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The cause of fetal death by sulfonylureas (SUs), used for diabetes in pregnancy in the early 1960s, remained unsolved for decades. In 1993, Nakanishi discovered constriction of ductus arteriosus (DA) strips in rabbit fetuses with glibenclamide, a SU and inhibitor of the KATP channel. Later, Momma showed dose-dependent fetal DA constriction by glibenclamide injected directly into the fetus in rats. Every first-generation SU constricted the fetal DA by oral administration to the pregnant rat. DA constriction with the clinical dose of these SUs was mild, whereas a 100 times larger dose was needed to close the DA completely. Coadministration of SUs and cylooxygenase inhibitors caused additive severe constriction and complete closure of the fetal DA. These data suggested that the aforementioned high fetal death rate (63% in 1962) with chlorpropamide was due to the coadministration of this SU and aspirin-like drugs.

Aim We encountered a case of fetal toxicity due to ductus arteriosus (DA) constriction in a 36-week pregnant woman who had applied multiple ketoprofen patches. The aim of the present study was to present the case and develop a model to predict quantitatively the fetal toxicity risk of transdermal administration of ketoprofen. Methods Human placenta perfusion studies were conducted to estimate transplacental pharmacokinetic (PK) parameters. Using a developed model and these parameters, human fetal plasma concentration profiles of ketoprofen administered to mothers were simulated. Using pregnant rats, DA constriction and fetal plasma drug concentration after ketoprofen administration were measured, fitted to an Emax model, and extrapolated to humans. Results Transplacental transfer value at the steady state of ketoprofen was 4.82%, which was approximately half that of antipyrine (passive marker). The model and PK parameters predicted almost equivalent mother and fetus drug concentrations at steady state after transdermal ketoprofen administration in humans. Maximum DA constriction and maximum plasma concentration of ketoprofen after administration to rat dams were observed at different times: 4 h and 1 h, respectively. The model accurately described the delay in DA constriction with respect to the fetal ketoprofen concentration profile. The model with effect compartment and the obtained parameters predicted that use of multiple ketoprofen patches could potentially cause severe DA constriction in the human fetus, and that fetal toxicity might persist after ketoprofen discontinuation by the mother, as observed in our case. Conclusion The present approach successfully described the sustained fetal toxicity after discontinuing the transdermal administration of ketoprofen.

Diazoxide, an ATP-sensitive potassium channel opener, is the main therapeutic agent for treating hyperinsulinemic hypoglycemia. The aim of this study was to determine the in vivo ductus arteriosus (DA)-dilating effects of diazoxide in fetal and neonatal rats.Near-term rat pups delivered via cesarean section were housed at 33°C. After rapid whole-body freezing, the ductus arteriosus (DA) diameter was measured using a microscope and a micrometer. Full-term pregnant rats (gestational day 21) were injected i.p. with diazoxide (10 and 100 mg/kg) 4 h before delivery, and the neonatal DA diameter was measured at 0, 30, or 60 min after birth. The newborn rats were also injected i.p. with diazoxide (10 and 100 mg/kg) at birth or 60 min after birth. DA was measured at 0, 30, or 60 min after injection. In the fetal investigation, the effect of diazoxide was studied via simultaneous application of indomethacin (10 mg/kg) and L-nitroarginine methyl ester (L-NAME) on gestational days 21 and 19.The control rats had rapid postnatal DA constriction (diameter, 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Diazoxide had a dose-dependent inhibitory effect on postnatal DA constriction. Prenatal diazoxide (10 mg/kg) inhibited postnatal DA closure (0.20 mm at 60 min after birth). The diazoxide injection (10 mg) at birth inhibited postnatal DA closure (0.14 mm at 60 min after birth). Diazoxide injection in 60-min-old rats dilated the constricted DA at 60 min (0.10 mm vs. 0.02 mm in the controls). In the fetal investigation, diazoxide inhibited the fetal DA constrictive effect of indomethacin and L-NAME.Diazoxide attenuates postnatal DA constriction and dilates a closing DA in fetal and neonatal rats.

The fetal patency and neonatal closure of the ductus arteriosus (DA) are regulated with oxygen and prostaglandins. The proposed oxygen sensors of fetal and neonatal DA include P450-endothelin and the Kv channel [1]. We hypothesized that the ATP-sensitive potassium channel (KATP channel) is another oxygen sensor [2].

Cardiovascular anomalies are present in 80% of neonates with 22q11.2 deletion syndrome. Three genes in chromosome 22q11.2 (TBX1, CRKL, and ERK2) have been identified whose haploinsufficiency causes dysfunction of the neural crest cell and anterior heart field and anomalies of 22q11.2 deletion syndrome. The most common diseases are conotruncal anomalies, which include tetralogy of Fallot (TF), TF with pulmonary atresia, truncus arteriosus, and interrupted aortic arch. A high prevalence of the deletion is noted in patients with TF with absent pulmonary valve, TF associated with pulmonary atresia and major aortopulmonary collateral arteries, truncus arteriosus, and type B interruption of aortic arch. Right aortic arch, aberrant subclavian artery, cervical origin of the subclavian artery, crossing pulmonary arteries, and major aortopulmonary collateral arteries are frequently associated with cardiovascular anomalies associated with 22q11.2 deletion syndrome. Virtually every type of congenital heart defect has been described early in the context of a 22q11.2 deletion. In conclusion, conotruncal anomaly associated with aortic arch and ductus arteriosus anomalies should increase the suspicion of 22q11.2 deletion.

