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.

Japan: perspectives in school health.

In Japan, the original Law of School Health was established some 65 years ago to improve the environment and to prevent infectious diseases in school. Most recently, new environmental problems and behavioral issues have emerged. In addition to environmental health and health education, a major aspect of school health has been the development of a mass screening system both to detect present problems and to prevent adult diseases. In this article, the school health system in Japan is described and the application of mass screening by reference to heart disease as detected in Shimane Prefecture is illustrated. In the future, mass screening may be combined with a computer-based analysis system for managing data on new kinds of problems. New disciplines may become involved and improved programs developed, based on the lessons already learned from mass screening.

[Partial anomalous pulmonary venous drainage to the high superior vena cava; repair by direct anastomosis between the superior vena cava and the right atrial appendage; report of a case].

A 10-year-old boy with partial anomalous pulmonary venous connection to the high superior vena cava (SVC) underwent surgical repair by Williams method. The SVC was divided above the orifice of the anomalous pulmonary vein. The proximal end of the SVC was closed and the distal end of the SVC was anastomosed to the right atrial appendage (RAA). The anomalous pulmonary vein was rerouted to the left atrium via the SVC and the surgically enlarged central type atrial septal defect (ASD). The postoperative course was uneventful except transient sinus bradycardia and catheter study showed no stenosis of the SVC and the RAA.

[Successful operation for isolated cardiac rhabdomyoma of the right atrium].

A 12-year-old girl has experienced palpitation and dizziness, and presented atrial flutter with maximal heart rate of 220/min. Two-dimensional echocardiogram and chest MRI revealed a mass attached to the inter-atrial septum. Complete excision of the tumor including the atrial septum was performed without damage to tricuspid valve. The interatrial septal defect was closed primarily. Histology of the tumor was compatible with cardiac rhabdomyoma. Sinus rhythm was present and no tachycardia occurred in the postoperative period. On the literature, only one case of isolated cardiac rhabdomyoma developing in the atrium was reported and this is considered as the oldest operative case in Japan.

[A quantitative study of regional cerebral blood flow in childhood using 123I-IMP-SPECT: with emphasis on age-related changes].

Single photon emission computed tomography (SPECT), using N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) was used for quantitative analysis of regional cerebral blood flow (rCBF) on 26 individuals between 0 and 19 years of age. The rCBF showed age-related changes; it was low in early infancy, increased in late infancy through early childhood, and decreased and remained constant after puberty. The rCBF through cerebral cortex varied more greatly than through thalamus and cerebellum, and seemed to depend more closely on age. In the case of 4 months of age rCBF was very low at the frontal region and was very high at the occipital region. In more older cases, rCBF in the cerebral cortex was higher than in the thalamus. In childhood, rCBF was very inconsistent and showed a great inter-individual variance.

Quantitative analysis of systolic blood pressure tracking during childhood and adolescence using a tracking index: the Shimane Heart Study.

We used a tracking index to carry out a quantitative analysis of blood pressure tracking in children and adolescents. The index was calculated according to changes in blood pressure quintiles for the whole population during the observation period. The study population consisted of 463 Japanese children living in Izumo, who were examined every 3 years from 6 to 12 years of age in cohort 1, and from 9 to 15 years of age in cohort 2. In both sexes, the tracking index decreased transiently during the period from 9 to 12 years of age and increased again thereafter. The index was higher in girls than in boys except for the period from 12 to 15 years. Correlation coefficients between blood pressure at the first and that at the second examination increased with age in both sexes. We conclude that the tracking index could quantify the degree of tracking. Systolic blood pressure tracked well during childhood and adolescence, and the degree of tracking increased after the age of 12 years in both sexes.

Histopathologic and coronary angiographic assessment of effectiveness of aspirin or aspirin-and-gammaglobulin in Kawasaki disease.

Coronary angiography and right ventricular endomyocardial biopsy were performed in 36 children during convalescence (days of illness 23-86; mean = 41.5 days) following acute Kawasaki disease. Treatment of the acute stage was not randomized; it consisted of aspirin alone in 14 subjects (during the years 1980-88), and gammaglobulin and aspirin in 22 subjects (1984-91). The dosage of aspirin was 30 mg/kg orally during the acute febrile stage and 5-10 mg/kg orally after lysis of fever. The dosage of gammaglobulin was 200 mg/kg x 5 days in 19 patients, 200 mg/kg x 3 days in one patient, 200 mg/kg x 1 day + 400 mg/kg x 4 days in one patient and 200 mg/kg x 4 days + 400 mg/kg x 4 days in one patient. Among the 14 patients treated with aspirin alone, large coronary aneurysms were noted in four, moderate aneurysms in three and transient aneurysms in one. Among 22 patients treated with gammaglobulin, only five had aneurysms and these were transient. The histopathological (HP) score based on myocardial disarrangement, degeneration and hypertrophy; interstitial edema, large mononuclear cell infiltration and fibrosis; and endocardial abnormalities was higher in the aspirin group than in gammaglobulin group. Moderate to severe HP changes were noted in five subjects in the aspirin group, while moderate HP changes were found in only two subjects in the gammaglobulin group. Gammaglobulin therapy not only reduced the incidence of the coronary arterial lesions but also reduced the severity of myocardial damage from moderate or severe to mild in Kawasaki disease.

