Dipyridamole stress ultrasonic myocardial tissue characterization in patients with Kawasaki disease.

Dipyridamole stress integrated backscatter (IBS) was used for evaluation of myocardial ischemia or damage in 31 children with coronary artery lesions caused by Kawasaki disease, in comparison with thallium-201 myocardial imaging. All patients underwent echocardiography at rest and after dipyridamole stress at the anterior interventricular septum, posterior wall (PW), and inferior wall (INF). At rest, no significant difference was seen in cyclic variation (CV) of IBS in the regions with normal or abnormal distribution on Tl-201 imaging. But in the regions showing abnormal distribution after stress, CV decreased significantly. A delayed study after stress showed the recovery of CV to the level at rest in all patients. Sensitivity of abnormal cyclic variation integrated backscatter was 75% in the PW and 91% in the INF, and specificity was 91% in the PW and 90% in the INF, compared with the results of thallium-201 imaging. Dipyridamole stress IBS can provide sensitive detection of myocardial ischemia or damage in Kawasaki disease.

Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome.

BACKGROUND: Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC or BTHS for mutations in G4.5 or other novel genes. METHODS AND RESULTS: DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha-dystrobrevin, changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T-->A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor mutation in exon 2 of G4.5 (398-2 A-->G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was identified in a sporadic case of BTHS. CONCLUSIONS: These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, alpha-dystrobrevin, identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.

Neutrophils and mononuclear cells express vascular endothelial growth factor in acute Kawasaki disease: its possible role in progression of coronary artery lesions.

Kawasaki disease (KD) is a syndrome of systemic vasculitis of unknown etiology that is complicated by coronary artery lesions (CAL), leading occasionally to cardiac ischemic sequelae. To examine whether vascular endothelial growth factor (VEGF) is responsible for CAL in KD, we determined serum VEGF levels by ELISA and peripheral blood mononuclear cell (PBMC) and neutrophil VEGF expression by immunoblot analysis. Significantly increased levels of VEGF were demonstrated in acute KD as well as in other vasculitis syndromes (p < 0.0001). In the 10 KD patients with CAL, serum VEGF levels were maximal approximately 2 wk post-onset when CAL generally develops and were significantly higher than in 20 patients without CAL (mean, 474 and 241 pg/mL, respectively; p = 0.00015). During the same period, immunoblot analysis revealed maximal VEGF expression in PBMC, corresponding to serum VEGF levels in most patients and being particularly marked in patients with CAL (p < 0.01). Neutrophils expressed VEGF only in the early stage of acute KD and declined rapidly in the majority of KD patients regardless of the presence of CAL, showing a strikingly different expression pattern than that for PBMC. Predominant VEGF expression by PBMC was also demonstrated in patients with other vasculitis syndromes and only faintly in normal controls. The results suggest that VEGF is generated dynamically in KD, presumably reflecting its disease activity. Neutrophil-derived VEGF may play a role in regulating early vascular responses, whereas PBMC-derived VEGF may contribute to later vascular injury and remodeling.

Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality. Two genes have been identified for the X-linked forms (dystrophin and tafazzin), whereas three other genes (actin, lamin A/C, and desmin) cause autosomal dominant DCM; seven other loci for autosomal dominant DCM have been mapped but the genes have not been identified. Hypothesizing that DCM is a disease of the cytoskeleton and sarcolemma, we have focused on candidate genes whose products are found in these structures. Here we report the screening of the human delta-sarcoglycan gene, a member of the dystrophin-associated protein complex, by single-stranded DNA conformation polymorphism analysis and by DNA sequencing in patients with DCM. Mutations affecting the secondary structure were identified in one family and two sporadic cases, whereas immunofluorescence analysis of myocardium from one of these patients demonstrated significant reduction in delta-sarcoglycan staining. No skeletal muscle disease occurred in any of these patients. These data suggest that delta-sarcoglycan is a disease-causing gene responsible for familial and idiopathic DCM and lend support to our "final common pathway" hypothesis that DCM is a cytoskeletalopathy.

Construction of a high-resolution physical map of the chromosome 10q22-q23 dilated cardiomyopathy locus and analysis of candidate genes.

Dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality and a leading cause of cardiac transplantation worldwide. Multiple loci and three genes encoding cardiac actin, desmin, and lamin A/C have been described for autosomal dominant DCM. Using recombination analysis, we have narrowed the 10q21-q23 locus to a region of approximately 4.1 cM. In addition, we have constructed a BAC contig, composed of 199 clones, which was used to develop a high-resolution physical map that contains the DCM critical region (approximately 3.9 Mb long). Seven genes, including ANX11, PPIF, DLG5, RPC155, RPS24, SFTPA1, and KCNMA1, have been mapped to the region of interest. RPC155, RPS24, SFTPA1, and KCNMA1 were excluded from further analysis based on their known functions and tissue-specific expression patterns. Mutational analysis of ANX11, DLG5, and PPIF revealed no disease-associated mutations. Multiple ESTs have also been mapped to the critical region.

A novel method for indexing echocardiographic left ventricular mass in infants, children and adolescents: evaluation of obesity-induced left ventricular hypertrophy.

BACKGROUND: Measurement of left ventricular mass (LVM) is important to the diagnosis of left ventricular hypertrophy in children with various cardiovascular diseases. The purpose of this study was to determine the most appropriate method for standardization of LVM and to evaluate obesity-induced left ventricular hypertrophy in children across the entire age range, from infancy through adolescence. METHODS: We studied 928 children and adolescents (527 males, 401 females), aged 0-17 years, who were classified into two groups by degree of obesity. Left ventricular mass was calculated by M-mode echocardiography using the formula of Devereux et al. and was indexed using body size (body length, bodyweight or body surface area) raised to a non-integer power using logarithmic transformation of measurements in children without obesity. RESULTS: The body length, bodyweight and body surface area exponents were 1.85, 0.88 and 1.15, respectively, in males, and 1.72, 0.82 and 1.08, respectively, in females. Whereas indexing of left ventricular mass by body length both in males and in females revealed significant differences between the two groups, indexing using bodyweight or body surface area exponents did not manifest left ventricular hypertrophy induced by obesity. CONCLUSION: It is suggested that applying body length exponents 1.85 in males and 1.72 in females is an appropriate method for indexation of LVM in children and adolescents. This method is particularly useful for the evaluation of left ventricular hypertrophy in children.

A novel technique using biplane cine magnetic resonance imaging to evaluate left ventricular volume in children.

The purpose of the study is to determine the feasibility of a novel simplified technique using cine magnetic resonance imaging (MRI) to assess left ventricular (LV) volume and ejection fraction (EF) validated by comparison with biplane LV angiography. Previous MRI studies to assess LV volumes have used multiple axial planes, which are compromised by partial volume effects and are time consuming to acquire and analyze. Accordingly, we developed a simplified imaging approach using biplane cine MRI and imaging planes aligned with the intrinsic cardiac axes of the LV. We studied 20 children (aged 4 months to 10 years) with various heart diseases. The accuracy of cine MRI was compared with that of LV angiography in all patients. LV volumes were calculated using Simpson's rule algorithm, for both MRI and LV angiography. LV volumes determined from MRI were slightly underestimated but correlated reasonably well with angiographic volumes (LVEDV: Y = 0.88X + 1.58, r = 0.99, LVESV: Y = 0.73X + 1.03, r = 0.98). Most importantly, even in patients who had abnormal ventricular curvature such as in tetralogy of Fallot, MRI determined LV volumes correlated well with angiographic values. The MR study was completed within 35 min in all patients. In conclusion, simplified biplane cine MRI, using the intrinsic LV axis planes, permits noninvasive assessment of LV volumes in views comparable to standard angiographic projections and appears practical for clinical use in childhood heart disease since the scan and analysis times are relatively short.

Evaluation of pulmonary blood supply by multiplanar cine magnetic resonance imaging in patients with pulmonary atresia and severe pulmonary stenosis.