Furosemide increases prostaglandin production and may be associated with patent ductus arteriosus (PDA). We aimed to clarify the in vivo ductus-dilating effects of furosemide in neonatal rats. Near-term rat pups delivered by a cesarean section were housed at 33 degrees C. After a rapid whole-body freezing, the DA diameter was measured using a microscope and a micrometer. Pregnant rats (gestational day 21) were s.c. injected with furosemide 4 h before delivery, and the neonatal DA was examined 0, 15, 30, 60, and 120 min after birth. Furosemide was also s.c. injected into 60-min-old rats and the DA diameter was examined 30, 60, and 120 min later. The control rats showed a rapid postnatal DA constriction (diameter: 0.80 and 0.08 mm at 0 and 60 min after birth, respectively). Prenatally administered furosemide delayed postnatal DA closure (0.36 mm at 60 min after birth). Furosemide injection in 60-min-old rats dilated the constricted DA at 60 min (0.25 versus 0.02 mm in the controls). Indomethacin inhibited furosemide-induced DA dilatation. Furosemide delays DA closure and dilates the constricted DA in neonatal rats. If furosemide has similar effects in human preterm neonates, caution may be warranted in its use in the treatment of infants with PDA.

Here we report on a patient with multiple lentigines, hypertelorism, short stature, arachnodactyly, scoliosis, dissecting aneurysm, hypertrophic cardiomyopathy and developmental delay, and a family history of Marfan syndrome. The patient is affected with both Marfan and LEOPARD syndromes. Mutational screening of the FBN1 gene showed a c.1464TA (p.C488X) mutation and screening of the PTPN11 gene showed a c.836AG (p.Y279C) mutation. We conclude that each mutation contributed independently to individual features in the ocular and cardiovascular systems, although short stature was more significantly influenced by the p.Y279C change in PTPN11 rather than the mutation in FBN1. To our knowledge, this is the first report of mutations in both FBN1 and PTPN11 with combined phenotypes of Marfan and LEOPARD syndromes.

Background: Magnesium sulfate (MgSO4) is used therapeutically for eclampsia and tocolysis. Some reports have suggested a relationship between therapeutic MgSO4 and patent ductus arteriosus (DA) in preterm infants. Objectives: To clarify patent DA induction by MgSO4 in preterm infants, we studied the increase in serum Mg concentrations and fetal dilatation and postnatal delayed closure of the ductus, using transplacental MgSO4 in rats. Methods: Fetal and neonatal ductus diameters were measured with a microscope and a micrometer after rapid whole-body freezing. In the postnatal study, 21-day pregnant dams were administered a subcutaneous injection of MgSO4 1–3 h before delivery, and the ductus was studied 0, 15, 30, 60 and 120 min after birth. In the fetal study, MgSO4 (1 g/kg) and indomethacin (10 mg/kg) were simultaneously administered to 21-day dams and the fetal ductus was studied 1, 2 and 4 h later. Serum Mg concentration was measured in the dams and newborns. Results: Neonatal Mg concentrations increased from 3.8 to 4.7 and 5.8 mg/dl at 1 and 3 h after maternal administration of MgSO4. Following MgSO4 administration 3 h before birth, closure of the neonatal DA was delayed. The ductus diameter was 0.88 mm (0.80 mm in control) at 0 min, and 0.26 mm (0.08 mm in the control) at 60 min after birth. In the fetal study, MgSO4 initially reversed and later attenuated the ductus-constricting effect of indomethacin. Conclusions: Hypermagnesemia induced by transplacental MgSO4 attenuates the fetal ductus-constricting effects of indomethacin, and delays postnatal ductal closure in rats.

Background: Indomethacin is used to close the patent ductus arteriosus in premature infants and for tocolysis of preterm labor. Clinically and experimentally, early in utero exposure to indomethacin induces the paradoxical delay of postnatal closure of the ductus arteriosus. Objectives: To clarify the pharmacological nature of the delay of closure of the ductus arteriosus in the rat. Methods: We studied early in utero exposure to indomethacin (dose and timing) in addition to other drugs, inducing a delay in postnatal ductal closure. Pregnant rats at near term were studied by cesarean section on gestational day 21 (D21), incubated in room air at 33°C, followed by rapid whole-body freezing. Results: The delay in closure of the ductus arteriosus was dose dependent. A large dose of indomethacin (10 mg/kg) 1 or 2 days before birth induced a delay of 3–4 times. A timing study revealed maximum delay with administration of indomethacin 2 days before birth and minimum delay with administration 5 days before. Aspirin, ibuprofen, the selective COX1 inhibitor SC 560, the selective COX2 inhibitor rofecoxib and a prostaglandin EP4 receptor blocker, ONO-208, all delayed neonatal ductal closure following maternal administration on D19 and D20. Conclusions: The delay by indomethacin was dose dependent. The maximum delay was induced by 2 doses of 10 mg/kg indomethacin on D19 and D20. The delay was induced by a decreased stimulus to the prostaglandin EP4 receptor system in the last 2 days in utero. The delay was temporary with recovery 3 days or more after exposure.

We studied the transplacental ductal constrictive effects of a selective cyclooxygenase (COX)-1 inhibitor (SC560), six selective COX-2 inhibitors including rofecoxib, and a non-selective COX inhibitor (indomethacin). Each drug was administered to the pregnant rats, and fetal ductus arteriosus (DA) was studied with a whole-body freezing method. The inner diameter ratio of the DA to the main pulmonary artery (DA/PA) was 1.02 ± 0.03 (mean ± S.E.M.) in controls. Every drug constricted the DA dose-dependently. In preterm rats on the 19th day of gestation, 10 mg/kg of SC560, rofecoxib and indomethacin caused ductal constriction, with DA/PA reduced to 0.76 ± 0.02, 0.80 ± 0.03 and 0.75 ± 0.02, respectively. In near-term on the 21st day, 10 mg/kg of them caused ductal constriction, with DA/PA to 0.74 ± 0.04, 0.26 ± 0.02 and 0.33 ± 0.05. In conclusion, both COX-1 and COX-2 selective inhibitors constrict fetal DA. They are not better alternatives for the fetus than non-selective COX inhibitors for tocolysis.

