Acid sphingomyelinase deficiency: cardiac dysfunction and characteristic findings of the coronary arteries.

Two sisters with type B Niemann-Pick disease (genotype: S436R/S436R) showed cardiac dysfunctions, not secondary to pulmonary disease, at the beginning of the third decade. In the younger sister, myocardial dysfunction was refractory to treatment, resulting in death. At autopsy, the distal branches of the coronary arteries showed narrowing of the arterial lumina due to swelling of the medial and intimal smooth-muscle cells. This is the first report describing characteristic findings of coronary arteries in type B Niemann-Pick disease.

Effects of acute preload reduction on myocardial velocity during isovolumic contraction and myocardial acceleration in pediatric patients.

We evaluated the effects of acute preload reduction with inferior vena cava (IVC) occlusion on myocardial velocities during systole (Sa), early (Ea) and late (Aa) diastole, isovolumic contraction (IVV), and myocardial acceleration (IVA) measured by tissue Doppler imaging (TDI) in pediatric patients. A total of 22 patients (5 +/- 3 years) were studied: 9 patients (4 +/- 3 years) with Kawasaki disease, 8 patients (6 +/- 3 years) with atrial septal defect and right ventricular (RV) volume overload, and 5 patients (5 +/- 4 years) with pulmonary stenosis and RV pressure overload. Using TDI, Sa, Ea, Aa, IVV were recorded at the base of the RV free wall from a four-chamber view. IVA was calculated by dividing IVV by the time interval from onset of IVV to the time at peak velocity of this wave. In each group, IVC occlusion caused significant decreases in peak Sa, peak Ea, and peak Aa (p < 0.05). However, IVV and IVA did not change during acute preload reduction. This study demonstrated the effects of acute preload reduction on TDI velocities. In contrast to peak Sa, peak Ea, and peak Aa, IVV and IVA were unaffected by preload within a physiological range.

Tei index determined by tissue Doppler imaging in patients with pulmonary regurgitation after repair of tetralogy of Fallot.

The myocardial performance index (Tei index) determined by the pulsed Doppler method is a simple and noninvasive measurement for assessing global right ventricular (RV) function. This index can also be obtained by tissue Doppler imaging (TDI). The effects of significant pulmonary regurgitation (PR) on the determination of the Tei index by these two methods have not been investigated. We examined 15 patients (6.3 +/- 2.2 years) with significant PR after repair of tetralogy of Fallot (TOF) and 24 age-matched healthy children. Myocardial wall motion velocities at the tricuspid annulus were assessed during systole (Sa), early diastole (Ea), and late diastole (Aa) from a four-chamber view. Pulsed Doppler-Tei index and TDI-Tei index were measured as reported previously. The Tei index obtained by the pulsed Doppler method in TOF patients did not differ from that in normal children (0.30 +/- 0. 12 vs 0.32 +/- 0.07, p = not significant). TDI showed that TOF patients had significantly decreased Ea, Aa, and Sa velocities compared to those of normal children. Both isovolumic contraction time and isovolumic relaxation time in TOF patients were significantly longer than those in normal children (88 +/- 18 vs 62 +/- 23 msec and 46 +/- 11 vs 21 +/- 12 msec, respectively; p < 0.0001), although the duration of Sa did not differ between the two groups. Consequently, the Tei index as measured by TDI was significantly greater in TOF patients than in normal children (0.48 +/- 0.07 vs 0.30 +/- 0.07, p < 0.0001). The Tei index measured by the pulsed Doppler method is limited in its ability to assess RV function in patients with significant PR. However, the Tei index determined by TDI is a sensitive indicator of RV function in these patients, and it appears to be a promising new means of assessing global RV function in patients with significant PR.