The purpose of this study was to assess the capability of multiplanar cine magnetic resonance imaging (MRI) for evaluating pre- and post-operative pulmonary circulation in patients with pulmonary atresia and severe pulmonary stenosis. Seventy-three multiplanar cine MRIs were performed in 30 patients, aged 1 month to 7 years (mean age, 27 months). The morphology and size of the central pulmonary arteries (PA), source of the major aortopulmonary collateral arteries (MAPCA), patency of Blalock-Taussig (BT) shunt vessels, and the post-operative pulmonary circulation were assessed. The accuracy of cine MRI was compared with that of angiography in all patients. The PA was visualized to the first hilar branch in 21 patients, but not in 8 patients in whom the central PA was absent. On follow-up MRI, PA growth was measured, and the results showed excellent correlation with the results obtained by angiography. In 17 patients who had undergone 23 BT shunt operations, cine MRI correctly demonstrated all patient shunts and 5 of 6 stenotic lesions. Multiplanar cine MRI provided excellent detail of the peripheral PA in all patients, 7 of 8 peripheral pulmonary stenoses, 3 of 4 nonconfluent pulmonary arteries, and 2 of 3 PA obstructions. Although the sources of MAPCA were identified in 7 of 9 patients, the distal connection of the MAPCA was not detected in all patients. Seven patients were reexamined after pulmonary plasty; they exhibited normal pulmonary flow patterns. Multiplanar cine MRI provides high-resolution imaging of PA with dynamic visualization of flow and is an effective noninvasive technique for evaluating pre- and post-operative patients with pulmonary atresia and severe pulmonary stenosis.

Evaluation of left ventricular volume using automatic border detection in children: a comparison with conventional off-line echocardiographic quantification.

BACKGROUND: Evaluation of the clinical usefulness of the one-line automatic border detection system for determination of left ventricular volume in children in comparison to the conventional off-line method. METHODS: Eighty consecutive patients in whom clear images were obtained by two-dimensional echocardiography were studied. Using the Hewlett-Packard Sonos 2500 with a 3.5 or 5.5 Mhz phased array transducer, all patients were studied in the apical four-chamber imaging plane for automatic border detection and apical four-chamber and two-chamber imaging planes for manual tracing. Left ventricular end-diastolic and end-systolic volumes were measured and compared using the bi-plane Simpson method. RESULTS: Left ventricular end-diastolic volumes obtained by automatic border detection correlated well but were slightly underestimated compared to those obtained by manual tracing (r = 0.98). Left ventricular end-systolic volumes obtained by automatic border detection also correlated well with those obtained by manual tracing (r = 0.96). Left ventricular ejection fractions compared favorably. However, left ventricular volumes obtained using the classical Pombo M-mode echocardiography showed poorer correlation with those obtained by manual tracing methods. CONCLUSIONS: Automatic border detection is a promising method for real-time estimation of left ventricular volume. In patients with good endocardial tracking, automatic border detection can be used for routine studies of cardiovascular disease, even in children.

Chronic effects of oral prostacyclin analogue on thromboxane A2 and prostacyclin metabolites in pulmonary hypertension.

Abnormal biosynthesis of thromboxane and prostacyclin has been implicated in patients with primary pulmonary hypertension and secondary pulmonary hypertension associated with congenital heart disease, and could be involved in the pathogenesis of pulmonary vascular disease. The chronic effects of an oral prostacyclin analogue, beraprost sodium, on thromboxane and prostacyclin biosynthesis and on pulmonary circulation were investigated in 15 children with pulmonary hypertension. The plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured, as was the urinary excretion of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, which are stable metabolites of thromboxane A2 and prostacyclin, respectively. In patients with pulmonary hypertension, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were greater than in healthy controls: 210 +/- 49 versus 28 +/- 4 pg/mL (P < 0.05) and 32.6 +/- 8.9 versus 5.7 +/- 1.8 (P < 0.01), respectively. After 3 months of administration of beraprost, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were reduced significantly: 210 +/- 49 to 98 +/- 26 pg/mL (P < 0.01) and 32.6 +/- 8.9 to 18.0 +/- 6.7 (P < 0.05), respectively. In contrast, the plasma concentrations of 6-keto-prostaglandin F1 alpha in patients were slightly but not significantly higher than in controls, and did not change significantly after administration of beraprost. The concentrations of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in urine correlated significantly with thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively, in plasma. Beraprost improved the imbalance of thromboxane and prostacyclin biosynthesis and has a potential efficacy for preventing the progressive development of pathological changes in pulmonary vasculature.