Background: The closing mechanisms of the ductus venosus (DV) have not yet been revealed. Objectives: The aims of this study were to document the perinatal closing process of the DV, to study the suppression of prostaglandins by indomethacin, and to determine the effects of umbilical blood flow to the fetal DV. Methods: The proximal and distal DV diameters were studied in near-term fetal and neonatal rats with the rapid whole-body freezing method. Results: The DV diameter changed sensitively at birth, and decreased by 10% immediately after the cessation of the umbilical circulation. Umbilical hemorrhage caused an additional decrease in the DV diameter compared with neonate without the hemorrhage. The neonates showed a DV diameter decreased by 20% at 30 min and 30% at 60 min after birth. The fetal DV was tubular, and the neonatal DV was horn-shaped with a smaller inlet than outlet. A small dose (0.1 mg/kg) of indomethacin administered to the pregnant rats induced a reduction in prostaglandins and decreased the fetal DV diameter to 80% of the control. Indomethacin at a large dose (10 mg/kg), administered to the dams, induced a reduction in prostaglandins, severe constriction of the ductus arteriosus, and decreased blood flow through the descending aorta umbilicus, and caused a further reduction in the DV diameter to 70–80% of the control. A large dose of nifedipine (10 mg/kg), which causes cardiac suppression and heart failure in the fetus, was administered to near-term rats to study the effect of decreased fetal cardiac output and blood flow passing through the DV. Nifedipine induced a 20% decrease in the DV diameter for 2–8 h. In all 1-hour-old neonates with or without pretreatment, the inlet diameter of the DV was reduced more than the outlet diameter, and the DV showed a horn-shaped morphology. Conclusion: In conclusion, perinatal cessation of the umbilical circulation and umbilical hemorrhage are associated with an immediate decrease in DV diameter. The DV diameter is also reduced in other conditions associated with decreased umbilical blood flow, such as induced by nifedipine which leads to heart failure and constricting of the ductus arteriosus induced by indomethacin. The constricting effect of a small dose of indomethacin suggests that prostaglandins dilate the DV physiologically.

Background: Clinically, it appears that phosphodiesterase 3 (PDE 3) inhibitors, which are used for acute cardiac failure in premature infants, dilate the ductus arteriosus (DA). Objectives: To clarify the ductus-dilating effects of PDE 3 inhibitors in near-term rat pups and their differential effects in near-term and preterm fetal rats, in in vivo studies. Methods: The in vivo ductal diameter of rat pups and fetuses was measured using a rapid whole-body freezing method, by cutting on a freezing microtome and measuring with a microscope and micrometer. Eight to twenty pups and fetuses were studied in each group. Milrinone and amrinone (specific inhibitors of PDE 3) were injected into 1-hour-old pups and the DA was studied 0.5 and 1 h later. The differential effects of these PDE 3 inhibitors on the near-term and preterm ductus were studied by injecting indomethacin (10 mg/kg) and PDE 3 inhibitors into 21D (21st day of pregnancy: term-21.5 days) and 19D dams and studying the fetal ductus 4 and 8 h later. Results: Milrinone and amrinone dilated the postnatal ductus dose-dependently. Large doses of these drugs dilated it completely, and clinically equivalent doses dilated it minimally. Milrinone and amrinone prevented constriction of the fetal ductus by indomethacin. Their ductus-dilating effects were more potent in the preterm than in the near-term fetuses, and clinically equivalent doses of these PDE 3 inhibitors dilated preterm ductus completely. Conclusion: In rats, PDE 3 inhibitors reopen the constricted postnatal DA slightly. PDE 3 inhibitors dilate the fetal DA constricted with indomethacin effectively and more sensitively in preterm than in near-term fetuses.

Prostaglandin E1 is used to reopen the constricted ductus arteriosus in neonates with ductus-dependent circulation. To clarify possible prostanoid receptor agonists that can reopen the neonatal ductus with fewer side effects, we studied in vivo reopening of the neonatal ductus arteriosus by AE1-329, a prostanoid EP4-receptor agonist, in the rat. Neonatal rats were incubated at 33 °C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing. Intraesophageal pressure was measured with a Millar micro-tip transducer. The ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 and 0.08 mm at 0 and 60 min after birth. PGE1 and AE1-329, injected subcutaneously at 60 min after birth, dilated the ductus dose-dependently. Thirty minutes after injection of 10 ng/g of PGE1 and AE1-329, the ductus diameter was 0.52 and 0.65 mm, respectively. The ductus-dilating effect of PGE1 was maximal at 15–30 min, and disappeared at 2 h. The ductus-dilating effect of AE1-329 was prolonged, the ductus was widely open at 6 h, and closed at 12 h after injection of 10 ng/g AE1-329. AE1-259-01 (EP2 agonist) (100 ng/g) did not dilate the neonatal ductus. Respiration was depressed by PGE1, but not by AE1-329. These results indicate the major role of EP4 in the neonatal ductus and that AE1-329, an EP4 agonist, can be used to dilate the neonatal constricted ductus without the side effects shown by EP3, including apnea.

Indomethacin is used to constrict the patent ductus arteriosus in premature infants. To clarify possible prostanoid receptor antagonists that can constrict the ductus, we studied in vivo constriction of the fetal and neonatal ductus arteriosus by AE3-208, a prostanoid EP4-receptor antagonist, in rats. Following quick cesarean section of near-term pregnant rats (21 d), neonates were incubated in room air at 33 degrees C. The inner diameter of the ductus was measured with a microscope and a micrometer following rapid whole-body freezing of the fetus and neonate, and sectioning of the thorax in the frontal plane on a freezing microtome. In the control, the ductus arteriosus constricted quickly after birth, and the inner diameter was 0.80 mm in the fetus and 0.06 mm at 90 min after birth. AE3-208, administered orogastrically to the dam, constricted the fetal ductus dose dependently. Maximal ductal constriction was observed 4 h after administration, and the ductal diameters were 0.06 mm and 0.26 mm after administration of 10 mg/kg and 10 ng/kg of AE3-208, respectively. In neonatal rats, AE3-208 injected subcutaneously at 30 min after birth, inhibited dilatation of the ductus by PGE1 dose dependently. PGE1 (10 microg/kg) was injected subcutaneously to the 1-h-old neonatal rat, and the ductal diameters were 0.53 mm and 0.19 mm without and with pretreatment of AE3-208 (10 microg/kg), respectively. These results indicate the major role of EP4 in the fetal and neonatal ductus and show that an EP4 antagonist can be used to constrict the patent ductus of premature infants.