Posterior descending coronary artery 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 and coronary flow velocity reserve (CFVR) in the posterior descending coronary artery (PD) in children, we examined 32 patients who had congenital heart disease (ventricular septal defect in 10, tetralogy of Fallot in 6, tricuspid atresia in 3, double-outlet right ventricle in 2, patent ductus arteriosus in 2, and aortic valve stenosis in 2) and 7 patients who had a history of Kawasaki disease without stenosis or aneurysm formation of the coronary artery. Average peak flow velocity (APV) in the PD was measured by transthoracic Doppler echocardiography at the time of intracoronary Doppler study. CFVR was defined as the ratio of hyperemic to basal APV. Clear envelopes of basal and hyperemic APV in the PD were obtained in 23 of 32 patients by transthoracic Doppler echocardiography. APV obtained from transthoracic Doppler echocardiography correlated highly with that from the Doppler guidewire method (r=0.91). The mean difference between transthoracic Doppler echocardiography and the Doppler guidewire method was 0.1+/-2.9. There was an excellent correlation between transthoracic Doppler echocardiography and the Doppler guidewire method for the measurements of CFVR (r=0.84). The mean difference between transthoracic Doppler echocardiography and Doppler guidewire was -0.016+/-0.198. Noninvasive measurement of coronary flow velocity and CFVR in the PD using transthoracic Doppler echocardiography accurately reflects invasive measurement of coronary flow velocity and CFVR by the Doppler guidewire method in pediatric patients with various heart diseases.

Effect of dobutamine on a Doppler echocardiographic index of combined systolic and diastolic performance.

Dobutamine stress echocardiography has become accepted in the evaluation of cardiac functional reserve. Although the Doppler-derived index of combined systolic/diastolic myocardial performance (Tei index) has been reported to be easily obtainable and useful for predicting left ventricular performance, the effect of dobutamine on the Tei index has not been determined in children. To assess the effect of dobutamine on the Tei index, 8 patients who had undergone surgery for ventricular septal defect and 7 patients who had a history of Kawasaki disease were examined. Echocardiographic recordings were obtained before and after dobutamine infusion (5 microg/kg per minute). Variables measured were transmitral flow velocities (E, A, E/A), rate-corrected mean velocity of circumferential fiber shortening (rate-corrected Vcf), and IMP. We measured isovolumic contraction time (ICT), isovolumic relaxation time (IRT), and ejection time (ET) and then calculated the Tei index using the following formula: Tei index = (ICT + IRT)/ET. Dobutamine infusion increased rate-corrected Vcf (29%, p < 0.01), peak E (7%, p < 0.05), and peak A (13%, p < 0.05). E/A ratio did not change during dobutamine infusion. ET, ICT, and IRT were found to decrease during dobutamine infusion. The magnitude of the change in the ICT (-21%, p < 0.01) was greater than those in IRT (-12%, p < 0.01) and ET (-8%, p < 0.05). The decrease in Tei index (-16%, p < 0.01) resulted in a decrease in ICT/ET (-21%, p < 0.01) and a slight decrease in IRT/ET (-12%, p < 0.05). The Tei index has potential as a sensitive indicator of the effects of inotropic stimilation on global left ventricular function.

Effects of carvedilol on left ventricular function, mass, and scintigraphic findings in isolated left ventricular non-compaction.

A four month old infant with isolated left ventricular non-compaction was treated with carvedilol. Haemodynamic studies and various types of imaging-including echocardiography, radiographic angiography, magnetic resonance imaging, and single photon emission computed tomography with (201)Tl, (123)I-beta-methyliodophenylpentadecanoic acid (BMIPP), and (123)I-metaiodobenzylguanidine (MIBG)-were performed before and 14 months after treatment. Left ventricular ejection fraction increased from 30% to 57%, and left ventricular end diastolic volume, end systolic volume, and end diastolic pressure showed striking reductions during treatment. Left ventricular mass decreased to about two thirds of the baseline value after treatment. Per cent wall thickening increased after carvedilol in the segments corresponding to non-compacted myocardium. A mismatch between (201)Tl and BMIPP uptake in the area of non-compaction observed before carvedilol disappeared after treatment. Impaired sympathetic neuronal function shown by MIBG recovered after treatment. Thus carvedilol had beneficial effects on left ventricular function, hypertrophy, and both metabolic and adrenergic abnormalities in isolated left ventricular non-compaction.