Additive effect of beraprost on pulmonary vasodilation by inhaled nitric oxide in children with pulmonary hypertension.

Combined administration of inhaled nitric oxide and beraprost sodium resulted in a more intense decrease in pulmonary vascular resistance than nitric oxide given alone (mean -33% vs -45%, p <0.05), without serious systemic hypotension. Combined therapy with nitric oxide and beraprost sodium is highly desirable in treating primary and secondary pulmonary hypertension in children.

Chronic infantile neurological cutaneous articular syndrome in a patient from Japan.

A case of chronic infantile neurological cutaneous articular (CINCA) syndrome in a Japanese girl, started at the age of 13 days with episodes of fever, rash followed by swollen joint, hepatosplenomegaly, generalized lymphadenopathy and chronic central nervous system involvement, is reported. Some of the findings suggest that this syndrome may be the result of an intrauterine infection. This is the first case of CINCA syndrome in a Japanese girl.

Acute effect of oral prostacyclin and inhaled nitric oxide on pulmonary hypertension in children.

The hemodynamic effects of acute oral administration of a newly-developed prostacyclin analogue (beraprost sodium; 1-2 micrograms/kg), inhaled nitric oxide (NO; 20 ppm) and tolazoline hydrochloride (1 mg/kg) were measured in 17 children (mean age 1 year and 9 months) with pulmonary hypertension complicating congenital heart disease or primary pulmonary hypertension. Beraprost, NO and tolazoline achieved approximately equivalent reductions in pulmonary vascular resistance (20%, 26% and 18%, p < 0.05), but the greatest percentage decrease of pulmonary to systemic resistance ratio was obtained after administration of NO (33%, p < 0.05). Furthermore, combined administration of beraprost and NO produced the maximum effect of pulmonary vasodilation without adverse effects (49%). Beraprost appears to be an effective and available substitute for NO and tolazoline in screening for pulmonary vasodilator responsiveness. The combined use of beraprost and NO may provide an alternative treatment for pulmonary hypertension in children without serious complications.

Successful thrombolytic therapy using tissue-type plasminogen activator in Kawasaki disease.

Thrombolytic therapy using tissue-type plasminogen activator was performed in a 7-month-old boy with massive mural thrombi in large coronary aneurysms due to Kawasaki disease. Magnetic resonance imaging successfully demonstrated mural thrombi in both proximal and distal coronary aneurysms and their disappearance after thrombolytic therapy. We conclude that for preventing acute myocardial infarction and sudden death intravenous and intracoronary thrombolytic therapy with tissue-type plasminogen activator may help in infants and children with Kawasaki disease who have thrombi in coronary aneurysms.

Bronchial hyper-responsiveness to inhaled histamine in children with congenital heart disease.

In order to assess bronchial responsiveness in patients with congestive heart failure secondary to congenital heart disease, we performed a histamine inhalation test while monitoring transcutaneous oxygen tension and compared the respiratory threshold to histamine with that obtained in patients with bronchial asthma. The inhalation test was performed by doubling concentrations of histamine solution for 2 min at 1 min intervals. The respiratory threshold of histamine was defined as the minimal concentration causing a drop in transcutaneous oxygen tension greater than 10% from baseline. Six of 10 patients with congenital heart disease and all of 12 patients with bronchial asthma had bronchial hyper-responsiveness to histamine. The mean of histamine concentration was 2750 micrograms/mL and 937 micrograms/mL, respectively. During the histamine inhalation test, respiratory resistance gradually increased in congenital heart disease patients. This was measured by the linear slope of transcutaneous oxygen pressure (-1.08 +/- 0.75 mmHg/min), whereas in the bronchial asthma patients it rapidly decreased at the infection point (-4.19 +/- 1.86 mmHg/min). We conclude that children with congestive heart failure had bronchial hyper-responsiveness. We suggest bronchial hyper-responsiveness to inhaled histamine in congestive heart failure was caused by the gradual increased respiratory resistance, which was different from that of bronchial asthma.