A recent in vitro study showed that sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted ductus arteriosus of neonatal rabbits. We studied the in vivo ductus-dilating effects of sildenafil in fetal and neonatal rats. Ductus diameters were measured with whole-body freezing and cutting on a freezing microtome. Indomethacin (10 mg/kg) constricted the fetal ductus severely at 4 and 8 h after orogastric administration to the dams. Sildenafil, administered orogastrically and simultaneously with indomethacin, dilated the near-term fetal [21 fetal days (FD)] ductus constricted by indomethacin completely with 1 mg/kg at 8 h after administration. The preterm fetal ductus was more sensitive to sildenafil at 19FD. The ductus constricted rapidly after birth, and the ductal diameter was only 10% of the fetal diameter at 1 h after birth. The ductus-dilating effect of sildenafil was studied by i.p. injection at 1 h after birth, and the ductus diameter was studied 30 and 60 min later. Sildenafil dilated the neonatal constricted ductus moderately with a massive dose (100 mg/kg) and only minimally with 1 mg/kg. In conclusion, sildenafil, a type 5 phosphodiesterase inhibitor, dilated the constricted fetal ductus completely at 8 h with 1 mg/kg in the near-term fetus and completely with a smaller dose (0.1 mg/kg) in the preterm fetus. However, sildenafil dilated the neonatal constricted ductus only moderately with large doses and minimally with 1 mg/kg. Probably, sildenafil is useful clinically for treating idiopathic and secondary fetal ductal constriction and not useful for dilation of the neonatal constricted ductus.

The mammalian heart is known to contain only two isoformic myosin heavy chain (MHC) genes, α and β. A previously uncharacterized MHC gene was isolated in Syrian hamster hearts (McCully et al., J Mol Biol 1991). We identified the novel MHC gene as a hamster embryonic skeletal MHC gene based on the developmental stage- and tissue-specific expression pattern: the restricted expression of mRNA to striated muscles was highest in embryonic skeletal muscle and was developmentally down-regulated. We confirmed that the embryonic skeletal MHC gene exhibited higher expression in cardiomyopathic than in normal hamster hearts, and was up-regulated during the development of cardiomyopathy. The sporadic expression was highly localized in the endocardium. The present study identified that a very small number of undifferentiated myogenic cells existed in adult hamster endocardium. Moreover, using RT-PCR, a homologue of embryonic skeletal MHC mRNA was also expressed in human embryonic, but not adult ventricles. Our data provide a new insight into the regulatory mechanisms of MHCs in the cardiomyopathic hamster heart.

Pulmonary hypertension (PH) due to elevated left atrial pressure (LAp) caused by restrictive left atrioventricular valve and interatrial communication sometimes precludes patients with univentricular heart from undergoing the Fontan operation. We have created atrial septal defect (ASD) for such patients to reduce LAp and then pulmonary arterial pressure (PAp) and pulmonary vascular resistance (Rp) in an attempt to qualify the patients for the Fontan repair. This study was performed to clarify the efficacy and limitation of this approach. Twelve patients with PH (mean PAp > 20 mm Hg and/or Rp > 3.0 Wood's unit/m2) due to obstruction at the LA exit underwent ASD creation at the age of 4.0 ± 4.0 (mean ± SD) years. Follow-up catheterization 14.9 ± 15.6 months after the ASD creation demonstrated marked reductions in mean LAp (from 21 ± 5 to 8 ± 2 mm Hg), mean PAp (from 39 ± 13 to 17 ± 4 mm Hg), and Rp (from 6.2 ± 4.5 to 2.7 ± 1.4 Wood's unit/m2) compared with those before the procedure (all P < 0.0001). Seven of the 12 patients (58%) qualified for the Fontan operation (mean PAp < 20 mm Hg, Rp < 3.0 Wood's unit/m2, and Nakata's PA index ≥ 250) after the ASD creation. Final surgical outcomes of the seven patients included successful Fontan operation in five and biventricular repair in two. Patients with severe PH [mean PAp ≥ 45 mm Hg (n = 6) or Rp ≥ 4.5 Wood's unit/m2 (n = 5)] before the ASD creation qualified less frequently for the Fontan repair than those with mild PH [mean PAp < 45 mm Hg (n = 6; 17% vs. 100%; P = 0.008) or Rp < 4.5 Wood's unit/m2 (n = 7; 20 vs. 86%; P = 0.045)]. Patients with PA banded after 6 months of age (n = 3) qualified less frequently for the Fontan operation than those banded before 6 months of age (n = 6; 0 vs. 83%; P = 0.048). These data suggest that ASD creation is an effective approach to qualify patients for the Fontan operation in the presence of restrictive left atrioventricular valve and interatrial obstruction, except those with longstanding severe PH following delayed PA banding. Cathet Cardiovasc Intervent 2002;56:528–532. © 2002 Wiley-Liss, Inc.

The role of endothelin in oxygen-induced contraction remains controversial. The present study was designed to investigate the role of endothelin in O2-induced contraction in the isolated ductal preparation of rabbit and rat, using the endothelin receptor antagonists, bosentan (antagonist for both ET-A and ET-B receptors) and BQ 485 (an ET-A selective antagonist). The ductus was isolated from fetal rabbits at 30 days of gestation (term 31 days) and fetal rats at 21 days of gestation (term 22 days). In the rabbit ductus with intact endothelium, 13% of the O2-induced contraction was inhibited by bosentan and 14% by BQ 485. In the rabbit ductus without endothelium, bosentan did not cause significant inhibition of the oxygen-induced contraction. In the rat ductus with intact endothelium, about 44% of the O2-induced contraction was inhibited by bosentan. In the rat ductus without endothelium, O2-induced contraction was 20% less than that in the ductus with intact endothelium. In the rat ductus without endothelium, bosentan further decreased the oxygen-induced contraction by about 24%. These data suggest that (1) endothelin plays a significant role in O2-induced contraction in the isolated ductus arteriosus, (2) there is a species difference in the degree of contribution of endothelin to the O2-induced ductal contraction, and (3) there is a species difference in the degree of contribution of the endothelium and vascular smooth muscle cells to the release of endothelin from the ductus arteriosus.