Successful percutaneous closure of a coronary artery fistula with a detachable balloon.

Percutaneous transcatheter closure technique of a coronary artery fistula with a detachable balloon was performed for a 14 year old male student. Complete closure of the fistula without any complications was confirmed by angiography after the procedure. When the patient underwent a second angiography 6 months after the closure, it was confirmed that the position of the balloon had not changed, that the interruption of the flow of the fistula had been maintained and that the diameter of the left coronary artery and the fistula were reduced. Percutaneous closure technique using a detachable balloon may become the primary treatment for a coronary artery fistula in place of surgical ligation.

Methacholine inhalation challenge in children with idiopathic chest pain.

Bronchial reactivity to inhaled methacholine (MCH) was evaluated in 32 patients with 'idiopathic' chest pain. Each pain was recurrent in nature. The incidence of cases with a provocative concentration causing a 20% fall in the forced expiratory volume in 1 sec (PC20) of 10 mg/ml or less was 62.5% (20 cases), while it was only 11.1% (three cases) in 27 healthy controls. Seventeen patients had no personal history of allergic diseases, elevated serum IgE level or positive house dust mite-specific IgE antibody. Among these 17, eight (47.1%) had a PC20 of 10 mg/ml or less, the incidence of which was also higher than that of the healthy controls. During the challenge, eight patients complained of chest pain similar to that experienced before. The present results indicate that bronchial hyper-reactivity is an important cause of 'idiopathic' chest pain. Patients with unexplained chest pain should be considered for inhalation challenge.

A longitudinal study of blood pressure, cholesterol and left ventricular muscle volume in children: the Shimane Heart Study.

Three hundred and forty-four healthy schoolchildren living in Izumo City, Shimane Prefecture, Japan, were assessed at 3 year intervals from 6 to 15 years, starting in 1978 (Cohort 1) or 1981 (Cohort 2). Tracking indices (Ti) were calculated as follows: Ti = (2x + y - z)/N/0.89, where x, y and z refer to the total number in the same, adjacent and remote trisections, respectively, and N = x + y + z. If Ti > 1, there is positive tracking. For systolic blood pressure (SBP) measurements (except at 6 years old) and serum cholesterol levels, all Ti were greater than 1.0 regardless of the time when tracking was commenced. Tracking indices were slightly greater in the serum cholesterol levels than in the SBP measurements. Left ventricular muscle volume indices (LVMVI) were calculated by echocardiographic measurements. In girls, the LVMVI was larger only in the above-median SBP group at the age of 12 years (P < 0.01), but the LVMVI of the higher SBP (above median) group was larger than in the lower (below median) group at every age in boys; the difference was statistically significant (P < 0.05) at 12 and 15 years of age. Left ventricular mass enlargement may occur in the prehypertensive stage in humans as well as in rats.

Effect of heart rate on the end-systolic wall stress-mean velocity of circumferential fiber shortening relation.

The correlation of left ventricular end-systolic wall stress (ESS) with the mean velocity of fiber shortening (mVcf) is an index of the myocardial contractile state, independent of the ventricular loading conditions (afterload). However, there have been few reported estimates of the effect of changes in the heart rate on the ESS-mVcf relationship. In the present study, 25 subjects with histories of Kawasaki disease (mucocutaneous lymph node syndrome: MCLS) were evaluated for the effects of changes in heart rate, afterload and preload, on the ESS-mVcf relationship. The latter was independent of afterload. After atrial pacing, ESS decreased and mVcf increased, both significantly, compared to those of subjects at rest. The change of the ESS-mVcf relationship induced by atrial pacing approximately paralleled the mean regression line obtained in the resting state. However, the shift induced by preload was not parallel to the mean regression line for the resting population. These data suggest that the ESS-mVcf relationship is independent of any change in heart rate, and that it may depend on preload.

Diastolic left ventricular function in normal children: the maximal positive dD/dt compared with the E/A ratio of mitral flow pattern.

