APV was significantly greater (27+/-6 vs 19+/-4 cm/s, p<0.01), although hyperemic APV was not significantly different (49+/-10 vs 48+/-14 cm/s, p=NS). CONCLUSIONS: PD CFVR is limited in patients with elevated RV pressure because of elevation of the baseline resting flow velocity.

Noninvasive visualization and measurement of middle cardiac vein flow by transthoracic Doppler echocardiography.

Transthoracic Doppler echocardiography offers a noninvasive approach for imaging posterior descending coronary artery (PD) running in the posterior longitudinal sulcus along the middle cardiac vein (MCV). To evaluate whether the MCV flow velocity reserve can reflect the PD flow reserve, 22 children with various heart diseases were examined using transthoracic Doppler echocardiography. Introduction of a modified transthoracic two chamber view with the transducer rotated counterclockwise and angulated posteriorly allows visualization of the MCV and PD. Peak systolic flow velocity and average peak systolic flow velocity in the MCV and peak diastolic flow velocity and average peak diastolic flow velocity in the PD were measured at rest and hyperemic conditions (intravenous administration of adenosine of 0.16 mg/kg/min). Coronary flow reserve was defined as the ratio of peak hyperemic to basal average peak flow velocity. ATP infusion induced significant increases in the peak systolic flow velocity and average peak systolic flow velocity in the MCV. The mean MCV flow velocity reserve in the patients was 1.94 +/- 0.44. Significant increases in the peak diastolic flow velocity and the average peak diastolic flow velocity in the PD were also observed during ATP infusion, and the mean PD flow velocity reserve (2.19 +/- 0.62) was significantly higher than the GCV flow velocity reserve (p < 0.0001). There was a good correlation between the MCV flow velocity reserve and PD flow velocity reserve (r = 0.86, p < 0.0001). This study demonstrated that it was possible to measure the MCV flow velocity and MCV flow velocity reserve in pediatric patients by transthoracic Doppler echocardiography. The MCV flow reserve correlated highly with the PD flow reserve. However, the degree of the MCV flow during hyperemia was less than that of the PD flow. This underestimation should be considered when the reactive hyperemic response is evaluated from the MCV flow velocity.

Usefulness of exercise-induced changes in plasma levels of brain natriuretic peptide in predicting right ventricular contractile reserve after repair of tetralogy of Fallot.

Elevated levels of brain natriuretic peptide (BNP) have been associated with ventricular dysfunction, and exercise tests have been used for assessing cardiac contractile reserve. We examined the relation between BNP and right ventricular (RV) contractile reserve during exercise in patients after repair of tetralogy of Fallot (TOF). A total of 45 patients, 26 of whom underwent repair of TOF at 2 to 3 years of age and 19 age-matched healthy children, were studied. Plasma levels of BNP were measured at baseline and at maximal exercise. Echocardiography combined with tissue Doppler imaging (TDI) was performed at rest and during supine bicycle submaximal exercise. The peak value of the first derivation of RV pressure (peak dP/dt) was measured by the continuous-wave Doppler method. The severity of pulmonary regurgitation (PR) (mild, moderate, or severe) was based on color Doppler findings. Plasma BNP levels were significantly higher in patients with TOF than in controls (44 +/- 34 vs 6 +/- 4 pg/ml, p <0.01). Exercise was associated with increased plasma BNP levels in both groups. A larger increment in BNP was noted in patients with TOF than in normal subjects (15 +/- 12 vs 2 +/- 2 pg/ml, p <0.01). The peak systolic myocardial velocity (Sa) and peak dP/dt values increased significantly in both groups during exercise; however, the magnitude of increase in both of these values was significantly less in patients with TOF than in controls (36 +/- 19% vs 70 +/- 19% and 42 +/- 11% vs 81 +/- 12%, respectively; p <0.01). There were significant correlations between the increment in BNP and changes in Sa and peak dP/dt values (r = -0.67 and -0.53, p <0.01, respectively), and the severity of PR (r = 0.74, p <0.01). Thus, exercise increases plasma levels of BNP, and greater increases are associated with impaired RV contractile reserve in patients with TOF with various degrees of PR.