A enzyme (ACE) inhibitors are effective for the treatment of heart failure, but their pharmacology and precise hemodynamic effects have not yet been well defined in pediatric patients. The purpose of the present study, therefore, was to clarify acute pharmacologic characteristics and to determine the effective dose of cilazapril, an ACE inhibitor, along with its cardiovascular effects. We chose cilazapril because our preliminary experience in children and data in adults has shown that this ACE inhibitor may have a less renotoxic effect. The present study consisted of 2 steps: the first step was to determine the effective dose of cilazapril and the second step was to show its cardiovascular effects by using the stress-velocity index and aortic blood flow pattern. • • • The first step study included 20 patients, age range from 3 months to 13 years (4.5 3.5 years), who were hospitalized for either diagnostic or interventional cardiac catheterization; none had cyanosis. The 20 patients were divided randomly into 3 groups according to cilazapril dose; group 1 included 7 patients who were given 0.01 mg/kg; group 2 included 8 patients who were given 0.02 mg/kg; and group 3 included 5 patients who received 0.04 mg/kg. Age and body weight were not statistically different in these 3 groups. We determined plasma concentration of cilazaprilat, which is a diacid body and active metabolite of cilazapril, and ACE activity by prevalidated radioenzymatic assays, at 2, 6, 12, and 24 hours after a single oral dose of the medicine. The second step study consisted of 13 patients with congestive heart failure. Heart failure was clinically defined as the use of anticongestive medicine, such as diuretics and/or digoxin, because of persistent cardiomegaly, hepatomegaly, or reduced physical activity. Accordingly, all patients were on diuretics, 4 were on digoxin, and 5 were on isosorbide dinitrate. During the present study, doses of these medications were not changed. Twelve patients took part in the study 1 to 2 months after open heart surgery, and the remaining patient had dilated cardiomyopathy (Table 1). They were in stable heart failure with conventional therapy. Their age averaged 5.0 3.6 years. Cilazapril was administered orally twice a day. The dose was initially 0.01 mg/kg/day to avoid unexpected hypotension, which is often seen after the first dose, and it was gradually increased until apparent cardiovascular effects were confirmed or the dose reached 0.04 mg/kg/day. The 0.04 mg/kg/day dose was determined to be effective by the first step study. After 5 days on the final dose, plasma concentration of cilazaprilat, plasma ACE activity, and plasma renin activity were measured 2 hours after oral ingestion of the drug. By Bor M-mode echocardiography, we measured left ventricular (LV) diastolic and systolic dimensions, end-systolic LV posterior wall thickness, and LV preejection and ejection time according to standard methods. The RR interval was also measured on an electrocardiogram that was recorded simultaneously with echocardiogrpahic recordings. Fractional shortening (FS) and systolic time interval were also calculated as

Endogenous retinoic acid may play a role in inducing smooth muscle differentiation in the fetal ductus arteriosus. Maternal administration of retinoic acid may accelerate the process. This study was designed to investigate the effect of vitamin A on developmental changes in the contractile system of the ductus. Vitamin A was injected into pregnant rats and the ductus was isolated from the fetus at 19, 20, or 21 d of gestation. The fetus at 19 d of gestation served as a model of the preterm fetus. The force of contraction and [Ca]i were measured. Membrane depolarization caused by high KCl induced ductal contraction in all age groups studied. In the 19-d fetus, O2 did not cause significant contraction or changes in [Ca]i in the control group, but it did induce a significant contraction and increases in [Ca]i in the vitamin A-treated group. In the 20- and 21-d fetuses, 5% O2-induced contraction in the vitamin A-treated group was significantly greater than in the control group. In the 19-d fetus, noradrenaline-induced contraction and increases in [Ca]i, indicators of the size of the intracellular Ca pool, were observed and they were similar in the control group and in the vitamin A-treated group. These data suggest that 1) in the preterm fetus, the contractile system, including membrane depolarization, [Ca]i increase, and its activation of contractile proteins, is already functioning, but the O2-sensing mechanism is underdeveloped, 2) vitamin A accelerates the development of the O2-sensing mechanism of the ductus arteriosus.

The inflammatory process is known to cause preterm delivery. Recently, a cyclooxygenase (COX)-2 inhibitor has been developed as an anti-inflammatory drug with few side-effects. We evaluated the COX-2 inhibitor, Celecoxib, for its tocolytic effects and side-effects on dams and pups using a lipopolysaccharide (LPS)-induced preterm delivery mouse model (preterm delivery rates; 95%). With administration of Celecoxib (50, 10, 1 and 0.3 mg/kg), the preterm labour rate was significantly reduced to 18, 30, 36 and 60% respectively. The prostaglandin F(2alpha)(PGF(2alpha)) and PGE(2) concentrations in murine uterine tissue 4 and 10 h after LPS treatment with Celecoxib (10 and 1 mg/kg) were significantly lower than those in the LPS-treated group without CELECOXIB: With administration of 10 or 100 mg/kg Celecoxib, the fetal ductus arteriosus was constricted significantly in preterm and near-term rats, although constriction rates in preterm rats were significantly lower than those in near-term rats. Reproductive and renal functions in offspring whose mothers were treated with LPS and Celecoxib were normal. These data demonstrate that Celecoxib could be used as a new therapy for preterm labour. However, careful attention to constriction of the fetal ductus arteriosus should be given.