Aneurysmal change of the ductus arteriosus after prostaglandin E1 administration for pulmonary atresia: demonstration with magnetic resonance imaging.

We report a case of pulmonary atresia in which the ductus arteriosus underwent aneurysmal dilatation after infusion of prostaglandin E1 incorporated in lipid microspheres. To our knowledge this is the first case in which this rare morphological change has been demonstrated with the noninvasive method of magnetic resonance imaging.

Coronary arterial lesions due to Kawasaki disease: selective coronary angiography in five cases with difficult-to-detect localized stenosis.

We report five cases of localized stenosis in coronary arterial lesions due to Kawasaki disease which were difficult to demonstrate by routine selective coronary angiography. Of these cases, three had localized stenosis overlapping the aneurysm, one had localized stenosis overlapping another adjacent branch, and the fifth had localized stenosis at the proximal left main trunk of the coronary artery. The reasons for difficulty in demonstrating the stenoses by routine study include: the localized stenosis was often superimposed on the aneurysm and/or the other adjacent branches, and the catheter was pushed into the inlet of the aneurysm on the proximal left main trunk. For a precise demonstration of a localized stenosis by selective coronary angiography, many angiograms from different perspectives should be taken. In addition, when a large aneurysm exists in the left main coronary artery, selective coronary angiography should be taken without pushing the catheter into the inlet of the aneurysm, and each frame of the cine coronary angiography should be carefully examined. Care should also be taken to compare with the initial view of the projection.

Analysis of left ventricular regional wall motion in normal neonates.

OBJECTIVE: To investigate neonatal circulatory change by quantitative analysis of left ventricular regional wall motion. DESIGN: Random prospective study. SETTING: Department of paediatrics in a teaching hospital. PARTICIPANTS: 66 neonates born after a normal pregnancy, labour, and delivery. INTERVENTIONS: Quantitative analysis of left ventricular regional wall motion was performed on cross sectional echocardiograms. M mode, cross sectional, and Doppler echocardiograms were obtained simultaneously. MAIN OUTCOME MEASURES: Manually traced endocardial contours at end diastole and at end systole were realigned by superimposing the centre of the ventricular mass and the axis. The contours were divided into 24 segments with 24 radii of equal arc from the centre. Then the ratio of the change in area between the outline of the contour and the two hemiaxes was calculated automatically. RESULTS: There was hyperkinesis of the interventricular septum in the first 24 hours after birth which continued until the end of the first week. Simultaneous echocardiographic examination showed evidence of pulmonary hypertension, as indicated by an increase in the ratio of the right pre-ejection period to the right ventricular ejection time (RPEP/RVET) and of the diameter ratio of the pulmonary artery to the aorta and a shortening of the acceleration time of pulmonary arterial blood flow. These features disappeared within a week. CONCLUSIONS: Hyperkinesis of the interventricular septum may reflect circulatory changes that are characteristic of the early neonatal period.

[Magnetic resonance imaging: evaluation of the Blalock-Taussig shunts and anatomy of the pulmonary artery].

The morphology and circulation of the pulmonary arteries and shunt vessels were evaluated by magnetic resonance imaging (MRI) in 8 patients with cyanotic heart disease after a Blalock-Taussig shunt operation. Their ages ranged from one month to 17 years. MRI permitted assessment of the size and patency of the Blalock-Taussig shunts, as well as the size and morphology of the pulmonary arteries in all patients. Measurements of the vessel diameters on MRI correlated well with the angiographic measurements (main pulmonary artery, r = 0.98; right pulmonary artery, r = 0.98; left pulmonary artery, r = 0.98; and Blalock-Taussig shunt, r = 0.97). MRI successfully imaged 3 of 4 shunt obstructions and 3 of 4 pulmonary stenoses with high resolution. In assessing peripheral pulmonary stenosis or obstruction, MRI was superior to echocardiography, the latter being unable to image peripheral pulmonary arteries satisfactorily. We concluded that MRI is an excellent noninvasive method for serially evaluating the anatomy and function of Blalock-Taussig shunts and pulmonary arteries, which is particularly useful for children with cyanotic congenital heart disease.