A comparison of tissue Doppler imaging and velocities of transmitral flow in children with elevated left ventricular preload.

Compared with transmitral velocities of flow, myocardial wall velocities obtained by tissue Doppler imaging are less influenced by left atrial pressure. The data supporting this assumption, however, are limited in patients with congenital cardiac disease. The aim of this study was to compare the effects of left ventricular preload on transmitral inflow and velocities assessed by tissue Doppler imaging. Tissue Doppler imaging, and conventional Doppler echocardiography with simultaneous invasive hemodynamic studies, were performed in 33 patients with a simple ventricular septal defect or patency of the arterial duct. Transmitral velocities (E, A) and mitral annular velocities (Ea, Aa) were measured, permitting calculation of the ratio of E to Ea. The ratio of pulmonary to systemic flows, and mean left atrial pressure, were also measured. In 10 of 33 patients, echocardiographic and hemodynamic studies were performed 4 to 5 months after surgery. The E and A values in the patients were greater than those in the controls (p < 0.01). In contrast, neither Ea nor Aa differed between the two group. The ratio of E to Ea in the patients increased significantly compared with that in the controls (8.9+/-2.1 vs 7.3+/-1.3, p < 0.01). The E value was directly related to mean left atrial pressure and the ratio of pulmonary to systemic flows. The velocities measured by Tissue Doppler imaging, however, had no significant relationship to either of these measurements. The ratio of E to Ea correlated well with mean left atrial pressure (r = 0.75, p < 0.01). In 10 post-operative patients, the values for E and A decreased from 119+/-14 to 89+/-10 cm/sec (p < 0.01) and from 91+/-22 to 61+/-9 cm/sec (p < 0.01), respectively. No significant changes were noted in the values of Ea and Aa. The ratio of E to Ea, and mean left atrial pressure, decreased from 10.3+/-1.9 to 8.2+/-1.5 (p < 0.01) and from 11.0+/-1.8 to 7.4+/-1.0 mmHg (p < 0.01), respectively. The percentage change in left atrial pressure correlated with the percent change in the ratio of E to Ea (r = 0.64, p < 0.05). The present study showed that the velocities obtained with tissue Doppler imaging are less dependent on mean left atrial pressure in children with elevated left ventricular preload caused by a left-to-right shunt.

A case of MERRF associated with chronic pancreatitis.

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.

Effects of dobutamine on coronary flow velocity response and their relations to age.

The purpose of this study was to assess the effects of low-dose dobutamine on left ventricular (LV) functional and coronary flow reserves using transthracic echocardiography. The study group consisted of 30 children aged from 5 months to 16 years (mean 4.8 +/- 4.4 years). Echocardiographic studies were repeated before and during dobutamine infusion (5 microg/kg per minute). The peak diastolic velocity in the left descending coronary artery (LAD) was recorded by pulsed-Doppler under the guidance of color Doppler flow mapping. The coronary flow velocity (CFV) response was calculated as the ratio of LAD peak flow velocity at dobutamine infusion to basal LAD peak flow velocity. Left ventricular contractility was calculated by two-dimensionally directed M-mode echocardiography. The rate-corrected mean velocity of circumferential fiber shortening (mVcfc) and LV end-systolic wall stress (ESS) were used as indices of contractility. Adequate spectral Doppler recordings of the LAD peak flow velocity for the assessment of CFV response were obtained in 26 of 30 patients (87%). The LAD peak flow velocity at dobutamine infusion increased significantly compared with the basal values. The CFV response in the younger children was low and increased significantly with age. The CFV response did not show significant correlations with the changes in heart rate, systolic blood pressure, rate-pressure product, nor ESS during dobutamine infusion. However, a significant relationship between the CFV response and the percent change of mVcfc was observed. In the present study using high frequency transthoracic echocardiography, we demonstrated the age-related changes in CFV response and LV functional reserve by dobutamine infusion. Responses of LV contractility and coronary flow to dobutamine are less sensitive in youngerchildren and increased with increasing age.