Effects of coil closure of patent ductus arteriosus on left anterior descending coronary artery blood flow using transthoracic Doppler echocardiography.

Transthoracic Doppler echocardiography provides noninvasive measurements of coronary blood flow in the left anterior descending coronary artery (LAD). This method has the potential to show the effects of acute changes in loading conditions on blood flow. Coil closure of patent ductus arteriosus (PDA) is a model of acute changes in blood pressure and left ventricular (LV) preload that influences coronary blood flow. We applied this technique to assess the coronary blood flow changes for patients with PDA before and immediately after PDA coil closure. We examined 9 patients (1.8 +/- 1.1 years) with simple PDA and 8 age-matched healthy children. LV dimensions and LV mass were measured. Maximum peak flow velocity and flow volume in the LAD were measured. Pulmonary to systemic flow ratios (Qp/Qs) were obtained by cardiac catheterization. After PDA coil closure, LV end-diastolic dimension decreased, and systolic and diastolic blood pressures increased significantly. The maximum peak flow velocity, LAD flow volume, and the ratio of LAD flow volume to LV mass increased significantly. The changes in maximum peak flow velocity and the ratio of LAD flow volume to LV mass (F/M) correlated positively with the changes in diastolic pressure and Qp/Qs. In 5 patients who had Qp/Qs > 1.5, the mean F/M was significantly lower compared with control subjects, but they increased to normal values after coil closure of PDA. PDA coil closure increases diastolic pressure and decreases Qp/Qs, resulting in improvement of myocardial perfusion. These findings provide new insights into the relationship between cardiac function and coronary circulation in pediatric patients with heart diseases associated with PDA.

Coronary flow velocity and coronary flow velocity reserve in children with ventricular septal defect.

To assess coronary flow characteristics in congenital heart defect with left ventricular (LV) volume overload, we examined 24 children (mean 12.1 +/- 7.1 months) with ventricular septal defect. The pulmonary to systemic flow ratio ranged from 1.1 to 3.0. Control group consisted of 10 age-matched children who had a history of Kawasaki disease with angiographically normal coronary artery in the acute phase. LV end-diastolic volume and LV mass were measured by left ventriculogram. With Doppler flow guide wire (0.014-inch), average peak flow velocity (APV) in left anterior descending coronary artery was recorded at rest and during hyperemia (0.16 mg/kg/min adenosine infusion intravenously). Coronary flow velocity reserve (CFVR) was calculated as the ratio of hyperemic/baseline APV. Seven patients were also studied 5-7 months after surgery. Compared with control subjects, CFVR was significantly reduced in patients with LVvolume overload (1.78 +/- 0.24 vs. 2.66 +/- 0.42, p < .0001) because baseline APV was significantly greater (30 +/- 8 vs. 23 +/- 5 cm/sec, p = 0.0027). Significant correlations were observed between CFVR and Qp/Qs, baseline APV, LV end-diastolic volume, or LVmass. Stepwise regression analysis showed that baseline APV and Qp/Qs were important determinants of CFVR (CFVR = 2.64-0.202 [Qp/Qs]-0.015 [APV] r = 0.83, p < 0.0001). In 7 patients with LVvolume overload, CFVR improved significantly after surgery because of reduction of baseline APV. CFVR is limited in patients with LV volume overload because of the elevation of baseline resting APV. LAD flow pattern is dependent on LV volume overload level and its changes after surgery.

Myocardial acceleration during isovolumic contraction as a new index of right ventricular contractile function and its relation to pulmonary regurgitation in patients after repair of tetralogy of Fallot.