Purpose: To clarify the clinical profiles of adolescents and young adults with tetralogy and 22q11.2 deletion, which has recently been identified as a cause of tetralogy of Fallot in about 15% of patients. Methods: Thirty-four patients with 22q11.2 deletion and tetralogy of Fallot, with or without pulmonary atresia, including 15 males and 19 females, with their age ranging from 16 to 35 years (mean = 25) were studied. Main outcome measurements include chromosome deletion identified by fluorescence in situ hybridization (FISH) of peripheral blood lymphocytes, medical states assessed with New York Heart Association classification, social activity assessed with Warnes index, IQ assessed by Wechsler test. Results: Eighteen of 20 patients with tetralogy and pulmonary stenosis had cardiac repair, and their cardiac conditions were good except one. Of 14 patients with tetralogy with pulmonary atresia, 7 had Rastelli type cardiac repair and were doing well, although 4 of them needed re-operation for conduit stenosis. No cardiac repair was done in the other 7 patients with tetralogy, pulmonary atresia and major collateral arteries because their peripheral pulmonary arteries were too small. In 28 of the 34 patients (82%), overall social activity was limited because of extracardiac diseases, including deafness, club feet, mental retardation, and schizophrenia. The IQ in 17 patients was 59 ± 13 (mean ± SD): range 41 to 79. In two patients, repeated IQ study showed a decrease. Four patients developed schizophrenia. Conclusion: Tetralogy with 22q11 deletion can be repaired surgically except in those patients with pulmonary atresia, major collateral arteries, and small peripheral pulmonary arteries. However, most of the adult patients show an inability to function in social life in contrast to most patients with tetralogy but without the deletion, who have a normal social life. Extracardiac diseases, including deafness, club feet, mental retardation, and schizophrenia were major handicaps limiting full social activities in postoperative adolescents and young adults with 22q11.2 deletion and tetralogy.

OBJECTIVESThis study examined whether long-term therapy with an angiotensin-converting enzyme (ACE) inhibitor reduces excessive increases in left ventricular (LV) mass as well as volume in growing children with aortic regurgitation or mitral regurgitation.BACKGROUNDThe ACE inhibitor reduces volume overload and LV hypertrophy in adults with aortic or mitral regurgitation.METHODSThis study included 24 patients whose ages ranged from 0.3 to 16 years at entry to the study. On echocardiography, we measured LV size, systolic function and mass. After obtaining baseline data, patients were allocated into two groups. Twelve patients were given an ACE inhibitor (ACE inhibitor group), and 12 patients were not (control group). Echo parameters were again assessed after an average 3.4 years of follow-up.RESULTSLeft ventricular parameters at baseline in the two groups were similar. The Z value of LV end-diastolic dimensions decreased from +0.82 ± 0.55 to +0.57 ± 0.58 in the ACE inhibitor group, whereas it increased from +0.73 ± 0.85 to +1.14 ± 1.04 in the control group (mean change −0.25 ± 0.33 for the ACE inhibitor group vs. +0.42 ± 0.48 for the control group, p = 0.0007). The mass normalized to growth also reduced from 221 ± 93% to 149 ± 44% of normal in the ACE inhibitor group and increased from 167 ± 46% to 204 ± 59% of normal in the control group (mean change −72 ± 89% of normal for the ACE inhibitor group vs. +37 ± 35% of normal for the control group, p = 0.0007).CONCLUSIONSLong-term treatment with ACE inhibitors is effective in reducing not only LV volume overload but also LV hypertrophy in the hearts of growing children with LV volume overload.

We isolated five complementary DNA (cDNA) clones, encoding the chick ventricular myosin heavy chain (MyHC) by reverse transcription polymerase chain reaction (RT-PCR). The entire cDNA consists of 5995 nucleotides with the 52 bp 5'-untranslated region and the 129 bp 3'-untranslated region. The complete cDNA encodes 1937 amino acids. Expression of the chick ventricular MyHC gene was also studied by Northern blot analysis. This gene continued to be strongly expressed in the ventricle during cardiac development. On the other hand, its expression was moderate in the early embryonic atria, and was down-regulated during development. In the adult atria, this gene was expressed at very low levels. To determine the localization of the ventricular MyHC protein, an immunohistochemical study was performed. The ventricular MyHC was present in early embryonic atrial myocytes. During development, the expression of this protein in the atrial myocytes was down-regulated, but continued to be present in the atrial conduction system. Our results indicate that the ventricular MyHC appears in the primary atrial myocardium and is then localized in the conduction cells of the atria.

In adult patients with severe chronic mitral regurgitation, many predictors for estimating postoperative left ventricular systolic function have been proposed. However, none has been defined in children. We analyzed the relationship between such predictors and postoperative left ventricular fractional shortening in children with isolated congenital mitral regurgitation. Eight patients with isolated congenital mitral regurgitation were examined before and after surgery with echocardiography. Fractional shortening, left ventricular end-diastolic and end-systolic dimension indices, and left ventricular end-systolic wall stress/left ventricular end-systolic dimension index in the preoperative status were poorly correlated with postoperative left ventricular fractional shortening. Predictive wall stress, which was calculated from preoperative data of end-diastolic dimension, end-diastolic wall thickness, and diastolic blood pressure, correlated well with postoperative left ventricular fractional shortening (r = -0.90, p = 0.0024). It is important to consider not only myocardial contractility but also postoperative afterload for estimating postoperative left ventricular performance in chronic severe mitral regurgitation.