Progressive facial hemiatrophy after epileptic seizures.

Intractable complex partial seizures developed in a 3-year-old female with normal intracranial findings on computed tomography. Frontal paramedian band-like depression of the skin gradually developed thereafter, and progressive facial hemiatrophy (Parry-Romberg syndrome) was diagnosed. Computed tomography scanning at 5 years of age revealed multiple parenchymal calcifications and low-density areas in the white matter of the frontoparietal lobes. Epileptic seizures, one of the major neurologic complications of progressive facial hemiatrophy, could precede the succeeding neurocutaneous changes.

Morphological adaptation of the cardiovascular system in fetal rats during late gestation.

The aim of this study was to evaluate morphological changes of the cardiovascular system in fetal rats during late gestation. We used the rapid whole-body freezing technique for rats of day 17 through 21 of gestation. The right and left ventricular volumes increased markedly and significantly during this period by about 11- and 24-fold, respectively. Although the right ventricular volume was 108% larger with statistical significance than the left ventricular volume on day 17, they were almost equal after day 19. The length of the primum septum of the atrium significantly increased by 92% within 4 days, but the opening distance of foramen ovale significantly decreased by 14%. The ratio of the inner diameter (the sum of right and left pulmonary arteries to ductus arteriosus) significantly increased from 0.72+/-0.03 on day 17 to 1.17+/-0.07 on day 21. There was also a significant increase in the ratio of the inner diameters of the ascending to descending aorta. These observations suggest that the reduction of the opening distance of foramen ovale reflect the growth of pulmonary arteries.

The role of nitric oxide in dilating the fetal ductus arteriosus in rats.

Prostaglandin E is a major dilator of the fetal ductus arteriosus (DA), but the role of nitric oxide in fetal ductal dilation has not been established. We studied the effects of a potent nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), on the fetal DA in rats. L-NAME was injected into the dorsum of pregnant rats, and fetal DA was studied 4 h later with a rapid whole body freezing method. The inner diameters of the DA and the main pulmonary artery were measured on a freezing microtome. The inner diameter ratio of DA to main pulmonary artery (DA/PA) was 1.02+/-0.03 (mean +/- SEM; number of fetuses [n], 21) in normal near-term fetuses. The effect of prostaglandin synthesis inhibition was studied after orogastric administration of indomethacin to pregnant rats. In near-term rats on the 21st day of gestation (term, 21.5 d), a large dose of L-NAME (100 mg/kg) caused only mild ductal constriction, with DA/PA reduced to 0.83+/-0.05 (n = 20). Indomethacin (1 mg/kg) caused moderate ductal constriction, and DA/PA was decreased to 0.65+/-0.05 (n = 21). Combined administration of L-NAME (10 mg/kg) and indomethacin (1 mg/kg) caused severe ductal constriction, with DA/PA of 0.26+/-0.03 (n = 16). In preterm rats on the 19th day of gestation, a moderate dose of L-NAME (10 mg/kg) caused severe ductal constriction, with a DA/PA of 0.32+/-0.05 (n = 24). Indomethacin (1 mg/kg) alone caused only mild ductal constriction, with DA/PA 0.86+/-0.02 (n = 16). In conclusion, prostaglandin has a major role and nitric oxide has a minor role in dilating the DA in the near-term fetal rat. In contrast, nitric oxide has a major role and prostaglandin has a minor role in dilating the DA in preterm fetal rats.

Abnormal left ventricular diastolic filling patterns in small-for-gestational-age infants.