BACKGROUND: Myocardial acceleration during isovolumic contraction (IVA) by Doppler tissue imaging has been proposed to be a new index of right ventricular contractile function that is unaffected by ventricular shape or loading conditions. OBJECTIVES: We sought to assess the use of IVA to evaluate right ventricular contractile function. METHODS: In all, 22 pediatric patients with pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) (8 +/- 3 years) and 27 age-matched children were examined. The degree of PR (mild, moderate, and severe) for patients with TOF was on the basis of pulsed and color Doppler findings. Using Doppler tissue imaging, the peak myocardial velocities during early diastole, late diastole, systole, and isovolumic contraction were recorded. RESULTS: Compared with healthy children, Doppler tissue imaging velocities for patients with TOF showed decreased myocardial velocities during early diastole (P =.007), late diastole (P <.0001), systole (P <.0001), and isovolumic contraction (P <.0001). Patients with TOF had a lower IVA when compared with healthy children (P <.0001). There was a stepwise decrease in the IVA from mild to severe PR. We found a significant relationship between the IVA and the degree of PR (r = -0.86, P <.0001). CONCLUSION: The analysis of IVA allows the assessment of right ventricular contractile function for patients with repaired TOF and various degrees of PR.

Effects of balloon valvuloplasty on left anterior descending coronary artery blood flow in a neonate with critical aortic stenosis with transthoracic doppler echocardiography.

Doppler echocardiography has recently been used in the assessment of coronary flow dynamics. We described the application of transthoracic Doppler echocardiography for the measurement of the coronary flow before and after balloon valvuloplasty in a neonate with critical aortic stenosis. In this case, coronary flow volume/left ventricular mass ratio increased after the procedure, suggesting the improvement of myocardial blood perfusion. Thus, this technique may provide additional information about coronary flow dynamics in patients with critical aortic stenosis.

The efficacy of using pulmonary vein wedge pressure for the estimation of pulmonary artery pressure in children with congenital heart disease.

The objectives of this study were to assess the accuracy of pulmonary vein wedge pressure (PVWP) in estimating pulmonary artery pressure (PAP) in various types of congenital heart disease, including single-ventricle physiology. The systolic, diastolic, and mean values of both PAPs and PVWPs were measured in 30 patients (a total of 46 points). Pulmonary artery pressure ranged from 13 to 74 (34 +/- 15) mm Hg in systole, 5 to 25 (13 +/- 6) mm Hg in diastole, and 6 to 48 (18 +/- 10) mm Hg in mean. As a whole, good correlations between PAPs and PVWPs were observed (systole, r = 0.70; diastole, r = 0.85; mean, r = 0.82; P < 0.0001). However, with an increase in PAP, the discrepancy between PAPs and PVWPs increased. When the mean PVWP was more than 18 mm Hg, the mean PVWP in 14 of 24 (58%) underestimated the mean PAP by up to 22 mm Hg (mean difference, -1.7 +/- 5.8 mm Hg). On the other hand, all of the patients with mean PVWPs less than 18 mm Hg (n = 22) had mean PAPs less than 18 mm Hg (r = 0.86; PAP = 1.11 x PVWP - 1.41; P < 0.0001), and the mean difference was -0.2 +/- 1.8 mm Hg. The mean PVWP can accurately estimate the mean PAP in children with congenital heart disease who have a mean PVWP less than 18 mm Hg.

Coronary flow reserve assessment by Doppler echocardiography in children with and without congenital heart defect: comparison with invasive technique.

To evaluate whether transthoracic Doppler echocardiography can reliably measure coronary flow velocity (CFV) and CFV reserve (CFVR) in the left anterior descending coronary artery (LAD) in children, we examined 12 patients who had a history of Kawasaki disease without stenosis or aneurysm formation of coronary artery and 9 patients who had congenital heart disease (ventricular septal defect in 6, patent ductus arteriosus in 2, tricuspid atresia in 1). The pulmonary-to-systemic flow ratio ranged from 1.7 to 2.8. CFV in the proximal LAD was measured by transthoracic Doppler echocardiography at the time of Doppler guidewire examination. CFV in the proximal LAD was measured at baseline and hyperemic conditions by both transthoracic Doppler echocardiography and Doppler guidewire techniques. CFVR was defined as "the ratio of peak hyperemic to basal CFV in the proximal LAD." Clear envelopes of basal and hyperemic CFV in the proximal LAD were obtained in 19 of 21 patients by transthoracic Doppler echocardiography. There was a significant correlation between transthoracic Doppler echocardiography and Doppler guidewire methods for the measurements of CFV (r = 0.84, P <.0001). The mean difference between the 2 methods was -0.5 +/- 5.9 cm/s. CFVR from transthoracic Doppler echocardiography correlated well with that from Doppler guidewire examinations (r = 0.83, P <.0001). The mean difference between the 2 methods was 0.06 +/- 0.24. Noninvasive measurement of CFV and CFVR in the proximal LAD using transthoracic Doppler echocardiography accurately reflects invasive measurement of CFV and CFVR by Doppler guidewire method in pediatric patients with various heart diseases.