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.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty replacement of the right ventricular myocardium. Recently, the myocardial loss in ARVC has been suggested to be related to apoptosis. However, it is still unknown whether this phenomenon is already established in the myocardium of pediatric cases with this disease. We examined the histopathologic characteristics of the ventricular myocardium in specimens obtained from 10 patients, including 3 children with ARVC, and investigated the occurrence of apoptosis in the myocardium by terminal deoxyribonucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay and agarose-gel electrophoresis of DNA. Endomyocardial biopsy specimens from the 10 cases and a necropsy sample from one adult case with ARVC were examined. Histopathologic examination of biopsy specimens from the pediatric cases revealed extensive fibrosis. Typical fatty infiltration was demonstrated in one of the 3 pediatric cases. These findings were similar to those in adult cases; the histopathologic index based on the severity of myocardial damage, including myocyte degeneration and fibrosis, was not significantly different from that in adult cases. TUNEL assay revealed positive reactivity of the myocardial cells. The apoptotic index was 1.4 ± 0.4% in children and 1.6 ± 0.5% in adults (difference not statistically significant). Agarose-gel electrophoresis of a DNA extract of the myocardial tissue of the autopsy case revealed DNA fragmentation. Cases with idiopathic ventricular tachycardia and control cases with a cardiac transplant (with no rejection) had minimal histopathologic findings and negative reactivity in the TUNEL assay. These results indicate that myocardial damage is already established in cases diagnosed as ARVC in childhood, and suggest that the myocardial damage is closely related to apoptosis in children, as well as in adults, in this disease.

Background —The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and a QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go–related gene ( HERG ), which encodes the rapidly activating component of the delayed rectifier current (I Kr ), cause chromosome 7–linked LQTS (LQT2). Studies of mutant HERG channels in heterologous systems indicate that the mechanisms mediating LQT2 are varied and include mutant subunits that form channels with altered kinetic properties or nonfunctional mutant subunits. We recently reported a novel missense mutation of HERG (G601S) in an LQTS family that we have characterized in the present work. Methods and Results —To elucidate the electrophysiological properties of the G601S mutant channels, we expressed these channels in mammalian cells and Xenopus oocytes. The G601S mutant produced less current than wild-type channels but exhibited no change in kinetic properties or dominant-negative suppression when coexpressed with wild-type subunits. To examine the cellular trafficking of mutant HERG channel subunits, enhanced green fluorescent protein tagging and Western blot analyses were performed. These showed deficient protein trafficking of the G601S mutant to the plasma membrane. Conclusions —-Our results from both the Xenopus oocyte and HEK293 cell expression systems and green fluorescent protein tagging and Western blot analyses support the conclusion that the G601S mutant is a hypomorphic mutation, resulting in a reduced current amplitude. Thus, it represents a novel mechanism underlying LQT2.

In a family with long QT syndrome (LQT2), some individuals who did not harbor the HERG mutation had a prolonged QTU interval on electrocardiograms after exercise. It may be determined or modified by other gene(s) or factor(s). The sequence analysis of mtDNA in these individuals of this family showed a candidate pathogenic mutation at 3394 in the ND1 gene. The cybrids (mutation at 3394) showed significantly reduced NADH-CoQ reductase (complex I) activity and O 2 consumption to normal levels. These inhibitory effects on respiratory function may result in the depletion of ATP and could possibly produce an increase in Ca 2+ concentration in cytosol, and it may lead to the prolongation of the QTU intervals on electrocardiograms. Therefore, we stated that the 3394 mutation in the ND1 gene is pathogenic and could be the cause of prolongation of the QTU intervals or modification of the phenotypes of not only congenital but also so-called “acquired drug-induced long QT syndrome.”

Previous reports regarding intravascular ultrasound (IVUS) imaging of the pulmonary arteries in children and its application to balloon pulmonary angioplasty are limited. This study was designed to compare findings of IVUS imaging and those of angiography of the pulmonary artery before and after the balloon angioplasty procedure. Thirty patients had significant pulmonary artery stenosis and underwent balloon angioplasty. In all, of 34 branch pulmonary arteries were dilated. All patients underwent both angiography and IVUS imaging at the time of balloon angioplasty. The mean age at balloon angioplasty was 5.7 +/- 4.0 yr. One echo-dense layer on IVUS was detected in 9% of the 34 stenotic vessels, and a two- or three-layered vascular wall pattern in 91%. The thickness of intima-medial layer (inner and middle layers) was greater than normal in 91% of stenotic vessels. After balloon angioplasty, intimal flaps and aneurysm were observed at 29 and 28 locations, respectively. Of these locations, the intimal flaps were detected by angiography in 44% and by IVUS in 100%; the aneurysm was detected by angiography in 61% and by IVUS in 93%. Media rupture was observed at 26 locations, and the change was detected only by IVUS. The present study suggests that intimal and medial changes in the pulmonary artery can be detected more precisely by IVUS than by angiography.

We analyzed the electron-microscopic features of endomyocardial biopsy from pediatric patients with dilated cardiomyopathy (DCM). The specimens examined were taken from the right ventricle of ten patients aged from 2 to 15 years (mean 9.7 years). Biopsy specimens from eight patients with congenital heart disease (tetralogy of Fallot), aged from 3 to 12 (mean 7.3 years), and ten adult patients with DCM, aged from 32 to 60 (mean 45 years), were also examined. Patients considered to have endocardial fibroelastosis, arrhythmogenic right ventricular cardiomyopathy, specific cardiomyopathy, or coronary heart disease were excluded from this study. Specimens from pediatric patients with DCM showed various degrees of ultrastructural abnormalities of myocytes, including myofibrillar fragmentation, mitochondrial abnormalities, and intracellular edema. The ultrastructurally determined contractility failure index based on the severity of myocardial degeneration at the electronmicroscopic level was 4.9 +/- 1.1. This value was significantly higher than that in patients with tetralogy of Fallot (0.9 +/- 0.6, P < 0.001) but was not significantly different from that in adult patients with DCM (6.1 +/- 2.6). The index of pediatric patients with DCM who died within 3 years was high (6.0 +/- 0.8). Basal lamina layering of a capillary (BLL) in the myocardium was revealed in 1 of the 10 (10%) pediatric patients with DCM and in 6 of the 10 (60%) adult patients with DCM (P < 0.05). No BLL was noted in the patients with tetralogy of Fallot. These findings may be related to the pathogenesis of DCM in children and adults.