Doppler transmitral flow velocity patterns in assessing left ventricular diastolic function in small-for-gestational-age infants have been poorly understood. The purpose of this study is to examine Doppler filling patterns in small-for-gestational-age infants (n = 13) and to compare them with those in age-matched appropriate-for-gestational-age infants (n = 29). We measured peak flow velocities of early diastole (peak E wave) and atrial contraction (peak A wave), ratio of peak E wave to peak A wave (peak E/A wave), velocity time integrals of E wave (VTIE wave) and A wave (VTIA wave), ratio of VTIE wave to VTIA wave (VTIE/A wave), first third filling fraction, peak filling rate normalized to stroke volume, and deceleration time. Mean gestational age and heart rate did not show a significant difference between the appropriate- and the small-for-gestational-age infants. The mean birth weight in the small-for-gestational-age infants was significantly lower than that in the appropriate-for-gestational-age infants (802+/-220 vs. 1184+/-260 g, P<0.01). In the small-for-gestational-age infants, the peak E wave, peak A wave, peak E/A wave,VTIE wave, first third filling fraction, and peak filling rate normalized to stroke volume were significantly lower than those in the age-matched appropriate-for-gestational-age infants (21.9+/-6.7 vs. 32.2+/-6.9 cm/s, 26.5+/-6.2 vs. 34.5+/-6.2 cm/s, 0.82+/-0.15 vs. 0.93+/-0.14, 1.88+/-0.45 vs. 2.39+/-0.51 cm, 0.36+/-0.04 vs. 0.41+/-0.04, 5.86+/-0.75 vs. 7.11+/-0.63/s, P<0.05, respectively). In the small and appropriate for gestational age infants, peak E wave, VTIE wave, and peak E/A increased significantly with increasing body weight. In the small-for-gestational-age infants, the slopes of regression lines between body weights and peak E wave and VTIE wave were significantly lower than those in the appropriate for gestational age infants, suggesting a significant reduction in E wave even when considering a difference in their body weight. This study suggests that the significant decreases in the early diastolic filling in the small-for-gestational-age infants may be related to the reduced left ventricular diastolic function.

Maturational changes in left ventricular contractile state.

It has been suggested from animal and human studies that age-related alterations in left ventricular contractility occur. However, there is little information about growth-related changes in left ventricular performance from preterm infants to older children. In 22 preterm infants, 23 fullterm infants, and 35 children, left ventricular contractility was evaluated by two-dimensional and M-mode echocardiography. The rate-corrected mean velocity of fiber shortening (mVcfc)-end-systolic wall stress (ESS) relation was used as an index of contractility. There were significant inverse linear correlations between ESS and mVcfc in the three groups (all P<0.01). The slopes and y-intercepts of the regression lines of mVcfc-ESS relation were both significantly greater in the premature infants (mVcfc=-0.0133 ESS+1.62) and neonates (mVcfc=-0.0107 ESS+1.55) than those in the children (mVcfc=-0.0047+1.29). However, there were no significant differences between the premature and fullterm infants. Thus, these findings suggest that the contractility and afterload sensitivity of the left ventricle in the premature infants may be similar to those in the fullterm infants. In addition, our serial study in the premature infants showed that the ESS increased significantly with growth while the mVcfc did not change, suggesting that the left ventricular performance in the premature infants during early life was preserved in the setting of a lower afterload.

Peak systolic stress-rate-corrected mean velocity of fiber shortening in preterm and fullterm infants.