The normal values for left ventricular diastolic function in children are influenced by numerous factors. As an index of this function, the maximum velocity of left ventricular internal dimension expansion (+ max dD/dt) was calculated from M-mode echocardiography for 33 normal persons who ranged in age from seven days to 18 years. This index showed a linear correlation with left ventricular end-diastolic dimension in the resting state. This index was compared with the E/A ratio which is ordinarily used as the diastolic functional index for children. Considering changes in physical development during childhood, both indices showed similar trends in relation to body surface area. The E/A ratio was strongly influenced by heart rate, but + max dD/dt was not. This was the major difference between two indices.

Determination of left to right shunt by thermodilution in patients with ventricular septal defect.

A modified thermodilution technique was used to determine the quantity of shunt in patients suffering from congenital heart disease with a left to right shunt. In our modification, the thermistor was placed within the pulmonary artery and an indicator was injected into both sides of the heart. In a series of 33 cardiac catheterizations in children (1-17 years) with ventricular septal defect (VSD), pulmonary blood flow (Qp), systemic blood flow (Qs) and the ratio of Qp to Qs (Qp/Qs) were determined by this and ordinary oximetry (Fick) methods. Correlation coefficients between indexes obtained by these methods were 0.54 (Qp), 0.78 (Qs), and 0.75 (Qp/Qs). The estimates of Qp and Qp/Qs obtained by thermodilution were smaller than those obtained by the Fick method. This modification of thermodilution is simple, rapid, and useful in clinical practice.

Clinical estimation of left ventricular size: precordial electrocardiographic voltage corrected by the measurement of thorax.

The left ventricular muscle volume (LVMV) was determined echocardiographically and the radius of the circle with equal circumference to the thorax (R1) was calculated from thorax-circumference in 688 children as a part of the Shimane Heart Study. correlation of the summed precordial voltage (SV1 + RV5) with LVMV was not close (r = 0.377 in boys and -0.095 in girls). The precordial voltage (SV1 + RV5) was corrected by the square of R1 to compensate for the diminution of electrical potential by distance. Correlation between (R1) 2 x (SV1 + RV5) and LVMV was good in boys (r = 0.681) and relatively good in girls (r= 0.554). This fact indicates that LVMV can be predicted from ECG and anthropometric measurements of thorax without using echocardiography. Therefore, (R1) 2 x (SV1 + RV5) seems to have clinical applicability as the index of LV size, if the differences in (R1) 2 x (SV1 + RV5) and in the correlation coefficient between both sexes are clarified further.

Relationship between left ventricular muscle volume and body surface area corrected by subcutaneous fat weight in normal children.

Left ventricular muscle volume (LVMV) was measured echocardiographically in 688 normal children ranging in age from 5 to 15. Lean body surface area (BSA) was obtained from height and lean body weight, which was estimated using triceps skinfold thickness, upper arm circumference and body weight. Regression lines of LVMV against BSA or lean-BSA were compared between boys and girls. There was statistically significant sex difference in regression lines when LVMV were plotted against BSA (p less than 0.005), but this difference disappeared when plotted against lean-BSA. We conclude that the sex difference of LVMV with a similar BSA originates from the difference of lean body weight between boys and girls.

Computer analysis of frank vectorcardiograms in normal children--maximal spatial QRS vector.

Frank vectorcardiograms recorded on magnetic tape were analyzed by a computer. The study population was 835 normal children aged from 6 to 16. Magnitudes, angles (azimuth, elevation) of the maximal spatial QRS vector and QRS duration were calculated. The magnitude of maximal spatial QRS vector increased significantly in males compared to those in females at ages 9-10, 11-12 (p less than 0.01) and 15-16 (p less than 0.001). Though there was no significant difference of elevation in either sex, azimuth tended to move more anteriorly in females than in males. QRS duration in males became longer with increasing age, while in females at age 15-16, it decreased (p less than 0.001).

Changes of left ventricular isovolumic relaxation time with growth in children.

We investigated the changes of left ventricular isovolumic relaxation time (LVIRT) with growth and the factors influencing them during childhood, in a 10-year follow-up study. We measured the body height (BH), body weight (BW), lean body weight (LBW), heart rate (HR), blood pressure (BP), left ventricular muscle volume index (LVMVI), and LVIRT corrected by the preceding R-R interval (IRT/R-R), of 187 healthy children at 3-year intervals (6, 9, 12, 15 years old). IRT/R-R were prolonged with growth in boys and girls. At the ages of 12 and 15, the IRT/R-R of girls were longer than those of boys. Significant correlation coefficients for IRT/R-R on systolic and diastolic, BW, and LVMVI were 0.28, 0.31, 0.20, 0.28, respectively. These data suggest that (1) IRT/R-R is mainly determined by the diastolic BP, (2) left ventricular diastolic function of children develops with growth of body size, especially BW, and (3) left ventricular early diastolic function in adolescents is related to sexual maturation.