Prostaglandin E1 incorporated in lipid microspheres (lipo PGE1) was administered to the umbilical vein of neonatal rats. Morphological measurement and quantitative autoradioluminography assessed the relationship between the vasodilating effect and tissue accumulation of lipo PGE1 in the ductus arteriosus. In the morphological measurement under microscopy, the inner diameter ratio of the ductus arteriosus to the main pulmonary artery after infusion of 3H-labeled lipo PGE1 (3H-lipo PGE1) continued to remain significantly higher than that of free 3H-PGE1. Autoradioluminography of the frozen frontal section of neonates after intravenous infusion of 3H-lipo PGE1 for 2 h revealed that the ductus levels of radioactivity were higher than those of free 3H-PGE1 in saline solution, although the blood levels were almost equal. Localization of lipo PGE1 labeled with a lipophilic fluorescent probe, 1,1'-dioctadecyl-3,3,3',3-tetramethyl-indocarbocyanine perchlorate (diI), in the endothelial cells of the ductus arteriosus was confirmed by confocal laser scanning microscopy. These findings suggest that the incorporation of lipid microspheres by the endothelial cells is one of the mechanisms that enables lipo PGE1 to accumulate to higher levels in the ductus tissue and to act more efficiently than free PGE1 in neonatal rats.

In patients with a diagnosis of congenital heart disease, the presence of associated chromosome 22q11.2 deletion [1], which is usually associated with additional mental and physical abnormalities [2], is very important. In this Issue of the Journal, Park et al. [3] and Baravelli et al. [4] have reported cardiovascular abnormalities associated with chromosome 22q11.2 deletion. Park et al., in a Korean multicenter study, described cardiovascular and other abnormalities in 222 patients with chromosome 22q11.2 deletion [3]. In their study, tetralogy of Fallot was the most prevalent anomaly and seen in 27% of all patients. They noted that tetralogy of Fallot was more prevalent in Asian patients with the deletion as reported by Matsuoka et al. [5] than in Caucasians as reported by Ryan et al. [6]. Table 1 shows the prevalence of cardiovascular anomalies associated with chromosome 22q11.2 deletion in four studies including a report by Marino et al. from Italy [7]. It is remarkable that the incidences of tetralogy of Fallot with pulmonary stenosis or pulmonary atresia were the same in Park’s study on Korean patients and Marino’s study on Italian patients. Matsuoka et al. included many patients with tetralogy of Fallot (TF) with pulmonary atresia (PA) and major aortopulmonary collateral arteries (MAPCA) as these patients were followed with particular attention for more than 15 years before their study was performed at their institute (personal communication). Therefore, high incidences of TF, and TF, PA and MAPCA in Matsuoka’s report reflected institutional patient population. More accurate incidences of cardiovascular anomalies are assessed in a prospective study of fetuses and neonates by Boudjemline et al., who described 54 fetuses with 22q11 deletion [9]. These include TF (26%), TF, PA (20%), TF, absent pulmonary valve (11%), aortic arch interruption (19%), truncus arterio

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.

Balloon dilation was performed in four patients with postoperative pulmonary stenosis who had undergone surgical creation of a coronary arterial tunnel in the pulmonary trunk. Two patients had complete transposition in whom the arterial switch operation had been performed using the modified Aubert method. The other two patients had anomalous origin of the left coronary artery from the pulmonary trunk treated with the Takeuchi procedure. Balloon dilation was performed at 11 locations. The pressure gradient decreased from 48 ± 22 to 24 ± 14mmHg (p

Deletion of chromosome 22 and DiGeorge syndrome are associated with inappropriate development of the neural crest and abnormalities of the ventricular outflow tracts. Bis-diamine induces comparable cardiac anomalies by inhibiting the normal development of the neural crest. In order to clarify the effect of damage on the development of the neural crest and its relation to the cardiac anomalies, the effects of giving a small dose of bis-diamine were compared with the results of a large dose of bis-diamine. A small dose of bis-diamine (20 mg), therefore, was administered to 40 pregnant rats on the 10th day of pregnancy, and 330 fetal hearts were studied on the 21st day with the rapid whole-body freezing method. Intracardiac anomalies were rare, being found in only 55 fetuses. The anomalies discovered were: aberrant origin of the subclavian artery in 88 fetuses, right aortic arch in 26 fetuses, interruption of the aortic arch in 23 fetuses, and high location of the aortic arch in 8 fetuses. Anomalies of the arterial duct were also common; with a vascular ring formed by the aortic arch and contra-lateral duct being seen in 21 fetuses, isolation of the right subclavian artery associated with either bilateral ducts (9 fetuses) or a right duct and absent left duct (9 fetuses), absent duct with tetralogy of Fallot in 7 fetuses, and with common arterial trunk in one fetus. In conclusion, a small dose of bis-diamine induced extra cardiac anomalies of the aortic arch and arterial duct, indicating a greater susceptibility of the aortic arch and the duct to inappropriate formation of the neural crest cells in the early developing embryo. Clinically, these anomalies of the aortic arch and the duct should be searched for in all patients suspected of having deletion of their 22nd chromosome.

We evaluated the physical characteristics of the pulmonary trunk in 32 patients with complete transposition after the arterial switch operation, calculating the pulmonary input impedance. In 6 of the patients, the characteristic impedance was equal to, or less than, the value in patients with ventricular septal defect. In those patients with an intact ventricular septum, or those with a ventricular septal defect who had undergone the arterial switch operation or banding of the pulmonary trunk before 3 months age, the frequency of the first modulus minimum also agreed with the values obtained in patients with ventricular septal defect. The value was high, however, in patients with complete transposition with ventricular septal defect who had undergone an arterial switch operation or banding of the pulmonary trunk after 4 months of age. Our data suggest decreased distensibility of the proximal pulmonary trunk after the arterial switch operation, and mild changes in the pulmonary vasculature in patients with complete transposition with ventricular septal defect who had undergone either an arterial switch operation or banding of the pulmonary trunk after 4 months of age. Long-term follow-up is needed clarify whether or not these features affect right ventricular function by means of an increase in afterload.