Blood flow in the left anterior descending coronary artery in children with ventricular septal defect.

High-frequency echocardiography offers a noninvasive approach for imaging left anterior descending coronary artery (LAD) blood flow from a transthoracic window. The purpose of this study was to assess the effects of left ventricular (LV) volume overload on LAD flow in pediatric patients with ventricular septal defect (VSD). The study subjects consisted of 38 children with VSD and 15 healthy children. LV mass, LAD diameter, and LAD flow were measured by using transthoracic echocardiography, then LAD diameter and LV mass were indexed for body surface area. Pulmonary to systemic flow ratios (Qp/Qs) were obtained by cardiac catheterization. The Qp/Qs ratios ranged from 1.2 to 3.1 (mean 2.1 +/- 0.5). The mean LAD flow velocities, flow velocity integrals, and flow volumes were significantly higher in the patients than in the control subjects. LAD flow velocity and flow volume showed significant positive correlations with Qp/Qs, LV mass, and LV end-diastolic volume. Stepwise regression analysis revealed that Qp/Qs was the most important determinant of both LAD flow velocity (r(2) = 0.45, P < .0001) and LAD flow volume (r(2) = 0.44, P < .0001). The ratios of LAD flow volume to LV mass did not differ between the 2 groups. In 8 patients who underwent surgical treatment, LAD flow velocity, flow velocity integral, and flow volume decreased significantly after surgery. The current results suggest that patients with VSD have a higher resting coronary blood flow, and that LAD flow pattern is dependent on LV volume overload and changes after surgery.

Left anterior descending coronary artery flow and its relation to age in children.

Recent advances in Doppler and color echocardiographic techniques enable coronary flow dynamics to be estimated even in children. To assess quantitatively left anterior descending coronary artery (LAD) volumetric flow and to determine its relation to age and left ventricular (LV) mass, healthy children participated in a study that used high-frequency transthoracic echocardiography. We also studied whether Doppler echocardiography can reliably measure LAD flow in a clinical setting. In 57 healthy children, 2-dimensional echocardiography was used to measure the diameter and cross-sectional area of the LAD and LV mass. LAD peak flow velocity, flow velocity integral, and flow volume were measured by Doppler echocardiography. We then calculated the ratio of LAD cross-sectional area to LV mass and the ratio of LAD flow volume to LV mass. In 12 patients with Kawasaki disease, LAD flow velocity and flow velocity integral were measured by Doppler echocardiography at the time of Doppler guide wire examination. There were significant correlations between echocardiographic and Doppler guide wire methods for flow velocity and flow velocity integral (r = 0.77 and 0.83, P <.01, respectively). The LAD flow velocity decreased significantly with age (r = -0.43, P <.01). The LAD flow volume per minute increased significantly with age (r = 0.55, P <.01). However, LAD flow volume/LV mass ratio in younger infants was high and decreased significantly with age (r = -0.66, P <.01). This study shows that LAD flow patterns can be reliably assessed by transthoracic Doppler echocardiography in the majority of pediatric subjects. In the current study, the LAD flow velocity and the ratio of LAD flow volume to LV mass in infants was high and decreased with age, suggesting high myocardial perfusion. High LAD peak velocity in infants may be related with high resting coronary flow. Age-related changes in the LAD flow characteristics must be taken into consideration in the study of the coronary circulation in children.