The relation of rate-corrected mean velocity of fiber shortening (mVcfc)-end-systolic wall stress (ESS) is a load-independent index of left ventricular contractility, but involves simultaneous M-mode echocardiography, carotid or axillary pulse tracing and blood pressure determination, which may be impractical in younger infants. We examined whether the relation of the peak systolic wall stress (PSS)-mVcfc could be used as a simpler method of assessing left ventricular contractility in preterm and fullterm infants. In 45 preterm and fullterm infants, mVcfc, ESS, and PSS were determined using echocardiography, axillary pulse tracing and blood pressure measurement. Five patients with left ventricular dysfunction or low cardiac output state were also studied. The relation of PSS and ESS was PSS=5.19+1.04 ESS (r=0.98, p<0.01). The slope of mVcfc=1.58-0.012 ESS (r=-0.78, p<0.01) was nearly identical to that of mVcfc=1.60-0.011 PSS (r=-0.75, p<0.01), with no difference in the regression coefficients. The relationship of PSS and ESS in 5 patients was very close and the slope of the regression line was nearly identical to that of 45 infants. The relation of mVcfc PSS correlates well with the relation using ESS and can be used as a simple method of assessing left ventricular contractility.

Accelerated maturation of fetal ductus arteriosus by maternally administered vitamin A in rats.

Maturation of fetal ductus arteriosus is associated with increased constriction in response to maternally administered indomethacin. Recently retinoic acid has been shown to be important in development of the fetal ductus arteriosus. To determine whether retinoid might be of value in the treatment of patent ductus arteriosus in premature infants, we studied the response of fetal ductus arteriosus to indomethacin with and without pretreatment with vitamin A (1 mg (3000 IU)/kg, intramuscular injection) in near-term and preterm rats. Maturation of the ductus arteriosus was studied by measuring the inner diameters of the ductus arteriosus (D) and main pulmonary artery (P) to get D/P ratio 4 h after orogastric administration of 1 mg/kg indomethacin. D/P was 1.0 in the fetus before administration of indomethacin. In near-term fetuses on the 21st d without vitamin A, D/P decreased to 0.54 with indomethacin, whereas it decreased to 0.27 (p < 0.05) in those with pretreatment with vitamin A on the 19th and 20th d. In preterm fetuses on the 20th d without pretreatment with vitamin A, D/P decreased to 0.82 with indomethacin, whereas it decreased to 0.66 (p < 0.05) in those with pretreatment with vitamin A on the 19th d. It is concluded that maternally administered vitamin A accelerates maturation of the ductus arteriosus in fetal rats.

Influence of right ventricular volume and pressure overloads on assessment of left ventricular volume using two-dimensional echocardiography in infants and children with congenital heart diseases.

In patients with right ventricular volume or pressure overload, the biplane Simpson's rule underestimates left ventricular volume more than the modified Simpson's rule. We suggest that the modified Simpson's rule should be used for estimation of left ventricular volumes rather than the biplane Simpson's rule in determining therapy for infants or children with complicated congenital heart disease.

Changes in left ventricular diastolic filling patterns before and after the closure of the ductus arteriosus in very-low-birth weight infants.

To evaluate serial changes in left ventricular diastolic filling patterns in preterm infants, we performed echocardiographic examinations in 18 very-low-birth weight infants and 20 fullterm infants before and after the closure of the ductus arteriosus. In the fullterm infants, the ductal closure induced significant decreases in the peak velocity and flow velocity integral of early diastole, first third filling fraction, and mitral stroke volume. In the preterm infants, by contrast, there were significant increases in the flow velocity integral of early diastole, first third filling fraction, and mitral stroke volume after the ductal closure. No differences following the ductal closure were found in the atrial phase of filling and peak filling rate normalized to stroke volume in either group. When the ductus arteriosus was open, essentially the same left-to-right shunting of the ductus arteriosus was detected in both preterm and fullterm infants, but the Doppler flow patterns of the patent foramen ovale were different: the fullterm infants had a single flow peak mainly during ventricular late systole and early diastole, but the preterm infants had two or three flow peaks with nearly equal amplitudes lasting from ventricular systole to diastole, which resembled the Doppler flow pattern of atrial septal defect. Only a faint Doppler flow signal of the foramen ovale was observed after the ductus arteriosus closed. Our results obtained from the preterms suggest that the left-to-right shunt through the foramen ovale may be one important factor to alter the Doppler transmitral filling patterns during the fetal to neonatal cardiovascular changes.